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CAS No. : | 184950-35-4 | MDL No. : | MFCD08448154 |
Formula : | C5H12ClNO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LZHYUVOFRJAJKS-UHFFFAOYSA-N |
M.W : | 137.61 | Pubchem ID : | 17750392 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 34.79 |
TPSA : | 35.25 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -9.77 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | -3.7 |
Log Po/w (WLOGP) : | 0.78 |
Log Po/w (MLOGP) : | 0.21 |
Log Po/w (SILICOS-IT) : | 0.78 |
Consensus Log Po/w : | -0.38 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 1.7 |
Solubility : | 6960.0 mg/ml ; 50.6 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 3.55 |
Solubility : | 486000.0 mg/ml ; 3530.0 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.47 |
Solubility : | 47.0 mg/ml ; 0.341 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.95 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | Stage #1: With hydrogen; ammonium chloride In methanol; water at 20℃; for 16 h; Stage #2: With sodium hydroxide In 1,4-dioxane; water at 20℃; for 16 h; Stage #3: With hydrogenchloride In 1,4-dioxane |
A. (Tetrahydrofuran-3-yl)methanamine hydrochloride. A solution of tetrahydrofuran-3-carboxaldehyde (50 wt. percent in water, 5 mL, 25 mmol), ammonium chloride (13 g, 25 mmol), Raney nickel (2 mL slurry) in methanol was reacted in a Parr shaker under 40 psi of hydrogen for 16 h at room temperature. The reaction was filtered through celite and the filtrate concentrated to an oil. The oil was added with dioxane (50 mL), IM sodium hydroxide (50 mL), and di-tert-butyl dicarbonate (5.5 g, 25 mmol). The solution was stirred at room temperature for 16 h. The reaction was extracted with ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered and concentrated to an oil. The oil was purified on silica gel column (0-20percent ethyl acetate in hexanes) to give a clear oil. The oil was treated with 4N hydrogen chloride in dioxane. The solution was concentrated and triturated with ether to give a white solid, (0.33 g, 10percent yield). MS (ESI) m/z 101.9 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10 g | Stage #1: With hydrazine hydrate In ethanol at 70℃; for 6 h; Inert atmosphere Stage #2: at 60℃; for 4 h; Inert atmosphere Stage #3: With hydrogenchloride In diethyl etherInert atmosphere |
Under a nitrogen atmosphere, to a mixture of 14 g of 2-(tetrahydrofuran-3-ylmethyl)-isoindole-1,3-dione and 150 ml of ethanol was added 4.6 g of hydrazine monohydrate, and the mixture was stirred at 70°C for 6 hours. Thereafter, the reaction mixture was filtered, and the residue was washed with ethanol. To the ethanol solution was added 1 ml of a suspension of Raney nickel, and the mixture was stirred at 60°C for 4 hours. The reaction solution was cooled to room temperature, and then filtered. To the filtrate was added 90 ml of a 1 mol/L solution of hydrogen chloride in diethyl ether. The mixture solution was concentrated under reduced pressure to obtain 10 g of a crude product of (tetrahydrofuran-3-yl)-methylamine hydrochloride represented by the following formula. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; triethylamine;palladium diacetate; CyJohnPhos; In 1,2-dimethoxyethane; for 8h;Heating / reflux; | Example 340: 4-{4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine To a mixture of starting material A (500 mg), palladium acetate (33 mg), 2-(dicyclohexylphosphino)biphenyl (102 mg), <strong>[184950-35-4](tetrahydrofuran-3-yl)methylamine hydrochloride</strong> (301 mg) and tripotassium phosphate (743 mg) were successively added dimethoxyethane (3 mL) and triethylamine (222 mg), and the mixture was heated under reflux for 8 hr. After cooling, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol=100:1) to give the title compound (130 mg) . 1H-NMR (400 MHz, DMSO-d6) delta: 1.5-1.6 (1H, m), 1.71 (3H, s), 1.9-2.1 (1H, m), 2.40 (3H, s), 2.4-2.5 (1H, m), 2.60 (3H, s), 3 .01 (2H, t, J=6 . 4 Hz), 3.4-3.5 (1H, m), 3.6-3.7 (1H, m), 3.7-3.8 (2H, m), 4.01 (1H, d, J=12.4 Hz), 5.10 (1H, d, J=12.4 Hz), 6.24 (1H, t, J=5.6 Hz), 6.55 (2H, d, J=8.0 Hz), 7.20 (2H, d, J=8.0 Hz) MS (ESI) m/z: 408 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | A. (Tetrahydrofuran-3-yl)methanamine hydrochloride. A solution of tetrahydrofuran-3-carboxaldehyde (50 wt. % in water, 5 mL, 25 mmol), ammonium chloride (13 g, 25 mmol), Raney nickel (2 mL slurry) in methanol was reacted in a Parr shaker under 40 psi of hydrogen for 16 h at room temperature. The reaction was filtered through celite and the filtrate concentrated to an oil. The oil was added with dioxane (50 mL), IM sodium hydroxide (50 mL), and di-tert-butyl dicarbonate (5.5 g, 25 mmol). The solution was stirred at room temperature for 16 h. The reaction was extracted with ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered and concentrated to an oil. The oil was purified on silica gel column (0-20% ethyl acetate in hexanes) to give a clear oil. The oil was treated with 4N hydrogen chloride in dioxane. The solution was concentrated and triturated with ether to give a white solid, (0.33 g, 10% yield). MS (ESI) m/z 101.9 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 200℃; for 2h;Microwave irradiation; | B. 6-Bromo-N2-((tetrahydrofuran-3-yl)methyl)pyrazine-2,3-diamine.3,5-Dibromopyrazin-2-amine (253 mg, 1 mmol), <strong>[184950-35-4](tetrahydrofuran-3-yl)methanamine hydrochloride</strong> (0.33 g, 2.4 mmol), diisopropylethylamine (0.5 mL), and n-butanol (2 mL) were heated in a Biotage Emrys Optimizer microwave reactor at 200 C for 2 h. The reaction was purified on silica gel column (0-10% methanol in ethyl acetate) to give a tan solid (140 mg, 51% yield). MS (ESI) m/z 303.3 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Under nitrogen atmosphere, to a mixture of 14 g of 2- (tetrahydrofuran-3-ylmethyl ) isoindol-1 , 3-dione and 150 ml of ethanol, 4.6 g of hydrazine monohydrate was added, and stirred for 6 hours at 70 C. The reaction mixture was filtered, then obtained residue was washed with ethanol. To the ethanol solution, 1 ml of a suspension of Raney nickel (trademark) was added, and stirred for 4 hours at 60 C. The reaction liquid was allowed to cool to room temperature, and filtered. To the filtrate, 90 ml of 1 mol/1 hydrogen chloride in diethyl ether was added, and concentrated under reduced pressure to obtain 10 g of crude preduct of (tetrahydrofuran-3-yl) methylamine hydrochloride of the following formula.The crude product was used for next process of production without further purification. | ||
To a mixture of 2-(tetrahydrofuran-3-ylmethyl)-isoindole-1,3-dione (14 g) and ethanol (150 mL) was addedhydrazine monohydrate (4.6 g) under nitrogen atmosphere, and the mixture was stirred at 70C for 6 hrs. Then, the mixture was allowed to cool to room temperature, and filtered, and the resultant residue was washed with ethanol.To the resulting filtrate was added a suspension of Raney nickel (1 mL), and the mixture was stirred at 60C for 4 hrs. The reaction mixture was cooled to room temperature, and then filtered. To the filtrate was added 1 mol/L solution of hydrogen chloride in diethyl ether (90 mL) The mixture was concentrated under reduced pressure to givea crude product (10 g) of (tetrahydrofuran-3-yl)-methylamine hydrochloride represented by the followingformula: | ||
Reference Production Example 3 Under a nitrogen atmosphere, to a mixture of 14 g of 2-(tetrahydrofuran-3-ylmethyl)-isoindole-1,3-dione and 150 ml of ethanol was added 4.6 g of hydrazine monohydrate, and the mixture was stirred at 70C for 6 hours. Thereafter, the reaction mixture was filtered, and the residue was washed with ethanol. To the ethanol solution was added 1 ml of a suspension of Raney nickel, and the mixture was stirred at 60C for 4 hours. The reaction solution was cooled to room temperature, and then filtered. To the filtrate was added 90 ml of a 11 mol/L solution of hydrogen chloride in diethyl ether. The mixture solution was concentrated under reduced pressure to obtain 10 g of a crude product of (tetrahydrofuran-3-yl)-methylamine hydrochloride represented by the following formula. |
10 g | Under a nitrogen atmosphere, to a mixture of 14 g of 2-(tetrahydrofuran-3-ylmethyl)-isoindole-1,3-dione and 150 ml of ethanol was added 4.6 g of hydrazine monohydrate, and the mixture was stirred at 70C for 6 hours. Thereafter, the reaction mixture was filtered, and the residue was washed with ethanol. To the ethanol solution was added 1 ml of a suspension of Raney nickel, and the mixture was stirred at 60C for 4 hours. The reaction solution was cooled to room temperature, and then filtered. To the filtrate was added 90 ml of a 1 mol/L solution of hydrogen chloride in diethyl ether. The mixture solution was concentrated under reduced pressure to obtain 10 g of a crude product of (tetrahydrofuran-3-yl)-methylamine hydrochloride represented by the following formula. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃; for 4h;Inert atmosphere; | Under nitrogen atmosphere, to a mixture of 1.4 g of <strong>[184950-35-4](tetrahydrofuran-3-yl)methylamine hydrochloride</strong> (Reference Production Example 3) and 20 ml of anhydrous tetrahydrofuran, 1.0 g of triethylamine was added at room temperature and: stirred for 30 minutes. To the mixed liquid, 0.63 g of (2E, 4E) -hepta-2 , 4-dienoic acid and 1.9 g of l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added, and stirred for 4 hours at room temperature. Then, to the reaction mixture, water was added and extracted with ethyl acetate 2 times. The organic layer was washed with brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 0.75 g of (2E, 4E) -N- (tetrahydrofuran-3-ylmethyl) hepta-2, 4-dienamide of the formula :(hereinafter, referred to as The Present Compound (5)).( 5 )[0105]The Present Compound (5)1H NMR (GDC13) : delta ppm: 7.24-7.16 (1H, m) , 6.15-6.10 (2H, m) , 5.74 (1H, d) , 5.61 (1H, brs), 3.89 (1H, td) , 3.81 (1H, dd) , 3.74 (1H, q) , 3.55 (1H, dd) , 3.42-3.31 (2H, m) , 2.57-2.47 (1H, m) , 2.22-2.14 (2H, m) , 2.09-1.99 (1H, m) , 1.67-1.57 (1H, m) , 1.03 (3H, t) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.48 g | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃; for 4h; | (E/Z)-2-Nonenoic acid (547 mg, 3.50 mmol), triethylamine (708 mg, 7.00 mmol) and <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (963mg, 7.00 mmol) were added to tetrahydrofuran (15 mL). To the mixture solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.33 g, 7.00 mmol) at room temperature, then the mixture was stirred at room temperature for 4 hours. Thereafter, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated salt solution, and dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column chromatography, to obtain 0.48 g of (E)-N-(tetrahydrofuran-3-ylmethyl)-2-nonenamide (hereinafter, described as Compound (2) of the present invention) represented by the following formula.1H-NMR (CDCl3, TMS) delta (ppm) : 0.88 (t, 3H), 1.24-1.35 (m, 6H), 1.39-1.48 (m, 2H), 1.59-1.68 (m, 1H), 2.00-2.09 (m, 1H), 2.17 (dq, 2H), 2.48-2.56 (m, 1H), 3.30-3.38 (m, 2H), 3.55 (dd, 1H), 3.74 (dd, 1H), 3.81 (dd, 1H), 3.89 (td, 1H), 5.63 (br s, 1H), 5.75 (dt, 1H), 6.84 (dt, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.37 g | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃; for 4h; | (E)-2-Undecenoic acid (369 mg, 2.00 mmol), triethylamine (304 mg, 3.00 mmol) and <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (413mg, 3.00 mmol) were added to tetrahydrofuran (4 mL). To the mixture solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (458 mg, 2.40 mmol) at room temperature, then the mixture was stirred at room temperature for 4 hours. Thereafter, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated salt solution, and dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column chromatography, to obtain 0.37 g of (E)-N-(tetrahydrofuran-3-ylmethyl)-2-undecenamide (hereinafter, described as Compound (5) of the present invention) represented by the following formula.1H-NMR (CDCl3, TMS) delta (ppm): 0.88 (t, 3H), 1.19-1.38 (m, 10H), 1.38-1.50 (m, 2H), 1.62-1.68 (m, 1H), 2.01-2.10 (m, 1H), 2.16 (q, 2H), 2.46-2.56 (m, 1H), 3.22-3.38 (m, 2H), 3.55 (dd, 1H), 3.72 (q, 1H), 3.83 (dt, 2H), 5.92 (d, 1H), 6.81 (dt, 1H), 7.43 (br s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.16 g | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃; for 4h; | (E)-6-Phenyl-2-hexenoic acid (0.29 mg, 1.5 mmol), triethylamine (0.23 mg, 2.3 mmol) and <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.31 g, 2.3 mmol) were added to tetrahydrofuran (4 mL). To the mixture solution wasadded 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.35 mg, 1.8 mmol) at room temperature, then themixture was stirred at room temperature for 4 hours. Thereafter, water was added to the reaction mixture, and the mixturewas extracted twice with ethyl acetate. The organic layer was washed with a saturated salt solution, and dried overanhydrous sodium sulfate, then filtered, and the filtrate was concentrated under reduced pressure. The residue wasapplied to a silica gel column chromatography, to obtain 0.16 g of(E)-N-(tetrahydrofuran-3-ylmethyl)-6-phenyl-2-hexeneamide (hereinafter, described as Compound (1) of the presentinvention) represented by the following formula.Compound (1) of the present invention[0627] 1H-NMR (CDCl3, TMS) delta (ppm) : 1.64 (dd, 1H), 1.75-1.83 (m, 2H), 2.00-2.09 (m, 1H), 2.18-2.25 (m, 2H),2.48-2.54 (m, 1H), 2.64 (t, 2H), 3.29-3.40 (m, 2H), 3.55 (dd, 1H), 3.73 (dd, 1H), 3.81 (dd, 1H), 3.89 (td, 1H), 5.58 (br s,1H), 5.76 (dt, 1H), 6.86 (dt, 1H), 7.15-7.21 (m, 3H), 7.26-7.31 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.25 g | With triethylamine; In tetrahydrofuran; at 20℃; for 4h;Cooling with ice; | Tetrahydrofuran-3-ylmethylamine hydrochloride (1.71 g, 12.4 mmol) and triethylamine (1.89 g, 18.7 mmol) were added to tetrahydrofuran (10 mL). To the mixture solution was added (E)-2-octenoic acid chloride (1.00 g, 6.22 mmol) under ice cooling, then the mixture was stirred at room temperature for 4 hours. Thereafter, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with an aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column chromatography, to obtain 1.25 g of (E)-N-(tetrahydrofuran-3-ylmethyl)-2-octenamide (hereinafter, described as Compound (1) of the present invention) represented by the following formula.1H-NMR (CDCl3, TMS) delta (ppm): 0.88 (t, 3H), 1.22-1.38 (m, 4H), 1.40-1.48 (m, 2H), 1.58-1.68 (m, 1H), 2.00-2.09 (m, 1H), 2.17 (dq, 2H), 2.46-2.57 (m, 1H), 3.30-3.38 (m, 2H), 3.55 (dd, 1H), 3.74 (dd, 1H), 3.82 (dd, 1H), 3.89 (td, 1H), 5.65 (br s, 1H), 5.75 (dt, 1H), 6.84 (dt, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.73 g | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 13h;Cooling with ice; | (Z)-2-Fluoro-2-nonoic acid (0.97 g, 5.5 mmol) and <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.92 g, 6.7 mmol) were added to N,N-dimethylformamide (15 mL). To the mixture solution was added triethylamine (1.45 g, 14.3 mmol) under ice cooling, then, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium salt (3.20 g, 7.2 mmol) was added. The mixture was stirred under ice cooling for 1 hour, then stirred at room temperature for 12 hours, and thereafter, the reaction solution was added to a mixture of 20 mL of 5% of hydrochloric acid and 50 mL of ice water, and the mixture was extracted twice with 100 mL of ethyl acetate. The ethyl acetate layers were combined, and washed with 50 mL of a saturated sodium bicarbonate solution, followed by 50 mL of a saturated salt solution. Thereafter, the organic layer was dried over magnesium sulfate and was concentrated under reduced pressure conditions, and the residue was applied to a silica gel column chromatography, to obtain 0.73 g of (Z)-N-(tetrahydrofuran-3-ylmethyl)-2-fluoro-2-nonenamide (hereinafter, described as Compound (7) of the present invention) represented by the following formula.1H-NMR (CDCl3, TMS) delta (ppm) : 0.88 (t, 3H), 1.24-1.36 (m, 6H), 1.40-1.47 (m, 2H), 1.61-1.68 (m, 1H), 2.02-2.10 (m, 1H), 2.20 (ddd, 2H), 2.48-2.58 (m, 1H), 3.32-3.42 (m, 2H), 3.56 (dd, 1H), 3.75 (dd, 1H), 3.83 (dd, 1H), 3.90 (td, 1H), 6.10 (dt, 1H), 6.35 (br s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.44 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 255 (0576) 5-(2-Fluorobenzyloxymethyl)isoxazole-3-carboxylic acid (0.75 g, 3.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.62 g, 4.5 mmol), triethylamine (0.46 g, 4.5 mmol) and 1-hydroxybenzotriazole (0.04 g, 0.3 mmol) were added to chloroform (amylene addition product) (7.5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.69 g, 3. 6 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.44 g of N-(tetrahydrofuran-3-ylmethyl)-5-(2-fluorobenzyloxymethyl)i soxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (264)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta (ppm)) : 1.62-1.73 (1H, m), 2.05-2.14 (1H, m), 2.52-2.63 (1H, m), 3.47 (2H, t), 3.59 (1H, dd), 3.73-3.80 (1H, m), 3.83-3.95(2H, m), 4.68(2H, s), 4.69(2H, s), 6.74 (1H, s), 6.95 (1H, br s), 7.03-7.10 (1H, m), 7.13-7.19 (1H, m), 7.28-7.35 (1H, m), 7.38-7.45 (1H, m) |
