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CAS No. : | 38041-19-9 | MDL No. : | MFCD02179436 |
Formula : | C5H11NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AHVQYHFYQWKUKB-UHFFFAOYSA-N |
M.W : | 101.15 | Pubchem ID : | 419223 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 27.83 |
TPSA : | 35.25 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.14 cm/s |
Log Po/w (iLOGP) : | 1.36 |
Log Po/w (XLOGP3) : | -0.31 |
Log Po/w (WLOGP) : | 0.12 |
Log Po/w (MLOGP) : | -0.16 |
Log Po/w (SILICOS-IT) : | 0.82 |
Consensus Log Po/w : | 0.36 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.27 |
Solubility : | 54.1 mg/ml ; 0.535 mol/l |
Class : | Very soluble |
Log S (Ali) : | 0.03 |
Solubility : | 108.0 mg/ml ; 1.07 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.34 |
Solubility : | 46.0 mg/ml ; 0.455 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.31 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P210-P233-P240-P241-P242-P243-P264-P270-P280-P301+P312+P330-P303+P361+P353-P305+P351+P338+P310-P370+P378-P403+P235-P501 | UN#: | 1993 |
Hazard Statements: | H226-H302-H318 | 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 |
---|---|---|
57% | With hydrogen In methanol at 20℃; for 5 h; | To a stirred solution of compound 2.2 (1.0 g, 8.7 mmol) in methanol (50 mL) was added Raney Ni (10percent), and the resulting mixture was stirred at room temperature under hydrogen for 5 h. The progress of the reaction was monitored by TLC. Upon completion of reaction, the methanol solvent was filtered and concentrated in vacuo to give compound 2.3 (0.5 g, 57percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: With ammonium formate In methanol; water at 20℃; Stage #2: With palladium on activated charcoal In methanol; water at 20℃; |
A mixture of dihydro-2H-pyran-4(3H)-one (2.3 ml, 25 mmol) and methanol (54 ml) wastreated with ammonium formate (15.8 g, 250 mmol) and H20 (6 ml). The resulting mixture wasmaintained at RT with vigorous stirring until it became homogeneous. The mixture was then treatedwith palladium on carbon (2.5 g), and maintained at RT overnight. The mixture was filtered and10 concentrated to remove the volatile organics, then the aqueous later was exhaustively extracted withethyl acetate. The combined organics were dried (MgS04), filtered and concentrated to afford15tetrahydro-2H-pyran-4-amine (2.2 g, 88percent) as an oil: 1H NMR (400 MHz, MeOD-d4) 8 3.89-3.99 (m, 2H), 3.35-3.51 (m, 2 H), 2.81-2.95 (m, 1 H), 1.75- 1.90 (m, 2 H), 1.31- 1.48 (m, 2 H); |
90 %Chromat. | at 20℃; for 2 h; Sonication; Green chemistry | General procedure: Ni-Al alloy (200 mg) and cyclohexanone (35 μL, 0.34 mmol) were suspended in 28–30percent NH4OH (3 mL) and sonicated (Branson 1510MTH ultrasonic bath) for 2 h. After the completion of the reaction, the excess alloy and solid by-products were removed by filtration. The filtrate was extracted with EtOAc (2 × 2 mL). The organic extracts were combined and dried over anhyd Na2SO4. The solvent was removed in vacuo and the crude product was purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.8% | With sodium hypobromide; sodium hydroxide In water at 5 - 50℃; for 3 h; | (2) cooling the 4-formamide tetrahydropyran mixed solution prepared in the step 1 to a temperature of 5 ° C, adding a NaOH solution,After stirring uniformly, NaBrO solution was added dropwise thereto. After the completion of the dropwise addition, the reaction was continued at this temperature for 2 hours, and then the temperature was raised to 50 ° C for 1 hour, then cooled to room temperature, extracted with dichloromethane, and the organic phase was combined. After dichloromethane was removed by pressure distillation, recrystallization was carried out to obtain 4-aminotetrahydropyran.Preferably, the molar volume ratio of tetrahydropyran-4-carboxylic acid to water in the step (1) is 5 mol/L.The concentration of ammonia water in the step (1) is 13 mol/L; the amount of tetrahydropyran-4-carboxylic acid and ammonia in the step (1)The molar volume ratio is 10:1 mol/L.The mass concentration of the NaOH solution in the step (2) is 40percent, the 4-formamide tetrahydropyran mixed solution and the NaOH solutionThe volume-to-volume ratio was 7:1; the mass concentration of the NaBrO solution in the step (2) was 15percent.The molar ratio of tetrahydropyran-4-carboxylic acid to NaBrO was 1:1.5.The obtained 4-aminotetrahydropyran had a purity of 99.2percent and a product yield of 91.8percent. |
73.7% | With sodium hypochlorite In water at 0 - 5℃; for 3 h; Reflux | Three-neck flask equipped with mechanical stirrer, thermometer, dropping funnel, 250ml of water was added to the flask, stirring was added 4-cyano-tetrahydropyran 111.14g (1mole), cooled to 0 ~ 5 ° C, was added at a concentration of 10 minutes 13.8percent sodium hydroxide solution, a total of 290 g (1 mole), temperature controlled at 0 ~ 10 ° C, after each addition incubated for 15 to 20 minutes, all the alkali was added, stirred for 1 to 3 hours, the reaction was complete by gas detecting material, controlling the temperature of 0 ~ 5 ° C, was slowly added to a concentration of 10percent sodium hypochlorite solution 1116.6g (1.5mole), plus Bi, 0 ~ 5 ° C for 1 hour, heated at reflux temperature for 2 hours to complete the reaction intermediate vapor detection, water cooling to 10 ~ 40 ° C, with 500ml dichloromethane and 50ml methanol solvent mixture and extracted 3 times, the combined extracts were recovered by distillation of methylene chloride, methylene chloride was distilled off to make, distillation to give 4-amino-tetrahydropyran 75.3 g, with a purity of 99.1percent, a yield of 73.7percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.2% | With hydrogenchloride; hydrogen In 1,3-dioxane; ethanol | A mixture of the amine (Step A) (13.2 g, 49.4 mmol), 4 N HCl/dioxane (12.5 ML, 49.4 mmol), Pd/C 10percent (1. 1 g), dioxane (30 mL), and ETOH (120 mL) was placed on a Parr Apparatus and hydrogenated at 35 lb pressure of H2 overnight. The reaction mixture was filtered through celite and concentrated to dryness. The concentrate was stirred in DCM. The precipitate was filtered and dried to yield Intermediate 3 (4. 9 G, 72.2percent). 1H NMR (400MHZ, CD30D) 8 3.99 (dd, J=12.1 Hz, 5.1 Hz, 2H), 1.89 (td, J=11. 9 Hz, 2.1 Hz, 2H), 3.38-3. 32 (m, 1H), 1.96-1. 92 (m, 2H), 1.70-1. 59 (m, 2H). |
72.2% | With hydrogenchloride In 1,4-dioxane; ethanol | A mixture of the amine (Step A, Intermediate 3) (13.2 g, 49.4 mmol), 4N HCl/dioxane (12.5 mL, 49.4 mmol), Pd/C 10percent (1.1 g), dioxane (30 mL), and EtOH (120 mL) was placed under par-shaker and shook at 35 Lb pressure overnight. The reaction mixture was filtered through celite and concentrated to dryness. The concentrate was stirred in DCM. The precipitate was filtered and dried to yield Intermediate 3 (4.91g, 72.2percent). 1H NMR (400MHz, CD30D) 5 3.99 (dd, J=12. 1 Hz, 5.1 Hz, 2H), 1.89 (td, J=11. 9 Hz, 2.1 Hz, 2H), 3.38-3. 32 (m, 1H), 1.96-1. 92 (m, 2H), 1.70-1. 59 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With hydrogen In ethanol at 75℃; for 6 h; | To a flask having an inner volume of 30 ml, made of glass and equipped with a stirring device, a thermometer and a reflux condenser were charged 260 mg (2.08 mmol) of 4-hydrazinotetrahydropyran with a purity of 93percent synthesised in the same manner as in the above-mentioned (1), 92 mg of developed Raney nickel and 2.5 ml of ethanol, and the mixture was reacted at 75°C for 6 hours under hydrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered, and the filtrate was analyzed (internal standard method) by gas chromatography, 136 mg (Reaction yield: 65percent) of 4-aminotetrahydropyran was found to be formed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With ammonium acetate; sodium cyanoborohydride In methanol | EXAMPLE 21 N-4-Tetrahydropyranyl-4-(1H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)-N-{3-[6-(3-pyrrolidin-1-yl-1-{4-tolyl}-prop-1E-enyl)-pyridin-2-yl]-prop-2E-enyl}-benzamide STR32 (a) 4-Amino-tetrahydropyran A mixture of tetrahydropyranone (1.0 g, 10.0 mmol), ammonium acetate (7.69 g, 100.0 mmol), 3 Å molecular sieve powder (2.5 g) and sodium cyanoborohydride (1.25 g, 20.0 mmol) suspended in dry methanol (50 ml) under a blanket of argon was refluxed for 2 hours and allowed to cool to room temperature. The suspension was filtered and concentrated under reduced pressure. The residue was partitioned between DCM and water. The organic layer was extracted with 1M HCl (*2). The combined extracts were basified with 5M sodium hydroxide solution and extracted with DCM. The combined organics were dried over magnesium sulphate, filtered and concentrated under reduced pressure to yield 4-amino-tetrahydropyran as a colourless oil (120 mg, 12percent). 1 H-NMR; δ (CDCl3), 3.95-3.86 (2H, m), 3.38-3.27 (2H, m), 2.85-2.73 (1H, m), 1.79-1.67 (2H, m), 1.40-1.24 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.8% | With sodium hypobromide; sodium hydroxide; In water; at 5 - 50℃; for 3h; | (2) cooling the 4-formamide tetrahydropyran mixed solution prepared in the step 1 to a temperature of 5 ° C, adding a NaOH solution,After stirring uniformly, NaBrO solution was added dropwise thereto. After the completion of the dropwise addition, the reaction was continued at this temperature for 2 hours, and then the temperature was raised to 50 ° C for 1 hour, then cooled to room temperature, extracted with dichloromethane, and the organic phase was combined. After dichloromethane was removed by pressure distillation, recrystallization was carried out to obtain 4-aminotetrahydropyran.Preferably, the molar volume ratio of tetrahydropyran-4-carboxylic acid to water in the step (1) is 5 mol/L.The concentration of ammonia water in the step (1) is 13 mol/L; the amount of tetrahydropyran-4-carboxylic acid and ammonia in the step (1)The molar volume ratio is 10:1 mol/L.The mass concentration of the NaOH solution in the step (2) is 40percent, the 4-formamide tetrahydropyran mixed solution and the NaOH solutionThe volume-to-volume ratio was 7:1; the mass concentration of the NaBrO solution in the step (2) was 15percent.The molar ratio of tetrahydropyran-4-carboxylic acid to NaBrO was 1:1.5.The obtained 4-aminotetrahydropyran had a purity of 99.2percent and a product yield of 91.8percent. |
