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CAS No. : | 15833-63-3 | MDL No. : | MFCD20483437 |
Formula : | C12H16O4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BNBVZUYOFJWGNJ-UHFFFAOYSA-N |
M.W : | 256.32 | Pubchem ID : | 15335290 |
Synonyms : |
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 63.79 |
TPSA : | 60.98 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.58 cm/s |
Log Po/w (iLOGP) : | 2.66 |
Log Po/w (XLOGP3) : | 1.81 |
Log Po/w (WLOGP) : | 2.82 |
Log Po/w (MLOGP) : | 1.73 |
Log Po/w (SILICOS-IT) : | 1.92 |
Consensus Log Po/w : | 2.19 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.57 |
Solubility : | 0.695 mg/ml ; 0.00271 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.71 |
Solubility : | 0.5 mg/ml ; 0.00195 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.48 |
Solubility : | 0.0853 mg/ml ; 0.000333 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.37 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P201-P202-P261-P264-P270-P271-P280-P302+P352-P304+P340-P308+P313-P310-P330-P361-P403+P233-P405-P501 | UN#: | 2810 |
Hazard Statements: | H301-H311-H331-H341 | Packing Group: | Ⅲ |
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 |
---|---|---|
at 80℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
aus (+)-β-Hydroxymethyl-tetrahydrofuran XV; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.18 g | In N,N-dimethyl-formamide at 80℃; for 4h; | |
In water; N,N-dimethyl-formamide | R.5 Preparation of N-{(tetrahydro-3-furanyl)methyl}phthalimide (Compound No. D4) REFERENCE EXAMPLE 5 Preparation of N-{(tetrahydro-3-furanyl)methyl}phthalimide (Compound No. D4) A mixture comprising 30.0 g of (tetrahydro-3-furanyl)methyl tosylate, 23.0 g of potassium phthalimide and 150 ml of DMF was stirred at 80° C. for 8 hours. Water was poured into the reaction mixture, and crystals precipitated out was separated by filtration to obtain 27.0 g of N-{(tetrahydro-3-furanyl)methyl}phthalimide. | |
In N,N-dimethyl-formamide at 80 - 100℃; for 24h; | 15.B To a solution of (tetrahydro-3-furanyl)methyl 4-methylbenzenesulfonate (i.e., the product of Step A) (11.0 g, 42.9 mmol) in N,N-dimethylformamide (160 mL) was added potassium phthalimide (7.9 g, 42.7 mmol) in one portion, and the resulting mixture was stirred at 80 ºC for 6 h. Additional potassium phthalimide (5 g, 27 mmol) was added, and stirring was continued at 100 ºC for 18 h. The cooled reaction mixture was partitioned between water and ethyl acetate and the aqueous layer was separated and extracted with ethyl acetate (5 x 75 mL). The combined extracts were dried over MgSθ4 and filtered, and the solvent was removed under reduced pressure to give a residue which was chromatographed on silica gel (40 g) eluted with 5% to 100% ethyl acetate in hexanes to give 4.5 g of the title compound as a white solid, m.p. 114-118 ºC.1H NMR (CDCl3) δ 7.87 (dd, 2H), 7.74 (dd, 2H), 3.94 (dt, IH), 3.67-3.87 (m, 4H), 3.62 (dd, IH), 2.70-2.79 (m, IH), 1.97-2.07 (m, IH), 1.74 (dt, IH). |
With potassium iodide In N,N-dimethyl-formamide at 80℃; for 3h; Inert atmosphere; | 2 Under nitrogen atmosphere, to a mixture of 29 g of p- toluenesulfonic acid tetrahydrofuran-3-ylmethyl ester, 23 g of potassium iodide and 300 ml of N, N-dimethylformamide, 22 g of phthalimide potassium salt was added, . and stirred for 3 hours at 80 °C. After ice-cooling, to the reaction mixture, water was added and stirred for 30 minutes, then filtered. The resulting solid was collected and dried under reduced pressure to obtain 14 g of 2- (tetrahydrofuran-3-ylmethyl) isoindol-1, 3-dione of the following formula.1H NMR (CDC13) : δ ppm: 7.86 (2H, dd) , 7.73 (2H, dd) , 3.94 (1H, td) , 3.85-3.67 (4H, m) , 3.61 (1H, dd) , 2.79-2.68 (1H, m) , 2.06-1.97 (1H, m) , 1.77-1.68 (1H, m) | |
14 g | With potassium iodide In N,N-dimethyl-formamide at 80℃; for 3h; Inert atmosphere; | To a mixture of tetrahydrofuran-3-ylmethyl p-toluenesulfonate (29 g), potassium iodide (23 g), and N,N-dimethylformamide (300 mL) was added phthalimide potassium salt (22 g) under nitrogen atmosphere, and the mixture was stirred at 8000 for 3 hrs. Then, the reaction mixture was cooled under ice-cooling. Water was added to the mixture, and the resulting mixture was stirred for 30 minutes. The reaction mixture was filtered to collect a solid. Thesolid was dried under reduced pressure to give 2-(tetrahydrofuran-3--ylmethyl)-isoindole-1,3-dione (14 g)represented by the following formula: 1H-NMR (CDCl3, TMS) 5(ppm) : 7.86(2H, dd), 7.73(2H, dd),3.94(1H, td), 3.85-3.67(4H, m), 3.61(1H, dd), 2.79-2.68(1H,m), 2.06-1.97(1H, m), 1.77-1.68(1H, m) |
With potassium iodide In N,N-dimethyl-formamide at 80℃; for 3h; Inert atmosphere; | 2 Under a nitrogen atmosphere, to a mixture of 29 g of tetrahydrofuran-3-ylmethyl p-toluenesulfonate, 23 g ofpotassium iodide and 300 ml of N,N-dimethylformamide was added 22 g of phthalimide potassium salt, and the mixturewas stirred at 80°C for 3 hours. Thereafter, the reaction mixture was ice-cooled, water was added to the mixture, andthe resulting mixture was stirred for 30 minutes. The reaction mixture was filtered to collect a solid. The solid was driedunder reduced pressure to obtain 14 g of 2-(tetrahydrofuran-3-ylmethyl)-isoindole-1,3-dione represented by the followingformula.1H-NMR (CDCl3, TMS) δ (ppm): 7.86 (2H, dd), 7.73 (2H, dd), 3.94 (1H, td), 3.85-3.67 (4H, m), 3.61 (1H, dd),2.79-2.68 (1H, m), 2.06-1.97 (1H, m), 1.77-1.68 (1H, m) | |
14 g | With potassium iodide In N,N-dimethyl-formamide at 80℃; for 3h; | 2 Under a nitrogen atmosphere, to a mixture of 29 g of tetrahydrofuran-3-ylmethyl p-toluenesulfonate, 23 g of potassium iodide and 300 ml of N,N-dimethylformamide was added 22 g of phthalimide potassium salt, and the mixture was stirred at 80°C for 3 hours. Thereafter, the reaction mixture was ice-cooled, water was added to the mixture, and the resulting mixture was stirred for 30 minutes. The reaction mixture was filtered to collect a solid. The solid was dried under reduced pressure to obtain 14 g of 2-(tetrahydrofuran-3-ylmethyl)-isoindole-1,3-dione represented by the following formula.1H-NMR (CDCl3, TMS) δ (ppm) : 7.86 (2H, dd), 7.73 (2H, dd), 3.94 (1H, td), 3.85-3.67 (4H, m), 3.61 (1H, dd), 2.79-2.68 (1H, m), 2.06-1.97 (1H, m), 1.77-1.68 (1H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyridine In dichloromethane at 20℃; for 3.25h; | 162A Example 162A Toluene-4-sulfonic acid tetrahydro-furan-3-ylmethyl ester To a solution of tetrahydro-3-furanmethanol (Aldrich, 1.0 mL, 10.4 mmol) in 5 mL CH2Cl2 and 5 mL pyridine was added para-toluenesulfonyl chloride (3.0 g, 15.6 mmol) portion-wise over 15 minutes. This mixture stirred at ambient temperature for 3 hours then 5 mL H2O was added. The layers were separated and the aqueous layer was extracted 2*5 mL CH2Cl2. The combined organics were dried over Na2SO4, filtered, concentrated under reduced pressure and dried under vacuum (~1 mm Hg) to afford the title compound (2.62 g, 10.2 mmol, 98% yield). 1H NMR (300 Mhz, CDCl3) δ ppm 1.49-1.63 (m, 1 H) 1.94-2.08 (m, 1 H) 2.46 (s, 3 H) 2.52-2.68 (m, 1 H) 3.49 (dd, J=9.16, 5.09 Hz, 1 H) 3.64-3.84 (m, 3 H) 3.88-4.03 (m, 2 H) 7.36 (d, J=8.14 Hz, 2 H) 7.76-7.82 (m, 2 H); MS (DCI/NH3) m/z 257 (M+H)+. |
98% | With pyridine In dichloromethane at 20℃; for 3.25h; | 162.A To a solution of tetrahydro-3-furanmethanol (Aldrich, 1.0 mL, 10.4 mmol) in 5 mL CH2Cl2 and 5 mL pyridine was added para-toluenesulfonyl chloride (3.0 g, 15.6 mmol) portion-wise over 15 minutes. This mixture stirred at ambient temperature for 3 hours then 5 mL H2O was added. The layers were separated and the aqueous layer was extracted 2 X 5 mL CH2Cl2. The combined organics were dried over Na2SO4, filtered, concentrated under reduced pressure and dried under vacuum (~1 mm Hg) to afford the title compound (2.62 g, 10.2 mmol, 98% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.49 - 1.63 (m, 1 H) 1.94 - 2.08 (m, 1 H) 2.46 (s, 3 H) 2.52 - 2.68 (m, 1 H) 3.49 (dd, J=9.16, 5.09 Hz, 1 H) 3.64 - 3.84 (m, 3 H) 3.88 - 4.03 (m, 2 H) 7.36 (d, J=8.14 Hz, 2 H) 7.76 - 7.82 (m, 2 H); MS (DCI/NH3) m/z 257 (M+H)+ |