0.44 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (2-fluorobenzyloxymethyl) isoxazole-3-carboxylic acid (0.7 5 g, 3.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.62 g, 4.5 mmol), Triethylamine (0.46 g, 4.5 mmol) And 1-hydroxybenzotriazole (0.04 g, 0.3 mmol) Was added to chloroform (amylene addition product) (7.5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.69 g, 3.6 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, And extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, Washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography , The following formula Indicated by N- (tetrahydrofuran-3-ylmethyl) -5- (2-fluorobenzyloxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as present amide compound (264)) 0.44 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.23 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 256 (0577) 5-(2-Bromsobenzyloxymethyl)isoxazole-3-carboxylic acid (0.94 g, 3.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.62 g, 4.5 mmol), triethylamine (0.46 g, 4.5 mmol) and 1-hydroxybenzotriazole (0.04 g, 0.3 mmol) were added to chloroform (amylene addition product) (7.5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0. 69 g, 3.6 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.23 g of N-(tetrahydrofuran-3-ylmethyl)-5-(2-bromobenzyloxymethyl)is oxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (265)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta (ppm)) : 1.62-1.73 (1H, m), 2.05-2.14 (1H, m), 2.53-2.63 (1H, m), 3.47 (2H, t), 3.59 (1H, dd), 3.73-3.80 (1H, m), 3.83-3.95(2H, m), 4.69(2H, s), 4.74(2H, s), 6.77 (1H, s), 6.95 (1H, br s), 7.18 (1H, dt), 7.34 (1H, dt), 7.47 (1H, dd), 7.56 (1H, dd) |
0.23 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (2-bromobenzyloxymethyl) isoxazole-3-carboxylic acid (0.94 g, 3.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.62 g, 4.5 mmol), Triethylamine (0.46 g, 4.5 mmol) And 1-hydroxybenzotriazole (0.04 g, 0.3 mmol) Was added to chloroform (amylene added product) (7.5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.69 g, 3.6 mmol) was added at room temperature, Stir overnight And then concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain N- (tetrahydrofuran-3-ylmethyl) -5- (2-bromobenzyloxymethyl) isoxazole-3-carboxamide (hereinafter referred to as present amide compound (265) ) 0.23 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.26 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 257 (0578) 5-(3,5-Difluorobenzyloxymethyl)isoxazole-3-carboxylic acid (1.35 g, 5.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (1.03 g, 7.5 mmol), triethylamine (0.76 g, 7.5 mmol) and 1-hydroxybenzotriazole (0.07 g, 0.5 mmol) were added to chloroform (amylene addition product) (12.5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.15 g, 6.0 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.26 g of N-(tetrahydrofuran-3-ylmethyl)-5-(3,5-difluorobenzyloxymeth yl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (266)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta (ppm)) : 1.62-1.74 (1H, m), 2.06-2.14 (1H, m), 2.53-2.64 (1H, m), 3.47 (2H, t), 3.59 (1H, dd), 3.73-3.80 (1H, m), 3.83-3.95(2H, m), 4.58(2H, s), 4.68(2H, s), 6.72-6.79(1H, m), 6.75(1H, s), 6.84-6.91(2H, m), 6.94(1H, br s) |
0.26 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (3,5-difluorobenzyloxymethyl) isoxazole-3-carboxylic acid (1.35 g, 5.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (1. 03 g, 7.5 mmol), Triethylamine (0.76 g, 7.5 mmol) And 1 - hydroxybenzotriazole (0.07 g, 0.5 mmol) Was added to chloroform (amylene-added product) (12.5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.15 g, 6.0 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, And extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, Washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography , The following formula Indicated by N- (tetrahydrofuran-3-ylmethyl) -5- (3,5-difluorobenzyloxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as present amide compound (266)) 0.26 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.25 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 258 (0579) 5-(3,4,5-Trifluorobenzyloxymethyl)isoxazole-3-carboxy lic acid (0.86 g, 3.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.62 g, 4.5 mmol), triethylamine (0.46 g, 4.5 mmol) and 1-hydroxybenzotriazole (0.04 g, 0.3 mmol) were added to chloroform (amylene addition product) (7.5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.69 g, 3.6 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.25 g of N-(tetrahydrofuran-3-ylmethyl)-5-(3,4,5-trifluorobenzyloxym ethyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (267)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta (ppm)) : 1.62-1.73 (1H, m), 2.04-2.14 (1H, m), 2.53-2.64 (1H, m), 3.47 (2H, t), 3.59 (1H, dd), 3.73-3.81 (1H, m), 3.83-3.95(2H, m), 4.53(2H, s), 4.68(2H, s), 6.75(1H, s), 6.93-7.02 (2H, m), 6.96 (1H, br s) |
0.25 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (3,4,5-trifluorobenzyloxymethyl) isoxazole-3-carboxylic acid (0.86 g, 3.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.62 g, 4.5 mmol), Triethylamine (0.46 g, 4.5 mmol) And 1-hydroxybenzotriazole (0.04 g, 0.3 mmol) Was added to chloroform (amylene added product) (7.5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.69 g, 3.6 mmol) was added at room temperature, After stirring overnight, Dilute hydrochloric acid was added to the residue, And extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5- (3,4,5-trifluorobenzyloxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as this amide compound (267)) 0.25 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.4 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 259 (0580) 5-(3-Chloro-5-fluorobenzyloxymethyl)isoxazole-3-carbo xylic acid (1.04 g, 3.6 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.75 g, 5.5 mmol), triethylamine (0.76 mL, 5.5 mmol) and 1-hydroxybenzotriazole (0.05 g, 0.4 mmol) were added to chloroform (amylene addition product) (10 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.84 g, 4.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.40 g of N-(tetrahydrofuran-3-ylmethyl)-5-(3-chloro-5-fluorobenzylox ymethyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (268)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta (ppm)) : 1.63-1.72 (1H, m), 2.07-2.13 (1H, m), 2.53-2.63 (1H, m), 3.47 (2H, t), 3.59 (1H, dd), 3.73-3.80 (1H, m), 3.84-3.94(2H, m), 4.57 (2H, s), 4.68 (2H, s), 6.74 (1H, s), 6.93 (1H, br s), 6.97 (1H, d), 7.04 (1H, dt), 7.13 (1H, s) |
0.4 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (3-chloro-5-fluorobenzyloxymethyl) isoxazole-3-carboxylic acid (1.04 g, 3.6 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.75 g, 5.5 mmol), Triethylamine (0.76 mL, 5.5 mmol) And 1-hydroxybenzotriazole (0.05 g, 0.4 mmol) Was added to chloroform (amylene added product) (10 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.84 g, 4.4 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, And extracted three times with ethyl acetate.The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, Washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5- (3-chloro-5-fluorobenzyloxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as the amide compound (268)) 0.40 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.06 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 260 (0581) 5-(2,3,5,6-Tetrafluorobenzyloxymethyl)isoxazole-3-car boxylic acid (0.18 g, 0.6 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.21 g, 1.5 mmol), triethylamine (0.15 g, 1.5 mmol) and 1-hydroxybenzotriazole (0.01 g, 0.1 mmol) were added to chloroform (amylene addition product) (2.5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.23 g, 1.2 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.06 g of N-(tetrahydrofuran-3-ylmethyl)-5-(2,3,5,6-tetrafluorobenzyl oxymethyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (269)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta (ppm)) : 1.63-1.73 (1H, m), 2.05-2.14 (1H, m), 2.52-2.63 (1H, m), 3.47 (2H, t), 3.59 (1H, dd), 3.73-3.80 (1H, m), 3.83-3.95 (2H, m), 4.70 (2H, s), 4.72 (2H, dt), 6.76 (1H, s), 6.94 (1H, br s), 7.04-7.16 (1H, m) |
0.06 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (2,3,5,6-tetrafluorobenzyloxymethyl) isoxazole-3-carboxylic acid (0.18 g, 0.6 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.21 g, 1.5 mmol), Triethylamine (0.15 g, 1.5 mmol) And 1-hydroxybenzotriazole (0.01 g, 0.1 mmol) Was added to chloroform (amylene added product) (2.5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.23 g, 1.2 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, Extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, Washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equation Indicated by N- (tetrahydrofuran-3-ylmethyl) -5- (2,3,5,6-tetrafluorobenzyloxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as the present amide compound (269)) 0.06 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.24 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 261 (0582) 5-(2,3,4-Trifluorobenzyloxymethyl)isoxazole-3-carboxy lic acid (0.57 g, 2.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.41 g, 3.0 mmol), triethylamine (0.30 g, 3.0 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.2 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added to the mixture at room temperature, and the mixture was stirred at room temperature overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.24 g of N-(tetrahydrofuran-3-ylmethyl)-5-(2,3,4-trifluorobenzyloxym ethyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (270)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta (ppm)) : 1.62-1.73 (1H, m), 2.05-2.14 (1H, m), 2.52-2.64 (1H, m), 3.47(2H, t), 3.59 (1H, dd), 3.73-3.80 (1H, m), 3.83-3.95(2H, m), 4.64(2H, s), 4.69(2H, s), 6.75 (1H, s), 6.95 (1H, br s), 6.95-7.01 (1H, m), 7.10-7.18 (1H, m) |
0.24 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (2,3,4-trifluorobenzyloxymethyl) isoxazole-3-carboxylic acid (0.57 g, 2.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.41 g, 3.0 mmol), Triethylamine (0.30 g, 3.0 mmol) And 1-hydroxybenzotriazole (0.03 g, 0.2 mmol) Was added to chloroform (amylene added product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added at room temperature, After stirring overnight at room temperature, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, And extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, Washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equation Indicated by N- (tetrahydrofuran-3-ylmethyl) -5- (2,3,4-trifluorobenzyloxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as this amide compound (270)) 0.24 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.31 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 262 (0583) 5-(3,5-Dimethylbenzyloxymethyl)isoxazole-3-carboxylic acid (1.06 g, 4.1 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.84 g, 6.1 mmol), triethylamine (0.85 mL, 6.1 mmol) and 1-hydroxybenzotriazole (0.05 g, 0.4 mmol) were added to chloroform (amylene addition product) (10 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.93 g, 4.9 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.31 g of N-(tetrahydrofuran-3-ylmethyl)-5-(3,5-dimethylbenzyloxymeth yl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (271)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta (ppm)) : 1.63-1.72 (1H, m), 2.05-2.12 (1H, m), 2.32(6H, s), 2.55-2.61 (1H, m), 3.47(2H, t), 3.59 (1H, dd), 3.73-3.79(1H, m), 3.84-3.94(2H, m), 4.53(2H, s), 4.63(2H, s), 6.72 (1H, s), 6.93 (1H, br s), 6.96 (3H, s) |
0.31 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (3,5-dimethylbenzyloxymethyl) isoxazole-3-carboxylic acid (1 .06 g, 4.1 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0. 84 g, 6.1 mmol), Triethylamine (0.85 mL, 6.1 mmol) And 1 - hydroxybenzotriazole (0.05 g, 0.4 mmol) Was added to chloroform (amylen added product) (10 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.93 g, 4.9 mmol) was added at room temperature, After stirring overnight , And concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, And extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, Washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equation Indicated by N- (tetrahydrofuran-3-ylmethyl) -5- (3,5-dimethylbenzyloxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as the amide compound (2 71)) 0.31 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.59 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 263 (0584) 5-(4-Bromo-3-fluorobenzyloxymethyl)isoxazole-3-carbox ylic acid (1.42 g, 4.3 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.89 g, 6.5 mmol), triethylamine (0.90 mL, 6.5 mmol) and 1-hydroxybenzotriazole (0.06 g, 0.4 mmol) were added to chloroform (amylene addition product) (10 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.99 g, 5.2 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.59 g of N-(tetrahydrofuran-3-ylmethyl)-5-(4-bromo-3-fluorobenzyloxy methyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (272)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta (ppm)) : 1.60-1.75 (1H, m), 2.04-2.14 (1H, m), 2.52-2.64 (1H, m), 3.48 (2H, t), 3.59 (1H, dd), 3.73-3.80 (1H, m), 3.82-3.94(2H, m), 4.56(2H, s), 4.66(2H, s), 6.73(1H, s), 6.92(1H, br s), 7.01(1H, d), 7.13(1H, d), 7.53(1H, t) |
0.59 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (4-bromo-3-fluorobenzyloxymethyl) isoxazole-3-carboxylic acid (1.42 g, 4.3 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.89 g, 6.5 mmol), Triethylamine (0.90 mL, 6.5 mmol) And 1-hydroxybenzotriazole (0.06 g, 0.4 mmol) Was added to chloroform (amylene added product) (10 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.99 g, 5.2 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, And extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, Wash with saturated brine , Dried over anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equation Indicated by N- (tetrahydrofuran-3-ylmethyl) -5- (4-bromo-3-fluorobenzyloxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as this amide compound (272)) 0.59 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.06 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 264 (0585) 5-(4-Methyl-2,3,5,6-tetrafluorobenzyloxymethyl)isoxaz ole-3-carboxylic acid (0.29 g, 0.9 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.21 g, 1.5 mmol), triethylamine (0.15 g, 1.5 mmol) and 1-hydroxybenzotriazole (0.01 g, 0.1 mmol) were added to chloroform (amylene addition product) (2.5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.23 g, 1.2 mmol) was added to the mixture at room temperature, and the mixture was stirred at room temperature overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.06 g of N-(tetrahydrofuran-3-ylmethyl)-5-(4-methyl-2,3,5,6-tetraflu orobenzyloxymethyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (273)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta (ppm)) : 1.63-1.74 (1H, m), 2.04-2.15 (1H, m), 2.29(3H, s), 2.53-2.65 (1H, m), 3.47(2H, t), 3.61 (1H, dd), 3.74-3.82(1H, m), 3.84-3.97(2H, m), 4.68(2H, s), 4.71 (2H, s), 6.76 (1H, s), 7.01 (1H, br s) |
0.06 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (4-methyl-2,3,5,6-tetrafluorobenzyloxymethyl) isoxazole-3-carboxylic acid (0.29 g, 0.9 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.21 g, 1.5 mmol), Triethylamine (0.15 g, 1.5 mmol) And 1-hydroxybenzotriazole (0.01 g, 0.1 mmol) Was added to chloroform (amylene added product) (2.5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.23 g, 1.2 mmol) was added at room temperature, After stirring overnight at room temperature, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, And extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, Washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equation Indicated by N- (tetrahydrofuran-3-ylmethyl) -5- (4-methyl-2,3,5,6-tetrafluorobenzyloxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as the present amide compound (273)) 0.06 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.25 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 265 (0586) 5-(2,3-Difluorobenzyloxymethyl)isoxazole-3-carboxylic acid (0.54 g, 2.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.41 g, 3.0 mmol), triethylamine (0.30 g, 3.0 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.2 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.25 g of N-(tetrahydrofuran-3-ylmethyl)-5-(2,3-difluorobenzyloxymeth yl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (274)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta (ppm)) : 1.63-1.73 (1H, m), 2.05-2.15 (1H, m), 2.53-2.64 (1H, m), 3.47(2H, t), 3.59 (1H, dd), 3.73-3.81 (1H, m), 3.83-3.96(2H, m), 4.69(2H, s), 4.70(2H, s), 6.75(1H, s), 6.94 (1H, br s), 7.07-7.22(3H, m) |