73.7% | With sodium hypochlorite; In water; at 0 - 5℃; for 3h;Reflux; | Three-neck flask equipped with mechanical stirrer, thermometer, dropping funnel, 250ml of water was added to the flask, stirring was added 4-cyano-tetrahydropyran 111.14g (1mole), cooled to 0 ~ 5 ° C, was added at a concentration of 10 minutes 13.8percent sodium hydroxide solution, a total of 290 g (1 mole), temperature controlled at 0 ~ 10 ° C, after each addition incubated for 15 to 20 minutes, all the alkali was added, stirred for 1 to 3 hours, the reaction was complete by gas detecting material, controlling the temperature of 0 ~ 5 ° C, was slowly added to a concentration of 10percent sodium hypochlorite solution 1116.6g (1.5mole), plus Bi, 0 ~ 5 ° C for 1 hour, heated at reflux temperature for 2 hours to complete the reaction intermediate vapor detection, water cooling to 10 ~ 40 ° C, with 500ml dichloromethane and 50ml methanol solvent mixture and extracted 3 times, the combined extracts were recovered by distillation of methylene chloride, methylene chloride was distilled off to make, distillation to give 4-amino-tetrahydropyran 75.3 g, with a purity of 99.1percent, a yield of 73.7percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With hydrogen;nickel; In methanol; at 20℃; for 5h; | To a stirred solution of compound 2.2 (1.0 g, 8.7 mmol) in methanol (50 mL) was added Raney Ni (10%), and the resulting mixture was stirred at room temperature under hydrogen for 5 h. The progress of the reaction was monitored by TLC. Upon completion of reaction, the methanol solvent was filtered and concentrated in vacuo to give compound 2.3 (0.5 g, 57%). |
palladium; In ethanol; | EXAMPLE XII 4-Amino-tetrahydropyran 4.2 g of 4-tetrahydropyranone oxime are dissolved in 100 ml of ethanol and, after addition of 0.5 g of palladium-on-charcoal (10%), are hydrogenated in a Parr apparatus at 90 C. under a hydrogen pressure of 5 bar for 2.5 hours. After cooling, the solvent is distilled off in a rotary evaporator and the residue is used further without further purification. Yield: 0.7 g (19% of theory) of a colourless oil, Rf value: 0.45 (silica gel; methylene chloride/ethyl acetate/methanol=10:4:2) | |
palladium; In ethanol; hydrogen; | EXAMPLE XXIV 4-Aminotetrahydropyran 4.2 g of 4-tetrahydropyranone oxime are dissolved in 100 ml of ethanol and, after addition of 0.5 g of palladium on carbon (10%), hydrogenated in a Parr apparatus at 90 C. under a pressure of 5 bar of hydrogen for 2.5 hours. After cooling, the solvent is distilled off in a rotary evaporator, and the residue is used further without further purification. Yield: 0.7 g (19% of theory) of a colourless oil,; Rf: 0.45 (silica gel; methylene chloride/ethyl acetate/methanol=10:4:2) |
With hydrogen;palladium; In ethanol; | EXAMPLE XVII 4-Aminotetrahydropyran 4.2 g of 4-tetrahydropyranone oxime are dissolved in 100 ml of ethanol and, after addition of 0.5 g of palladium on carbon (10%), hydrogenated under a pressure of 5 bar of hydrogen in a Parr apparatus at 90 C. for 2.5 hours. After cooling, the solvent is distilled off in a rotary evaporator, and the residue is used further without further purification. Yield: 0.7 g (19% of theory) of a colourless oil, Rf: 0.45 (silica gel; methylene chloride/ethyl acetate/methanol=10:4:2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 90℃; | ||
With potassium carbonate In N,N-dimethyl-formamide at 115℃; | ||
With potassium carbonate In N,N-dimethyl-formamide at 115℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; butan-1-ol;Product distribution / selectivity; | To a flask having an inner volume of 100 ml, made of glass and equipped with a stirring device, a thermometer and a reflux condenser were charged 30.0 g (158.7 mmol) of 4-hydrazinotetrahydropyran hydrochloride with a purity of 99percent and synthesized in the same manner as in Example 2(1), 3.0 g (0.70 mmol calculated as palladium atom) of 5percent by weight palladium/carbon (50percent wet product) and 150 ml of ethanol, and the mixture was reacted at 75°C for 24 hours under hydrogen atmosphere (0.1 MPa. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. When the concentrate was analyzed (internal standard method) by gas chromatography, 15.9 g (Reaction yield: 72percent) of 4-aminotetrahydropyran was found to be formed. Then, 200 ml of n-butyl alcohol and 17.4 g (166.8 mmol) of 12 mol/l hydrochloric acid were added to the concentrate, and the mixture was concentrated under reduced pressure to obtain 14.3 g (Isolation yield: 65percent) of 4-aminotetrahydropyran hydrochloride with a purity of 98percent (areal percentage by gas chromatography) as white crystals. Physical properties of the 4-aminotetrahydropyran hydrochloride were the same as those in Example 2(2).; To a flask having an inner volume of 100 ml, made of glass and equipped with a stirring device, a thermometer and a reflux condenser were charged 1.0 g (5.55 mmol) of 4-hydrazinotetrahydropyran hydrochloride with a purity of 99percent and synthesized in the same manner as in Example 2(1), 6.2 ml of ethanol, 1.2 ml (1.20 mmol) of 1 mol/l aqueous sodium hydroxide solution and 1.5 g (10 mmol) of copper (I) oxide, and the mixture was reacted at 65°C for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. When the concentrate was analyzed (internal standard method) by gas chromatography, 0.47 g (Reaction yield: 50percent) of 4-aminotetrahydropyran was found to be formed. Then, 5 ml of n-butyl alcohol and 10 ml (12.0 mmol) of 12 mol/l hydrochloric acid were added to the concentrate, and the resulting mixture was concentrated under reduced pressure to obtain 0.42 g (Isolation yield: 45percent) of 4-aminotetrahydropyran hydrochloride with a purity of 98percent (areal percentage by gas chromatography) as white crystals. Physical properties of the 4-aminotetrahydropyran hydrochloride were the same as those in Example 2(2). | |
With hydrogenchloride; In water;Industry scale;Product distribution / selectivity; | To a flask having an inner volume of 20 L, made of glass and equipped with a stirring device, a thermometer, a dropping funnel and a reflux condenser were charged 5873 g (115 mol) of 98percent aqueous hydrazine solution and 2072 ml of ethanol, and the mixture was heated to 75°C with stirring. Then, a solution in which 2136 g (11.5 mol) of tetrahydropyranyl-4-methanesulfonate with a purity of 70percent had been dissolved in 2072 ml of ethanol was gradually added dropwise to the mixture, and the mixture was reacted at the same temperature for 4 hours with stirring. After completion of the reaction, the mixture was cooled to room temperature to obtain a reaction mixture comprising 4-hydrazinotetrahydropyran as a main product. Then, to a flask having an inner volume of 20 L, made of glass and equipped with a stirring device, a thermometer, a dropping funnel and a reflux condenser were charged 414.4 g (4.6 mol calculated as nickel atom) of 65percent by weight developed Raney nickel and 2072 ml of water, and the mixture was heated up to 60°C with stirring. Then, the reaction mixture was gradually added dropwise, and the resulting mixture was reacted at 80°C for 2 hours with stirring. After completion of the reaction, the reaction mixture was cooled up to 40°C, Raney nickel was filtered off, and the filtrate was concentrated under reduced pressure to obtain 818.0 g of the reaction solution containing 4-aminotetrahydropyran as a main product. To a flask having an inner volume of 20 L, made of glass and equipped with a stirring device, a thermometer, a dropping funnel, a reflux condenser and a distillation device under reduced pressure were charged the above reaction solution, 2072 ml (10.9 mol) of tetraethylenepentamine and 4100 ml of n-butyl alcohol, and the mixture was stirred at 80°C for 2 hours under reduced pressure. Then, 4-aminotetrahydropyran and n-butyl alcohol were removed by azeotropic distillation under reduced pressure. Thereafter, 4100 ml of n-butyl alcohol was added again, 4-aminotetrahydropyran and n-butyl alcohol were removed by azeotropic distillation under reduced pressure. This operation was repeated to three times to obtain 15000 ml of a distilled solution in total. To the distilled solution was added 575 ml (6.90 mol) of conc. hydrochloric acid, and then, the mixture was concentrated under reduced pressure. To the concentrate was again added 8200 ml of n-butyl alcohol, and water and n-butyl alcohol were removed by azeotropic distillation under reduced pressure. Then, 7460 ml of n-butyl alcohol and 3730 ml of ethanol were added to the residue, and the resulting mixture was once heated up to 115°C and stirred, then, it was gradually cooled to -5°C and stirred for 30 minutes. After the filtration, the filtrate was washed with cooled toluene and dried to obtain 788.9 g (Isolation yield based on tetrahydropyranyl-4-methanesulfonate: 50percent) of 4-aminotetrahydropyran hydrochloride with a purity of 99percent (internal standard method by gas chromatography) as white needle-like crystals. Physical properties of the 4-aminotetrahydropyran hydrochloride were the same as those in Example 2(2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With triethylamine In tetrahydrofuran at 20℃; for 16.0833h; | 30 Tetrahydro-2H-pyran-4-amine (5.0 g, 49.4 mmol) and triethylamine (8.3 ml, 59.3 mmol) were stirred in TΗF (200 ml) under an inert atmosphere. 4-Iodobenzoyl chloride (13.2 g, 49.4 mmol) was added in portions over 5 mins. Stirring was continued for a further 16 hours, then the solvent was removed in vacuo. The resulting solid was sonicated in IM NaOH solution (100 ml) for 10 mins then isolated by filtration and washed with fresh water (3 x 100 ml). The solid obtained was dried in vacuo at 60°C for 24 hours (10.3 g, 57%). NMR 8.32 (d, 1Η), 7.83 (d, 2Η), 7.62 (d, 2H), 4.05-3.90 (m, IH), 3.86 (d, 2H), 3.36 (app t, 2H), 1.73 (d, 2H), 1.64-1.46 (m, 2H); m/z 332. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; | Boc2O was added in one portion at r.t. to a solution of (4-aminomethyl-phenyl)-methanol Compound 3a (21.2 mmol, 2.9 g) in CH2C12 (100 mL). The resulting solution wasstirred for 48h, then washed with a 10percent citric acid solution (50 mL) followed by brine. Theorganic layer was separated, then dried over Na2SC>4 and filtered. The solvent was removed invacua to obtain (4-hydroxymethyl-benzyl)-carbamic acid tert-butyl ester Compound 3b as awhite solid (5.2 g, 99percent yield), which was used in the next step without further purification.MnO2 (9.6 g) was added to a solution of Compound 3b (21.2 mmol, 5.2 g) inchloroform (60 mL), forming a black suspension that was stirred at r.t. overnight then filteredthrough a pad of celite. The solvent was evaporated in vacua to obtain (4-forinyl-benzyl)-carbamic acid tert-butyl ester Compound 3c as a white solid (4.3 g, 87percent yield), which was usedin the next step without purification.; NaB(OAc)3H (2.8 mmol, 0.58 g) was added to a mixture of Compound 3c (2.6 mmol,0.6 g) and tetrahydro-pyran-4-ylamine Compound 3d (2.6 mmol, 0.26 g) in CH2C12 (25 mL)and the resulting suspension was stirred at r.t. An aliquot of the reaction mixture showed theformation of product (MS m/e 321; 100percent). An aqueous solution of formaldehyde (37percentsolution, 8.6 mmol, 0.7 mL) was added to the reaction mixture, followed by NaB(OAc)3H (2.8mmol, 0.58 g) added in one portion under ice cooling. The reaction mixture was stirred at r.t.for about 2h, then made basic with a 2N NaOH solution and extracted with CH2C12. Theorganic layer was washed with brine, then separated and dried over Na2SO4. The drying agentwas filtered and the solvent was removed in vacua to yield (4-[methyl-(tetrahydro-pyran-4-yl)-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester Compound 3e as a pale yellow oil.MS m/e 235 (M+H, 100percent). The product was purified by column chromatography (4:1CH2Cl2:MeOH) to yield a colorless oil (0.52 g, 59percent yield).; Compound 3e was dissolved in CH2Cl2, then HC1 in dioxane was added and themixture was stirred at r.t. for 12 hrs. The solvent was removed and the gummy residue wasmade basic with 2N NaOH and extracted with EtOAc. The organic layer was washed withbrine, then separated and dried over Na2SO4. The drying agent was filtered and the solvent wasremoved in vacua to obtain (4-aminomethyl-benzyl)-methyl-(tetrahydro-pyran-4-yl)-amineCompound 3f as a pale yellow oil (0.3 g, 83percent yield). MS m/e 235 (M+H, 100percent).; A solution of 3-(3-trifluoromethyl-phenyl)-acryloyl chloride Compound 3g (0.3 mrnol,0.07 g) in THF (2 mL) was added dropwise to a solution of Compound 3f (0.2 mmol, 0.05 g)and Et3N (0.8 mmol, 0.14 mL) in THF (10 mL) at 0°C. The resulting suspension was allowedto warm to r.t. overnight. The reaction mixture was made basic with a 2N NaOH solution andextracted with EtOAc (25 mL). The aqueous layer was extracted with EtOAc (2X10 mL) andthe organic layers were washed with brine, then dried over Na2SO4 and filtered. The solventwas removed in vacua to yield a yellow solid (with methane) as the product. The crude productwas purified by preparative TLC (9:1 EtOAc-.MeOH, Rf = 0.2) to yield N-(4-[methyl-(tetrahydro-pyran-4-yi)-amino]-methyl}-benzyi)-3-(3-trifluoromethyl-phenyl)-acrylamideCompound 3h (0.06 g, 49percent yield). MS m/e 433 (M+H, 100percent).; Mel (0.08 mL, 1.28 mmol) was added dropwise to a solution of Compound 3h (0.07mmol, 0.03 g) in a mixture of acetone:acetonitrile (2 mL). The resulting solution was stirred atr.t. for 24h to provide a residue. The residue was washed with ether (2x 1 mL) and dried undera high vacuum to provide Compound 64 (0.04 g, 93percent yield) as an iodide salt. MS m/e 584(M+H, 100percent). | |
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; | NaB(OAc)3H (2.8 mmol, 0.58 g) was added to a mixture of Compound 3c (2.6 mmol, 0.6 g) and tetrahydro-pyran-4-ylamine Compound 3d (2.6 mmol, 0.26 g) in CH2Cl2 (25 mL) and the resulting suspension was stirred at r.t. An aliquot of the reaction mixture showed the formation of product (MS m/e 321; 100percent). An aqueous solution of formaldehyde (37percent solution, 8.6 mmol, 0.7 mL) was added to the reaction mixture, followed by NaB(OAc)3H (2.8 mmol, 0.58 g) added in one portion under ice cooling. The reaction mixture was stirred at r.t. for about 2 h, then made basic with a 2N NaOH solution and extracted with CH2Cl2. The organic layer was washed with brine, then separated and dried over Na2SO4. The drying agent was filtered and the solvent was removed in vacuo to yield (4-[methyl-(tetrahydro-pyran-4-yl)-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester Compound 3e as a pale yellow oil. MS m/e 235 (M+H, 100percent). The product was purified by column chromatography (4:1 CH2Cl2:MeOH) to yield a colorless oil (0.52 g, 59percent yield). |
Yield | Reaction Conditions | Operation in experiment |
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[0380] Tetrahydro-2H-pyran-4-amine (90 mg, 0.9 mmol) was added to a solution of formaldehyde (37% solution in water, 0.09I mL, 1.13 mmol) and acetic acid (0.162 mL) in ACN (0.8 mL). After stirring for 5 minutes, Na(CN)BH3 (60 mg, 1.13 mmol) was added in one portion at RT. After 1 hour, excess Cs2COa was added to the reaction until made alkaline. After stirring for 15 minutes, the reaction was filtered to remove solids and the solvent evaporated under reduced pressure. The crude product, N- methyltetrahydro-2H-pyran-4-amine, was used for the following displacement without further purification. LC/MS (m/z): 116.1 (MH+), Rt 0.34 minutes. |
Yield | Reaction Conditions | Operation in experiment |
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32% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 150℃; for 0.333333h; | Example 8a Preparation of 4-Fluoro-2-(tetrahydro-pyran-4-ylamino)-benzonitrile A mixture of <strong>[3939-09-1]2,4-difluorobenzonitrile</strong> (0.420 g, 3.0 mmol), 4-aminotetrahydropyran (0.306 g, 3.0 mmol) and DIPEA (0.523 mL, 3.0 mmol) in DMSO (5.0 mL) is stirred at 150 C. (preheated oil-bath) for 20 min. After cooling to room temperature, the resulting mixture is poured into saturated aqueous NH4Cl solution and extracted with ethyl acetate (3*20 mL). The combined organic layer is washed with brine (3*15 mL) and dried over Na2SO4, filtered and concentrated at reduced pressure to dryness. The residue obtained is purified by column chromatography (silica gel, 40:60 ethyl acetate/hexane) to afford 4-Fluoro-2-(tetrahydro-pyran-4-ylamino)-benzonitrile (0.214 g, 32%) as a pale yellow solid: ESI MS m/z 221 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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Intermediate 522-Chloro-N-(5-methyl-lH-pyrazol-3-yl)-5-nitro-lambda/'-(tetrahvdro-2H-pyran-4-yl)pyrimidine-4,6- diamine; To a solution of 2,4,6-trichloro-5-nitro pyrimidine (Intermediate 37, Ig, 4.4 mmol) in EtOH at - 50ºC were added 5 -methyl- lH-pyrazo 1-3 -amine (255 mg) and DIPEA (1.6 ml) drop-wise. The resulting mixture was stirred at this temperature for 5 minutes whereupon 4-amino pyran (300 mg) was added. The resulting mixture was allowed to warm to ambient temperature for 4 hours. The mixture was diluted with eta2O and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, saturated NaHCO3 (aq) solution, dried and evaporation of the volatiles under reduced pressure gave a colored residue. Purification by Gilson (MeCN/H20, 5%^95%, 15 minutes) gave the title compound (120 mg). LCMS: 354 [M+l]. |
Yield | Reaction Conditions | Operation in experiment |
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46% | In ethanol; water; for 16h;Heating / reflux; | Intermediate 5: 2,6-dioxo-5-((tetrahydro-2H-pyran-4-ylamino)methyl)- 1 ,2,3 ,6- tetrahydropyrimidine-4-carboxylic acid; To a solution of <strong>[65-86-1]orotic acid</strong> monohydrate (20.0 g, 0.11 mol) and formaldehyde (51.3 mL, 0.69 mol, 37% in water) in EtOH (1 L) was slowly added tetrahydro-2H-pyran-4-amine (Intermediate 4) (0.69 mol). The resulting solution was refluxed for 16 h. The reaction mixture was cooled to 0 0C and filtered to afford the title compound as a solid (14.4 g, 46%), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-J6) delta ppm 1.44- 1.58 (m, 2H), 1.89 (d, J= 10.7 Hz, 2H), 3.16-3.32 (m, 4H), 3.87 (dd, J= 11.6, 2.5 Hz, IH), 3.94 (s, 2H), 9.61 (br s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In chloroform; at 20℃; for 24.0833h; | To a stirred solution of tetrahydro-2H-pyran-4-amine (0.84g, 8.03mmol) and triethylamine (1.17ml_) in chloroform (25ml_) was added <strong>[55854-46-1]5-bromo-2-thiophenesulfonyl chloride</strong> (2.Og, 7.65mmol) over 5 min and stirred at ambient temperature for 24 h. The reaction was washed sequentially with water (5OmL), saturated aqueous sodium carbonate (5OmL), saturated aqueous citric acid (5OmL), dried (hydrophobic frit) and concentrated in vacuo, azeotroping with diethyl ether furnished the title compound as a white solid (2.245g). LCMS MH+ = 326/328, rt = 2.78min |
Yield | Reaction Conditions | Operation in experiment |
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With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1-methyl-pyrrolidin-2-one; at 40 - 110℃; | A solution of <strong>[139102-34-4]4-bromo-2-methoxybenzoic acid methyl ester</strong> (0.1 mol) and tetrahydro- 2H"-pyran-4-amine (0.3 mol) in 1 -methyl-2-pyrrolidinone (800 ml) was stirred at 400C. Cs2CO3 (0.2 mol) was added. The reaction mixture was stirred for 5 minutes. Pd2(dba)3 (0.002 mol) and BINAP (0.003 mol) were added. The reaction solution was degassed by applying alternating nitrogen atmosphere and vacuum. The reaction mixture was stirred overnight at 110C. The 1 -methyl-2-pyrrolidinone solvent was evaporated. The residue was purified by high-performance liquid chromatography. The product fractions were collected and the solvent was evaporated, yielding 13 g of intermediate (29). |