97% | With triethylamine In dichloromethane at 20℃; | 85.B (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate Example 85B (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate To a solution of (tetrahydrofuran-3-yl)methanol (5.15 g, 50.4 mmol) in dichloromethane (200 mL) were added triethylamine (21.08 mL, 151 mmol) and p-toluenesulfonyl chloride (9.61 g, 50.4 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was washed with water (100 mL) and brine (100 mL). The organic layer was dried with sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using an Analogix Intelliflash280 (SiO2, 0-40% ethyl acetate in hexane) to provide the title compound (12.5 g, 97%) as colorless viscous liquid. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.40-1.51 (m, 1H) 1.83-1.95 (m, 1H) 2.43 (s, 3H) 3.28-3.31 (m, 1H) 3.31-3.37 (m, 1H) 3.51-3.67 (m, 3H) 3.90-4.00 (m, 2H) 7.48-7.51 (m, 2H) 7.78-7.82 (m, 2H); MS (DCI/NH3) m/z 274 (M+NH4)+. |
97% | With triethylamine In dichloromethane at 20℃; | 85.85B Example 85B; (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate; To a solution of (tetrahydrofuran-3-yl)methanol (5.15 g, 50.4 mmol) in dichloromethane (200 mL) were added triethylamine (21.08 mL, 151 mmol) and p-toluenesulfonyl chloride (9.61 g, 50.4 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was washed with water (100 mL) and brine (100 mL). The organic layer was dried with sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using an Analogix Intelliflash280 (SiO2, 0-40% ethyl acetate in hexane) to provide the title compound (12.5 g, 97%) as colorless viscous liquid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.40-1.51 (m, 1H) 1.83-1.95 (m, 1H) 2.43 (s, 3H) 3.28-3.31 (m, 1H) 3.31-3.37 (m, 1H) 3.51-3.67 (m, 3H) 3.90-4.00 (m, 2H) 7.48-7.51 (m, 2H) 7.78-7.82 (m, 2H); MS (DCI/NH3) m/z 274 (M+NH4)+. |
97% | With dmap In dichloromethane at 25℃; | 6 EXAMPLE 6 2-(3-Chloro-4-methanesulfonylphenyl)-N-pyrazin-2-yl-3-(tetrahydrofuran-3-yl)propionamide [0164] A solution of tetrahydro-3-furanmethanol (3.0 g, 29.4 mmol) in methylene chloride (45 mL) at 25° C. was treated with 4-(dimethylamino)pyridine (3.99 g, 32.31 mmol) and p-toluenesulfonyl chloride (5.60 g, 29.37 mmol), and the reaction mixture was allowed stir at 25° C. overnight. The reaction was then transferred to a separatory funnel and was then washed with a 1N aqueous hydrochloric acid solution (30 mL) and a saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 60/40 hexanes/ethyl acetate) afforded toluene-4-sulfonic acid tetrahydro-furan-3-yl methyl ester (6.57 g, 97%) as a colorless oil: (ES)+-HRMS m/e calcd for C12H16O4S (M+Na)+ 279.0661, found 279.0664. [0165] A solution of toluene-4-sulfonic acid tetrahydro-furan-3-yl methyl ester (6.50 g, 25.36 mmol), sodium iodide (11.02 g, 73.54 mmol), and acetone (200 mL) was heated to 60° C. for 16 h. The resulting suspension was then cooled to 10° C. and filtered. The salts were rinsed with cold acetone (50 mL). The filtrate and washings were then concentrated in vacuo to a thick slurry. To this slurry was added methylene chloride (100 mL), and the precipitate was filtered off and washed with methylene chloride (20 mL). The filtrate and washings were then dried over magnesium sulfate, filtered through a pad a silica gel, and then concentrated in vacuo to afford 3-iodomethyl-tetrahydro-furan as a light yellow oil. [0166] A solution of diisopropylamine (0.84 mL, 5.98 mmol) in tetrahydrofuran (10 mL) was cooled to -78° C. under an argon atmosphere and then was treated with a 2.5M solution of n-butyllithium in hexanes (2.29 mL, 5.72 mmol). The reaction mixture was stirred at -78° C. for 15 min. At this time, the reaction was slowly treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in Example 4, 1.20 g, 5.20 mmol) in tetrahydrofuran (5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.75 mL). The bright yellow solution was allowed to stir at -78° C. for 1 h, after which time, a solution of 3-iodomethyl-tetrahydro-furan (2.21 g, 10.4 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.69 mL) and tetrahydrofuran (5 mL) was added via a cannula. The reaction mixture was then allowed to warm to 25° C., where it was stirred for 48 h. The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were then combined and washed with a 10% aqueous sulfuric acid solution (25 mL) and a saturated aqueous sodium bicarbonate solution (25 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 75/25 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-3-yl-propionic acid methyl ester (663 mg, 41%) as a light yellow oil: EI-HRMS m/e calcd for C15H19ClO3S (M+) 314.0743, found 314.0729. [0167] A solution of 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-3-yl-propionic acid methyl ester (663 mg, 2.11 mmol) in formic acid (0.79 mL) and tetrahydrofuran (2.89 mL) was cooled in an ice bath to 0° C. and then was treated with a 30% aqueous hydrogen peroxide solution (1.19 mL, 10.53 mmol). The reaction was then slowly warmed to 25° C. and was stirred at 25° C. for 16 h. At this time, the reaction was cooled to 0° C. and was then quenched with a saturated aqueous sodium sulfite solution. This solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 50/50 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3 |
86% | Stage #1: 3-tetrahydrofuranmethanol With triethylamine In dichloromethane at 0℃; for 0.0833333h; Stage #2: p-toluenesulfonyl chloride With dmap In dichloromethane for 2h; | 40.1a Step 1 a Synthesis of (Tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate Step 1 a Synthesis of (Tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate To a solution of (tetrahydrofuran-3-yl)methanol (500 mg, 4.90 mM) in DCM (10 ml), triethyl amine (991 mg, 9.79 mM) was added. The reaction mixture was stirred for 5 min at 0 QC, followed by the addition of 4-methylbenzene-1 -sulfonyl chloride (933 mg, 4.90 mM) and DMAP (1 mg). The reaction mixture was further stirred for 2h, concentrated and purified by coloumn chromatography to afford the title compound (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (1 .07 g) as a white solid; Yield: 86%; 1 H NMR (DMSO-d6, 300 MHz): δ 7.82 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 4.03-3.90 (m, 2H), 3.84-3.66 (m, 4H), 3.53-3.49 (m, 1 H), 2.47 (s, 3H), 1 .60-1 .51 (m, 2H); MS: m/z 279 (M+Na). |
85.69% | With triethylamine In dichloromethane at 0 - 10℃; for 18h; | 29.1 Step 1: 21-2 To a mixture of 21-1 (4.65 g, 45.53 mmol) and TEA (7.37 g, 72.85 mmol) in DCM (100 mL) was added 4-methylbenzenesulfonyl chloride (10.42 g, 54.64 mmol) at 0 . After addition, the resulting mixture was warmed up to 10 and stirred for 18 hr. The reaction mixture was poured into ice water (100 mL) and extracted with DCM (100 mL × 3) . The combined organic layers were washed with brine (50 mL × 3) and dried over anhydrous sodium sulfate. The solvent was removed under vacuum. The residue was purified by flash chromatography over silica gel eluting with ethyl acetate in petroleum ether (30%) to afford 21-2 (10.0 g, 85.69%) .1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H) , 7.32 (d, J = 8.2 Hz, 2H) , 3.91-3.88 (m, 2H) , 3.77-3.61 (m, 3H) , 3.46 (dd, J = 9.1, 5.1 Hz, 1H) , 2.60-2.49 (m, 1H) , 2.42 (s, 3H) , 2.01-1.90 (m, 1H) , 1.57-1.46 (m, 1H) ppm. |