0.25 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (2,3-difluorobenzyloxymethyl) isoxazole-3-carboxylic acid (0.54 g, 2.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.41 g, 3.0 mmol), Triethylamine (0.30 g, 3.0 mmol) And 1 - hydroxybenzotriazole (0.03 g, 0.2 mmol) Was added to chloroform (amylen added product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, And extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, Washed with saturated brine, After drying with anhydrous sodium sulfate, Reduction It was concentrated under pressure. The residue was subjected to silica gel column chromatography, The following equation Indicated by N- (tetrahydrofuran-3-ylmethyl) -5- (2,3-difluorobenzyloxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as the present amide compound (274)) 0.25 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.34 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 266 (0587) 5-(2,6-Difluorobenzyloxymethyl)isoxazole-3-carboxylic acid (0.54 g, 2.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.41 g, 3.0 mmol), triethylamine (0.30 g, 3.0 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.2 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.34 g of N-(tetrahydrofuran-3-ylmethyl)-5-(2,6-difluorobenzyloxymeth yl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (275)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta (ppm)) : 1 . 62-1 . 73 (1H, m), 2.04-2.14 (1H, m), 2.52-2.63 (1H, m), 3.46(2H, t), 3.59 (1H, dd), 3.73-3.80 (1H, m), 3.83-3.95(2H, m), 4.68 (2H, s), 4.70 (2H, s), 6.74 (1H, s), 6.93 (1H, br s), 6.93(2H, t), 7.28-7.37 (1H, m) |
0.34 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (2,6-difluorobenzyloxymethyl) isoxazole-3-carboxylic acid (0.54 g, 2.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.41 g, 3.0 mmol), Triethylamine (0.30 g, 3.0 mmol) And 1 - hydroxybenzotriazole (0.03 g, 0.2 mmol) Was added to chloroform (amylen added product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, And extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, Washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equation Indicated by N- (tetrahydrofuran-3-ylmethyl) -5- (2,6-difluorobenzyloxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as present amide compound (275)) 0.34 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.18 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 267 (0588) 5-(4-Chloro-3-fluorobenzyloxymethyl)isoxazole-3-carbo xylic acid (0.54 g, 2.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.41 g, 3.0 mmol), triethylamine (0.30 g, 3.0 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.2 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.18 g of N-(tetrahydrofuran-3-ylmethyl)-5-(4-chloro-3-fluorobenzylox ymethyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (276)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta (ppm)) : 1.62-1.74 (1H, m), 2.05-2.14 (1H, m), 2.52-2.64 (1H, m), 3.47 (2H, t), 3.59 (1H, dd), 3.73-3.80 (1H, m), 3.83-3.95 (2H, m), 4.57 (2H, s), 4.67 (2H, s), 6.74 (1H, s), 6.94 (1H, br s), 7.04-7.08 (1H, m), 7.16 (1H, dd), 7.38 (1H, t) |
0.18 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (4-chloro-3-fluorobenzyloxymethyl) isoxazole-3-carboxylic acid (0.54 g, 2.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.41 g, 3.0 mmol), Triethylamine (0.30 g, 3.0 mmol) And 1-hydroxybenzotriazole (0.03 g, 0.2 mmol) Was added to chloroform (amylene added product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added at room temperature , After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, And extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, Wash with saturated brine , Dried over anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equation Indicated by N- (Tetrahydrofuran-3-ylmethyl) -5- (4-chloro-3-fluorobenzyloxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as this amide compound (276)) 0.18 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.38 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 268 (0589) 5-(3-Fluoro-4-methoxybenzyloxymethyl)isoxazole-3-carb oxylic acid (1.10 g, 3.9 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.81 g, 5.9 mmol), triethylamine (0.82 mL, 5.9 mmol) and 1-hydroxybenzotriazole (0.05 g, 0.4 mmol) were added to chloroform (amylene addition product) (10 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.90 g, 4.7 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.38 g of N-(tetrahydrofuran-3-ylmethyl)-5-(3-fluoro-4-methoxybenzylo xymethyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (277)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta (ppm)) : 1.62-1.73 (1H, m), 2.04-2.14 (1H, m), 2.52-2.63 (1H, m), 3.47(2H, t), 3.59 (1H, dd), 3.73-3.80 (1H, m), 3.83-3.95(2H, m), 3.89 (3H, s), 4.52 (2H, s), 4.63(2H, s), 6.72 (1H, s), 6.93 (1H, brs), 6.94 (1H, t), 7.04 (1H, d), 7.09 (1H, dd) |
0.38 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (3-fluoro-4-methoxybenzyloxymethyl) isoxazole-3-carboxylic acid (1.10 g, 3.9 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.81 g, 5.9 mmol), Triethylamine (0.82 mL, 5.9 mmol) And 1-hydroxybenzotriazole (0.05 g, 0.4 mmol) Was added to chloroform (amylene added product) (10 mL). To the mixture, 1 - ethyl - 3- (3 - dimethylaminopropyl) carbodiimide hydrochloride (0.90 g, 4.7 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, And extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, Washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equation Indicated by N- (tetrahydrofuran-3-ylmethyl) -5- (3-fluoro-4-methoxyxybenzyloxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as present amide compound (277)) 0.38 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.78 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 269 (0590) 5-(2,4-Difluorobenzyloxymethyl)isoxazole-3-carboxylic acid (1.20 g, 4.5 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.92 g, 6.7 mmol), triethylamine (0.93 mL, 6.7 mmol) and 1-hydroxybenzotriazole (0.06 g, 0.4 mmol) were added to chloroform (amylene addition product) (10 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.03 g, 5.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.78 g of N-(tetrahydrofuran-3-ylmethyl)-5-(2,4-difluorobenzyloxymeth yl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (278)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta (ppm)) : 1.63-1.72 (1H, m), 2.04-2.14 (1H, m), 2.52-2.63 (1H, m), 3.47 (2H, t), 3.59 (1H, dd), 3.73-3.80 (1H, m), 3.83-3.95(2H, m), 4.62(2H, s), 4.68 (2H, s), 6.74(1H, s), 6.81(1H, dt), 6.89(1H, dt), 6.93(1H, br s), 7.35-7.42(1H, m) |
0.78 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (2,4-difluorobenzyloxymethyl) isoxazole-3-carboxylic acid (1.20 g, 4.5 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.92 g, 6.7 mmol), Triethylamine (0.93 mL, 6.7 mmol) And 1-hydroxybenzotriazole (0.06 g, 0.4 mmol) Was added to chloroform (amylene-added product) (10 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.03 g, 5.4 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue, And extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, Washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography , The following formula Indicated by N- (tetrahydrofuran-3-ylmethyl) -5- (2,4-difluorobenzyloxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as the present amide compound (278)) 0.78 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.13 g | Production Example 322 (0642) 1-Hydroxybenzotriazole (0.01 g, 0.08 mmol) was added to 2.0 ml of a chloroform (amylene addition product) solution of 5-[(5-benzothiophenyl)methoxymethyl]isoxazole-3-carboxylic acid (0.24 g, 0.83 mmol), and the mixture was stirred at room temperature for 15 minutes. Tetrahydrofuran-3-ylmethylamine hydrochloride (0.14 g, 1.0 mmol) and triethylamine (0.14 mL, 1.0 mmol) were added to the mixture at room temperature, and the mixture was stirred for 30 minutes. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.19 g, 1.0 mmol) was further added thereto at room temperature, and the mixture was stirred overnight. Then, 1 N hydrochloric acid was added thereto, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.13 g of N-(tetrahydrofuran-3-ylmethyl)-5-[(5-benzothiophenyl)methox ymethyl]isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (336)) represented by the following formula. 1H-NMR(CDCl3, TMS)delta(ppm): 7.88(1H, d), 7.80(1H, s), 7.48(1H, d), 7.34(2H, dt), 6.97-6.90(1H, m), 6.74(1H, s), 4.73(2H, s), 4.67(2H, s), 3.92(1H, td), 3.86(1H, dd), 3.77(1H, dd), 3.59(1H, dd), 3.47(2H, t), 2.63-2.53(1H, m), 2.10(1H, tt), 1.68(1H, tt) | |
0.13 g | 5 - [(5-benzothiophenyl) methoxymethyl] isoxazole-3-carboxylic acid (0.24 g, 0.83 mmol) Of chloroform (amylene added product) solution, 1-Hydroxybenzotriazole (0.01 g, 0.08 mmol) was added, And the mixture was stirred at room temperature for 15 minutes. To the mixture, At room temperature, <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.14 g, 1.0 mmol) And triethylamine (0.14 mL, 1.0 mmol) were added, And the mixture was stirred for 30 minutes. further, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.19 g, 1.0 mmol) was added at room temperature, After stirring overnight, 1N hydrochloric acid was added, And extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equation Indicated by N- (tetrahydrofuran-3-ylmethyl) -5 - [(5-benzothiophenyl) methoxymethyl] isoxazole-3-carboxamide (Hereinafter referred to as present amide compound (336)) 0.13 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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2.95 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 325 (0645) 5-Propargyloxymethylisoxazole-3-carboxylic acid (2.88 g, 15.9 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (2.72 g, 19.8 mmol), triethylamine (1.94 g, 19.8 mmol) and 1-hydroxybenzotriazole (0.22 g, 1.59 mmol) were added to chloroform (amylene addition product) (30 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (3.80 g, 19.8 mmol) was added to the mixed liquid at room temperature, and then the mixture was stirred at room temperature overnight. Thereafter, the resulting mixture was concentrated under reduced pressure. Dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 2.95 g of N-(tetrahydrofuran-3-ylmethyl)-5-propargyl.oxymethylzsoxazol e-3-carboxamide (hereinafter, referred to as Compound of Present Invention (339)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):1.62-1.73(m, 1H), 2.04-2.14(m, 1H), 2.52-2.63(m, 2H), 3.44-3.49(m, 2H), 3.59(dd, 1H), 3.73-3.80(m, 1H), 3.83-3.95(m, 2H), 4.25(d, 2H), 4.75(d, 2H), 6.75(s, 1H), 6.94(br s, 1H) |
2.95 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5-propargyloxymethyl isoxazole-3-carboxylic acid (2.88 g, 15.9 mmol),Tetrahydrofuran-3-ylmethylamine hydrochloride (2.72 g, 19.8 mmol),Triethylamine (1.94 g, 19.8 mmol)And 1-hydroxybenzotriazole (0.22 g, 1.59 mmol)Was added to chloroform (amylene addition product) (30 mL).To the mixture,1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.80 g, 19.8 mmol) was added at room temperature,Stir at room temperature overnight,And concentrated under reduced pressure.Dilute hydrochloric acid was added to the concentrate,Extracted twice with ethyl acetate.The organic layer was washed with saturated brine,After drying with anhydrous sodium sulfate, decreaseAnd concentrated under reduced pressure.The residue was subjected to silica gel column chromatography,Represented by the following equationN- (tetrahydrofuran-3-ylmethyl) -5-propargyloxymethylisoxazole-3-carboxamide(Hereinafter referred to as the present amide compound (339))2.95 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In N,N-dimethyl-formamide; at 40℃; for 0.333333h;Sonication; | Reference Production Example 1 (0647) Triethylamine (1.6 mL) and <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (1.12 g, 8.14 mmol) were added to an N,N-dimethylformamide (6 mL) solution of ethyl 5-pent-1-ynyl-1,3,4-thiadiazole-2-carboxylate (950 mg, 4.24 mmol). The mixture was stirred at 40C for 20 minutes under ultrasonic irradiation, and cooled. Then, the mixture was diluted with ethyl acetate, and sequentially washed with 3% hydrochloric acid and saturated saline water, and then the organic layer was dried over anhydrous sodium sulfate. The dried matter was concentrated under reduced pressure, and the residue was applied to a silica gel column chromatography to obtain 850 mg of N-(tetrahydrofuran-3-ylmethyl)-5-(pent-1-ynyl)-1,3,4-thiadi azole-2-carboxamide represented by the following formula: as a crude product. The crude product was subjected to a next reaction as it was. |
Yield | Reaction Conditions | Operation in experiment |
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0.03 g | Production Example 57 (0372) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.07 g, 0.48 mmol) was dissolved in 0.8 mL of chloroform (amylene addition product), and triethylamine (0.07 mL, 0.48 mmol) was added thereto. Then, the mixture was stirred at room temperature for 30 minutes. 1.2 ml of a chloroform (amylene addition product) solution of 5-butylisoxazole-3-carboxylic acid (0.08 g, 0.40 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.09 g, 0.48 mmol) and 1-hydroxybenzotriazole (0.005 g, 0.04 mmol) were added to the mixture at room temperature, and the mixture was stirred at room temperature overnight. Then, 2 ml of 1 N hydrochloric acid was added thereto, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.03 g of N-(tetrahydrofuran-3-ylmethyl)-5-butylisoxathiazole-3-carbo xamide (hereinafter, referred to as Compound of Present Invention (62)) represented by the following formula. 1H-NMR(CDCl3, TMS)delta(ppm):7.58-7.56(1H, m), 7.47-7.32(1H, m), 3.96-3.85(2H, m), 3.77(1H, dd), 3.60(1H, dd), 3.45(2H, td), 2.93(2H, t), 2.64-2.53(1H, m), 2.13-2.04(1H, m), 1.70(3H, tt), 1.41(2H, td), 0.95(3H, t) | |
0.03 g | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.07 g, 0.48 mmol) was dissolved in 0.8 mL of chloroform (amylene addition product), triethylamine (0.07 mL, 0.48 mmol) was added, and the mixture was stirred at room temperature for 30 minutes did. To the mixture were added 1.2 ml of a solution of 5-butylisothiazole-3-carboxylic acid (0.08 g, 0.40 mmol) in chloroform (with amylene addition) at room temperature and 1 ml of 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide Hydrochloride (0.09 g, 0.48 mmol) and 1-hydroxybenzotriazole (0.005 g, 0.04 mmol) were added and after stirring overnight at room temperature, 2 ml of 1N hydrochloric acid was added and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain N- (tetrahydrofuran-3-ylmethyl) -5-butylisothiazole-3-carboxamide (hereinafter referred to as the present amide compound (62)) represented by the following formula .) 0.03 g. |
Yield | Reaction Conditions | Operation in experiment |
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0.42 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 110 (0426) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.24 g, 1.78 mmol) and triethylamine (0.18 g, 1.78 mmol) were added to chloroform (amylene addition product) (10 mL). 5-(4-Phenylbenzyl)oxymethylisoxazole-3-carboxylic acid (0.40 g, 1.19 mmol), 1-hydroxybenzotriazole (0.02 g, 0.18 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0. 34 g, 1. 78 mmol) were added to the mixture at room temperature, and the mixture was stirred overnight. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.42 g of N-(tetrahydrofuran-3-ylmethyl)-5-(4-phenylbenzyloxymethyl)i soxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (115)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)): 1.64-1.72 (1H, m), 2.05-2.13(1H, m), 2.53-2.63(1H, m), 3.45-3.49(2H, m), 3.57-3.61(1H, m), 3.74-3.80(1H, m), 3.84-3.95(2H, m), 4.65(2H, s), 4.69 (2H, s), 6.75(1H, s), 6.94(1H, br s), 7.34-7.38(1H, m), 7.42-7.47(4H, m), 7.58-7.61(4H, m) |