Yield | Reaction Conditions | Operation in experiment |
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1% | Stage #1: 4-aminotetrahydropyran; 3-(imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium triflate In acetonitrile at 20℃; Stage #2: (6-Amino-quinolin-2-yl)-(R)-indan-1-yl-amine In acetonitrile at 80℃; | 80 N-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}-N'-(tetrahydro-2H-pyran-4-yl)sulfamide Example 80 N-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}-N'-(tetrahydro-2H-pyran-4-yl)sulfamide 3-(1H-midazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate (0.394 g, 1.10 mmol) and 4-amino-tetrahydropyran (0.10 g, 1.0 mmol) were dissolved in acetonitrile (5 mL) and stirred for 30 min at ambient temperature. Then (R)-N2-indan-1-yl-quinoline-2,6-diamine (0.054 g, 0.20 mmol) were added and the reaction mixture was stirred at 80° C. for 16 h. The solvent was removed and the residue subjected twice to column chromatography (silica gel, first chromatography heptane/ethyl acetate 4:1/1:1/2:1; second chromatography heptane/ethyl acetate 1:1) to yield the title compound (5 mg, 1%) as a yellow solid; MS: m/e=439.7 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
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After dissolving <strong>[3069-67-8]5-methyl-3H-[1,3,4]oxadiazol-2-one</strong> (CAS 3069-67-8) (500 mg) in methanol (5 ml), 4-aminotetrahydropyran (1.01 g) was added and the mixture was heated to reflux for 15 hours. The reaction mixture was concentrated under reduced pressure, and then a 1N aqueous solution of sodium hydroxide (5.5 ml) was added to the residue and the mixture Was stirred at 100 C. for 2 hours. After then adding 5N hydrochloric acid (1.1 ml) to the reaction mixture, it was stirred at room temperature for 3 hours. The precipitate was collected by filtration and washed with water and ethyl acetate in that order to obtain the title compound (400 mg).1H-NMR (400 MHz, DMSO-d6); delta 1.55-1.62 (m, 2H), 2.17 (s, 3H), 2.22-2.38 (m, 2H), 3.28-3.38 (m, 1H), 3.88-3.95 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile at 0 - 20℃; for 2.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 1.5h; | 146.A Step A(5-bromo-2-nitroph 2H-pyran-4-ylamine[00358] An orange mixture of 4-bromo-2-fluoro-1 -nitrobenzene (2 g, 9.09 mmol), tetrahydro-2H-pyran-4-amine (0.920 g, 9.09 mmol) and K2C03 (2.51 g, 18.18 mmol) in DMF (20 mL) was heated at 90 °C for 90 min. The resulting mixture was allowed to cool to room temperature, diluted with EtOAc (100 mL) and washed with a 5% aq. LiCI solution (3x100 mL). The organic layer was concentrated onto Celite and purified by column chromatography (silica gel, 0-40% EtOAc/hexane) obtain (5-bromo-2-nitrophenyl)tetrahydro-2H-pyran-4-ylamine (2.68 g, 8.90 mmol, 98 % yield) as a yellow solid: H NMR (400 MHz, DMSO-d6) δ ppm 1.45 - 1.67 (m, 2 H) 1.91 (dd, J=12.51 , 1.95 Hz, 2 H) 3.49 (td, J=11.43, 2.05 Hz, 2 H) 3.77 - 4.03 (m, 3 H) 6.84 (dd, J=9.09, 1.95 Hz, 1 H) 7.42 (d, J=1.86 Hz, 1 H) 7.85 - 8.06 (m, 2 H); ES LC-MS m/z =301.4 (Br79, M+H)+; ES LC-MS m/z =303.4 (Br81, M+H)+. |
92% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; | |
92% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; |
92% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; | |
With potassium carbonate | ||
With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 16h; Sealed tube; | 1 Step 1: N-(5-bromo-2-nitrophenyl)tetrahydro-2H-pyran-4-amine To a solution of 4-bromo-2-fluoro- 1 -nitrobenzene (1.1 g, 4.95 mmol) and tetrahydro-2H-pyran-4-amine (500 mg, 4.95 mmol) in DMF (6 mL) was added K2C03 (1.37 g, 9.9 mmol) and the mixture stirred in sealed tube at 85°C for 16h. After cooling, water (100 mL) was added to the mixture and extracted with DCM (3x50 mL). The combined organic layers were washed with water (2x50 mL), brine (50 mL) and dried over anhydrous Na2S04 then filtered and concentrated to yield the title compound which was directly used for next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100℃; for 2h; | Example 93; Lambda/-Hydroxy-2-(4-(pyridin-3-ylethynyl)phenyl)-6-(tetrahydro-2H-pyran-4- ylamino)isonicotinamide; A. 2-Chloro-6-(tetrahydro-pyran-4-ylamino)-isonicotinic acid methyl ester; To a stirred solution of methyl 2,6-dichloropyridine-4-carboxylate (Example 81, step A) (0.700 g, 3.41 mmol) in JV-methylpyrrolidone (10 mL) was added A- aminotetrahydro-2H-pyran (0.517 g, 5.12 mmol) and diisopropylethylamine (0.880 mL, 5.12 mmol). The reaction mixture was heated at 100 0C for 2 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to afford the crude product. The crude product was purified by column chromatography (Silica gel, 100-200 mesh) using 30% ethyl acetate in pet ether as the mobile phase to give 2-chloro-6-(tetrahydro-pyran-4-ylamino)-isonicotinic acid methyl ester (0.300 g, 32% ) as a white solid. LC-MS: [M+H] + 271.0.1H NMR (400 MHz, DMSO-d6) delta: ppm 7.98 (s, IH), 7.40 (d, IH), 6.99 (s, IH), 6.80 (s, IH), 3.80 (m, 5H), 3.40 (t, 2H), 1.80 (m, 2H), 1.40 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃; | 0.68 g (II) are placed in 6 ml dioxane, then 1.72 ml diisopropylethylamine and then 0.6 g 4-aminotetrahydropyran are added. The reaction mixture is heated to 130 C. until no further reaction takes place, then cooled and evaporated down. The product is treated with water in the ultrasound bath and the solid is suction filtered and dried. 0.66 g (III-3) are obtained. Analytical HPLC-MS (method A): RT=1.08 min. | |
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃; | Example 6 6.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine (III-6) 0.68 g (II) are placed in 6 ml dioxane, then first 1.72 ml diisopropylethylamine, then 0.6 g 4-aminotetrahydropyran are added. The reaction mixture is heated to 130 C., until there is no further reaction, and cooled, then evaporated down. The product is treated with water in the ultrasound bath, then suction filtered and dried. 0.66 g (III-6) are obtained as a solid. Analytical HPLC-MS (method C): RT=1.08 min. | |
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃; | 1.5.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine (III-4) 0.68 g (II) are placed in 6 ml dioxane, then 1.72 ml diisopropylethylamine are added followed by 0.6 g of 4-aminotetrahydropyran. The reaction mixture is heated at 130 C until no further reaction takes place, and after cooling, evaporated down. The product is treated with water in the ultrasound bath, the solid is suction filtered and dried. 0.66 g (III-4) are obtained. Analytical HPLC-MS (method B): RT=1.08 min. |
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃; | 6. SYNTHESIS OF [2-(5-BENZOXAZOL-2-YL-2,5-DIAZABICYCLO[2,2,1]HEPT-2-YL)-5-OXO-6,7-DIHYDRO-5H-5lambda4-THIENO[3,2-D]PYRIMIDIN-4-YL]-(TETRAHYDROPYRAN-4-YL)-AMINEExample 296.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine (III-5)0.68 g (II) are placed in 6 ml dioxane, then 1.72 ml diisopropylethylamine followed by 0.6 g 4-aminotetrahydropyran are added. The reaction mixture is heated at 130 C. until there is no further reaction and after cooling evaporated down. The product is treated with water in the ultrasound bath, suction filtered and dried. 0.66 g (III-5) are obtained as a solid.Analytical HPLC-MS (method A): RT=1.08 min. | |
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; water; | 4.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine (III-3) 0.68 g (II) are placed in 6 ml dioxane, then 1.72 ml diisopropylethylamine are added followed by 0.6 g 4-aminotetrahydropyran. The reaction mixture is heated to 130 C. until there is no further reaction, then cooled and evaporated down. The product is treated with water in the ultrasound bath and the solid is suction filtered and dried. 0.66 g (III-3) are obtained. Analytical HPLC-MS (method A): RT=1.08 min. | |
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; water; | 6.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine (III-6) 0.68 g (II) are placed in 6 ml dioxane, then first 1.72 ml diisopropylethylamine are added, followed by 0.6 g of 4-aminotetrahydropyran. The reaction mixture is heated to 130 C. until there is no further reaction then cooled and evaporated down. The product is treated with water in the ultrasound bath, then suction filtered and dried. 0.66 g (III-6) are obtained in the form of a solid. Analytical HPLC-MS (method C): RT=1.08 min. | |
0.66 g | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃; | 4.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine (III-3) 0.68 g (II) are placed in 6 ml dioxane, then 1.72 ml diisopropylethylamine followed by 0.6 g 4-aminotetrahydropyran are added. The reaction mixture is heated to 130 C. until there is no further reaction and after cooling evaporated down. The product is treated with water in the ultrasound bath and the solid is suction filtered and dried. 0.66 g (III-3) are obtained. Analytical HPLC-MS (method A): RT=1.08 min. |