72% | With triethylamine In tetrahydrofuran for 34h; Heating / reflux; | 15.A To a solution of tetrahydro-3-furanmethanol (6.2 g, 60.8 mmol) in 60 mL tetrahydrofuran was added p-toluenesulfonyl chloride (11.6 g, 60.9 mmol) in one portion, followed by the drop-wise addition of triethylamine (9.2 mL, 66.4 mol) over 10 min. The resulting mixture was stirred at reflux for 16 h and then treated with triethylamine (1.6 mL, 11.5 mmol). Heating was continued for an additional 18 h. The cooled mixture was diluted with diethyl ether, washed with water and brine, and dried over MgSO4. The mixture was then filtered and concentrated under reduced pressure. The resulting residue was placed on a column of silica gel (30 g) and eluted with 5% to 80% ethyl acetate in hexanes to give 11.0 g (72%) of the title compound as an orange oil.1H NMR (CDCl3) δ 7.79 (m, 2H), 7.36 (m, 2H), 3.88-4.04 (m, 2H), 3.64-3.84 (m, 3H), 3.50 (dd, IH), 2.53-2.67 (m, IH), 2.46 (s, 3H), 1.96-2.05 (m, IH), 1.50-1.64 (m, IH). |
69% | With pyridine at 0 - 20℃; | 150.1 Preparation of (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate Step 1 Preparation of (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate To a stirred solution of (tetrahydrofuran-3-yl)methanol (5.0 g, 49.0 mmol) in pyridine (30 mL) was added TsCl (11.2 g, 58.8 mmol) slowly at 0° C. The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc (150 mL), washed with saturated aqueous citric acid (100 mL*5) and saturated aqueous NaHCO3 (100 mL*3), dried over Na2SO4, filtered and concentrated in vacuo. The resulting product was purified by column chromatography on silica gel (0-15% EtOAc in petroleum ether) to afford (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (8.7 g, 69%) as a colorless oil. |
60% | With triethylamine In dichloromethane at 20℃; | 1 Step 1: to a solution of compound 6a-1 (2 g, 102 mmol) in dichloromethane (40 ml) was added triethylamine(3.96 g, 39.17 mmol) and TsCl (4.48 g, 23.50 mmol), and the reaction solution was stirred overnight at room temperature.The reaction solution was poured into water and extracted with dichloromethane. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 6a-2 as anoil (3 g, 60%). MS m/z (ESI): 257.0 [M+H]+. |
36% | With dmap; triethylamine In dichloromethane at 20℃; for 3h; | 17.2 Step 2: (Tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate To a solution of (tetrahydrofuran-3-yl)methanol (1.0 g, 9.8 mmol) inDCM (15 ml) was added N,N-dimethylpyridin-4-amine (122 mg, 1 mmol), TEA (2.0 g, 20mmol) and 4-methylbenzenesulfonyl chloride (1.86 g, 9.8 mmol). The reaction mixture wasstirred at rt for 3 h. The mixture was concentrated and residue was purified by columnchromatography using ethyl acetate in petroleum ether (1/4) to afford tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (900 mg, 36% yield). LCMS (ESI) m/z: 257.4 (M + 1t |
With pyridine at 0 - 20℃; | ||
With triethylamine In tetrahydrofuran | R.6 Preparation of (tetrahydro-3-furanyl)methyl tosylate (Compound No. D5) REFERENCE EXAMPLE 6 Preparation of (tetrahydro-3-furanyl)methyl tosylate (Compound No. D5) A mixture comprising 50 g of (tetrahydro-3-furanyl)methanol, 95 g of tosyl chloride, 52 g of triethylamine and 450 ml of THF was refluxed for 8 hours. After separation of insolubles by filtration, the reaction fluid was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/7) to obtain 114.5 g of (tetrahydro-3-furanyl)methyl tosylate. | |
With triethylamine In tetrahydrofuran at 0 - 20℃; for 19h; | 6.1 (1) Tetrahydrofuran-3-ylmethyl 4-methylbenzenesulfonate Tetrahydro-3-furanmethanol (4.09 g) and triethylamine (7.81 mL) were dissolved in tetrahydrofuran (30 mL). p-Toluenesulfonyl chloride (9.53 g) was added under ice-cooling, followed by stirring for one hour. Then, the mixture was heated to room temperature and further stirred for 18 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was sequentially washed with a saturated sodium chloride solution and a saturated sodium bicarbonate solution, dried over magnesium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to obtain the title compound (8.9 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.50-1.60 (m, 1H) , 1.96-2.04 (m, 1H), 2.45 (s, 3H), 2.53-2.64 (m, 1H), 3.47-3.51 (m, 1H), 3.65-3.81 (m, 3H), 3.88-3.93 (m, 1H), 3.96-4.00 (m, 1H), 7.32-7.36 (m, 2H), 7.76-7.79 (m, 2H). | |
With triethylamine In dichloromethane at 20℃; for 12.25h; | 64.A Example 64A 3-(tosylmethyl)tetrahydrofuran To a solution of (tetrahydrofuran-3-yl)methanol (1.0 g, 9.8 mmol) in CH2Cl2 (5 mL) and triethylamine (1.98 g, 19.6 mmol) was added p-toluenesulfonyl chloride (2.8 g, 14.7 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 12 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2*10 mL) The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. MS (DCI/NH3) m/z 257 (M+H)+. | |
With pyridine for 4h; Inert atmosphere; Cooling with ice; | 1 To a mixture of 25 g of ( tetrahydrofuran-3-yl ) methanol of the following formula:and 125 ml of pyridine, 56 g of p-toluenesulfonyl chloride was added under nitrogen atmosphere and under ice-cooling, and stirred for 4 hours under ice-cooling. To the reaction mixture, water was added and extracted with tert-butyl methyl ether 2 times. The organic layer was washed with 1 mol/1 of hydrochloric acid and brine successively. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 58 g of a crude product of p- toluenesulfonic acid tetrahydrofuran-3-ylmethyl ester of the following formula.The crude product was used for Reference Production Example 2 without further purification. | |
With pyridine for 4h; Inert atmosphere; Cooling with ice; | Under nitrogen atmosphere, to a mixture of (tetrahydrofuran-3-yl)-methanol represented by the following formula: (25 g) and pyridine (125 ml) was added p-toluenesulfonyl chloride (56 g) under ice-cooling, and the mixture wasstirred under ice-cooling for 4. hrs. Then, water was added to the reaction mixture, and the mixture was extracted twice with tert-butyl methyl ether. The organic layer was washed with 1 mol/L hydrochloric acid followed by saturated brine. The organic layer was dried over anhydrous sodiumsulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (58 g) of tetrahydrofuran-3-ylmethyl p-toluenesulfonate represented by the following formula: | |
With pyridine for 4h; Inert atmosphere; Cooling with ice; | 1 Under a nitrogen atmosphere, to a mixture of 25 g of (tetrahydrofuran-3-yl)-methanol represented by the followingformula and 125 ml of pyridine was added 56 g of p-toluenesulfonyl chloride under ice cooling, and the mixture was stirred underice cooling for 4 hours. Thereafter, water was added to the reaction mixture, and the mixture was extracted twice withtert-butyl methyl ether. The organic layer was washed with 1 mol/L hydrochloric acid followed by a saturated salt solution.The organic layer was dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated underreduced pressure to obtain 58 g of a crude product of tetrahydrofuran-3-ylmethyl p-toluenesulfonate represented by thefollowing formula | |
58 g | With pyridine for 4h; Inert atmosphere; Cooling with ice; | 1 Under a nitrogen atmosphere, to a mixture of 25 g of (tetrahydrofuran-3-yl)-methanol represented by the following formulaand 125 ml of pyridine was added 56 g of p-toluenesulfonyl chloride under ice cooling, and the mixture was stirred under ice cooling for 4 hours. Thereafter, water was added to the reaction mixture, and the mixture was extracted twice with tert-butyl methyl ether. The organic layer was washed with 1 mol/L hydrochloric acid, followed by a saturated salt solution. The organic layer was dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain 58 g of a crude product of tetrahydrofuran-3-ylmethyl p-toluenesulfonate represented by the following formula. |