0.42 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.24 g, 1.78 mmol) And triethylamine (0.18 g, 1.78 mmol) Was added to chloroform (amylene added product) (10 mL). To the mixture, 5- (4-phenylbenzyl) oxymethylisoxazole-3-carboxylic acid (0.40 g, 1.19 mmol) at room temperature, 1-Hydroxybenzotriazole (0.02 g, 0.18 mmol) And 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide hydrochloride (0.34 g, 1.78 mmol) was added, After stirring overnight, Dilute hydrochloric acid was added, It was extracted twice with chloroform. The organic layer was washed with saturated sodium bicarbonate water, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5- (4-phenylbenzyl) oxymethyl isoxazole-3-carboxamide (Hereinafter referred to as present amide compound (115)) 0.42 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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3.03 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 3 (0314) 1-Methyl-3-propyl-1H-pyrazole-5-carboxylic acid (1.68 g, 10 mmol), tetrahydrofuran-3-ylmethylamine hydrochloride (1.38 g, 10 mmol), triethylamine (1.01 g, 10 mmol) and 1-hydroxybenzotriazole (0.15 g, 1.0 mmol) were added to chloroform (amylene addition product) (60 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.92 g, 10 mmol) was added to the mixture at room temperature, and the mixture was stirred at room temperature overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 2.02 g of N-(tetrahydrofuran-3-ylmethyl)-1-methyl-3-propyl-1H-pyrazol e-5-carboxamide (hereinafter, referred to as Compound of Present Invention (3)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):0.96(3H, t), 1.64-1.68(3H, m), 2.05-2.14(1H, m), 2.56-2.58(3H, m), 3.41-3.43(2H, m), 3.61-3.63(1H, m), 3.75-3.77(1H, m), 3.82-3.84(1H, m), 3.92-3.94(1H, m), 4.11(3H, s), 6.15(1H, s), 6.26(1H, s) |
2.02 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | <strong>[139755-99-0]1-methyl-3-propyl-1 H-pyrazole-5-carboxylic acid</strong> (1.68 g, 10 mmol) Tetrahydrofuran-3-ylmethylamine hydrochloride (1.38 g, 10 mmol), Triethylamine (1.01 g, 10 mmol) And 1-hydroxybenzotriazole (0.15 g, 1.0 mmol) Was added to chloroform (amylene added product) (60 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.92 g, 10 mmol) was added at room temperature, After stirring overnight at room temperature, it was concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -1-methyl-3-propyl-1 H-pyrazole-5-carboxamide (Hereinafter referred to as present amide compound (3)) 2.02 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.31 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 4 (0315) 1-Methyl-3-butyl-1H-pyrazole-5-carboxylic acid (1.82 g, 10 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (1.38 g, 10 mmol), triethylamine (1.01 g, 10 mmol) and 1-hydroxybenzotriazole (0.15 g, 1.0 mmol) were added to chloroform (amylene addition product) (60 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.92 g, 10 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 2.31 g of N-(tetrahydrofuran-3-ylmethyl)-1-methyl-3-butyl-1H-pyrazole -5-carboxamide (hereinafter, referred to as Compound of Present Invention (4)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):0.93(3H, t), 1.35-1.39(2H, m), 1.57-1.72(3H,m), 2.05-2.14(1H, m), 2.53-2.62(3H, m), 3.42(2H, t), 3.61-3.63(1H, m), 3.74-3.78(1H, m), 3.82-3.84(1H, m), 3.92-3.94(1H, m), 4.10(3H, s), 6.17(1H, br s), 6.26(1H, s) |
2.31 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 1-methyl-3-butyl-1 H-pyrazole-5-carboxylic acid (1.82 g, 10 mmol) Tetrahydrofuran-3-ylmethylamine hydrochloride (1.38 g, 10 mmol), Triethylamine (1.01 g, 10 mmol) And 1-hydroxybenzotriazole (0.15 g, 1.0 mmol) Was added to chloroform (amylene added product) (60 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.92 g, 10 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -1-methyl-3-butyl-1 H-pyrazole-5-carboxamide (Hereinafter referred to as amide compound (4)) 2.31 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.61 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; | Production Example 5 (0316) 1-Methyl-3-pentyl-1H-pyrazole-5-carboxylic acid (1.82 g, 10 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (1.38 g, 10 mmol), triethylamine (1.01 g, 10 mmol) and 1-hydroxybenzotriazole (0.15 g, 1.0 mmol) were added to chloroform (amylene addition product) (60 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.92 g, 10 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 2.61 g of N-(tetrahydrofuran-3-ylmethyl)-1-methyl-3-pentyl-1H-pyrazol e-5-carboxamide (hereinafter, referred to as Compound of Present Invention (5)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):0.90(3H, t), 1.29-1.39(3H, m), 1.59-1.72(5H, m), 2.05-2.14(2H, m), 2.53-2.62(2H, m), 3. 42 (2H, t), 3.61-3.63(1H, m), 3.74-3.76(1H, m), 3.79-3.85(1H, m), 3.92-3.94(1H, m), 4.11(3H, s), 6.15(1H, br s), 6.26(1H, s) |
2.61 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 1-methyl-3-pentyl-1 H-pyrazole-5-carboxylic acid (1.82 g, 10 mmol) Tetrahydrofuran-3-ylmethylamine hydrochloride (1.38 g, 10 mmol), Triethylamine (1.01 g, 10 mmol) And 1-hydroxybenzotriazole (0.15 g, 1.0 mmol) Was added to chloroform (amylene added product) (60 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.92 g, 10 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (Tetrahydrofuran-3-ylmethyl) -1-methyl-3-pentyl-1 H-pyrazole-5-carboxamide (Hereinafter referred to as present amide compound (5)) 2.61 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.11 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 6 (0317) 1-Butyl-5-methyl-1H-pyrazole-4-carboxylic acid (1.82 g, 10 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (1.38 g, 10 mmol), triethylamine (1.01 g, 10 mmol) and 1-hydroxybenzotriazole (0.15 g, 1.0 mmol) were added to chloroform (amylene addition product) (60 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.92 g, 10 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 2.11 g of N-(tetrahydrofuran-3-ylmethyl)-1-butyl-5-methyl-1H-pyrazole -4-carboxamide (hereinafter, referred to as Compound of Present Invention (6)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):0.97(3H, t), 1.33-1.37(2H, m), 1.65-1.73(1H, m), 1.77-1.81(2H, m), 2.02-2.12(1H, m), 2.28(3H, s), 2.56-2.61(1H, m), 3.40-3.45(2H, m), 3.57-3.60(1H, m), 3.73-3.79(1H, m), 3.86-3.90(2H, m), 4.00(2H, t), 6.52(1H, s), 6.96 (1H, br s) |
2.11 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 1-Butyl-5-methyl-1 H-pyrazole-4-carboxylic acid (1.82 g, 10 mmol) Tetrahydrofuran-3-ylmethylamine hydrochloride (1.38 g, 10 mmol), Triethylamine (1.01 g, 10 mmol) And 1-hydroxybenzotriazole (0.15 g, 1.0 mmol) Was added to chloroform (amylene added product) (60 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.92 g, 10 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (Tetrahydrofuran-3-ylmethyl) -1-butyl-5-methyl-1 H-pyrazole-4-carboxamide (Hereinafter referred to as present amide compound (6)) 2.11 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.62 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 7 (0318) 1-Methyl-5-propoxy-1H-pyrazole-3-carboxylic acid (1.82 g, 10 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (1.38 g, 10 mmol), triethylamine (1.01 g, 10 mmol) and 1-hydroxybenzotriazole (0.15 g, 1.0 mmol) were added to chloroform (amylene addition product) (60 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.92 g, 10 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 1.62 g of N-(tetrahydrofuran-3-ylmethyl)-1-methyl-5-propoxy-1H-pyrazo le-3-carboxamide (hereinafter, referred to as Compound of Present Invention (7)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):1.03(3H, t), 1.66-1.71(1H, m), 1.75-1.86(2H, m), 2.05-2.08(1H, m), 2.53-2.60(1H, m), 3.39-3.45(2H, m), 3.57-3.59(1H, m), 3.65(3H, s), 3.75-3.77(1H, m), 3.86-3.90(2H, m), 4.02(2H, t), 6.04(1H, s), 6.96(1H, br s) |
1.62 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 1-methyl-5-propoxy-1 H-pyrazole-3-carboxylic acid (1.82 g, 10 mmol) Tetrahydrofuran-3-ylmethylamine hydrochloride (1.38 g, 10 mmol), Triethylamine (1.01 g, 10 mmol) And 1-hydroxybenzotriazole (0.15 g, 1.0 mmol) were added to chloroform (amylene addition product) (60 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.92 g, 10 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (Tetrahydrofuran-3-ylmethyl) -1-methyl-5-propoxy-1 H-pyrazole-3-carboxamide (Hereinafter referred to as the present amide compound (7)).1.62 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.86 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 8 (0319) 1-Butyl-1H-pyrazole-3-carboxylic acid (0.82 g, 4.8 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.66 g, 4.8 mmol), triethylamine (0.48 g, 4.8 mmol) and 1-hydroxybenzotriazole (0.07 g, 0.48 mmol) were added to chloroform (amylene addition product) (30 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.92 g, 4.8 mmol) was added to the mixture at room temperature, and the mixture was stirred at room temperature overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.86 g of N-(tetrahydrofuran-3-ylmethyl)-1-butyl-1H-pyrazole-3-carbox amide (hereinafter, referred to as Compound of Present Invention (8)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)): 0.93(3H, t), 1.31-1.35(2H, m), 1.68-1.70(1H, m), 1.79-1.86(2H, m), 2.05-2.14(1H, m), 2.54-2.64(1H, m), 3.44(2H, t), 3.63(1H, dd), 3.75-3.77(1H, m), 3.81-3.86(1H, m), 3.92-3.94(1H, m), 4.55(2H, t), 6.22(1H, br s), 6.46(1H, d), 7.46(1H, d) |
0.86 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 1-butyl-1 H-pyrazole-3-carboxylic acid (0.82 g, 4.8 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.66 g, 4.8 mmol), Triethylamine (0.48 g, 4.8 mmol) And 1-hydroxybenzotriazole (0.07 g, 0.48 mmol) Was added to chloroform (amylene addition product) (30 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.92 g, 4.8 mmol) was added at room temperature, After stirring overnight at room temperature, it was concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -1-butyl-1 H-pyrazole-3-carboxamide (hereinafter referred to as the present amide compound (8)) 0.86 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.86 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 9 (0320) 1-Benzyl-1H-1,2,3-triazole-4-carboxylic acid (0.96 g, 4.7 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.71 g, 5.2 mmol), triethylamine (1.01 g, 10 mmol) and 1-hydroxybenzotriazole (0.08 g, 0.52 mmol) were added to chloroform (amylene addition product) (30 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.00 g, 4.2 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.86 g of 31-benzyl-1H-1,2,3-triazole-4-carboxamide (hereinafter, referred to as Compound of Present Invention (9)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)): 1. 6.4-1 . 72 (1H, m), 2.03-2.11(1H, m), 2.54-2.59(1H, m), 3.46(2H, dd), 3.58(1H, dd), 3.75(1H, q), 3.93-3.84(2H, m), 5.55(2H, s), 7.41-7.27(5H, m), 7.97(1H, s) |
0.86 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 1-benzyl-1 H-1,2,3-triazole-4-carboxylic acid (0.96 g, 4.7 mmol) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.71 g, 5.2 mmol), Triethylamine (1.01 g, 10 mmol) And 1-hydroxybenzotriazole (0.08 g, 0.52 mmol) Was added to chloroform (amylene addition product) (30 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.00 g, 4.2 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate and it was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, 1-benzyl-1H-1,2,3-triazole-4-carboxamide represented by the following formula (hereinafter referred to as present amide compound (9)) 0.86 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.1 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 10 (0321) 5-Propylisoxazole-3-carboxylic acid (0.25 g, 1.6 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.27 g, 1.9 mmol), triethylamine (0.19 g, 1.9 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.19 mmol) were added to chloroform (amylene addition product) (10 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0. 36 g, 1. mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.10 g of N-(tetrahydrofuran-3-ylmethyl)-5-propylisoxazole-3-carboxam ide (hereinafter, referred to as Compound of Present Invention (10)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)) :1.01(3H, t), 1.65-1.82(3H, m), 2.05-2.13(1H, m), 2.54-2.64(1H, m), 2.79(2H, t), 3.41-3.52(2H, m), 3.60-3.62(1H, m), 3.76-3.96(3H, m), 6.46(1H, s), 7.04(1H, br s) |
0.1 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5-Propylisoxazole-3-carboxylic acid (0.25 g, 1.6 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.27 g, 1.9 mmol), Triethylamine (0.19 g, 1.9 mmol) And 1-hydroxybenzotriazole (0.03 g, 0.19 mmol) Was added to chloroform (amylene added product) (10 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.36 g, 1.9 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5-propylisoxazole-3-carboxamide (Hereinafter, this amide compound (10) It is written. ) 0.10 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.28 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 11 (0322) 5-Butylisoxazole-3-carboxylic acid (0.50 g, 3.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.50 g, 3.6 mmol), triethylamine (0.36 g, 3.6 mmol) and 1-hydroxybenzotriazole (0.05 g, 0.36 mmol) were added to chloroform (amylene addition product) (20 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.69 g, 3.6 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.28 g of N-(tetrahydrofuran-3-ylmethyl)-5-butylisoxazole-3-carboxami de (hereinafter, referred to as Compound of Present Invention (11)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):0.92(3H, t), 1.34-1.36(2H, m), 1.69-1.73(3H, m), 2.08-2.10(1H, m), 2.59-2.63(1H, m), 2.77-2.79(2H, m), 3.46-3. 48 (2H, m), 3.62(1H, dd), 3.79(1H, dd), 3.86-3.97(2H, m), 6.46(1H, s), 7.10(1H, br s) |
0.28 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5-butylisoxazole-3-carboxylic acid (0.50 g, 3.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.50 g, 3.6 mmol), Triethylamine (0.36 g, 3.6 mmol) And 1-hydroxybenzotriazole (0.05 g, 0.36 mmol) Was added to chloroform (amylene added product) (20 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.69 g, 3.6 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5-butylisoxazole-3-carboxamide (Hereinafter referred to as the present amide compound (11)) 0.28 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.1 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 12 (0323) 5-Pentylisoxazole-3-carboxylic acid (0.28 g, 1.5 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.25 g, 1.8 mmol), triethylamine (0.18 g, 1.8 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.18 mmol) were added to chloroform (amylene addition product) (10 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.35 g, 1.8 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.10 g of N-(tetrahydrofuran-3-ylmethyl)-5-pentylisoxazole-3-carboxam ide (hereinafter, referred to as Compound of Present Invention (12)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):0.96-0.89(3H, m), 1.40-1.31(4H, m)1.77-1.65(3H, m), 2.09(1H, tt), 2.61(1H, td), 2.84-2.76(2H, t), 3.47(2H, dt), 3.62(1H, dd), 3.79(1H, dd), 3.97-3.86(2H, m), 6.46(1H, s), 7.10(1H, br s) |
0.1 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5-Pentylisoxazole-3-carboxylic acid (0.28 g, 1.5 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.25 g, 1.8 mmol), Triethylamine (0.18 g, 1.8 mmol) And 1-hydroxybenzotriazole (0.03 g, 0.18 mmol) Was added to chloroform (amylene added product) (10 mL). To the mixture, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.35 g, 1.8 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5-pentylisoxazole-3-carboxamide (Hereinafter referred to as present amide compound (12)) 0.10 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.35 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 13 (0324) 5-Benzyloxymethylisoxazole-3-carboxylic acid (0.59 g, 2.5 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.39 g, 2.8 mmol), triethylamine (0.28 g, 2.8 mmol) and 1-hydroxybenzotriazole (0.04 g, 0.28 mmol) were added to chloroform (amylene addition product) (15 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.54 g, 2.8 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.35 g of N-(tetrahydrofuran-3-ylmethyl)-5-benzyloxymethylisoxazole-3 -carboxamide (hereinafter, referred to as Compound of Present Invention (13)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta(ppm)): 1.66-1.69(1H, m), 2.05-2.13(1H, m), 2.53-2.63(1H, m), 3.47-3.49(2H, m), 3.58-3.60(1H, m), 3.76-3.78(1H, m), 3.84-3.95(2H, m), 4.61(2H, s), 4. 65 (2H, s), 6.73(1H, d), 6.95(1H, br s), 7.31-7.40(5H, m) |
0.35 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5-Benzyloxymethyl isoxazole-3-carboxylic acid (0.59 g, 2.5 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.39 g, 2.8 mmol), Triethylamine (0.28 g, 2.8 mmol) And 1-hydroxybenzotriazole (0.04 g, 0.28 mmol) Was added to chloroform (amylene added product) (15 mL). To the mixture, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.54 g, 2.8 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying over anhydrous sodium sulfate , And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5-benzyloxymethyl isoxazole-3-carboxamide (hereinafter referred to as present amide compound (13) It is written. ) 0.35 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.1 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 19 (0330) 5-Cyclopentyloxymethylisoxazole-3-carboxylic acid (0.26 g, 1.2 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.20 g, 1.5 mmol), triethylamine (0.15 g, 1.5 mmol) and 1-hydroxybenzotriazole (0.02 g, 0.15 mmol) were added to chloroform (amylene addition product) (15 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.28 g, 1.5 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.10 g of N-(tetrahydrofuran-3-ylmethyl)-5-cyclopentyloxymethylisoxaz ole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (19)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta(ppm)): 1.54-1.59(2H, m), 1.68-1.72(7H, m), 2.04-2.13(1H, m), 2.56-2.58(1H, m), 3.46(2H, t), 3.57-3.60(1H, m), 3.75-3.78(1H, m), 3.84-3.94(-2H, m), 4.03-4.04(1H, m), 4.58(2H, s), 6.69(1H, s), 6.93(1H, br s) |