0.66 g | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃; | 6.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine (III-6) 0.68 g (II) are placed in 6 ml dioxane, first 1.72 ml diisopropylethylamine, then 0.6 g 4-aminotetrahydropyran are added. The reaction mixture is heated to 130 C. until there is no further reaction and after cooling it is evaporated down. The product is treated with water in the ultrasound bath, then suction filtered and dried. 0.66 g (III-6) are obtained as a solid. Analytical HPLC-MS (method C): RT=1.08 min. |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 1h; | DIPEA (33.6 mL, 193 mmol) and tetrahydropyran-4-amine ( 11.7 g, 116 mmol) was added to a suspension of <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> (20.0 g, 96.6 mmol) in DMF (50 mL). The mixture was stirred at 100 C for 1 hour before it cooled to room temperature and poured into water (600 mL). The suspension was then stirred at room temperature for 10 minutes. The precipitate was filtered off, washed twice with water (2 x 100 mL) and tert-butyl methyl ether (2 x 20 mL). The solid material was dried under reduced pressure, before it was re-dissolved in a warm toluene: DCM (2 : 1) solution (300 mL). The mixture was concentrated to approximately 100 mL and left to stand for 1 hour at room temperature. The formed precipitate was filtered off, washed with toluene (20 mL) and dried under reduced pressure. The title compound was obtained as off-white solid material.1H NMR (DMSO-d6) delta: 7.14 (d, J = 7.8 Hz, 1H), 4.21 - 3.99 (m, 1H), 3.95 - 3.77 (m, 2H), 3.46 - 3.33 (m, 4H), 3.14 (td, J = 8.2, 1.1 Hz, 2H), 1.81 - 1.68 (m, 2H), 1.67 - 1.48 (m, 2H). | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 120℃; for 2h;Inert atmosphere; Sealed tube; | DIPEA (62.31 g, 483 mmol) was added at room temperature to a stirred solution of <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> (50.0 g, 242 mmol) and tetrahydropyran-4-amine (29.3 g, 290 mmol) in DMF (150 mL). The mixture was then heated for 2 hours under a N2 atmosphere in a sealed tube at 120C. The reaction mass allowed to cool to room temperature and poured into ice cold water. The resulting solid was filtered off and washed with water, diethyl ether and a toluene/DCM mixture (2 : 1 ratio). The solid was dried under reduced pressure to afford the pure title compound as a solid. *H NMR (400 MHz DMSO-d6) : d (ppm) 7.20-7.13 (m, 1H), 4.16 - 3.95 (m, 1H), 3.90-3.84 (m, 2H), 3.42 - 3.32 (m, 4H), 3.20 - 3.07 (m, 2H), 1.81 - 1.68 (m, 2H), 1.62-1.56 (m, 2H); LCMS (ES): m/z 272 [M + H]?; 97.6%; RT = 1.8 min; (AQUITY UPLC BEH C18 column, 0.1% FORMIC ACID in water with MeCN). | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere; Sealed tube; | DIPEA (62.31 g, 483 mmol) was added at room temperature to a stirred solution of <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> (50.0 g, 242 mmol) and (0173) tetrahydropyran-4-amine (29.3 g, 290 mmol) in DMF (150 mL). The mixture was then heated for 2 hours under a N2 atmosphere in a sealed tube at 120C. The reaction mass allowed to cool to room temperature and poured into ice cold water. The resulting solid was filtered off and washed with water, diethyl ether and a toluene/DCM mixture (2 : 1 ratio). The solid was dried under reduced pressure to afford the pure title compound as a solid. *H NMR (DMSO-d6, 400 MHz) : d (ppm) 7.20-7.13 (m, 1H), 4.16 - 3.95 (m, 1H), 3.90-3.84 (m, 2H), 3.42 - 3.32 (m, 4H), 3.20 - 3.07 (m, 2H), 1.81 - 1.68 (m, 2H), 1.62-1.56 (m, 2H); LCMS (ESI) : m/z 272 [M + H]?; 97.6%; RT = 1.8 min; (AQUITY UPLC BEH C18 column, 0.1% FORMIC ACID in water with MeCN). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; In N,N-dimethyl-formamide; at 0℃; for 3.5h; | (1) To a solution of <strong>[6299-85-0]methyl 2,4-dichloropyrimidine-6-carboxylate</strong> (1.00 g, 4.83 mmol) and triethylamine (0.940 mL, 6.76 mmol) in N,N-dimethylformamide (6.0 mL) was added 4-aminotetrahydro-2H-pyran (537 mg, 5.31 mmol) at 0 C. After being stirred for 3.5 hour at 0 C., the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to 1:2) to give methyl 2-chloro-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-carboxylate as a colorless solid (1.12 g, 85%). mp 190-192 C. MS (APCI): m/z 272/274 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With boron trifluoride diethyl etherate In chloroform |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 105℃; for 0.666667h; Inert atmosphere; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 1.16667h; | 5.001.d To a solution of ethyl 5,7-dichloropyrazolo[l,5-a]pyrimidine-2-carboxylate (7.82 g, 30.1 mmol) in N,N-dimethylformamide (100 mL) was added 4-amino-tetrahydropyran (3.65 g, 36.1 mmol) and triethylamine (9.12 g, 90.2 mmol) at 0 °C. The reaction mixture was stirred for 70 min at room temperature, and then pored into water. The resulting precipitate was collected to give ethyl 5-chloro-7-(tetrahydro-2H-pyran-4- ylamino)pyrazolo[l,5-a]pyrimidine-2-carboxylate. MS (APCI): m/z 325 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 20℃; Cooling with ice; | viii Intermediate (viii)4-Chloro-2-methyl-N-(tetrahydro-pyran-4-yl)-benzamide4-Chloro-2-methylbenzoic acid (2.06 g, 12 mmol) was dissolved in DCM (50 mL) and DMF (10 mL) and the solution was cooled to an ice-water bath. To this solution was added a solution of tetrahydropyran- 4-yl amine (1 .22 g, 12 mmol, 1 .05 equiv.) in 10 mL of DCM, followed by N-methylmorpholine (5.75 g, 8 mL, 75 mmol, 3 equiv.), 1 -hydroxylbenzotriazole (HOBT) (4.4 g, 32.5 mmol, 1 .3 equiv.), sequentially, and finally EDC.HCI (2.97 g, 15.6 mmol, 1 .3 equiv. ). The resultant clear light brown solution was stirred at r.t. overnight. TLC (5 % MeOH in DCM) and LC/MS detected the product peak at retention time of 2.878 min with MS 284/286. The reaction was quenched with saturated sodium bicarbonate aqueous solution (10 mL) and 10 mL of DCM. The two layers were separated, and the aqueous layer was extracted with DCM (15 mLx2). The combined DCM extracts were washed with sodium bicarbonate (10 ml_), and brine (10 ml_),dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo to get 2.09 g (69% yield) of the titled compounds as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃;Cooling with ice; | Intermediate (iv)6-Bromo-naphthalene-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide Bromo-naphthalene-2-carboxylic acid (0.63g, 2.5 mmol) was dissolved in DCM (20 ml_) and DMF (5ml_) and the solution was cooled to an ice-water bath. To this solution was added a solution of tetrahydropyran-4-yl amine (0.26 g, 2.5 mmol, 1 equiv.) in 1 ml_ of DCM, followed by N-methylmorpholine (0.575 g, 0.8 ml_, 7.5mmol, 3 equiv.), 1 -Hydroxylbenzotriazole (HOBT) (0.44 g, 3.25 mmol, 1 .3 equiv.), sequentially, and finally EDC.HCI (0.625g, 3.25 mmol, 1 .3 equiv. ). The resultant clear light brown solution was stirred at r.t. overnight. TLC (10% MeOH in DCM) and LC/MS detected the product peak at retention time of 3.608 min with MS 334/336. The reaction was quenched with saturated sodium bicarbonate aqueous solution (10 ml_) and 10 mL of DCM. The two layers were separated, and the aqueous layer was extracted with DCM (15 ml_x2). The combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (10 mL), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo to get 0.85g ( 100% yield) of the title compounds.TLC (5% MeOH in DCM) Rf = 0.7.LCMS: RT = 2.85 minutes, MS: 335 (M+H+).1 H NMR (CDCIs, 300MHz), delta (ppm): 8.24 (s, 1 H), 8.04 (s, 1 H), 7.82 (m, 3H), 7.62 (m, 1 H), 6.13 (m, 1 H), 4.03 (m, 2H), 3.56 (dt, 2.2Hz, 1 1 .7Hz, 2H), 2.06 (m, 2H), 1 .62 (m, 1 H). |
100% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 16h;Cooling with ice; | General procedure: 4-Bromo-2-methylbenzoic acid (5.38g, 25mmol) was dissolved in DCM (100mL) and DMF (25mL) and the solution was cooled to an ice-water bath. To this solution was added a solution of tetrahydropyran-4-yl amine (2.60g, 25mmol, 1.0equiv) in 10mL of DCM, followed by N-methylmorpholine (5.75g, 8mL, 75mmol, 3.0equiv), 1-hydroxylbenzotriazole (HOBt) (4.40g, 32.5mmol, 1.3equiv), sequentially, and finally EDC·HCl (6.25g, 32.5mmol, 1.3equiv). The resultant clear light brown solution was stirred at rt overnight. TLC (10% MeOH in DCM) and LCMS detected a product peak with m/z of 299 (M+H+). The reaction was quenched with saturated sodium bicarbonate aqueous solution (10mL) and DCM (10mL). The two layers were separated, and the aqueous layer was extracted with DCM (15mL×2). The combined DCM extracts were washed with sodium bicarbonate aqueous solution (10mL) and brine (10mL), and dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo to get 6.87g (yield 92%) of the title compound as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 8 h / Reflux 2: triethylamine; triphenylphosphine; tetrachloromethane / dichloromethane / 8 h / 45 °C | ||
Multi-step reaction with 2 steps 1: 12 h / 70 °C / Inert atmosphere 2: triethylamine; triphenylphosphine / dichloromethane; tetrachloromethane / 12 h / 45 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20 - 50℃; for 21h; | b) The 3-chloro-N-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[4,3-b]-pyridazin-6-amine can be prepared in the following way:2.1 cm3 of tetrahydro-2H-pyran-4-amine and 3 cm3 of triethylamine are added to a solution of 2 g of commercial <strong>[33050-38-3]3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine</strong> in 20 cm3 of N,N-dimethylformamide. The reaction mixture is stirred at 20 C. for 18 h and 3 h at 50 C., and then cooled to 20 C., before the addition of 20 cm3 of water. The white precipitate is spin-filter-dried and then washed successively with water and ether. 1.3 g of 3-chloro-N-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-6-amine are thus obtained in the form of a white powder, the characteristics of which are as follows:MASS SPECTRUM: Waters ZQ: MH+m/z=254+; MH-=252- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In butan-1-ol; at 20 - 180℃; for 1h;Microwave irradiation; | Intermediate 53-lodo-1-(4-methoxybenzyl)-N-(tetrah dro-2H^yran-4-yl)-1H^yrazolo[4,3-c]To a solution of Intermediate 4 (5 g, 12.5 mmol) in 1-butanol (25 ml) at room temperature was added 4-aminotetrahydropyran (5 g, 50 mmol). The resulting mixture was transferred into two 20 ml microwave vials and then irradiated at 180 C for 1 h in a Biotage I-60 microwave reactor. The mixture was then evaporated to dryness and the crude residue was purified by flash chromatography gradient elution from 0-20% methanol in ethyl acetate to give a white solid (5.36 g, 92 %) 1H NMR (400 MHz, DMSO-d6) delta ppm 1.46 - 1.60 (m, 2 H), 1.95 - 2.09 (m, 2 H), 3.43 - 3.60 (m, 2 H), 3.70 (s, 3 H), 3.87 (m, 2 H), 4.21 - 4.32 (m, 1 H), 5.45 (s, 2 H), 5.97 (d, J=7.3 Hz, 1 H), 6.84 - 6.93 (m, 2 H), 6.99 (d, J=6.4 Hz, 1 H), 7.15 - 7.26 (m, 2 H), 7.78 (d, J=6.4 Hz, 1 H); m/z (ES+APCI)+: 465 [M + H]+. |
78% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 180℃; for 4h; | A microwave vial equipped with a magnetic stirrer was charged with 4-chloro-3-iodo-l-(4-methoxybenzyl)-lH-pyrazolo[4,3-c]pyridine (2.60 g, 6.50 mmol), tetrahydro-2H-pyran-4-amine (1.97 g, 19.5 mmol), n-BuOH (15 mL), and DIPEA (2.53 g, 19.5 mmol). The reaction mixture was heated at 180 C for 4 h under microwave irradiation. After cooling down, the solid was collected and washed with EtOH to afford the title compound as a white solid (2.35 g, 78%). |
78% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 180℃; for 4h;Microwave irradiation; | A microwave vial equipped with a magnetic stirrer was charged with <strong>[1246349-97-2]4-chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine</strong> (2.60 g, 6.50 mmol), tetrahydro-2H-pyran-4-amine (1.97 g, 19.5 mmol), n-BuOH (15 mL), and DIPEA (2.53 g, 19.5 mmol). The reaction mixture was heated at 180 C. for 4 h under microwave irradiation. After cooling down, the solid was collected and washed with EtOH to afford the title compound as a white solid (2.35 g, 78%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 100℃; for 0.5h;Microwave irradiation; | Step 6.1 5-nitro-2-(tetrahydro-2H-pyran-4-ylamino)benzoic acid A mixture of 5.1 g of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> and 6.21 g of tetrahydro-2H-pyran-4-amine in 5 ml of DMF is irradiated in a microwave field for 15 minutes at 100 C. The mixture is irradiated a second time for 15 minutes at 100 C. The same reaction is repeated on identical amounts of reagents. All the reaction mixtures are pooled and the solvent is evaporated off under reduced pressure. The residue is recrystallized from EtOAc to give 6 g of expected product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 25 - 80℃; for 20h; Inert atmosphere; Microwave irradiation; | ||
With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 23 - 75℃; for 20h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In methanol; at 140℃; for 0.5h;Microwave irradiation; | General procedure: A solution of <strong>[1187-59-3]N-methylacrylamide</strong> (2) (1.88 g, 22.0 mmol) and cyclopentylamine (1.98 mL, 20.0 mmol) in MeOH (14 mL) was heated under microwave irradiation to 140 C for 30 min (Biotage Initiator). The volatiles were removed under reduced pressure, the residue diluted with MeOH (20 mL) and purified by strong cation exchange filtration (50 g SCX-2 cartridge) washing with MeOH (100 mL) and eluting with 7 M methanolic NH3 (100 mL). The eluted product was concentrated under reduced pressure to afford the title compound 3 as a brown oil (3.09 g, 18.2 mmol, 91%). This was used directly with no further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In 1,4-dioxane; at 100℃; for 6.0h;Inert atmosphere; | [01654] Step 5: Synthesis of methyl 3-methyl-2-[(oxan-4-yl)amino]pyridine-4-carboxylate[01655] . A nitrogen purged suspension of Pd(OA.c)2 (77 mg, 0.34 mmol) and 1 , 1 '- binaphthalene-2,2'-diylbis(diphenylphosphane) (430 mg, 0.69 mmol) in 1 ,4-dioxane ( 1 1 ml) was heated at 40 C for 1 hour. Oxan-4-amine (237 mu, 2.3 mmol), a solution of methyl 2- chloro-3-methylpyridine-4-carboxylate (213 mg, 1 .2 mmol) in degassed dioxane (2 ml) and Cs2C03 (562 mg, 1 .7 mmol) were then added and the red suspension was heated at 100 C for 6 hours. After cooling to room temperature, the mixture was diluted with CH2C12 (30 ml) and water (20 ml). The layers were separated and the aqueous phase was extracted with CH2CI2 (3 x 15 ml). The combined organic phases were washed with brine (25 ml), dried (MgS04), filtered and concentrated in-vacuo. The crude residue was purified by column chromatography (25g SNAP cartridge, Isolera, 0-28% ethyl acetate:heptanes) followed by prep-HPLC(MeCN/Water) to give the title compound ( 1 12 mg, 39%) as a white crystalline solid. LC-MS 100%, m/z = 251.0; 1H NMR (500 MHz, MeOD) delta ppm 7.91 (d, J=5.20 Hz, 1 H) 6.77 (d, J=5.36 Hz, 1 H) 4.07 - 4.17 (m, 1 H) 3.98 (dd, J=12.06, 1 .81 Hz, 2 H) 3.88 (s, 3 H) 3.55 (td, J=1 1 .78, 1.66 Hz, 2 H) 2.22 (s, 3 H) 1.97 (dd, J=12.69, 1.97 Hz, 2 H) 1.62 (qd, J=12.03, 4.41 Hz, 2 H). NH not observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | In ethanol at 80℃; for 13h; | General procedure: The mixture of 2-chloro-4-nitropyridine 1-oxide (1) (325 mg, 1.86 mmol) and cyclohexylamine (0.38 mL, 3.35 mmol) in EtOH (9 ml) was heated at 80 °C until compound 1 disappeared in TLC. After reaction termination, the mixture was cooled to ambient temperature and solvent was removed in vacuo. The concentrated crude product was purified by flash column chromatography with EA/Hex (1:1) as the eluent to produce cyclohexyl-(4-nitro-1-oxy-pyridin-2-yl)-amine (2a) as a yellow solid (76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 4,6-dimethyl-1H-indole-2-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 4-aminotetrahydropyran In N,N-dimethyl-formamide at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 100 - 120℃; for 70h; | General procedure: Step 2 A solution of C-2 (1.01 g, 4.47 mmol, 1.00 equiv.) in DMA (3.0 mL) was treated dropwise with (S)-2-aminopropan-1-ol (403 mg, 5.37 mmol, 1.20 equiv.) and DIPEA (1.17 mL, 6.70 mmol, 1.50 equiv.), and the mixture was heated to 100 C. for 22 h. LCMS analysis revealed a mixture of desired product (MH+281/283) and starting material (MH+ 226/228) in the ratio 1.5:1 (254 nm). The mixture was heated to 120 C. for 48 h and then cooled to RT. LCMS indicated a mixture of desired product and starting material in the ratio 9:1 (254 nm) contaminated by some O-arylated byproduct. The dark brown mixture was concentrated in vacuo to afford 1.56 g of a yellow-brown oily solid. The crude product was treated with EtOAc and washed twice with water then brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting green-yellow solid (1.08 g) by NMR was a 1:1.5 mixture of desired product to starting material. The crude was purified by automated SiO2 flash chromatography eluting with an EtOAc/heptane gradient (0 to 100% EtOAc) to afford 388 mg (31%) of (S)-2-(6-bromoisoquinolin-3-ylamino)propan-1-ol (C-3, R2=(S)-1-hydroxypropan-2-ylamino). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 16h; | To a stirred solution of <strong>[16588-16-2]ethyl 4-chloro-3-nitrobenzoate</strong> (1.0 g, 4.4 mmol) in DMSO (10 mL) was added potassium carbonate (1.2 g, 8.7 mmol) and tetrahydro-2H-pyran-4-amine (0.53 g, 5.2 mmol) at RT. Then the reaction mixture was heated to 70 C. and stirred for 16 h and then cooled to RT. The reaction mixture was diluted with cold water and the solid obtained was filtered and dried under vacuum to afford the title compound (1.1 g, 86%); 1H NMR (400 MHz, DMSO-d6): δ 8.62 (d, J=2.0 Hz, 1H), 8.23 (d, J=7.8 Hz, 1H), 7.97 (dd, J=1.9 Hz, J=8.8 Hz, 1H), 7.29 (d, J=9.3 Hz, 1H), 4.29 (q, J=7.3 Hz, 2H), 3.96-3.94 (m, 1H), 3.90-3.83 (m, 2H), 3.51-3.45 (m, 2H), 1.96-1.93 (m, 2H), 1.66-1.61 (m, 2H), 1.31 (t, J=7.3 Hz, 3H); LC-MS: m/z 294.8 (M+1)+. |
With potassium carbonate; In dimethyl sulfoxide; at 60℃; for 17h; | General procedure: SI, Figure 2. General procedure for the synthesis of the nitro aniline compounds (3, Scheme 1). To the ester compounds (2) (1equiv.) in dry DMSO (20 mL) was added K2CO3(2 equiv.) and various amines (1.2 equiv.). The mixture was stirred for 17 h at 60oC. The solution was poured into water and the organic layer was extracted three times with ethyl acetate. After drying with anhydrous magnesium sulfate the solvents were removed under vacuum. The residue was purified by flash column chromatography on silica gel, using amixture of solvent of DCM: MeOH (50:1), to provide the desired nitro aniline compounds (3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In tetrahydrofuran; for 2.16667h; | To a solution of <strong>[4487-56-3]2,4-dichloro-5-nitropyridine</strong> (386 mg, 2.0 mmol), and triethylamine (417 muEpsilon, 3.0 mmol) in THF (6 mL) was added dropwise tetrahydropyran-4-ylamine (242 mg, 2.4 mmol) over 10 min and the reaction mixture was stirred for 1 h. An additional amount of tetrahydropyran-4- ylamine (50 mg) was added and the stirring was continued for 1 h. The volatiles were removed in vacuo and the resulting residue was partitioned between water and EtOAc. The organic phase was dried (MgSO and concentrated in vacuo to afford the title compound as a yellow solid (514 mg, quantitative). LCMS (ESI): [M+H]+ 258.2. |
88% | With N-ethyl-N,N-diisopropylamine; In ethanol;Inert atmosphere; Autoclave; | General procedure: To a stirred solution of chloro nitro pyridine / pyrimidine (1.0 equiv) in EtOH (0.5 mL per 0.52 mmol) was added DIPEA (3.0 equiv) followed by amine (1.05 equiv) at 0oC. The reaction mixture was stirred at 60-80oC for 3-6 h (the reaction was monitored by TLC). After completion of the reaction EtOH was distilled-off under a reduced pressure. The residue was dissolved in EtOAc (50 mL per 1g of crude). The organic layer was washed with water (20 mL), and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resultant crude compound was purified by silica gel column chromatography (100-200 mesh) using 10-20 percent ethyl acetate - hexane to afford the desired compound (yield: 85-95 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With acetic acid; at 160℃;Inert atmosphere; Autoclave; | General procedure: To a pressure bottle containing <strong>[82437-64-7]methyl 3-amino-4-phenylthiophene-2-carboxylate</strong> (100 mg, 0.43 mmol), CH(OEt)3 (1 mL) was added, followed by allylamine hydrochloride (93 mg, 0.99 mmol) and AcOH (0.1 mL). The reaction mixture was stirred and refluxed at 160 C overnight. After the reaction, the mixture was evaporated then solidified with ether. The produced white crystals were filtered and dried in vacuo to give the title compound 4-1 (66 mg, 0.25 mmol, 58 % yield): 1HNMR (300 MHz, CDCl3) delta 8.11 (s, 1H), 7.84-7.79 (m, 3H), 7.50-7.44 (m, 2H), 7.41-7.36 (m, 1H), 6.08-5.95 (m, 1H), 5.34-5.24 (m, 2H), 4.72-4.67 (m, 2H); 13C NMR (100 MHz, CDCl3) delta 157.3, 154.3, 147.3, 138.1, 133.7, 131.9, 130.5,128.7, 128.3, 128.0, 124.9, 119.1, 48.0; LC/MS (ESI+): m/z: calcd for C15H12N2OS: 268.34, [M + H]+; found: 269.05 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 15 - 25℃; for 2h; | I-84.1 4-bromo-2-methyl-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide To a 250 mL 3 -necked round-bottom flask was placed a solution of tetrahydro- 2H-pyran-4-amine (2.00 g, 19.7 mmol) in DCM (100 mL) followed by triethyl amine (7.97 g, 78.8 mmol) at ambient temperature. 4-Bromo-2-methylbenzene-l-sulfonyl chloride (5.00 g, 19.7 mmol) was then added at the same temperature. The reaction was stirred at ambient temperature for 2 hours and then poured into water (100 mL). The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford a residue which was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (1/1) to afford the title compound. LCMS (ESI) calc'd for Ci2Hi7BrN03S [M + H]+: 334, 336 (1 : 1), found 334, 336 (1 : 1); 1H NMR (400 MHz, CDC13) δ 7.90 (d, / = 4.8 Hz, 1H), 7.52-7.48 (m, 2H), 4.70 (d, / = 8.0 Hz, 1H), 3.92-3.87 (m, 2H), 3.41-3.32 (m, 3H), 2.67 (s, 3H), 1.79-1.75 (m, 2H), 1.56-1.50 (m, 2H). | |