With triethylamine In dichloromethane at 0 - 20℃; | The tosylate of (tetrahydrofuran-3-yl)methanol was prepared by reaction with tosyl chloride and triethylamine in DCM at 0 °C, with warming to ambient temperature. Λ/-[1 - (Fluoromethyl)cyclopropyl]-3-[(1 -methylpyrazol-4-yl)methyl]-2,4-dioxo-1 1H-quinazoline-6- sulfonamide (100 mg, 0.260 mmol), the crude tosylate (73 mg, 0.286 mmol) and potassium carbonate (43 mg, 0.312 mmol) in DMF was conventionally heated to 70 °C for 4 h. Usual work-up afforded the desired product (17 mg, 0.035 mmol, 13%) as a white powder. | |
14.2 g | With trimethylamine hydrochloride; triethylamine In chloroform at 20℃; for 14h; | 1-17.1 (1) a chloroform solution (100 mL) of tetrahydrofuran-3-ylmethanol (5.1 g), at room temperature, triethylamine (13.8 mL), trimethylamine hydrochloride (1.43 g), p-toluenesulfonyl chloride (11.4 g ), and the mixture was stirred for 14 hours. The reaction mixture was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate.After filtration over anhydrous magnesium sulfate, and N, and N- dimethylformamide (100 mL) was added a solution under reduced pressure the solvent was distilled off the resulting residue was (14.2 g). Then potassium carbonate (13.8 g), and stirred for 2 hours 30 minutes at 65 ° C. was added 2-mercaptobenzothiazole and (10.0g).Distilled water was added to the reaction mixture and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried with anhydrous magnesium sulfate.After filtration over anhydrous magnesium sulfate, toluene under azeotropic vacuo, and evaporated to give a residue (10.4 g). It was dissolved adding chloroform (75mL), under ice-cooling, and the mixture was stirred for 18 hours added m- chloroperbenzoic acid (24.9g). After stirring added a saturated aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate sulfate, and extracted with chloroform. The organic layer was concentrated under reduced pressure 2- (tetrahydrofuran-3-yl-methyl-sulfonyl) -1,3-benzothiazole (11.4 g) as a yellow oily substance. |
1.1 g | With dmap; triethylamine In dichloromethane at 15℃; for 16h; | 75.1 Step 1: Preparation of tetrahydrofuran-3-ylmethyl 4-methylbenzenesulfonate Step 1: Preparation of tetrahydrofuran-3-ylmethyl 4-methylbenzenesulfonate To a stirred solution of tetrahydro-3-furanmethanol (500 mg, 4.90 mmol) in DCM (5 mL) was added Et3N (892 mg, 8.81 mmol) and DMAP (60 mg, 0.49 mmol). Then to the mixture was added a solution of 4-methylbenzenesulfonyl chloride (1.4 g, 7.34 mmol) in DCM (5 mL) dropwise. After being stirred at 15 oC for 16 hrs, the resulting mixture was diluted with DCM (50 mL), washed with H2O (20 mL), 2 N HCl (20 mL) and brine (10 mL), then dried over anhydrous Na2SO4 and concentrated in vacuo to give tetrahydrofuran-3-ylmethyl 4- methylbenzenesulfonate (1.1 g) as a colorless oil, which was used in the next step directly without further purification. |
With triethylamine In toluene at 110℃; for 7h; | 1.1 S1, Preparation of intermediate A: The reaction vessel was evacuated to a vacuum vacuum tetrahydrofuran methanol, toluene, triethylamine stirred from the solid feeding port into p-toluenesulfonyl chloride, steam heated to 110 ° C reflux 7h, The layers were separated and the reaction was stopped under negative pressure. The solvent was distilled off to 122 ° C. Toluene was circulated and replaced with a high-pressure vacuum at an internal temperature of 130 ° C to obtain a light yellow solution, namely Intermediate A, in which tetrahydrofuran, methanol, toluene and triethylamine And p-toluenesulfonyl chloride molar ratio of 15: 25: 3: 8; | |
With pyridine at 20℃; for 5.5h; | General procedure for synthesis of compounds 11k-11n, 11v, 11y-11z. 11m. To a solution of compound 11b (120 mg, 0.45 mmol) dissolved in NMP (5 mL) were added K2CO3 (513 mg, 3.71 mmol) and (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (crude product 427 mg, 1.67 mmol). (Tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate was synthesized through a simple and regular sulfonylation on hydroxyl group of (tetrahydrofuran-3-yl)methanol (1.0 eq) with 4-methylbenzenesulfonyl chloride (2.0 eq) using pyridine as base and solvent at RT stirring for 5.5 h. The mixture was stirred at 95 °C for 4 h. Then the mixture was cooled, poured into water and extracted with EtOAc. The organic layer was washed with saturated brine, dried over NaSO4, concentrated under reduced pressure. The residue was purified by silica gel chromatography with petroleum ether/ EtOAc (1/1) to give the target product 11m (154 mg, 97% yield). |
Yield | Reaction Conditions | Operation in experiment |
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25% | With lithium bromide In N,N-dimethyl-formamide at 85℃; for 16h; | 162B Example 162B 5-Methyl-3-tetrahydro-furan-3-ylmethyl)-3H-thiazol-2-ylideneamine A mixture of the product of Example 162A (1.62 g, 6.3 mmol), 2-amino-5-methylthiazole (0.72 g, 6.3 mmol) and LiBr (55 mg, 0.63 mmol) in 2 mL DMF was warmed to 85° C. and allowed to stir for 16 hours. The mixture was then allowed to cool to ambient temperature, diluted with 10 mL CH2Cl2 and washed with 1*5 mL 10% aqueous Na2CO3 solution. The layers were separated and the aqueous layer was extracted 2*5 mL CH2Cl2. The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by column chromatography (SiO2, 9:1:0.1 CH2Cl2:CH3OH:NH4OH) to afford the title compound (0.31 g, 1.6 mmol, 25% yield). 1H NMR (300 MHz, CD3OD) δ ppmn 1.61-1.74 (m, 1 H) 1.96-2.04 (m, 1 H) 2.05 (d, J=1.36Hz, 3H)2.69-2.84 (m, 1 H) 3.53 (dd, J=8.82, 5.76 Hz, 1 H) 3.63 (dd, J=7.63, 2.20 Hz, 2 H) 3.69-3.81 (m, 2 H) 3.89 (ddd, J=8.31, 5.42 Hz, 1 H) 6.36-6.42 (m, 1 H); MS (DCI/NH3) m/z 199 (M+H)+. |
25% | Stage #1: 5-methyl-2-thiazol-2-amine; (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate With lithium bromide In N,N-dimethyl-formamide at 85℃; for 16h; Stage #2: With sodium carbonate In dichloromethane; water; N,N-dimethyl-formamide at 20℃; | 162.B A mixture of the product of Example 162A (1.62 g, 6.3 mmol), 2-amino-5-methylthiazole(0.72 g, 6.3 mmol) and LiBr (55 mg, 0.63 mmol) in 2 mL DMF was warmed to 85 0C and allowed to stir for 16 hours. The mixture was then allowed to cool to ambient temperature, diluted with 10 mL CH2Cl2 and washed with 1 X 5 mL 10% aqueous Na2CO3 solution. The layers were separated and the aqueous layer was extracted 2 X 5 mL CH2Cl2. The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by column chromatography (SiO2, 9:1 :0.1 CH2C12:CH3OH:NH4OH) to afford the title compound (0.31 g, 1.6 mmol, 25% yield). 1H NMR (300 MHz, CD3OD) δ ppm 1.61 - 1.74 (m, 1 H) 1.96 - 2.04 (m, 1 H) 2.05 (d, J=I.36 Hz, 3 H) 2.69 - 2.84 (m, 1 H) 3.53 (dd, J=8.82, 5.76 Hz, 1 H) 3.63 (dd, J=7.63, 2.20 Hz, 2 H) 3.69 - 3.81 (m, 2 H) 3.89 (ddd, J=8.31, 5.42 Hz, 1 H) 6.36 - 6.42 (m, 1 H); MS (DCI/NH3) m/z 199 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
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Multi-step reaction with 2 steps 1: 12 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