0.1 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5-Cyclopentyloxymethyl isoxazole-3-carboxylic acid (0.26 g, 1.2 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.20 g, 1.5 mmol), Triethylamine (0.15 g, 1.5 mmol) And 1-hydroxybenzotriazole (0.02 g, 0.15 mmol) Was added to chloroform (amylene added product) (15 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.28 g, 1.5 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5-cyclopentyloxymethyl isoxazole-3-carboxamide (Hereinafter referred to as "present amide compound (19)") 0.10g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.37 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 20 (0331) 5-(2-Naphthylmethoxymethyl)isoxazole-3-carboxylic acid (0.57 g, 2.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.33 g, 2.4 mmol), triethylamine (0.24 g, 2.4 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0. 4 6 g, 2.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.37 g of N-(tetrahydrofuran-3-ylmethyl)-5-(2-naphthylmethoxymethyl)i soxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (20)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta(ppm)): 1.67-1.70(1H, m), 2.05-2.14(1H, m), 2.56-2.60(1H, m), 3.47(2H, t), 3.58-3.60(1H, m), 3.76-3.78(1H, m), 3.84-3.95(2H, m), 4.69(2H, s), 4.77(2H, s), 6.76(1H, s), 6.94(1H, br s), 7.46-7.53(3H, m), 7.80-7.87(4H, m) |
0.37 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (2-naphthylmethoxymethyl) isoxazole-3-carboxylic acid (0.57 g, 2.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.33 g, 2.4 mmol), Triethylamine (0.24 g, 2.4 mmol) And 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) Was added to chloroform (amylene added product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5- (2-naphthylmethoxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as the amide compound (20)) 0.37 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 22 (0333) 5-(3-Phenylpropyl)isoxazole-3-carboxylic acid (0.46 g, 2.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.33 g, 2.4 mmol), triethylamine (0.24 g, 2.4 mmol) and 1-hydroxybenzotriazole (0.04 g, 0.24 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.49 g of N-(tetrahydrofuran-3-ylmethyl)-5-(3-phenylpropyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (22)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta(ppm) :1.62-1.72 (1H, m), 2.02-2.13(3H, m), 2.52-2.62(1H, m), 2.69(2H, t), 2.80(2H, t), 3.44-3.47 (2H, m), 3.57-3.60(1H, m), 3.75-3.78(1H, m), 3.84-3.94(2H, m), 6.46(1H, s), 6.93(1H, br s), 7.18-7.22(3H, m), 7.29-7.32(2H, m) | |
0.49 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (3-phenylpropyl) isoxazole-3-carboxylic acid (0.46 g, 2.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.33 g, 2.4 mmol), Triethylamine (0.24 g, 2.4 mmol) And 1-hydroxybenzotriazole (0.04 g, 0.24 mmol) Was added to chloroform (amylene added product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5- (3-phenylpropyl) isoxazole-3-carboxamide (Hereinafter referred to as amide compound (22)) 0.49 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.15 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 23 (0334) 5-Phenyloxymethylisoxazole-3-carboxylic acid (0.31 g, 1.4 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.24 g, 1.7 mmol), triethylamine (0.17 g, 1.7 mmol) and 1-hydroxybenzotriazole (0.02 g, 0.17 mmol) were added to chloroform (amylene addition product) (3 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.33 g, 1.7 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.15 g of N-(tetrahydrofuran-3-ylmethyl)-5-phenyloxymethylisoxazole-3 -carboxamide (hereinafter, referred to as Compound of Present Invention (23)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta(ppm)): 1.66-1.69 (1H, m), 2.06-2.14 (1H, m), 2.56-2.60(1H, m), 3.46(2H, t), 3.60(1H, dd), 3.76-3.78(1H, m), 3.85-3.87(1H, m), 3.91-3.93(1H, m), 5.20(2H, s), 6.80(1H, s), 6.94-6.97(3H, m), 7.00-7.05(1H, m), 7.29-7.34(2H, m) |
0.15 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5-Phenyloxymethylisoxazole-3-carboxylic acid (0.31 g, 1.4 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.24 g, 1.7 mmol), Triethylamine (0.17 g, 1.7 mmol) And 1-hydroxybenzotriazole (0.02 g, 0.17 mmol) Was added to chloroform (amylene addition product) (3 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.33 g, 1.7 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5-phenyloxymethyl isoxazole-3-carboxamide (Hereinafter referred to as present amide compound (23)) 0.15 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.15 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 24 (0335) 5-(2-Phenylethyl)isoxazole-3-carboxylic acid (0.43 g, 2.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.33 g, 2.4 mmol), triethylamine (0.24 g, 2.4 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.15 g of N-(tetrahydrofuran-3-ylmethyl)-5-(2-phenylethyl)isoxazole-3 -carboxamide (hereinafter, referred to as Compound of Present Invention (24)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta(ppm)): 1.65-1.69(1H, m), 2.04-2.13(1H, m), 2.53-2.60(1H, m), 3.01-3.05(2H, m), 3.10-3.14(2H, m), 3.43-3.47(2H, m), 3.57-3.59(1H, m), 3.75-3.78(1H, m), 3.85-3.87(1H, m), 3.90-3.92(1H, m), 6.41(1H, s), 6.91(1H, br s), 7.18-7.19(2H, m), 7.22-7.24(1H, m), 7.29-7.31(2H, m) |
0.15 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (2-phenylethyl) isoxazole-3-carboxylic acid (0.43 g, 2.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.33 g, 2.4 mmol), Triethylamine (0.24 g, 2.4 mmol) And 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) were dissolved in chloroform (amylene addition product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5- (2-phenylethyl) isoxazole-3-carboxamide (Hereinafter referred to as "present amide compound (24)") 0.15 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.6 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 142 (0462) 5-(2-Phenoxyethoxymethyl)isoxazole-3-carboxylic acid (1.40 g, 5.3 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.88 g, 6.4 mmol), triethylamine (0.65 g, 6.4 mmol) and 1-hydroxybenzotriazole (0.08 g, 0.64 mmol) were added to chloroform (amylene addition product) (20 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.23 g, 6.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 1.60 g of N-(tetrahydrofuran-3-ylmethyl)-5-(2-phenoxyethoxymethyl)iso xazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (149)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):1.66-1.69(1H, m), 2.05-2.13(1H, m), 2.56-2.60(1H, m), 3.47(2H, t), 3.56-3.61(1H, m), 3.74-3.80(1H, m), 3.84-3.88(1H, m), 3.91-3.93(3H, m), 4.15-4.17(2H, m), 4.77(2H, s), 6.76(1H, s), 6.90-7.00(4H, m), 7.27-7.32(2H, m) |
1.6 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (2-phenoxyethyloxymethyl) isoxazole-3-carboxylic acid (1.40 g, 5.3 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.88 g, 6.4 mmol), Triethylamine (0.65 g, 6.4 mmol) And 1-hydroxybenzotriazole (0.08 g, 0.64 mmol) were added to chloroform (amylene addition product) (20 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.23 g, 6.4 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5- (2-phenoxyethyloxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as present amide compound (149)) 1.60 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.32 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 26 (0337) 5-Benzylisoxazole-3-carboxylic acid (0.27 g, 1.3 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.22 g, 1.6 mmol), triethylamine (0.16 g, 1.6 mmol) and 1-hydroxybenzotriazole (0.02 g, 0.16 mmol) were added to chloroform (amylene addition product) (3 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0. 31 g, 1. 6 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.32 g of N-(tetrahydrofuran-3-ylmethyl)-5-benzylisoxazole-3-carboxam ide (hereinafter, referred to as Compound of Present Invention (26)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta(ppm)): 1.63-1.68 (1H, m), 2.03-2.11(1H, m), 2.52-2.59(1H, m), 3.44(2H, dd), 3.57(1H, dd), 3.74-3.77(1H, m), 3.82-3.93(2H, m), 4.12(2H, s), 6.39(1H, s), 6.90(1H, br s), 7.24-7.37(5H, m) |
0.32 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5-Benzylisoxazole-3-carboxylic acid (0.27 g, 1.3 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.22 g, 1.6 mmol), Triethylamine (0.16 g, 1.6 mmol) And 1-hydroxybenzotriazole (0.02 g, 0.16 mmol) were added to chloroform (amylene addition product) (3 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.31 g, 1.6 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5-benzylisoxazole-3-carboxamide (Hereinafter referred to as present amide compound (26)) 0.32 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.31 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 27 (0338) 5-(1-Naphthylmethoxymethyl)isoxazole-3-carboxylic acid (0.46 g, 1.6 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.26 g, 1.9 mmol), triethylamine (0.19 g, 1.9 mmol) and 1-hydroxybenzotriazole (0.02 g, 0.19 mmol) were added to chloroform (amylene addition product) (3 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.37 g, 1.9 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.31 g of N-(tetrahydrofuran-3-ylmethyl)-5-(1-naphthylmethoxymethyl)i soxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (27)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta(ppm)): 1.66-1.69(1H, m), 2.04-2.13(1H, m), 2.53-2.63(1H, m), 3.46(2H, t), 3.58-3.60(1H, m), 3.75-3.79(1H, m), 3.84-3.94(2H, m), 4.68(2H, s), 5.06(2H, s), 6.72(1H, s), 6.95(1H, br s), 7.43-7.58(4H, m), 7.84-7.89(2H, m), 8.11(1H, d) |
0.31 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (1-naphthylmethoxymethyl) isoxazole-3-carboxylic acid (0.46 g, 1.6 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.26 g, 1.9 mmol), Triethylamine (0.19 g, 1.9 mmol) And 1-hydroxybenzotriazole (0.02 g, 0.19 mmol) Was added to chloroform (amylene addition product) (3 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.37 g, 1.9 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5- (1-naphthylmethoxymethyl) isoxazole-3-carboxamide (Hereinafter referred to as the amide compound (27)) 0.31 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.42 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 28 (0339) 5-[1-(2-Naphthyl)ethyl]oxymethylisoxazole-3-carboxyli c acid (0.59 g, 2.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.33 g, 2.4 mmol), triethylamine (0.24 g, 2.4 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.42 g of N-(tetrahydrofuran-3-ylmethyl)-5-[1-(2-naphthyl)ethyl]oxyme thylisoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (28)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)): 1.57(3H, d), 1.66-1.69(1H, m), 2.04-2.13(1H, m), 2.56-2.61(1H, m), 3.46(2H, t), 3.59(1H, dd), 3.77(1H, dd), 3.84-3.95(2H, m), 4.49(2H, dd), 4.70(1H, q), 6.69(1H, s), 6.93(1H, br s), 7.48-7.52(3H, m), 7.76(1H, s), 7.84-7.89(3H, m) |
0.42 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- [1- (2-naphthyl) ethyl] oxymethyl isoxazole-3-carboxylic acid (0.59 g, 2.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.33 g, 2.4 mmol), Triethylamine (0.24 g, 2.4 mmol) And 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) Was added to chloroform (amylene added product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added at room temperature, After stirring overnight, it was concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5- [1- (2-naphthyl) ethyl] oxymethyl isoxazole-3-carboxamide (Hereinafter referred to as the present amide compound (28)) 0.42 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.12 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 29 (0340) 5-(4-Methoxymethyl-2,3,5,6-tetrafluorobenzyl)oxymethy lisoxazole-3-carboxylic acid (0.20 g, 0.6 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.10 g, 0.9 mmol), triethylamine (0.07 g, 0.7 mmol) and 1-hydroxybenzotriazole (0.01 g, 0.07 mmol) were added to chloroform (amylene addition product) (2 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.13 g, 0.7 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.12 g of N-(tetrahydrofuran-3-ylmethyl)-5-(4-methoxymethyl-2,3,5,6-t etrafluorobenzyl)oxymethylisoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (29)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta(ppm)):1.63-1.68(1H, m), 2.03-2.12(1H, m), 2.51-2.61(1H, m), 3.39(3H, s), 3.45(2H, t), 3.58(1H, dd), 3.75(1H, dd), 3.83-3.85(1H, m), 3.89-3.91(1H, m), 4.57(2H, t), 4.68(2H, s), 4.71(2H, t), 6.74(1H, s), 6.94(1H, br s) |
0.12 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (4-methoxymethyl-2,3,5,6-tetrafluorobenzyl) oxymethyl isoxazole-3-carboxylic acid (0.20 g, 0.6 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.10 g, 0.9 mmol), Triethylamine (0.07 g, 0.7 mmol) And 1-hydroxybenzotriazole (0.01 g, 0.07 mmol) were added to chloroform (amylene addition product) (2 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.13 g, 0.7 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure.Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5- (4-methoxymethyl-2,3,5,6-tetrafluorobenzyl) oxymethyl isoxazole-3-carboxamide (hereinafter, this amide compound (29) I write down. 0.12 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.22 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 43 (0356) 5-Phenoxymethythiazole-2-carboxylic acid (0.28 g, 1.1 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.19 g, 1.4 mmol), triethylamine (0.14 g, 1.4 mmol) and 1-hydroxybenzotriazole (0.02 g, 0.14 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.27 g, 1.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.22 g of N-(tetrahydrofuran-3-ylmethyl)-5-phenoxymethythiazole-2-car boxamide (hereinafter, referred to as Compound of Present Invention (47)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta(ppm)):1.69-1.73(1H, m), 2.05-2.15 (1H, m), 2.58-2.65 (1H, m), 3.45-3.51(2H, m), 3.62(1H, dd), 3.78(1H, dd), 3. 86-3. 95 (2H, m), 5.20(2H, s), 6.99-7.01(3H, m), 7.31-7.33(2H, m), 7.39(1H, s), 7.58(1H, s) |
0.22 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5-phenoxymethylthiazole-2-carboxylic acid (0.28 g, 1.1 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.19 g, 1.4 mmol), Triethylamine (0.14 g, 1.4 mmol) And 1-hydroxybenzotriazole (0.02 g, 0.14 mmol) Was added to chloroform (amylene added product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.27 g, 1.4 mmol) was added at room temperature, After stirring overnight, it was concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5-phenoxymethylthiazole-2-carboxamide (Hereinafter referred to as present amide compound (47)) 0.22 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.42 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 45 (0358) 3-Benzyloxymethylisoxazole-5-carboxylic acid (0.46 g, 2.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.33 g, 2.4 mmol), triethylamine .(0.25 g, 2.4 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.42 g of N-(tetrahydrofuran-3-ylmethyl)-3-benzyloxymethylisoxazole-5 -carboxamide (hereinafter, referred to as Compound of Present Invention (49)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta(ppm)):1.66-1.72(1H, m), 2.05-2.15(1H, m), 2.57-2.61(1H, m), 3.48(2H, dd), 3.61(1H, dd), 3.75-3.79 (1H, m), 3.85-3.87 (1H, m), 3.92-3.94(1H, m), 4.58(2H, s), 4.65(2H, s), 6.68(1H, s), 6.99(1H, s), 7.34-7.36(5H, m) |
0.42 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 3-Benzyloxymethyl isoxazole-5-carboxylic acid (0.46 g, 2.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.33 g, 2.4 mmol), Triethylamine (0.25 g, 2.4 mmol) And 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) Was added to chloroform (amylene added product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -3-benzyloxymethyl isoxazole-5-carboxamide (Hereinafter referred to as present amide compound (49)) 0.42 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.51 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 46 (0359) 5-Benzyloxymethyl-1H-pyrazole-3-carboxylic acid (0.50 g, 2.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.33 g, 2.4 mmol), triethylamine (0.24 g, 2.4 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.51 g of N-(tetrahydrofuran-3-ylmethyl)-5-benzyloxymethyl-1H-pyrazol e-3-carboxamide (hereinafter, referred to as Compound of Present Invention (50)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta(ppm)): 1.66-1.71(1H, m), 2.06-2.09 (1H, m), 2.56-2.62 (1H, m), 3.39-3.51(2H, m), 3.62(1H, dd), 3.75-3. 77 (1H, m), 3.84-3.94(2H, m), 4.57(2H, s), 4.63(2H, s), 6.71(1H, s), 7.01(1H, s), 7.33-7.38(5H, m) |