With triethylamine In dichloromethane at 15 - 25℃; for 2h; Inert atmosphere; | 1 Step 1: .4-bromo-2-rnethyl-N-(tetrahydro-21-I-pyran-4-yl)benzenesulfonamide To a room temperature solution of tetrahydro-211-pyran-4-amine (2.00 g, 19.7 mmoi) inDCM (100 mL), was added trielhyiamine (7.97 g, 78.8 mmoi) followed by 4-bromo-2-methyibenzene-1-suifonyi chloride (5.00 g, 19.7 mmoi). The reaction was stirred at ambienttemperature for 2 hours and then quenched with water (100 mL), and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to afford a residue which was purified by silica chromatography, eluting with 50% EtOAc/hexanes to afford the title compound as a solid. LRMS (ES1) calc’d for,2HrBrN0,S [M+H1 334 i36 (I fl found 334 336(11) ‘HNMR(400 MHz cDCl, 6 7.90 (d, J 4.8 Hz, 1H), 7.52-7.48 (m, 2H), 4.70 (d, J= 8.0 Hz, iH), 3.92-3.87 (m, 2H), 3.41-3.32 (m, 3H), 2.67 (s, 3H), 1.79-1.75 (m, 2H), 1.56-1.50 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: orthoformic acid triethyl ester; 5-Bromo-2-aminobenzoic acid With acetic acid In toluene at 110℃; for 2.5h; Stage #2: 4-aminotetrahydropyran In toluene at 110℃; for 72h; | A17.58 Preparation of intermediate 58: 2-Amino-5-bromobenzoic acid (30 g; 138.9 mmo), triethy orthoformate (30.9 g; 208.3mmo) and acetic acid (0.9 mL) were dssoved fl touene (1.5 L). The mixture washeated at 110 00 for 2.5 hours. Then, tetrahydro-2H-pyran-4-amine (14.05 g; 138.9mmol) was added and the reaction mixture was refluxed for 3 days. The resultingmixture was cooled at room temperature and filtered. The filtrate was concentrated and crystallized from a mixture of DCM and petroleum ether to afford 26.9 g (62 %) of intermediate 58. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 16h; Cooling with ice; | 5.1 Step 1. Synthesis of 2-(4-bromo-phenyl)-N-(tetrahydro-pyran-4-yl)-acetamide. General procedure: 4-Bromo-2-methylbenzoic acid (5.38g, 25mmol) was dissolved in DCM (100mL) and DMF (25mL) and the solution was cooled to an ice-water bath. To this solution was added a solution of tetrahydropyran-4-yl amine (2.60g, 25mmol, 1.0equiv) in 10mL of DCM, followed by N-methylmorpholine (5.75g, 8mL, 75mmol, 3.0equiv), 1-hydroxylbenzotriazole (HOBt) (4.40g, 32.5mmol, 1.3equiv), sequentially, and finally EDC·HCl (6.25g, 32.5mmol, 1.3equiv). The resultant clear light brown solution was stirred at rt overnight. TLC (10% MeOH in DCM) and LCMS detected a product peak with m/z of 299 (M+H+). The reaction was quenched with saturated sodium bicarbonate aqueous solution (10mL) and DCM (10mL). The two layers were separated, and the aqueous layer was extracted with DCM (15mL×2). The combined DCM extracts were washed with sodium bicarbonate aqueous solution (10mL) and brine (10mL), and dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo to get 6.87g (yield 92%) of the title compound as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 1h;Microwave irradiation; | General procedure: 5.1.3 Ethyl 4-(cycloheptylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (5c) A mixture of 4 (112 mg, 0.50 mmol), cycloheptanamine (76 muL, 0.60 mmol), and Et3N (209 muL, 1.5 mmol) in NMP (3.0 mL) was heated in a microwave reactor at 180 C for 1 h. After cooling to room temperature, the reaction mixture was quenched with water, extracted with EtOAc, dried over MgSO4, and evaporated in vacuo. The crude mixture was purified by column chromatography on silica gel (CHCl3/MeOH = 100:0 to 90:10) to give the product (135 mg, 90%). 5.1.11 Ethyl 4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (5k) Compound 5k was prepared in quantitative yield as a white solid by a method similar to that described for 5c. 1H NMR (DMSO-d6) delta 1.32 (t, J = 7.2 Hz, 3H), 1.42-1.63 (m, 2H), 1.98-2.11 (m, 2H), 3.50-3.65 (m, 2H), 3.81-3.93 (m, 2H), 4.19-4.35 (m, 3H), 6.62 (d, J = 3.8 Hz, 1H), 7.21 (d, J = 3.8 Hz, 1H), 8.56 (s, 1H), 8.86 (d, J = 8.0 Hz, 1H), 11.72 (br s, 1H); MS (ESI) m/z 290 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: 4-aminotetrahydropyran With sodium methylate In methanol at 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 4-formyl-2-methoxybenzoate With acetic acid In methanol for 1h; Stage #3: With sodium tris(acetoxy)borohydride In methanol at 0 - 20℃; for 18.25h; | 14B 1 4B. Methyl 2-methoxy-4-[(tetrahydroyran-4-ylamino)methyl]benzoate 1 4B. Methyl 2-methoxy-4-[(tetrahydroyran-4-ylamino)methyl]benzoateSodium methoxide (0.83 g, 15.4 mmol) was added to a stirred solution of tetrahydro2H-pyran-4-amine hydrochloride (2.12 g, 15.4 mmol) in MeOH (35 mL) at roomtemperature under a nitrogen atmosphere and the mixture stirred for 30 minutes. Thesolution was passed through a Millipore filter and the resulting clear solution added toa stirred solution of methyl 4-formyl-2-methoxy-benzoate (3.0 g, 15.4 mmol) in MeOH(35 mL). Glacial acetic acid (1.8 mL, 30.8 mmol) was added and the mixture stirred forone hour then the solution was cooled to 0°C and sodium triacetoxyborohydride (9.79g, 4.62 mmol) was added in portions over 15 minutes. The mixture was allowed towarm to room temperature and stirring continued for 18 hours before partitioning between saturated NaHCO3 solution (200 mL) and EtOAC (200 mL). The separated aqueous phase was extracted with EtOAc (2 x 200 mL) then the combined organic extracts were washed with brine (75 mL), dried (Na2504) and evaporated underreduced pressure. The residue was purified by column chromatography on neutral silica gel using 2% MeOH/DCM as the eluentto give the title compound (3.1 g, 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | General procedure: Rifaldehyde (250.0 mg, 0.34 mmol) was dissolved in 50 ml CH2Cl2 and after the addition of catalyst (0.025 mmol HCl/EtOH) respective mixtures were prepared with each of the following compounds taken separately: 4-aminotetrahydropyran, 4-aminomethyltetrahydropyran and 4-aminodibenzo-18-crown-6 (0.34 mmol) in 1 ml of CH3OH. The mixtures were stirred at 45C for half an hour and after that 3/4 of the solvent volume was distilled off. To the cooled reaction mixture (room temperature) the reductant NaBH3CN (13 mg, 0.15 mmol) was added portionwise over 1 min. The reaction mixture was stirred for one hour. Next the reaction mixture was evaporated to dryness, dissolved in 50 ml of CH2Cl2 and extracted twice with 50 ml of water and brine. The separated organic layer was evaporated and the synthesized derivatives of <strong>[13292-22-3]<strong>[13292-22-3]3-formylrifamycin</strong> SV</strong> (compounds 1, 2 and 9) were next purified by column chromatography with silica gel (25 cm × 1 cm, silica gel 60, 0.040-0.063 mm/230-400 mesh ASTM, Fluka) with dichloromethane/methanol applied as eluent (40:1).Compound 1 - Yield: 55%; 1H NMR (DMSO-d6, 600 MHz) delta [ppm]: 16.08 (1H, s, OH-1), 12.82 (1H, s, OH-4), 9.43 (1H, s, NH-amide), 8.69 (1H, m, N-38b-H), 8.31 (1H, m, N-38a-H), 6.61 (1H, dd, 3JH18-H19=15.8 Hz, 3JH17-H18=10.8 Hz, H-18), 6.35 (1H, d, 3JH17-H18=10.8 Hz, H-17), 6.25 (1H, d, 3JH28-H29=12.8 Hz, H-29), 6.09 (1H, dd, 3JH18-H19=15.8 Hz, 3JH19-H20=7.4 Hz, H-19), 5.09 (1H, d, 3JH25-H26=10.9 Hz, H-25), 5.00 (1H, d, 3JHO-H21=4.1 Hz, OH-21), 4.92 (1H, dd, 3JH28-H29=12.8 Hz, 3JH27-H28=8.5 Hz, H-28), 4.47 (1H, d, 2J=12.1 Hz, 3JNH-H38=7.7 Hz, 3JNH-H38=4.2 Hz, H-38a), 4.35 (1H, ddd, H-38b), 3.99 (1H, d, 3JHO-H23=8.7 Hz, OH-23), 3.89 (1H, m, H-41b, 42b), 3.70 (1H, m, H-21), 3.39 ( 1H, m, H-39), 3.30 (1H, m, H-41a, 42a), 3.24 (1H, d, 3JH27-H28=8.5 Hz, H-27), 2.89 (3H, s, H-37), 2.84 (1H, m, H-23), 2.28 (1H, m, H-20), 1.99 (3H, s, H-30, 36), 1.95 (1H, m, H-40a), 1.94 (1H, m, H-43a), 1.92 (3 H, s, H-14), 1.68 (1H, m, H-22), 1.65 (1.65, s, H-13), 1.57 (1H, m, H-40b), 1.55 (1H, m, H-43b), 1.27 (1H, dq3JH24-H33=7.2 Hz, 3JH23-H24=14.5 Hz, H-24), 0.98 (1H, m, H-26), 0.91 (3H, d, 3JH22-H32=6.9 Hz, H-32), 0.85 (3H, d, 3JH20-H31=6.9Hz, H-31), 0.50 (3H, d, 3JH24-H33=6.8 Hz, H-33), -0.31 (3H, d, 3JH34-H26=6.8 Hz, H-34); 13C NMR (DMSO-d6, 150 MHz) delta [ppm]: 185.4 (C-11), 184.1 (C-8), 171.8 (C-6), 170.7 (C-15), 169.4 (C-35), 148.9 (C-1), 144.8 (C-4), 143.0 (C-29), 139.4 (C-19), 131.7 (C-17), 131.2 (C-16), 126.0 (C-18), 118.2 (C-2), 117.7 (C-28), 116.3 (C-10), 115.1 (C-9), 114.7 (C-3), 108.8 (C-12), 101.3 (C-7), 98.5 (C-5), 76.3 (C-27), 75.7 (C-23), 73.2 (C-25), 72.7 (C-21), 65.1 (C-41, 42), 55.6 (C-37), 53.5 (C-39), 40.3 (C-26), 39.7 (C-38), 38.1 (C-24), 38.0 (C-20), 32.7(C-22), 29.3 (C-40), 28.7 (C-43), 22.0 (C-13), 20.7 (C-36), 19.8 (C-30), 18.2 (C-31), 11.3 (C-32), 9.0 (C-34), 8.8 (C-33), 7.4 (C-14); HR-MALDI-TOF [M+H]+ = 811.4023; FT-IR (CH3CN, 0.05 molL-1): 3485 cm-1 nu(O21-H) + nu(O23-H), 3367 cm-1 delta(N-H)amide, 3145 cm-1nu(N38+-H···O15), ~2590 cm-1 nu(O1-H···O8- ) + nu(O4-H···O11- ), 1732 cm-1 nu(C35=O), 1646 cm-1 nu(C15=O)amid + nu(C11=O) + nu(C8=O), 1581 cm-1 nu(C=C), 1575 cm-1 nu(C=C), 1538 cm-1 delta(NH)amide II, 1244 cm-1 nu(C-O), 1153 cm-1 nu(C-O), 1093 cm-1 nu(C-O); Elemental analysis C43H58N2O13: calculated: C=63.69%; H=7.21%; N=3.45%; measured: C=63.52%; H=7.32%; N=3.49%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 90 °C 2: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichloroisocyanuric acid / methanol / 0.5 h / 0 - 20 °C 3: sodium hydroxide; tetrabutylammomium bromide / water; dichloromethane / 16 h / 20 °C 4: chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II); potassium carbonate / water; ethanol / 0.5 h / 77 - 80 °C | ||