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With sodium iodide In acetone at 60℃; for 16h; | 6 EXAMPLE 6 2-(3-Chloro-4-methanesulfonylphenyl)-N-pyrazin-2-yl-3-(tetrahydrofuran-3-yl)propionamide [0164] A solution of tetrahydro-3-furanmethanol (3.0 g, 29.4 mmol) in methylene chloride (45 mL) at 25° C. was treated with 4-(dimethylamino)pyridine (3.99 g, 32.31 mmol) and p-toluenesulfonyl chloride (5.60 g, 29.37 mmol), and the reaction mixture was allowed stir at 25° C. overnight. The reaction was then transferred to a separatory funnel and was then washed with a 1N aqueous hydrochloric acid solution (30 mL) and a saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 60/40 hexanes/ethyl acetate) afforded toluene-4-sulfonic acid tetrahydro-furan-3-yl methyl ester (6.57 g, 97%) as a colorless oil: (ES)+-HRMS m/e calcd for C12H16O4S (M+Na)+ 279.0661, found 279.0664. [0165] A solution of toluene-4-sulfonic acid tetrahydro-furan-3-yl methyl ester (6.50 g, 25.36 mmol), sodium iodide (11.02 g, 73.54 mmol), and acetone (200 mL) was heated to 60° C. for 16 h. The resulting suspension was then cooled to 10° C. and filtered. The salts were rinsed with cold acetone (50 mL). The filtrate and washings were then concentrated in vacuo to a thick slurry. To this slurry was added methylene chloride (100 mL), and the precipitate was filtered off and washed with methylene chloride (20 mL). The filtrate and washings were then dried over magnesium sulfate, filtered through a pad a silica gel, and then concentrated in vacuo to afford 3-iodomethyl-tetrahydro-furan as a light yellow oil. [0166] A solution of diisopropylamine (0.84 mL, 5.98 mmol) in tetrahydrofuran (10 mL) was cooled to -78° C. under an argon atmosphere and then was treated with a 2.5M solution of n-butyllithium in hexanes (2.29 mL, 5.72 mmol). The reaction mixture was stirred at -78° C. for 15 min. At this time, the reaction was slowly treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in Example 4, 1.20 g, 5.20 mmol) in tetrahydrofuran (5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.75 mL). The bright yellow solution was allowed to stir at -78° C. for 1 h, after which time, a solution of 3-iodomethyl-tetrahydro-furan (2.21 g, 10.4 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.69 mL) and tetrahydrofuran (5 mL) was added via a cannula. The reaction mixture was then allowed to warm to 25° C., where it was stirred for 48 h. The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were then combined and washed with a 10% aqueous sulfuric acid solution (25 mL) and a saturated aqueous sodium bicarbonate solution (25 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 75/25 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-3-yl-propionic acid methyl ester (663 mg, 41%) as a light yellow oil: EI-HRMS m/e calcd for C15H19ClO3S (M+) 314.0743, found 314.0729. [0167] A solution of 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-3-yl-propionic acid methyl ester (663 mg, 2.11 mmol) in formic acid (0.79 mL) and tetrahydrofuran (2.89 mL) was cooled in an ice bath to 0° C. and then was treated with a 30% aqueous hydrogen peroxide solution (1.19 mL, 10.53 mmol). The reaction was then slowly warmed to 25° C. and was stirred at 25° C. for 16 h. At this time, the reaction was cooled to 0° C. and was then quenched with a saturated aqueous sodium sulfite solution. This solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 50/50 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3 |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide | 7 EXAMPLE 7 Preparation of 1-[N-{(tetrahydro-3-furanyl)methyl}-N-ethylamino]-1-methylamino-2-nitroethylene (Compound No. 12) A mixture comprising 4.09g of (tetrahydro-3 -furanyl)methyl tosylate, 17 ml of 70% aqueous ethylamine solution and 8.2 ml of 2 N aqueous sodium hydroxide solution was stirred at 75° C. for 6 hours. The reaction fluid was concentrated under a reduced pressure to obtain crude N-{(tetrahydro-3-furanyl)methyl}-N-ethylamine. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine In tetrahydrofuran; hexane; acetone | R.4 [(Tetrahydro-3-furanyl)methyl]p-toluenesulfonate REFERENCE EXAMPLE 4 [(Tetrahydro-3-furanyl)methyl]p-toluenesulfonate A mixture of 5.0 g of (tetrahydro-3-furanyl)methanol, 10.3 g of tosyl chloride, 5.44 g of triethylamine and 50 ml of tetrahydrofuran was stirred at 70° C. for 3 hours, Since the reaction did not finish, the mixture was further stirred at 80° C. for 3 hours. After the completion of the reaction, the reaction mixture was poured into water, extracted with the mixture of acetone and hexane (1:1). The organic layer was washed with water twice, washed with salt Water, dried over sodium sulfate, anhydrous, and then concentrated under a reduced pressure. The resultant oily substance was purified by silica gel column chromatography (1:1 ethyl acetate/hexane) to obtain 9.81 g of [(tetrahydro-3-furanyl)methyl] p-toluenesulfonate. Next, the compositions of the present invention will be described in detail with reference to examples of formulations. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride In pyridine | 16 Toluene-4-sulfonic acid tetrahydro-furan-3-ylmethyl ester Toluene-4-sulfonic acid tetrahydro-furan-3-ylmethyl ester To a solution of 5 g (48.9 mmol) of tetrahydro-3-furanomethanol in pyridine (30 mL) cooled to 0° C. was added a solution of p-toluenesulfonyl chloride (9.3 g, 48.9 mmol) and DCM (30 mL) and the resulting solution was stirred at RT for 12 h. The reaction mixture was poured onto a mixture of 6 N HCl and ice. The aqueous phase was thrice extracted with DCM and the combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated to afford 9.5 g of the title compound as an oil. The enantiomers were separated by chiral HPLC to afford the two enantiomers with an enantiomeric excess of >95% |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 70℃; for 20h; | 6.2 (2) tert-Butyl 4-{2-[7-hydroxymethyl-6-(tetrahydrofuran-3-ylmethoxy)benz[d]isoxazol-3-yl]ethyl}piperidine-1-carboxylate Tetrahydrofuran-3-ylmethyl 4-methylbenzenesulfonate (1.03 g) and tert-butyl 4-[2-(6-hydroxy-7-hydroxymethylbenz[d]isoxazol-3-yl)ethyl]piperidine-1-carboxylate obtained in Preparation Example 2-(6) (752 mg) were dissolved in N,N-dimethylformamide (8 mL). Potassium carbonate (829 mg) and sodium iodide (600 mg) were added and the mixture was stirred at 70°C for 20 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to obtain the title compound (616 mg). 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.08-1.20 (m, 2H), 1.46 (s, 9H), 1.49 (m, 1H), 1.75-1.82 (m, 5H), 2.14-2.23 (m, 1H), 2.63-2.70 (m, 2H), 2.77-2.83 (m, 1H), 2.92-2.98 (m, 2H), 3.76-4.14 (m, 8H), 5.00 (s, 2H), 6.91 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H). ESI-MS m/z: 483 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
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97% | With sodium hydride; sodium iodide In N,N-dimethyl-formamide at 60℃; for 6h; | 85.C (3-tert-butyl-1-((tetrahydrofuran-3-yl)methyl)-N-trityl-1H-pyrazol-5-amine Example 85C (3-tert-butyl-1-((tetrahydrofuran-3-yl)methyl)-N-trityl-1H-pyrazol-5-amine In a 200 mL round-bottomed flask, to a solution of Example 85A (5 g, 13.11 mmol) in N,N-dimethyl formamide (25 mL) was added sodium iodide (0.786 g, 5.24 mmol), Example 85B (4.03 g, 15.73 mmol), followed by addition of sodium hydride (1.310 g, 32.8 mmol) and the mixture was stirred at 60° C. for 6 hour. LC-MS, m/z 466 (M+H)+ indicated an almost complete reaction. Water (150 mL) was added and the mixture was extracted with ethyl acetate (3*40 mL). The organics were combined, dried and concentrated in vacuo. The residue was purified by column chromatography using an Analogix Intelliflash280 (SiO2, 10-70% ethyl acetate in hexanes) to afford the title compound (5.9 g, 97%) which was carried on without further spectral characterization. |