0.51 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5-Benzyloxymethyl-1 H-pyrazole-3-carboxylic acid (0.50 g, 2.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.33 g, 2.4 mmol), Triethylamine (0.24 g, 2.4 mmol) And 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) Was added to chloroform (amylene added product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5-benzyloxymethyl-1 H-pyrazole-3-carboxamide (Hereinafter referred to as present amide compound (50)) 0.51 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.32 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 47 (0360) 1-Butyl-1H-pyrazole-4-carboxylic acid (0.34g, 2.0mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.35 g, 2.5 mmol), triethylamine (0.25 g, 2.5 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.25 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.48 g, 2.5 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.32 g of N-(tetrahydrofuran-3-ylmethyl)-1-butyl-1H-pyrazole-4-carbox amide (hereinafter, referred to as Compound of Present Invention (51)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):0.94(3H, t), 1.27-1.37(2H, m), 1.65-1.70(1H, m), 1.85(2H, tt), 2.04-2.13(1H, m), 2.55-2.61(1H, m), 3.43(2H, t), 3.62(1H, dd), 3.75-3.77(1H, m), 3.84(1H, dd), 3.92(1H, td), 4.13(2H, t), 5.93(1H, s), 7.71(1H, s), 7.85(1H, s) |
0.32 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 1-butyl-1 H-pyrazole-4-carboxylic acid (0.34 g, 2.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.35 g, 2.5 mmol), Triethylamine (0.25 g, 2.5 mmol) And 1-hydroxybenzotriazole (0.03 g, 0.25 mmol) Was added to chloroform (amylene added product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.48 g, 2.5 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -1-butyl-1 H-pyrazole-4-carboxamide (Hereinafter referred to as amide compound (51)) 0.32 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.63 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 49 (0364) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.54 g, 3.96 mmol) and triethylamine (0.40 g, 3.96 mmol) were added to chloroform (amylene addition product) (13 mL). 1-Butyl-1H-1,2,3-triazole-4-carboxylic acid (0.56 g, 3.30 mmol), 1-hydroxybenzotriazole (0.05 g, 0.33 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.76 g, 3.96 mmol) were added to the mixture at room temperature, and the mixture was stirred for 3 hours. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.63 g of N-(tetrahydrofuran-3-ylmethyl)-1-butyl-1H-1,2,3-triazole-4-carboxamide (hereinafter, referred to as Compound of Present Invention (54)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)): 0.96(3H, t), 1.30-1.39(2H, m), 1.65-1.74(1H, m), 1.92-1.99(2H, m), 2.05-2.13(1H, m), 2.54-2.63(1H, m), 3.41-3.52(2H, m), 3.59-3.63(1H, m), 3.74-3.80(1H, m), 3.85-3.95(2H, m), 4.43(2H, t), 6.85(1H, br s), 8.03(1H, s) |
0.63 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; for 3h; | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.54 g, 3.96 mmol) And triethylamine (0.40 g, 3.96 mmol) Was added to chloroform (amylene added product) (13 mL). To the mixture, 1-Butyl-1 H-1,2,3-triazole-4-carboxylic acid (0.56 g, 3.30 mmol) 1-Hydroxybenzotriazole (0.05 g, 0.33 mmol) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.76 g, 3.96 mmol) After stirring for 3 hours, Dilute hydrochloric acid was added, It was extracted twice with chloroform. The organic layer was washed with saturated sodium bicarbonate water, After drying over anhydrous magnesium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -1-butyl-1 H-1,2,3-triazole-4-carboxamide (Hereinafter referred to as amide compound (54)) 0.63 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.11 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 50 (0365) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.20 g, 1.20 mmol) and triethylamine (0.12 g, 1.20 mmol) were added to chloroform (amylene addition product) (4 mL). 2-Butyl-2H-1,2,3-triazole-4-carboxylic acid (0.17 g, 1.00 mmol), 1-hydroxybenzotriazole (0.01 g, 0.10 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.23 g, 1.20 mmol) were added to the mixture at room temperature, and the mixture was stirred for 3 hours. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0. 11 g of N-(tetrahydrofuran-3-ylmethyl)-2-butyl-2H-1,2,3-triazole-4-carboxamide (hereinafter, referred to as Compound of Present Invention (55)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)): 0.97(3H, t), 1.31-1.41(2H, m), 1.65-1.74(1H, m), 1.87-1.95(2H, m), 2.05-2.13(1H, m), 2.54-2.64(1H, m), 3.46-3.50(2H, m), 3.58-3.61(1H, m), 3.74-3.80(1H, m), 3.86-3.94(2H, m), 4.40(2H, t), 7.28(1H, br s), 8.04(1H, s) |
0.11 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 3h; | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.20 g, 1.20 mmol) And triethylamine (0.12 g, 1.20 mmol) Was added to chloroform (amylene added product) (4 mL). To the mixture, Butyl-2H-1,2,3-triazole-4-carboxylic acid (0.17 g, 1.00 mmol) at room temperature, 1-Hydroxybenzotriazole (0.01 g, 0.10 mmol) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.23 g, 1.20 mmol) After stirring for 3 hours, Dilute hydrochloric acid was added, It was extracted twice with chloroform. The organic layer was washed with saturated sodium bicarbonate water, The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (Tetrahydrofuran-3-ylmethyl) -2-butyl-2H-1,2,3-triazole-4-carboxamide (Hereinafter referred to as the present amide compound (55))0.11 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.51 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 51 (0366) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.38 g, 2.75 mmol) and triethylamine (0.28 g, 2.75 mmol) were added to chloroform (amylene addition product) (8 mL). 2-Butyl-2H-tetrazole-5-carboxylic acid (0.39 g, 2.29 mmol), 1-hydroxybenzotriazole (0.03 g, 0.23 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.53g, 2. 75 mmol) were added to the mixture at room temperature, and the mixture was stirred overnight. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.51 g of N-(tetrahydrofuran-3-ylmethyl)-2-butyl-2H-tetrazole-5-carbo xamide (hereinafter, referred to as Compound of Present Invention (56)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):0.97(3H, t), 1.32-1.41(2H, m), 1.66-1.75(1H, m), 2.01-2.13(3H, m), 2.58-2.68(1H, m), 3.53-3.56(2H, m), 3.61-3.64(1H, m), 3.75-3.80(1H, m), 3.85-3.96(2H, m), 4.69(2H, t), 7.31(1H, br s) |
0.51 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.38 g, 2.75 mmol) And triethylamine (0.28 g, 2.75 mmol) Was added to chloroform (amylene added product) (8 mL). To the mixture, At room temperature 2-butyl-2H-tetrazole-5-carboxylic acid (0.39 g, 2.29 mmol), 1-Hydroxybenzotriazole (0.03 g, 0.23 mmol) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.53 g, 2.75 mmol) After stirring overnight, Dilute hydrochloric acid was added, It was extracted twice with chloroform. The organic layer was washed with saturated sodium bicarbonate water, After drying over anhydrous magnesium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, N- (tetrahydrofuran-3-ylmethyl) -2-butyl-2H-tetrazole-5-carboxamide (Hereinafter referred to as present amide compound (56)) 0.51 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.76 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 52 (0367) 5-Butyl-1,2,4-oxadiazole-3-carboxylic acid (1.36 g, 8 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (1.65 g, 12 mmol), triethylamine (1.21 g, 12 mmol) and 1-hydroxybenzotriazole (0.11 g, 0.8 mmol) were added to chloroform (amylene addition product) (16 mL). 1-Ethyl-3-(3-dimetrylaminopropyl) carbodiimide hydrochloride (1.83 g, 12 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight. Then, water was added thereto, and the mixture was extracted three times with chloroform. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.76 g of N-(tetrahydrofuran-3-ylmethyl)-5-butyl-1,2,4-oxadiazole-3-c arboxamide (hereinafter, referred to as Compound of Present Invention (57)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):0.96(3H, t), 1.38-1.49(2H, m), 1.62-1.73(1H, m), 1.80-1.87(2H, m), 2.05-2.15(1H, m), 2.55-2.67(1H, m), 2.95(2H, t), 3.45-3.55(2H, m), 3.61(1H, dd), 3.73-3.80(1H, m), 3.85(1H, dd), 3.92(1H, td), 7.10(1H, brs) |
0.76 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5-Butyl-1,2,4-oxadiazole-3-carboxylic acid (1.36 g, 8 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (1.65 g, 12 mmol), Triethylamine (1.21 g, 12 mmol) And 1-hydroxybenzotriazole (0.11 g, 0.8 mmol) Was added to chloroform (amylene added product) (16 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.83 g, 12 mmol) was added at room temperature, After stirring overnight, Add water, It was extracted three times with chloroform. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5-butyl-1,2,4-oxadiazole-3-carboxamide (Hereinafter referred to as the amide compound (57)) 0.76 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.43 g | With N-ethyl-N,N-diisopropylamine; In ethanol; at 20℃; for 2h; | Production Example 53 (0368) Ethyl 3-butyl-1,2,4-oxadiazole-5-carboxylate (0.40 g, 2 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (2.75 g, 20 mmol) and diisopropylethylamine (2.58 g, 20 mmol) were added to ethanol (40 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, then water was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.43 g of N-(tetrahydrofuran-3-ylmethyl)-3-butyl-1,2,4-oxadiazole-5-c arboxamide (hereinafter, referred to as Compound of Present Invention (58)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):0.96(3H, t), 1.36-1.46(2H, m), 1.64-1.79(3H, m), 2.07-2.16(1H, m), 2.58-2.65(1H, m), 2.79(2H, t), 3.45-3.55(2H, m), 3.62(1H, dd), 3.74-3.81(1H, m), 3.85(1H, dd), 3.93(1H, td), 7.19(1H, brs) |
0.43 g | With N-ethyl-N,N-diisopropylamine; In ethanol; at 20℃; for 2h; | Ethyl 3-butyl-1,2,4-oxadiazole-5-carboxylate (0.40 g, 2 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (2.75 g, 20 mmol) And diisopropylethylamine (2.58 g, 20 mmol) Was added to ethanol (40 mL) And the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, Water was added to the residue, And extracted three times with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -3-butyl-1,2,4-oxadiazole-5-carboxamide (Hereinafter referred to as amide compound (58)) 0.43 g. |
Yield | Reaction Conditions | Operation in experiment |
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0.13 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 54 (0369) 2-Butyloxazole-5-carboxylic acid (0.10 g, 0.6 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.12 g, 0.9 mmol), triethylamine (0.09 g, 0.9 mmol) and 1-hydroxybenzotriazole (0.01 g, 0.1 mmol) were added to chloroform (amylene addition product) (1.2 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.14 g, 0.7 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight. Then, water was added thereto, and the mixture was extracted three times with ethyl acetate. The organic layer was.washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.13 g of N-(tetrahydrofuran-3-ylmethyl)-2-butyloxazole-5-carboxamide (hereinafter, referred to as Compound of Present Invention (59)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):0.95(3H, t), 1.36-1.45(2H, m), 1.63-1.80(3H, m), 2.03-2.13(1H, m), 2.50-2.63(1H, m), 2.76(2H, t), 3.37-3.50(2H, m), 3.59(1H, dd), 3.73-3.80(1H, m), 3.84-3.94(2H, m), 7.02(1H, brs), 8.08(1H, s) |
0.13 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 2-Butyloxazole-5-carboxylic acid (0.10 g, 0.6 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.12 g, 0.9 mmol), Triethylamine (0.09 g, 0.9 mmol) And 1-hydroxybenzotriazole (0.01 g, 0.1 mmol) Was added to chloroform (amylene added product) (1.2 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.14 g, 0.7 mmol) was added at room temperature, After stirring overnight, Add water, And extracted three times with ethyl acetate. The organic layer was washed with saturated brine , Dried over anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -2-butyloxazole-5-carboxamide (Hereinafter referred to as present amide compound (59)) 0.13 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.39 g | With N-ethyl-N,N-diisopropylamine; In ethanol; for 10h;Reflux; | Production Example 55 (0370) Ethyl 5-butyloxazole-2-carboxylate (0.39 g, 2 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (2.75 g, 20 mmol) and diisopropylethylamine (2.58 g, 20 mmol) were added to ethanol (40 mL), and the mixture was stirred under heating and refluxing for 10 hours, and then concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.39 g of N-(tetrahydrofuran-3-ylmethyl)-5-butyloxazole-2-carboxamide (hereinafter, referred to as Compound of Present Invention (60)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):0.94(3H, t), 1.33-1.44(2H, m), 1.63-1.73(3H,m), 2.04-2.13(1H, m), 2.52-2.63(1H, m), 2.73(2H, t), 3.40-3.51(2H, m), 3.59(1H, dd), 3.73-3.80(1H, m), 3.83-3.95(2H, m), 6.83(1H, brs), 7.12(1H, s) |
0.39 g | With N-ethyl-N,N-diisopropylamine; In ethanol; for 10h;Reflux; | Ethyl 5-butyloxazole-2-carboxylate (0.39 g, 2 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (2.75 g, 20 mmol) And diisopropylethylamine (2.58 g, 20 mmol) Was added to ethanol (40 mL), and After stirring under heat reflux for 10 hours, And concentrated under reduced pressure. Water was added to the residue, And extracted three times with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, N- (tetrahydrofuran-3-ylmethyl) -5-butyloxazole-2-carboxamide represented by the following formula (Hereinafter referred to as present amide compound (60)) 0.39 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.12 g | Production Example 56 (0371) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.13 g, 0.93 mmol) was dissolved in 1 mL of chloroform (amylene addition product), and triethylamine (0.13 mL, 0.93 mmol) was added thereto. Then, the mixture was stirred at room temperature for 30 minutes. 2.0 ml of a chloroform (amylene addition product) solution of 5-benzylisoxathiazole-3-carboxylic acid (0.17 g, 0.77 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.23 g, 0.93 mmol) and 1-hydroxybenzotriazole (0.01 g, 0.08 mmol) were added to the mixture at room temperature, and the mixture was stirred overnight. Then, 2 ml of 1 N hydrochloric acid was added thereto, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.12 g of N-(tetrahydrofuran-3-ylmethyl)-5-benzylisoxathiazole-3-carb oxamide (hereinafter, referred to as Compound of Present Invention (61)) represented by the following formula. 1H-NMR(CDCl3, TMS)delta(ppm):7.57(1H, t), 7.39-7.21(6H, m), 4.24(2H, s), 3.90(1H, td), 3.86(1H, dd), 3.76(1H, dd), 3.59(1H, dd), 3.44(2H, td), 2.60-2.54(1H, m), 2.12-2.03(1H, m), 1.74-1.60(1H, m) | |
0.12 g | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.13 g, 0.93 mmol) was dissolved in 1 mL of chloroform (amylene addition product), triethylamine (0.13 mL, 0.93 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added 2.0 ml of a solution of 5-benzylisothiazole-3-carboxylic acid (0.17 g, 0.77 mmol) in chloroform (amylene addition product) at room temperature and 1 ml of 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide Hydrochloride (0.23 g, 0.93 mmol) and 1-hydroxybenzotriazole (0.01 g, 0.08 mmol) were added and after stirring overnight, 2 ml of 1N hydrochloric acid was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain N- (tetrahydrofuran-3-ylmethyl) -5-benzylisothiazole-3-carboxamide (hereinafter referred to as the present amide compound (61)) represented by the following formula .) 0.12 g. |
Yield | Reaction Conditions | Operation in experiment |
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0.4 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 58 (0373) 5-(4-Trifluoromethylbenzyloxymethyl)isoxazole-3-carbo xylic acid (0.60g, 2.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.33 g, 2.4 mmol), triethylamine (0.25 g, 2.4 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) were added to 5 mL of chloroform (amylene addition product). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.40 g of N-(tetrahydrofuran-3-ylmethyl)-5-(4-trifluoromethylbenzylox ymethyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (63)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):1.65-1.70(1H, m), 2.05-2.13(1H, m), 2.55-2.61(1H, m), 3.47(2H, dd), 3.60(1H, dd), 3.77(1H, dd,), 3.86(1H, dd), 3.91-3.93(1H, m), 4.67(2H, s), 4.69(2H, s), 6.75(1H, s), 6.94(1H, s), 7.47(2H, d), 7.63(2H, d) |