97% | With sodium hydride In N,N-dimethyl-formamide at 60℃; for 6h; | 85.85C Example 85C; (3-tert-butyl-1-((tetrahydrofuran-3-yl)methyl)-N-trityl-1H-pyrazol-5-amine; In a 200 mL round-bottomed flask, to a solution of Example 85A (5 g , 13.11 mmol) in N,N-dimethyl formamide (25 mL) was added sodium iodide (0.786 g, 5.24 mmol), Example 85B (4.03 g, 15.73 mmol), followed by addition of sodium hydride (1.310 g, 32.8 mmol) and the mixture was stirred at 60° C. for 6 hours. LC-MS, m/z 466 (M+H)+ indicated an almost complete reaction. Water (150 mL) was added and the mixture was extracted with ethyl acetate (3×40 mL). The organics were combined, dried and concentrated in vacuo. The residue was purified by column chromatography using an Analogix Intelliflash280 (SiO2, 10-70% ethyl acetate in hexanes) to afford the title compound (5.9 g, 97%) which was carried on without further spectral characterization. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 50℃; for 4h; | 10 Production Example 10; To a solution of 0.81 g of (3,3,3- trifluoropropylsulfonyl) acetonitrile in 4 ml of N, N- dimethylformamide were added 0.55 g of potassium carbonate, 0.66 g of potassium iodide and 1.00 g of tetrahydrofuran-3- ylmethyl-p-toluenesulfonate, followed by stirring at 50°C for 4 hours. The reaction mixture was cooled to room temperature, and 30 ml of ethyl acetate and then 30 ml of an aqueous 1 N hydrochloric acid solution were sequentially added thereto. The organic layer was separated and the aqueous layer was extracted twice with 30 ml of ethyl acetate. Organic layers were combined, washed with 30 ml of an aqueous saturated sodium hydrogen carbonate solution and then 30 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.62 g of 3- (tetrahydrofuran-3-yl) -2- (3,3,3- trifluoropropylsulfonyl) propionitrile (hereinafter referred to as the present compound (H)) represented by the following formula.1H-NMR (CDCl3, TMS, 5 (ppm) ) : 1.53-1.76 (IH, m) , 2.12-2.32(3H, m) , 2.49-2.59 (IH, m) , 2.73-2.84 (2H, m) , 3.43-3.58 (3H, m) , 3.77-3.84 (IH, m) , 3.87-4.02 (3H, m) |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: Z-5-chloro-N-(5,5-dimethyl-4,5-dihydrothiazol-2-yl)-2-methoxybenzamide With potassium <i>tert</i>-butylate In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate In tetrahydrofuran; N,N-dimethyl-formamide at 85℃; for 12h; | 64.B Example 64B 5-chloro-N-[(2Z)-5,5-dimethyl-3-(tetrahydrofuran-3-ylmethyl)-1,3-thiazolidin-2-ylidene]-2-methoxybenzamide To a solution of Example 1A (200 mg, 0.67 mmol) in dry THF/DMF (2:1) (15 mL) was added potassium tert-butoxide (95%)(118 mg, 1 mmol). The mixture was stirred at room temperature for 10 minutes followed by the dropwise addition of Example 64A (192 mg, 0.8 mmol). The mixture was heated at 85° C. for 12 hours after which the mixture was poured into water, and extracted with ethyl acetate (2*). The combined organic layers were dried over MgSO4, filtered and purified by HPLC on a Waters Symmetry C8 column (40 mm*100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile:ammonium acetate (10 mM) over 15 minutes at a flow rate of 70 mL/minute to provide the title product. 1H NMR (400 MHz, CDCl3) δ ppm 1.52 (s, 6H) 1.70-1.82 (m, 1H) 2.02-2.11 (m, 1H) 2.69-2.81 (m, 1H) 3.43-3.49 (m, 2H) 3.61 (dd, J=8.59, 5.83 Hz, 1H) 3.69 (dd, J=13.81, 7.67 Hz, 1H) 3.76-3.91 (m, 4H) 3.89 (s, 3H) 6.88 (d, J=8.90 Hz, 1H) 7.34 (dd, J=8.90, 2.76 Hz, 1H) 7.93 (d, J=2.76 Hz, 1H); MS (DCI/NH3) m/z 383 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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Multi-step reaction with 3 steps 1.1: potassium iodide / N,N-dimethyl-formamide / 3 h / 80 °C / Inert atmosphere 2.1: hydrazine hydrate / ethanol / 6 h / 70 °C / Inert atmosphere 2.2: Raney nickel / 4 h / 60 °C 3.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / tetrahydrofuran / 4 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 2h; | 40.1b Step 1 b Ethyl 2-(3-(4-((2',6'-dimethyl-4'-((tetrahydrofuran-3-yl)methoxy)-[1 ,r-biphenyl]-3-yl) methoxy)phenyl)oxetan-3-yl)acetate Step 1 b Ethyl 2-(3-(4-((2',6'-dimethyl-4'-((tetrahydrofuran-3-yl)methoxy)-[1 ,r-biphenyl]-3-yl) methoxy)phenyl)oxetan-3-yl)acetate To a stirred solution of ethyl 2-(3-(4-((4'-hydroxy-2',6'-dimethyl-[1 ,1 '-biphenyl]- 3-yl)methoxy)phenyl)oxetan-3-yl)acetate (100 mg, 0.224 mM, compound of Step 1 c of Example 39), (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (86 mg, 0.336 mM, compound of Step 1 a) in DMF (5 ml) and cesium carbonate (146 mg, 0.448 mM) were added. The reaction mixture was stirrred at 60 QC for 2h. The reaction mixture was quenched with water, extracted with ethyl acetate and purified by column chromatography to afford the title compound ethyl 2-(3-(4-((2',6'-dimethyl- 4'-((tetrahydrofuran-3-yl)methoxy)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)oxetan-3-yl) acetate (95 mg) as a colorless liquid. Yield: 80%; 1 H NMR (CDCI3, 300 MHz): δ 7.44 -7.56 (m, 2H), 7.19 (s, 1 H), 7.1 1 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.7 Hz, 2H), 6.67 (s, 2H), 5.15 ( s, 2H), 5.00 (d, J=6.1 Hz, 2H), 4.84 (d, J=6.1 Hz, 2H), 4.05-3.57 (m, 8H), 3.10 (s, 2H), 2.76 (m, 2H), 2.12 (m, 2H), 2.00 (s, 6H), 1 .07 (t, J= 8.7 Hz, 3H); MS: m/z 530 (M)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 60 °C 2: methanol; lithium hydroxide / tetrahydrofuran / 6 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.8 mg | Stage #1: 4-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide With sodium hydride In N,N-dimethyl-formamide; mineral oil at 10 - 35℃; for 1h; Stage #2: (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate In N,N-dimethyl-formamide; mineral oil at 10 - 35℃; | 115 Example 115 4-(4-oxo-1-(tetrahydrofuran-3-ylmethyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide Example 115 4-(4-oxo-1-(tetrahydrofuran-3-ylmethyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide [0671] To a solution of 4-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (28.7 mg) obtained in Step B of Example 100 in DMF (2 mL) was added sodium hydride (60% dispersion in mineral oil, 4.35 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added tetrahydrofuran-3-ylmethyl 4-methylbenzenesulfonate (27.8 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (11.8 mg). 1H NMR (300 MHz, DMSO-d6) 5 1.60-1.75 (1H, m), 1.86-2.03 (1H, m), 2.74-2.86 (1H, m), 3.52 (1H, dd, J = 8.7, 5.7 Hz), 3.59-3.74 (2H, m), 3.81 (1H, td, J = 8.1, 5.7 Hz), 4.28-4.42 (2H, m), 6.73 (1H, d, J = 7.6 Hz), 7.29 (1H, d, J = 7.2 Hz), 7.40 (2H, brs), 7.81-7.91 (2H, m), 8.43-8.56 (2H, m), 11.18 (1H, brs). MS (ESI+): [M+H]+ 375.1. MS (ESI+), found: 375.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 48 h / 55 - 80 °C 2: hydrogen; palladium 10% on activated carbon / methanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; N-ethyl-N,N-diisopropylamine; potassium iodide In N,N-dimethyl-formamide at 55 - 80℃; for 48h; | 3 General procedure for the synthesis of compounds 10a, 10b and 12) A mixture of 7a (0.2 mmol), an appropriate bromide or methanesulfonate (0.4 mmol), K2CO3 (0.6 mmol), DIEA (0.4 mmol) and KI (0.04 mmol) in 4 mL DMF was heated at 55 o C-80 o C for 2 days until the completion of the reaction. The mixture was treated with EtOAc (100 mL), washed with brine and then dried over with Na2SO4, filtered, and evaporated. The crude product was purified by chromatograph (CHCl3/MeOH) to give the corresponding products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | In N,N-dimethyl-formamide at 70℃; | 7.1 Step 1: 2-(tetrahydrofuran-3-yl)acetonitrile Step 1: 2-(tetrahydrofuran-3-yl)acetonitrile [00285] A mixture of (tetrahydrofuran-3-yl) methyl 4-methylbenzenesulfonate (17.0 g, 66.4 mmol) and NaCN (6.51 g, 132.8 mmol) in DMF (30 mL) was stirred at 70 °C overnight. The resulting mixture was diluted with EtOAc (200 mL), washed with brine (100 mL x 3), dried over Na2S04, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography (0-25% EtOAc in petroleum ether) to afford 2-(tetrahydrofuran-3-yl) acetonitrile (4.0 g, 54%) as a colorless oil. m/z: 112.30 [M + H] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 70 °C 2: diisobutylaluminium hydride / dichloromethane / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 70 °C 2: diisobutylaluminium hydride / dichloromethane / 0 - 20 °C / Inert atmosphere 3: 5,5-dibromobarbituric acid; hydrogen bromide / dichloromethane; water / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N,N-dimethyl-formamide / 70 °C 2: diisobutylaluminium hydride / dichloromethane / 0 - 20 °C / Inert atmosphere 3: 5,5-dibromobarbituric acid; hydrogen bromide / dichloromethane; water / 2 h / 20 °C 4: sodium hydrogencarbonate / 90 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: N,N-dimethyl-formamide / 70 °C 2: diisobutylaluminium hydride / dichloromethane / 0 - 20 °C / Inert atmosphere 3: 5,5-dibromobarbituric acid; hydrogen bromide / dichloromethane; water / 2 h / 20 °C 4: sodium hydrogencarbonate / 90 °C / Inert atmosphere 5: potassium hydroxide; water / methanol / 7 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17 mg | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 4h; | 598 N-[ 1 -(Fluoromethyl)cyclopropyl]-3-[(1 -methylpyrazol-4-yl)methyl]-2,4-dioxo-1- (tetrahydrofuran-3-ylmethyl)quinazoline-6-sulfonamide The tosylate of (tetrahydrofuran-3-yl)methanol was prepared by reaction with tosyl chloride and triethylamine in DCM at 0 °C, with warming to ambient temperature. Λ/-[1 - (Fluoromethyl)cyclopropyl]-3-[(1 -methylpyrazol-4-yl)methyl]-2,4-dioxo-1 1H-quinazoline-6- sulfonamide (100 mg, 0.260 mmol), the crude tosylate (73 mg, 0.286 mmol) and potassium carbonate (43 mg, 0.312 mmol) in DMF was conventionally heated to 70 °C for 4 h. Usual work-up afforded the desired product (17 mg, 0.035 mmol, 13%) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.4 g | Stage #1: (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate; 2-Mercaptobenzothiazole With potassium carbonate at 65℃; for 2.5h; Stage #2: With 3-chloro-benzenecarboperoxoic acid In chloroform for 18h; Cooling with ice; | 1-17.1 (1) a chloroform solution (100 mL) of tetrahydrofuran-3-ylmethanol (5.1 g), at room temperature, triethylamine (13.8 mL), trimethylamine hydrochloride (1.43 g), p-toluenesulfonyl chloride (11.4 g ), and the mixture was stirred for 14 hours. The reaction mixture was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate.After filtration over anhydrous magnesium sulfate, and N, and N- dimethylformamide (100 mL) was added a solution under reduced pressure the solvent was distilled off the resulting residue was (14.2 g). Then potassium carbonate (13.8 g), and stirred for 2 hours 30 minutes at 65 ° C. was added 2-mercaptobenzothiazole and (10.0g).Distilled water was added to the reaction mixture and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried with anhydrous magnesium sulfate.After filtration over anhydrous magnesium sulfate, toluene under azeotropic vacuo, and evaporated to give a residue (10.4 g). It was dissolved adding chloroform (75mL), under ice-cooling, and the mixture was stirred for 18 hours added m- chloroperbenzoic acid (24.9g). After stirring added a saturated aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate sulfate, and extracted with chloroform. The organic layer was concentrated under reduced pressure 2- (tetrahydrofuran-3-yl-methyl-sulfonyl) -1,3-benzothiazole (11.4 g) as a yellow oily substance. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: potassium carbonate / 2.5 h / 65 °C 1.2: 18 h / Cooling with ice 2.1: lithium chloride; potassium hexamethylsilazane / tetrahydrofuran; toluene / 0.5 h / -80 °C 2.2: 0.5 h / -80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium carbonate / 2.5 h / 65 °C 1.2: 18 h / Cooling with ice 2.1: lithium chloride; potassium hexamethylsilazane / tetrahydrofuran; toluene / 0.5 h / -80 °C 2.2: 0.5 h / -80 °C 3.1: bromine / chloroform / 0.5 h / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate; sodium iodide / acetonitrile / 4 h / 70 °C 2: ethanol / 8 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 4 h / 70 °C 2.1: ethanol / 8 h / Reflux 3.1: hydrogenchloride / acetonitrile / 5 h / 20 °C 3.2: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; sodium iodide In acetonitrile at 70℃; for 4h; | 9.1 7.68 g (0.03 mol) of 4-methylbenzenesulfonic acid (tetrahydrofuran-3-yl)methyl ester, 9.00 g (0.15 mol) of ethylenediamine, 8.280 g (0.06 mol) of potassium carbonate, 0.20 g of sodium iodide, and 120 mL of acetonitrile was placed in a 250 mL round bottom flask. It was heated to 70°C for 4h. It was then filtered. The filtrate was concentrated to give crude N-((tetrahydrofuran-3-yl)methyl)ethylenediamine. The crude product obtained was dissolved in 100 mL ethanol and was added 1.125 g (0.025 mol) of 1,1-dimethylthio-2-nitroethylene in a 250 mL round bottom flask. Under reflux conditions, reaction for 8h. It was cooled and solid precipitated. Concentrate, filter, and dried to give 5.32 g of a light yellow powdery solid in 88% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In N,N-dimethyl-formamide at 120℃; | 150.2 Preparation of 1-(4-chloro-1-((tetrahydrofuran-3-yl)methyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone Step 2 Preparation of 1-(4-chloro-1-((tetrahydrofuran-3-yl)methyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone A mixture of 1-(4-chloro-1H-indol-3-yl)-2,2,2-trifluoroethanone (2.48 g, 10.0 mmol), (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (3.07 g, 12.0 mmol) and K2CO3 (4.14 g, 30.0 mmol) in DMF (40 mL) was stirred at 120° C. overnight. The resulting mixture was diluted with EtOAc (150 mL), washed with saturated aqueous NaHCO3 (100 mL*5), dried over Na2SO4, filtered and concentrated in vacuo to afford 1-(4-chloro-1-((tetrahydrofuran-3-yl)methyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone (3.3 g, 100%) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 120 °C 2: sodium hydroxide / ethanol / 2 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 120 °C 2: sodium hydroxide / ethanol / 2 h / 80 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / tetrahydrofuran / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15 mg | With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 12h; | 75.2 Step 2: Preparation of 6-[3,4-difluoro-5-(tetrahydrofuran-3-ylmethoxy)phenyl]-5- methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine Step 2: Preparation of 6-[3,4-difluoro-5-(tetrahydrofuran-3-ylmethoxy)phenyl]-5- methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine A mixture of 2,3-difluoro-5-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl)phenol (100 mg, 0.28 mmol), tetrahydrofuran-3-ylmethyl 4- methylbenzenesulfonate (87 mg, 0.34 mmol) and Cs2CO3 (138 mg, 0.42 mmol) in DMF (3 mL) was heated at 80 oC with stirring for 12 hrs. After being cooled down to rt, the reaction mixture was diluted with EA (20 mL), washed with brine (10 mL), then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by pre-HPLC to give 6-[3,4-difluoro-5- (tetrahydrofuran-3-ylmethoxy)phenyl]-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3- d]pyrimidine (15 mg) as a white solid. 1H NMR (400 MHz, CDCl3) 9.04 (d, 2 H), 8.79 (s, 1 H), 7.45 (s, 1 H), 6.28 - 6.49 (m, 2 H), 4.88 - 5.05 (m, 1 H), 3.65 - 4.09 (m, 8 H), 3.40 - 3.58 (m, 1 H), 3.20 - 3.37 (m, 2 H), 2.71 - 2.86 (m, 1 H), 2.14 (s, 1 H), 1.32 - 1.54 (m, 3 H). MS obsd. (ESI+) [(M+H)+] : 440. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With caesium carbonate; sodium iodide In N,N-dimethyl-formamide at 60℃; for 2h; | 335.1 (Step 1) A mixture of 6-bromo-7-fluoro-1-isopropylquinazoline-2,4(1H,3H)-dione (0.301 g, 1.00 mmol), (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (0.248 g, 1.50 mmol), cesium carbonate (0.384 g, 1.50 mmol) and sodium iodide (0.225 g, 1.50 mmol) in DMF (2 mL) was stirred at 60°C for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→100% ethyl acetate/hexane) to give 6-bromo-7-fluoro-1-isopropyl-3-((tetrahydrofuran-3-yl)methyl)quinazoline-2,4(1H,3H)-dione (0.350 g, 91.0%) as a white solid. 