0.4 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5 - [(4-trifluoromethylbenzyl) oxymethyl] isoxazole-3-carboxylic acid (0.60 g, 2.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.33 g, 2.4 mmol), Triethylamine (0.25 g, 2.4 mmol) And 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) Was added to 5 mL of chloroform (amylene addition product). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added at room temperatureAfter stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5 - [(4-trifluoromethylbenzyl) oxymethyl] isoxazole-3-carboxamide (Hereinafter referred to as the present amide compound (63)) 0.40 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.2 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 59 (0374) 5-(3-Trifluoromethylbenzyloxymethyl)isoxazole-3-carbo xylic acid (0.60 g, 2.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.33 g, 2.4 mmol), triethylamine (0.25 g, 2.4 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0. 46 g, 2.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.20 g of N-(tetrahydrofuran-3-ylmethyl)-5-(3-trifluoromethylbenzylox ymethyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (64)) represented by the following formula. 1H-NMR (CDCl3, TMS, delta(ppm)):1.64-1.72(1H, m), 2.08-2.11(1H, m), 2.55-2.63(1H, m), 3.47(2H, t), 3.59(1H, dd), 3.77(1H, dd), 3.84-3.95 (2H, m), 4.66(2H, s), 4.70(2H, s), 6.75(1H, s), 6.95(1H, s), 7.50-7.58(4H, m) |
0.2 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5 - [(3-trifluoromethylbenzyl) oxymethyl] isoxazole-3-carboxylic acid (0.60 g, 2.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.33 g, 2.4 mmol), Triethylamine (0.25 g, 2.4 mmol) And 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) Was added to chloroform (amylene added product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added at room temperature, After stirring overnight , And concentrated under reduced pressure.Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5 - [(3-trifluoromethylbenzyl) oxymethyl] isoxazole-3-carboxamide (Hereinafter referred to as present amide compound (64)) 0.20 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.21 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 3h; | Production Example 108 (0424) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.16 g, 1.2 mmol) and triethylamine (0.12 g, 1.2 mmol) were added to chloroform (amylene addition product) (5 mL). 5-(3-Phenylbenzyloxymethyl)isoxazole-3-carboxylic acid (0.25 g, 0.8 mmol), 1-hydroxybenzotriazole (0.01 g, 0.08 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.22 g, 1.2 mmol) were added to the mixture at room temperature, and the mixture was stirred for 3 hours. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.21 g of N-(tetrahydrofuran-3-ylmethyl)-5-(3-phenylbenzyloxymethyl)i soxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (113)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)): 1.63-1.71(1H, m), 2.04-2.13(1H, m), 2.52-2.63(1H, m), 3.45-3.48(2H, m), 3:57-3.61(1H, m), 3.74-3.79 (1H, m), 3.84-3.94 (2H, m), 4.68(2H, s), 4.69 (2H, s), 6.74(1H, s), 6.95(1H, br s), 7.32-7.38(2H, m), 7.43-7.47(3H, m), 7.55-7.61(4H, m) |
0.21 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 3h; | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.16 g, 1.2 mmol) And triethylamine (0.12 g, 1.2 mmol) Was added to chloroform (amylene added product) (5 mL). To the mixture, 5- (3-phenylbenzyl) oxymethyl isoxazole-3-carboxylic acid (0.25 g, 0.8 mmol) at room temperature, 1-Hydroxybenzotriazole (0.01 g, 0.08 mmol) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.22 g, 1.2 mmol) After stirring for 3 hours, Dilute hydrochloric acid was added, It was extracted twice with chloroform. The organic layer was washed with saturated sodium bicarbonate water, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5- (3-phenylbenzyl) oxymethyl isoxazole-3-carboxamide (Hereinafter referred to as present amide compound (113)) 0.21 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.54 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 109 (0425) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.23 g, 1.69 mmol) and triethylamine (0.17 g, 1.69 mmol) were added to chloroform (amylene addition product) (10 mL). 5-(3-Phenoxybenzyloxymethyl)isoxazole-3-carboxylic acid (0.46g, 1.41 mmol), 1-hydroxybenzotriazole (0.02 g, 0.14 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.32 g, 1.69 mmol) were added to the mixture at room temperature, and the mixture was stirred overnight. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.54 g of N-(tetrahydrofuran-3-ylmethyl)-5-(3-phenoxybenzyloxymethyl) isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (114)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):1.63-1.72(1H, m), 2.04-2.11(1H, m), 2.53-2.63(1H, m), 3.45-3.48(2H, m), 3.57-3.61(1H, m), 3.74-3.79(1H, m), 3.84-3.94(2H, m), 4.57(2H, s), 4.65 (2H, s), 6.71(1H, s), 6.94-7.03(5H, m), 7.07-7.14(2H, m), 7.30-7.37(3H, m) |
0.54 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.23 g, 1.69 mmol) And triethylamine (0.17 g, 1.69 mmol) Was added to chloroform (amylene added product) (10 mL). To the mixture, 5- (3-phenoxybenzyl) oxymethyl isoxazole-3-carboxylic acid (0.46 g, 1.41 mmol) at room temperature, 1-Hydroxybenzotriazole (0.02 g, 0.14 mmol) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.32 g, 1.69 mmol) were added, After stirring overnight, Dilute hydrochloric acid was added, It was extracted twice with chloroform. The organic layer was washed with saturated sodium bicarbonate water, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5- (3-phenoxybenzyl) oxymethyl isoxazole-3-carboxamide (Hereinafter referred to as the amide compound (11 4)) 0.54 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.4 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 111 (0427) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.24 g, 1.78 mmol) and triethylamine (0.18 g, 1.78 mmol) were added to chloroform (amylene addition product) (10 mL). 5-(2-Phenylbenzyloxymethyl)isoxazole-3-carboxylic acid (0.40 g, 1.19 mmol), 1-hydroxybenzotriazole (0.02 g, 0.18 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.34 g, 1.78 mmol) were added to the mixture at room temperature, and the mixture was stirred overnight. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.40 g of N-(tetrahydrofuran-3-ylmethyl)-5-(2-phenylbenzyl)oxymethyli soxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (116)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)): 1.63-1.72(1H, m), 2.05-2.13(1H, m), 2.53-2.63(1H, m), 3.45-3.48(2H, m), 3.57-3.61(1H, m), 3.74-3.80(1H, m), 3.84-3.95(2H, m), 4.50(2H, s), 4.56 (2H, s), 6.61(1H, s), 6.92(1H, br s), 7.30-7.44(8H, m), 7.51-7.55(1H, m) |
0.4 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.24 g, 1.78 mmol) And triethylamine (0.18 g, 1.78 mmol) Was added to chloroform (amylene added product) (10 mL). To the mixture, 5- (2-phenylbenzyl) oxymethylisoxazole-3-carboxylic acid (0.40 g, 1.19 mmol) at room temperature, 1-Hydroxybenzotriazole (0.02 g, 0.18 mmol) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.34 g, 1.78 mmol) were added, After stirring overnight, Dilute hydrochloric acid was added, It was extracted twice with chloroform. The organic layer was washed with saturated sodium bicarbonate water, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5- (2-phenylbenzyl) oxymethyl isoxazole-3-carboxamide (Hereinafter referred to as present amide compound (116)) 0.40 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.29 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 5h; | Production Example 112 (0428) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.23 g, 1.69 mmol) and triethylamine (0.17 g, 1.69 mmol) were added to chloroform (amylene addition product) (10 mL). 5-(4-Phenoxybenzyloxymethyl)isoxazole-3-carboxylic acid (0.46g, 1. 41 mmol), 1-hydroxybenzotriazole (0.02 g, 0.14 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.32 g, 1.69 mmol) were added to the mixture at room temperature, and the mixture was stirred at room temperature for 5 hours. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.29 g of N-(tetrahydrofuran-3-ylmethyl)-5-(4-phenoxybenzyloxymethyl) isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (117)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)): 1.63-1.72(1H, m), 2.05-2.13(1H, m), 2.53-2.63(1H, m), 3.45-3.49(2H, m), 3.57-3.61(1H, m), 3.74-3.80(1H, m), 3.84-3.94(2H, m), 4.57(2H, s), 4.66 (2H, s), 6.73(1H, s), 6.94(1H, br s), 6.99-7.03(4H, m), 7.10-7.14(1H, m), 7.30-7.37(4H, m) |
0.29 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 5h; | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.23 g, 1.69 mmol) And triethylamine (0.17 g, 1.69 mmol) Was added to chloroform (amylene added product) (10 mL). To the mixture, 5- (4-phenoxybenzyl) oxymethyl isoxazole-3-carboxylic acid (0.46 g, 1.41 mmol) at room temperature, 1-Hydroxybenzotriazole (0.02 g, 0.14 mmol) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.32 g, 1.69 mmol) were added, After stirring at room temperature for 5 hours, Dilute hydrochloric acid was added, Extracted twice with chloroform . The organic layer was washed with saturated sodium bicarbonate water, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5- (4-phenoxybenzyl) oxymethyl isoxazole-3-carboxamide (Hereinafter referred to as the amide compound (11 7)) 0.29 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.5 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 6h; | Production Example 113 (0429) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.29 g, 2.09 mmol) and triethylamine (0.21 g, 2.09 mmol) were added to chloroform (amylene addition product) (8 mL). 5-(1,2,3,4-Tetrahydronaphthalen-2-ylmethoxymethyl)isoxazole -3-carboxylic acid (0.40 g, 1.39 mmol), 1-hydroxybenzotriazole (0.02 g, 0.14 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.40 g, 2.09 mmol) were added to the mixture at room temperature, and the mixture was stirred at room temperature for 6 hours. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.50 g of N-(tetrahydrofuran-3-ylmethyl)-5-(1,2,3,4-tetrahydronaphtha len-2-ylmethoxymethyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (118)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):1.41-1.51(1H, m), 1.63-1.70(1H, m), 1.97-2.05(1H, m), 2.07-2.11(2H, m), 2.47-2.63(2H, m), 2.80-2.91(3H, m), 3.45-3.51(4H, m), 3.58-3.61(1H, m), 3.74-3.80(1H, m), 3.84-3.95(2H, m), 4.66(2H, s), 6.72(1H, s), 6.96(1H, br s), 7.07-7.11(4H, m) |
0.5 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 6h; | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.29 g, 2.09 mmol) And triethylamine (0.21 g, 2.09 mmol) Was added to chloroform (amylene added product) (8 mL). To the mixture, At room temperature 5- (1,2,3,4-tetrahydronaphthalen-2-ylmethyl) oxymethyl isoxazole-3-carboxylic acid (0.40 g, 1.39 mmol), 1-Hydroxybenzotriazole (0.02 g, 0.14 mmol) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.4Og, 2.09 mmol) were added, After stirring at room temperature for 6 hours, Dilute hydrochloric acid was added, It was extracted twice with chloroform.The organic layer was washed with saturated sodium bicarbonate water, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5- (1,2,3,4-tetrahydronaphthalen-2-ylmethyl) oxymethyl isoxazole-3-carboxyamide (Hereinafter referred to as present amide compound (118)) 0.50 g was obtained |
Yield | Reaction Conditions | Operation in experiment |
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0.8 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 5h; | Production Example 114 (0430) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.55 g, 3.97 mmol) and triethylamine (0.40 g, 3.97 mmol) were added to chloroform (amylene addition product) (15 mL). 5-(5,6,7,8-Tetrahydronaphthalen-2-ylmethoxymethyl)isoxazole -3-carboxylic acid (0.76 g, 2.65 mmol), 1-hydroxybenzotriazole (0.04 g, 0.26 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.76 g, 3.97 mmol) were added to the mixture at room temperature, and the mixture was stirred at room temperature for 5 hours. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.80 g of N-(tetrahydrofuran-3-ylmethyl)-5-(5,6,7,8-tetrahydronaphtha len-2-ylmethoxymethyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (119)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)): 1.64-1.72 (1H, m), 1.78-1.81(4H, m), 2.04-2.13(1H, m), 2.53-2.63(1H, m), 2.76(4H, br s), 3.45-3.48(2H, m), 3.57-3.61(1H, m), 3.74-3.80(1H, m), 3.84-3.94(2H, m), 4.53(2H, s), 4.62 (2H, s), 6.71(1H, s), 6.96(1H, br s), 7.04(1H, s), 7.06(2H, s) |
0.8 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 5h; | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.55 g, 3.97 mmol) And triethylamine (0.40 g, 3.97 mmol) Was added to chloroform (amylene added product) (15 mL). To the mixture, At room temperature 5- (5,6,7,8-tetrahydronaphthalen-2-ylmethyl) oxymethyl isoxazole-3-carboxylic acid (0.76 g, 2.65 mmol) 1-Hydroxybenzotriazole (0.04 g, 0.26 mmol) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0. 76 g, 3.97 mmol) After stirring at room temperature for 5 hours, Dilute hydrochloric acid was added, It was extracted twice with chloroform. The organic layer was washed with saturated sodium bicarbonate water, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equationIndicated by N- (tetrahydrofuran-3-ylmethyl) -5- (5,6,7,8-tetrahydronaphthalen-2-ylmethyl) oxymethyl isoxazole-3-carboxyamide (Hereinafter referred to as present amide compound (119)) 0.80 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.08 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 6h; | Production Example 115 (0431) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.07 g, 0.49 mmol) and triethylamine (0.05 g, 0.49 mmol) were added to chloroform (amylene addition product) (3 mL). 5-(1,4-Benzodioxan-2-ylmethoxymethyl)isoxazole-3-carboxylic acid (0.12 g, 0.41 mmol), 1-hydroxybenzotriazole (0.01 g, 0.04 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.10 g, 0.49 mmol) were added to the mixture at room temperature, and the mixture was stirred at room temperature for 6 hours. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.08 g of N-(tetrahydrofuran-3-ylmethyl)-5-(1,4-benzodioxan-2-ylmetho xymethyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (120)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)): 1.63-1.72(1H, m), 2.05-2.13(1H, m), 2.53-2.63(1H, m), 3.45-3.48(2H, m), 3.58-3.61(1H, m), 3.74-3.94(5H, m), 4.07-4.11(1H, m), 4.27-4.30(1H, m), 4.34-4.39(1H, m), 4.73 (2H, s), 6.74(1H, s), 6.83-6.90(4H, m), 7.03(1H, br s) |
0.08 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 6h; | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.07 g, 0.49 mmol) And triethylamine (0.05 g, 0.49 mmol) Was added to chloroform (amylene addition product) (3 mL). To the mixture, At room temperature 5- (1,4-benzodioxan-2-ylmethyl) oxymethyl isoxazole-3-carboxylic acid (0.12 g, 0.41 mmol) 1-Hydroxybenzotriazole (0.01 g, 0.04 mmol) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.10 g, 0.49 mmol) were added, After stirring at room temperature for 6 hours, Dilute hydrochloric acid was added, It was extracted twice with chloroform. The organic layer was washed with saturated sodium bicarbonate water, After drying with anhydrous sodium sulfate, It was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (tetrahydrofuran-3-ylmethyl) -5- (1,4-benzodioxan-2-ylmethyl) oxymethyl isoxazole-3-carboxamide (Hereinafter referred to as the present amide compound (120)) 0.08 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.43 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 116 (0432) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.19 g, 1.13 mmol) and triethylamine (0.14 g, 1.36 mmol) were added to chloroform (amylene addition product) (8 mL). 5-(3-Benzyloxymethylbenzyloxymethyl)isoxazole-3-carboxylic acid (0.40 g, 1.22 mmol), 1-hydroxybenzotriazole (0.02 g, 0.11 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.26 g, 1.36 mmol) were added to the mixture at room temperature, and the mixture was stirred overnight. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.43 g of N-(tetrahydrofuran-3-ylmethyl)-5-(3-benzyloxymethylbenzylox ymethyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (121)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)): 1.62-1.70(1H, m), 2.02-2.11(1H, m), 2.51-2.62(1H, m), 3.43-3.47(2H, m), 3.56-3.60(1H, m), 3.72-3.78(1H, m), 3.82-3.93(2H, m), 4.56(2H, s), 4.57(2H, s), 4.60(2H, s), 4.64(2H, s), 6.73(1H, s), 7.07(1H, br s), 7.26-7.37(9H, m) |