1H NMR (300 MHz, CDCl3):δ 1.60(6H,d,J=6.0 Hz), 1.68-1.82(1H,m), 1.92-2.06(1H,m), 2.66-2.80(1H,m), 3.60(1H,dd,J=3.0 Hz,12.0 Hz), 3.74-3.84(2H,m), 3.91-3.99(1H,m), 4.05(1H,dd,J=6.0 Hz,12.0 Hz), 4.17(1H,dd,J=6.0 Hz,12.0 Hz), 4.91(1H,brs), 7.13(1H,d,J=12.0 Hz), 8.43(1H,d,J=9.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In water; N,N-dimethyl-formamide at 35 - 60℃; for 3.3h; | 1.3 S3, preparation of intermediate C: vacuum 38% of the caustic soda sucked into the slot, the intermediate A, intermediate B and DMF into the reaction kettle, stirred 0.8h, the temperature was controlled at 35 dropping caustic soda , Dropwise added to complete the temperature was raised to 60 ° C and stirred 2.5h, cooled to room temperature and then added 37.5% hydrochloric acid, stirring was continued at 60 ° C 2.5h, and then extracted with dichloromethane, concentrated, cooled crystallization, suction filtration, drying intermediates C , Wherein the molar ratio of caustic soda, intermediate A, intermediate B, DMF and hydrochloric acid in step S3 is 2: 10: 10: 6: 2; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; | 17.3 Step 3: Ethyl1 0'-formyl-2'-oxo-9'-((tetrahydrofuran-3-yl)methoxv)-2' .7'dihydrospiro[ cyclobutane-1 .6'-pyrido[2. 1-a]isoqu inoline 1-3 '-carboxylate To a solution of ethyl 1 0'-formyl-9'-hydroxy-2'-oxo-2', 7'-dihydrospiro[cyclobutane-1 ,6'-pyrido[2, 1-a]isoquinoline]-3'-carboxylate (1 00 mg, 0.28 mmol)in DMF (4 ml) was added (tetrahydrofuran-3-yl)methyl4 methylbenzenesulfonate (144 mg,0.56 mmol) and K2C03 (116 mg, 0.84 mmol). The mixture was heated at 90 oc overnight,poured into water (30 ml), and extracted with DCM (25 X 2 ml). The combined organiclayers were washed with brine (30 X 4 ml), concentrated, and the residue purified bycolumn chromatography eluting with MeOH in DCM (1/15) to afford ethyl1 0'-formyl-2'-oxo-9'-((tetrahydrofu ran-3-yl)methoxy)-2', 7'-dihydrospiro[ cyclobutane-1 ,6'-pyrido[2, 1-a]isoquinoline]-3'-carboxylate (1 02 mg, 84% yield). LCMS (ESI) m/z: 438.4 (M + 1f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 90 °C 2: diethylamino-sulfur trifluoride / dichloromethane / 0 - 20 °C / Inert atmosphere 3: water; sodium hydroxide / ethanol / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 90 °C 2: diethylamino-sulfur trifluoride / dichloromethane / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethyl 6-(tert-butyl)-10-hydroxy-2-oxo-6,7-dihydro-2H-pyrido[2’,1‘:3,4]pyrazino[1,2-b]indazole-3-carboxylate With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate In N,N-dimethyl-formamide at 70℃; for 3h; | 2.8.1 Step 1: ethyl 6-(tert-butyl)-2-oxo-1 0-((tetrahydro- furan-3-yl)methoxy)-6,7-dihydro-2H-pyrido[2’, 1:3,4]pyrazino[1 ,2-b]indazole-3-carboxylate [2.8a] 10411] To 2.lh (18 mg, 0.047 mmol) was added DMF (Volume: 0.5 mE) and cesium carbonate (53.8 mg, 0.165 mmol). The reaction was stirred at room temperature for 5 minutes then (tetrahydrothran-3-yl)methyl 4-methylbenze- nesulfonate (24.19 mg, 0.094 mmol) was added. The reaction was heated to 70° C. and stirred for 3 hours or until done by ECMS. The reaction was cooled, 0.5 ml of DMF was added, then filtered through a 0.45 nM in line filtet The DMF solution with the desired product 2.8a was used as is for the next step, assume quantitative yield. EC-MS (mlz):466.5 [M+H], 0.79 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With potassium carbonate; potassium iodide In acetone for 8h; Reflux; | 2 Step 2: a solution of compound 5a-5 (2 g, 6.67 mmol), compound 6a-2 (2.56 g, 10 mmol), potassium carbonate(1.84 g, 13.33 mmol), and potassium iodide (1.66 g, 10 mmol) in acetone was refluxed for 8 h. The reaction solutionwas cooled to room temperature, filtered, and the filtrate was concentrated and purified by column chromatography togive compound 6a as a brown solid (600 mg, 23%). MS m/z (ESI): 386.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
154 mg | With potassium carbonate In 1-methyl-pyrrolidin-2-one at 95℃; for 4h; | General procedure for synthesis of compounds 11k-11n, 11v, 11y-11z. 11m. To a solution of compound 11b (120 mg, 0.45 mmol) dissolved in NMP (5 mL) were added K2CO3 (513 mg, 3.71 mmol) and (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (crude product 427 mg, 1.67 mmol). (Tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate was synthesized through a simple and regular sulfonylation on hydroxyl group of (tetrahydrofuran-3-yl)methanol (1.0 eq) with 4-methylbenzenesulfonyl chloride (2.0 eq) using pyridine as base and solvent at RT stirring for 5.5 h. The mixture was stirred at 95 °C for 4 h. Then the mixture was cooled, poured into water and extracted with EtOAc. The organic layer was washed with saturated brine, dried over NaSO4, concentrated under reduced pressure. The residue was purified by silica gel chromatography with petroleum ether/ EtOAc (1/1) to give the target product 11m (154 mg, 97% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile / 4 h / 100 °C 2: Oxone / water; methanol / 2 h / 10 °C 3: Daicel chiralpak OD Prep C18 / ethanol / Resolution of racemate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile / 4 h / 100 °C 2: Oxone / water; methanol / 2 h / 10 °C 3: potassium hydroxide; tert-butyl XPhos; tris-(dibenzylideneacetone)dipalladium(0) / water; 1,4-dioxane / 1 h / 100 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: potassium carbonate / acetonitrile / 4 h / 100 °C 2: Oxone / water; methanol / 2 h / 10 °C 3: potassium hydroxide; tert-butyl XPhos; tris-(dibenzylideneacetone)dipalladium(0) / water; 1,4-dioxane / 1 h / 100 °C / Inert atmosphere 4: caesium carbonate / acetonitrile / 15 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: potassium carbonate / acetonitrile / 4 h / 100 °C 2: Oxone / water; methanol / 2 h / 10 °C 3: potassium hydroxide; tert-butyl XPhos; tris-(dibenzylideneacetone)dipalladium(0) / water; 1,4-dioxane / 1 h / 100 °C / Inert atmosphere 4: caesium carbonate / acetonitrile / 15 h / 80 °C 5: hydrogenchloride / dichloromethane; ethyl acetate / 1 h / 10 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 4 h / 100 °C 2: Oxone / water; methanol / 2 h / 10 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.8% | With potassium carbonate In acetonitrile at 100℃; for 4h; | 29.2 Step 2: 21-3 To a mixture of 21-2 (3.1 g, 12.09 mmol) and 4-bromobenzenethiol (2.52 g, 13.30 mmol) in MeCN (50 mL) was added K2CO3(5.01 g, 36.28 mmol) . The resulting mixture was heated up to 100 and stirred for 4 hr. After that, the reaction mixture was cooled down to 10 and poured into water (100 mL) . The aqueous mixture was extracted with DCM (100 mL × 3) . The combined organic layers were washed with brine (50 mL × 3) , dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column eluted with ethyl acetate in petroleum ether (8%) to afford 21-3 (3.0 g, 90.80%) .1H NMR (400 MHz, CDCl3) δ 7.43-7.36 (m, 2H) , 7.22-7.17 (m, 2H) , 3.87-3.82 (m, 2H) , 3.78-3.71 (m, 1H) , 3.56 (dd, J = 8.7, 5.8 Hz, 1H) , 2.99-2.86 (m, 2H) , 2.51-2.39 (m, 1H) , 2.09-2.01 (m, 1H) , 1.74-1.63 (m, 1H) ppm. |
Tags: 15833-63-3 synthesis path| 15833-63-3 SDS| 15833-63-3 COA| 15833-63-3 purity| 15833-63-3 application| 15833-63-3 NMR| 15833-63-3 COA| 15833-63-3 structure
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Oxetan-3-ylmethyl 4-methylbenzenesulfonate
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
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 |
Sorry,this product has been discontinued.
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