0.43 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.19 g, 1.13 mmol) And triethylamine (0.14 g, 1.36 mmol) Was added to chloroform (amylene added product) (8 mL). To the mixture, 5- (3-benzyloxymethylbenzyl) oxymethyl isoxazole-3-carboxylic acid (0.40 g, 1.22 mmol) at room temperature, 1-Hydroxybenzotriazole (0.02 g, 0.11 mmol) And 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide hydrochloride (0.26 g, 1.36 mmol) was added thereto, After stirring overnight, Dilute hydrochloric acid was added, It was extracted twice with chloroform. The organic layer was washed with saturated sodium bicarbonate water, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography , The following formulaIndicated by N- (tetrahydrofuran-3-ylmethyl) -5- (3-benzyloxymethylbenzyl) oxymethyl isoxazole-3-carboxamide (Hereinafter referred to as amide compound (121)) 0.43 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.1 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 117 (0433) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.06 g, 0.41 mmol) and triethylamine (0.04 g, 0.41 mmol) were added to chloroform (amylene addition product) (2 mL). 5-(1,3-Benzodioxolan-2-ylmethoxymethyl)isoxazole-3-carboxyl ic acid (0.10 g, 0.34 mmol), 1-hydroxybenzotriazole (0.01 g, 0.03 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.08 g, 0.41 mmol) were added to the mixture at room temperature, and the mixture was stirred overnight. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.10 g of N-(tetrahydrofuran-3-ylmethyl)-5-(1,3-benzodioxolan-2-ylmet hoxymethyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (122)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):1.63-1.71(1H, m), 2.05-2.13(1H, m), 2.53-2.63(1H, m), 3.44-3.48(2H, m), 3.57-3.60(1H, m), 3.73-3.79(1H, m), 3.83-3. 94 (4H, m), 4.10-4.15(1H, m), 4.78 (2H, s), 6.23-6.25(1H, t), 6.72(1H, s), 6.82(4H, br s), 6.96(1H, br s) |
0.1 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.06 g, 0.41 mmol) And triethylamine (0.04 g, 0.41 mmol) Was added to chloroform (amylene added product) (2 mL). To the mixture , At room temperature 5- (1,3-benzodioxolane-2-ylmethyl) oxymethyl isoxazole-3-carboxylic acid (0.10 g, 0.34 mmol), 1-Hydroxybenzotriazole (0.01 g, 0.03 mmol) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.08 g, 0.4 1 mmol) were added, After stirring overnight, Dilute hydrochloric acid was added, Extracted twice with chloroform . The organic layer was washed with saturated sodium bicarbonate water, After drying over anhydrous magnesium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equationIndicated by N- (tetrahydrofuran-3-ylmethyl) -5- (1,3-benzodioxolan-2-ylmethyl) oxymethyl isoxazole-3-carboxamide (Hereinafter referred to as present amide compound (122)) 0.10 g was obtained |
Yield | Reaction Conditions | Operation in experiment |
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0.38 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 3h; | Production Example 118 (0434) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.20 g, 1.48 mmol) and triethylamine (0.15 g, 1.48 mmol) were added to chloroform (amylene addition product) (8 mL). 5-(2-Methyl-3-phenylbenzyloxymethyl)isoxazole-3-carboxylic acid (0.40 g, 1.24 mmol), 1-hydroxybenzotriazole (0.02 g, 0.12 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.28 g, 1.48 mmol) were added to the mixture at room temperature, and the mixture was stirred for 3 hours. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.38 g of N-(tetrahydrofuran-3-ylmethyl)-5-(2-methyl-3-phenylbenzylox ymethyl)isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (123)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)): 1.63-1.72 (1H, m), 2.04-2.13(1H, m), 2.21(3H, s), 2.52-2.63(1H, m), 3.45-3.48 (2H, m), 3.57-3.61(1H, m), 3.74-3.79(1H, m), 3.83-3.94(2H, m), 4.67(2H, s), 4.71 (2H, s), 6.74(1H, s), 6.96(1H, br s), 7.21-7.30(4H, m), 7.32-7.36(2H, m), 7.39-7.43(2H, m) |
0.38 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 3h; | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.20 g, 1.48 mmol) And triethylamine (0.15 g, 1.48 mmol) Was added to chloroform (amylene added product) (8 mL). To the mixture, 5- (2-methyl-3-phenylbenzyl) oxymethyl isoxazole-3-carboxylic acid (0.40 g, 1.24 mmol) at room temperature, 1-Hydroxybenzotriazole (0.02 g, 0.12 mmol) And 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide hydrochloride (0.28 g, 1.48 mmol) was added, After stirring for 3 hours, Dilute hydrochloric acid was added, It was extracted twice with chloroform. The organic layer was washed with saturated sodium bicarbonate water, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equationIndicated by N- (tetrahydrofuran-3-ylmethyl) -5- (2-methyl-3-phenylbenzyl) oxymethyl isoxazole-3-carboxamide (Hereinafter referred to as amide compound (123)) 0.38 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.35 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 3h; | Production Example 119 (0435) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.22 g, 1.60 mmol) and triethylamine (0.16 g, 1.60 mmol) were added to chloroform (amylene addition product) (8 mL). 5-(5-Phenylfurfuryloxymethyl)isoxazole-3-carboxylic acid (0.40 g, 1.34 mmol), 1-hydroxybenzotriazole (0.02 g, 0.13 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.31 g, 1.60 mmol) were added to the mixture at room temperature, and the mixture was stirred for 3 hours. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, and concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.35 g of N-(tetrahydrofuran-3-ylmethyl)-5-(5-phenylfurfuryloxymethyl )isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (124)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)): 1.64-1.71(1H, m), 2.03-2.12(1H, m), 2.51-2.61(1H, m), 3.43-3.46(2H, m), 3.56-3.60(1H, m), 3.73-3.79(1H, m), 3.83-3. 94 (2H, m), 4.60(2H, s), 4.69 (2H, s), 6.46(1H, d), 6.62(1H, d), 6.72(1H, s), 6.91(1H, br s), 7.26-7.29(1H, m), 7.37-7.41(2H, m), 7.66-7.68(2H, m) |
0.35 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 3h; | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.22 g, 1.60 mmol) And triethylamine (0.16 g, 1.60 mmol) Was added to chloroform (amylene added product) (8 mL). To the mixture, 5- (5-phenylfurfuryl) oxymethylisoxazole-3-carboxylic acid (0.40 g, 1.34 mmol) at room temperature, 1-Hydroxybenzotriazole (0.02 g, 0.13 mmol) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.31 g, 1.60 mmol) were added, After stirring for 3 hours, Dilute hydrochloric acid was added, It was extracted twice with chloroform. The organic layer was washed with saturated sodium bicarbonate water, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equationIndicated by N- (tetrahydrofuran-3-ylmethyl) -5- (5-phenylfurfuryl) oxymethyl isoxazole-3-carboxamide (Hereinafter referred to as the present amide compound (12 4)) 0.35 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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0.51 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 120 (0436) 5-[(1-Phenylethyl)oxymethyl]isoxazole-3-carboxylic acid (0.50 g, 2.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.33 g, 2.4 mmol), triethylamine (0.24 g, 2.4 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.51 g of N-(tetrahydrofuran-3-ylmethyl)-5-[(1-phenylethyl)oxymethyl] isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (125)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):1.49(3H, d), 1.66-1.69(1H, m), 2.04-2.13(1H, m), 2.53-2.63(1H, m), 3.46(2H, t), 3.59(1H, dd), 3.77(1H, dd), 3.86(1H, dd), 3.92(1H, td), 4.48(3H, ddd), 6.67(1H, s), 6.94(1H, s), 7.29-7.40(5H, m) |
0.51 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5 - [(1-phenylethyl) oxymethyl] isoxazole-3-carboxylic acid (0.5Og, 2.0 mmol) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.33 g, 2.4 mmol), Triethylamine (0.24 g, 2.4 mmol) And 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) Was added to chloroform (amylene added product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equationIndicated by N- (tetrahydrofuran-3-ylmethyl) -5 - [(1-phenylethyl) oxymethyl] isoxazole-3-carboxamide (Hereinafter referred to as the present amide compound (125).) 0.51 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.37 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 121 (0437) 5-Diphenylmethoxymethylisoxazole-3-carboxylic acid (0.62 g, 2.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.33 g, 2.4 mmol), triethylamine (0.25 g, 2.4 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.37 g of N-(tetrahydrofuran-3-ylmethyl)-5-diphenylmethoxymethylisoxa zole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (126)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):1.63-1.72(1H, m), 2.06-2.13(1H, m), 2.56-2.59(1H, m), 3.45-3.48(2H, m), 3.59(1H, dd), 3.76-3.78(1H, m), 3.84-3.94(2H, m), 4.64(2H, s), 5.49(1H, s), 6.73(1H, s), 6.94(1H, s), 7.27-7.37(10H, m) |
0.37 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5-diphenylmethoxymethyl isoxazole-3-carboxylic acid (0.62 g, 2.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.33 g, 2.4 mmol), Triethylamine (0.25 g, 2.4 mmol) And 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) Was added to chloroform (amylene added product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equationIndicated by N- (tetrahydrofuran-3-ylmethyl) -5-diphenylmethoxymethylisoxazole-3-carboxamide (Hereinafter referred to as the present amide compound (126)) 0.37 g was obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.51 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 122 (0438) 5-[(1-Phenyl-2,2,2-trifluoroethyl)oxymethyl]isoxazole -3-carboxylic acid (0.50 g, 2.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.33 g, 2.4 mmol), triethylamine (0.24 g, 2.4 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.46g, 2.4 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.51 g of N-(tetrahydrofuran-3-ylmethyl)-5-[(1-phenyl-2,2,2-trifluoro ethyl)oxymethyl]isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (127)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):1.65-1.72(1H, m), 2.06-2.13(1H, m), 2.56-2.60(1H, m), 3.47(2H, t), 3.59(1H, dd), 3.74-3.80(1H, m), 3.86 (1H, dd), 3.91-3.93(1H, m), 4.62-4.76(3H, m), 6.70-6.80(1H, m), 6.96(1H, brs), 7.41-7.49(5H, m) |
0.51 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5 - [(1-phenyl-2,2,2-trifluoroethyl) oxymethyl] isoxazole-3-carboxylic acid (0.50 g, 2.0 mmol) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.33 g, 2.4 mmol), Triethylamine (0.24 g, 2.4 mmol) And 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) Was added to chloroform (amylene added product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equation Indicated by N- (Tetrahydrofuran-3-ylmethyl) -5 - [(1-phenyl-2, 2,2- trifluoroethyl) oxymethyl] isoxazole-3-carboxamide (Hereinafter referred to as present amide compound (127)) 0.51 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.32 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 123 (0439) 5-[(2,2,2-Trifluoroethyl)oxymethyl]isoxazole-3-carbox ylic acid (0.30 g, 1.3 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.22 g, 1.6 mmol), triethylamine (0.16 g, 1.6 mmol) and 1-hydroxybenzotriazole (0.02 g, 0.16 mmol) were added to chloroform (amylene addition product) (4 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0. 31 g, 1.6 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.32 g of N-(tetrahydrofuran-3-ylmethyl)-5-[(2,2,2-Trifluoroethyl)oxy methyl]isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (128)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):1.64-1.72(1H, m), 2.06-2.13(1H, m), 2.53-2.64(1H, m), 3.47 (2H, t), 3.60(1H, dd), 3.74-3.80(1H, m), 3.84-3.96(4H, m), 4.80(2H, s), 6.78(1H, brs), 7.00(1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.58 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 124 (0440) 5-[1-(Benzyloxy)ethyl]isoxazole-3-carboxylic acid (0.60 g, 2.0 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.33 g, 2.4 mmol), triethylamine (0.24 g, 2.4 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) were added to chloroform (amylene addition product) (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added to the mixture at room temperature, and the mixture was stirred at room temperature overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.58 g of N-(tetrahydrofuran-3-ylmethyl)-5-[1-(benzyloxy)ethyl]isoxaz ole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (129)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):1.59(3H, d), 1.63-1.73(1H, m), 2.07-2.12(1H, m), 2.55-2.62(1H, m), 3.47(2H, t), 3.60(1H, dd), 3.76-3.78(1H, m), 3.86(1H, dd), 3.91-3.93(1H, m), 4.47(1H, d), 4.60(1H, d), 4.70-4.75(1H, m), 6.69(1H, d), 6.95(1H, s), 7.30-7.38(5H, m) |
0.58 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- [1- (benzyloxy) ethyl] isoxazole-3-carboxylic acid (0.60 g, 2.0 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0.33 g, 2.4 mmol), Triethylamine (0.24 g, 2.4 mmol) And 1-hydroxybenzotriazole (0.03 g, 0.24 mmol) Was added to chloroform (amylene added product) (5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g, 2.4 mmol) was added at room temperature, After stirring overnight at room temperature, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equationIndicated by N- (tetrahydrofuran-3-ylmethyl) -5- [1- (benzyloxy) ethyl] isoxazole-3-carboxamide (Hereinafter referred to as present amide compound (129)) 0.58 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.45 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | Production Example 125 (0441) 5-[(1-Benzyloxy-1-phenylmethyl]isoxazole-3-carboxylic acid (0.44 g, 1.4 mmol), <strong>[184950-35-4]tetrahydrofuran-3-ylmethylamine hydrochloride</strong> (0.23 g, 1.7 mmol), triethylamine (0.17 g, 1.7 mmol) and 1-hydroxybenzotriazole (0.02 g, 0.17 mmol) were added to chloroform (amylene addition product) (4 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.32 g, 1.7 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight and then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.45 g of N-(tetrahydrofuran-3-ylmethyl)-5-[(1-benzyloxy-1-phenylmeth yl]isoxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (130)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):1.63-1.68(1H, m), 2.02-2.11(1H, m), 2.55-2.56(1H, m), 3.42-3.46(2H, m), 3.57(1H, dd), 3.75(1H, dd), 3.84(1H, dd), 3.89-3.91(1H, m), 4.60(2H, dd), 5.57(1H, s), 6.62(1H, s), 6.91(1H, s), 7.32-7.44(10H, m) |
0.45 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; | 5- (1-benzyloxy-1-phenylmethyl) isoxazole-3-carboxylic acid (0.44 g, 1.4 mmol), Tetrahydrofuran-3-ylmethylamine hydrochloride (0 .23 g, 1.7 mmol), Triethylamine (0.17 g, 1.7 mmol) And 1 - hydroxybenzotriazole (0.02 g, 0.17 mmol) Was added to chloroform (ammylene added product) (4 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.32 g, 1.7 mmol) was added at room temperature, After stirring overnight, And concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate, Extracted twice with ethyl acetate. The organic layer was washed with saturated brine, After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, The following equation Indicated by N- (tetrahydrofuran-3-ylmethyl) -5- (1-benzyloxy-1-phenylmethyl) isoxazole-3-carboxamide (Hereinafter referred to as present amide compound (130)) 0.45 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.33 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 5h; | Production Example 126 (0442) Tetrahydrofuran-3-ylmethylamine hydrochloride (0.20 g, 1.44 mmol) and triethylamine (0.15 g, 1.44 mmol) were added to chloroform (amylene addition product) (6 mL). 5-Cyclopentylmethoxymethylisoxazole-3-carboxylic acid (0.27 g, 1.20 mmol), 1-hydroxybenzotriazole (0.02 g, 0.12 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.28 g, 1.44 mmol) were added to the mixture at room temperature, and the mixture was stirred for 5 hours. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.33 g of N-(tetrahydrofuran-3-ylmethyl)-5-cyclopentylmethoxymethylis oxazole-3-carboxamide (hereinafter, referred to as Compound of Present Invention (131)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):1.18-1.28(2H, m), 1.50-1.60(4H, m), 1.64-1.78(3H,m), 2.05-2.23(2H, m), 2.53-2.63(1H, m), 3.39(2H, d), 3.45-3.48(2H, m), 3.57-3.61(1H, m), 3.74-3.80(1H, m), 3.84-3.94(2H, m), 4.62(2H, s), 6.70(1H, s), 6.96(1H, br s) |
0.33 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 5h; | Tetrahydrofuran-3-ylmethylamine hydrochloride (0.20 g, 1.44 mmol) And triethylamine (0.15 g, 1.44 mmol) Was added to chloroform (amylene added product) (6 mL). To the mixture, At room temperature 5-cyclopentylmethoxymethyl isoxazole-3-carboxylic acid (0.27 g, 1.20 mmol), 1-Hydroxybenzotriazole (0.02 g, 0.12 mmol) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.28 g, 1.44 mmol) After stirring for 5 hours, Dilute hydrochloric acid was added, It was extracted twice with chloroform. The organic layer was washed with saturated sodium bicarbonate water, After drying with anhydrous sodium sulfate, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography , The following formulaIndicated by N- (tetrahydrofuran-3-ylmethyl) -5-cyclopentylmethoxymethyl isoxazole-3-carboxamide (Hereinafter referred to as amide compound (131)) 0.33 g was obtained. |
Tags: 184950-35-4 synthesis path| 184950-35-4 SDS| 184950-35-4 COA| 184950-35-4 purity| 184950-35-4 application| 184950-35-4 NMR| 184950-35-4 COA| 184950-35-4 structure
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H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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