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 90 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichloroisocyanuric acid / methanol / 0.5 h / 0 - 20 °C 3.1: sodium hydroxide; tetrabutylammomium bromide / water; dichloromethane / 16 h / 20 °C 4.1: 3-(di-tert-butylphosphino)-propane-1-sulfonic acid; sodium tetrachloropalladate(II); potassium carbonate / 1,4-dioxane; water / 16 h / 20 - 80 °C 5.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1.33 h / 10 - 20 °C / Inert atmosphere 5.2: 6.73 h / 10 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 16 h / 20 - 60 °C 2.1: sodium hydroxide; water / methanol / 2 h / 20 - 70 °C 3.1: triethylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 3.2: 2.5 h / 20 - 60 °C 4.1: sodium hydroxide; tetrabutylammomium bromide / water; dichloromethane / 16 h / 20 °C 5.1: chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II); potassium carbonate / water; ethanol / 0.5 h / 77 - 80 °C |
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 16 h / 20 - 60 °C 2.1: sodium hydroxide; water / methanol / 2 h / 20 - 70 °C 3.1: triethylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 3.2: 2.5 h / 20 - 60 °C 4.1: sodium hydroxide; tetrabutylammomium bromide / water; dichloromethane / 16 h / 20 °C 5.1: 3-(di-tert-butylphosphino)-propane-1-sulfonic acid; sodium tetrachloropalladate(II); potassium carbonate / 1,4-dioxane; water / 16 h / 20 - 80 °C 6.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1.33 h / 10 - 20 °C / Inert atmosphere 6.2: 6.73 h / 10 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
515 mg | Synthesis of tetrahydro-2H-pyran-4-ylcarbamoyl-[D-Pro24,Pya(4)26,Cha27,36,Aib28,31,Lys30]-PYY(23-36) (0317) H-Asn(Trt)-Lys(Boc)-Aib-Thr(But)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Cha-Sieber Amide resin (0.289 mmol/g, 1.73 g, 0.5 mmol) obtained by condensing amino acids in the same manner as in Example 12 and using Sieber Amide resin as a starting material, ABI433A peptide synthesizer DCC/HOBt 0.25 mmol protocol was swollen with DMF. Then, the resin was treated with Fmoc-Aib-OH (651 mg, 2.0 mmol), HOAt in DMF (0.5 M, 4.0 mL, 2.0 mmol), DIPCDI (318 muL, 2.0 mmol) for 1.5 hr. Fmoc group was removed with 20% piperidine in DMF, and the resin was treated with Fmoc-Cha-OH (787 mg, 2.0 mmol), HOAt in DMF (0.5 M, 4.0 mL, 2.0 mmol), DIPCDI (318 muL, 2.0 mmol) for 1.5 hr. The resin was washed, and further treated overnight with Fmoc-Cha-OH (787 mg, 2.0 mmol), HOAt in DMF (0.5 M, 4.0 mL, 2.0 mmol), DIPCDI (318 muL, 2.0 mmol). The resin was washed, and subjected to a capping treatment with decanoic anhydride (737 muL, 2. 0 mmol), DIEA (348 muL, 2.0 mmol) in DMF for 30 min. Fmoc group was removed with 20% piperidine in DMF, and the resin was treated with Fmoc-Pya(4)-OH (767 mg, 2.0 mmol), HOAt in DMF (0.5 M, 4.0 mL, 2.0 mmol), DIEA (348 muL, 2.0 mmol), DIPCDI (318 muL, 2.0 mmol) for 2.5 hr. The resin was washed with DMF, Fmoc group was removed with 20% piperidine in DMF, and the resin was treated with Fmoc-Arg(Pbf)-OH (1.30 g, 2.0 mmol), HOAt in DMF (0.5 M, 4.0 mL, 2.0 mmol), DIPCDI (318 muL, 2.0 mmol) for 2 hr. The resin was washed, and subjected to a capping treatment with decanoic anhydride (737 muL, 2.0 mmol), DIEA (348 muL, 2.0 mmol) in DMF for 30 min. Fmoc group was removed with 20% piperidine in DMF, and the resin was treated with Fmoc-D-Pro-OH (674 mg, 2.0 mmol), HOAt in DMF (0.5 M, 4.0 mL, 2.0 mmol), DIPCDI (318 muL, 2.0 mmol) for 12 hr. The resin was washed, and further treated overnight with Fmoc-D-Pro-OH (674 mg, 2.0 mmol), HOAt in DMF (0.5 M, 4.0 mL, 2.0 mmol), DIPCDI (318 muL, 2.0 mmol). The resin was washed, and subjected to a capping treatment with decanoic anhydride (737 muL, 2.0 mmol), DIEA (348 muL, 2.0 mmol) in DMF for 30 min. The resin was washed with DMF, Fmoc group was removed with 20% piperidine in DMF, and the resin was treated with Fmoc-Ser(But)-OH (767 mg, 2.0 mmol), HOAt in DMF (0.5 M, 4.0 mL, 2.0 mmol), DIPCDI (318 muL, 2.0 mmol) for 2 hr. The resin was washed successively with DMF, MeOH, and dried under reduced pressure. The total amount of the obtained H-Ser(But)-D-Pro-Arg(Pbf)-Pya(4)-Cha-Aib-Asn(Trt)-Lys(Boc)-Aib-Thr(But)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Cha-Sieber Amide resin was swollen again with DMF, and treated with CDI (405 mg, 2.5 mmol), DIEA (436 muL, 2.5 mmol) in DMF for 2 hr. The resin was washed with DMF, and treated overnight with 4-aminotetrahydropyrane (404 mg, 4.0 mmol) in DMF. The resin was washed successively with DMF, MeOH, dried under reduced pressure and the total amount of the obtained resin was suspended in TFA: thioanisole: m-cresol: H2O: EDT: TIS (80:5:5:5:2.5:2.5) (15 mL), and the mixture was stirred at room temperature for 4 hr. The reaction solution was added to stirring diethyl ether under ice-cooling while removing the resin by a filter to obtain precipitation, and an operation to remove the supernatant after centrifugation was repeated 3 times. The residue was extracted with 50% aqueous acetic acid solution, passed through a disc filter with a pore diameter 0.45 mum to remove fine granules, and purified in 9 portions by HPLC. The HPLC conditions were YMC Pack R&D-ODS-5-B S-5 120A column (30x250 mm), Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 15 mL/min, A/B: 77/23-67/33 linear concentration gradient elution (60 min). Each fraction was analyzed by HPLC to specify fractions containing only the object product. The fractions with low purity obtained by the first purification were concentrated, and subjected to HPLC separation in 2 portions under the same conditions. All the fractions containing only the object product were combined and freeze-dried to give 685 mg of a white powder. The obtained purified sample (685 mg) was dissolved in CHCN/HO (15/30 mL), and AG 1x8 AcO resin (7.54 mL, 9.05 mmol equivalents) was added. The solution was stood for 1 hr while occasionally stirring with hand, passed through a disc filter with a pore diameter 0.45 mum to remove fine granules, concentrated in an evaporator to reduce the liquid amount to about 5 mL, and the solution was freeze-dried to give 515 mg of a white powder. MALDI-TOF-MS analysis, (M+H)1893.2 (Calculated 1893.1) HPLC elution time: 7.5 min elution condition (HPLC mode g): column: SHISEIDO CAPCELL PAK C18 MGII(4.6×100 mm) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 80/20 - 30/70 linear concentration gradient elution (25 min) flow rate: 1.0 mL/min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
173 mg | [Example 26] (0324) (Synthesis method Z): Production of (Tetrahydro-2H-pyran-4-yl)carbamoyl-[Glu23,D-Pro24,Pya(4)26,Cha27,36,Aib28,31,Lys30]-PYY(23-36) (compound No. 282) Compound No. 282: (0325) Synthesis of (Tetrahydro-2H-pyran-4-yl)carbamoyl-[Glu23,D-Pro24, Pya(4)26, Cha27,36,Aib28,31, Lys30]-PYY(23-36) (0326) Cha-Aib-Asn(Trt)-Lys(Boc)-Aib-Thr(But)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Cha-Sieber Amide resin (SEQ ID NO:179)(0.375 mmol) obtained by condensing amino acids in the same manner as in Example 12 and using commercially available Sieber Amide resin as a starting material, and ABI433A peptide synthesizer DCC/HOBt 0.25 mmol protocol was weighed and placed in a reaction vessel, washed with DMF, and stirred in DMF for 20 min to swell the resin. Then, the resin was treated with Fmoc-Pya(4)-OH (1165.3 mg, 3 mmol), 0.5 M HOAt/DMF solution (3 mL, 4 mmol), DIPCDI (0.477 mL, 3 mmol) for 75 min to introduce Pya(4) residue. In this case, DIEA (0.5226 mL, 3 mmol) was added to the reaction solution during condensation. The N-terminal Fmoc group was removed by 20% piperidine/DMF treatment. By a similar procedure, Arg(Pbf) was introduced. In the same manner, removal of Fmoc group and condensation were repeated to introduce D-Pro, Glu(OBut), and the obtained resin was washed with MeOH and dried to give H-Glu(OBut)-D-Pro-Arg(Pbf)-Pya(4)-Cha-Aib-Asn(Trt)-Lys(Boc)-Aib-Thr(But)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Cha-NH-Sieber Amide resin. The obtained resin was washed with DMF and, after swelling, treated with CDI (304.0 mg, 1.88 mmol), DIEA (0.327 mL, 1.88 mmol), DMF (3 mL) for 60 min. The resin was washed, and further treated for 60 min under similar conditions. The resin was washed with DMF, treated with 4-aminotetrahydropyrane (303.0 mg, 3 mmol), DMF (3 mL) for 4 hr, and washed successively with DMF, MeOH and dried. The obtained resin (1.63 g) was treated with TFA: thioanisole: m-cresol: H2O: EDT: TIS (80:5:5:5:2.5:2.5) (20 mL) for 4 hr, an operation to add diethyl ether to the reaction solution, precipitate a white powder by centrifugation, and remove ether by decantation was repeated twice. The residue was dissolved in aqueous acetic acid solution, passed through a disc filter with a pore diameter 0.45 mum to remove fine granules, and concentrated in an evaporator. After confirmation of the purity of the obtained crude peptide solution by HPLC, it was purified in 10 portions by preparative HPLC using Daisopak-SP100-5-ODS-P 2×25 cm (Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 80/20-70/30 linear concentration gradient elution (60 min)). The eluted object product was fractionated in test tubes, and each fraction was analyzed by HPLC to specify fractions containing only the object product. They were combined and freeze-dried to give 316 mg of a white powder. (0327) The obtained purified sample (316 mg) was dissolved in HO (40 mL), and AG 1x8 AcO resin (2.85 mL, 3.42 mmol equivalents) was added. The solution was stood for 1 hr while occasionally stirring with hand, passed through a disc filter with a pore diameter 0.45 mum to remove fine granules, concentrated in an evaporator to reduce the liquid amount to about 5 mL, and the solution was freeze-dried to give 173 mg of a white powder. MALDI-TOF-MS analysis, (M+H) 1935.5 (Calculated 1935.1) HPLC elution time: 7.6 min elution condition (HPLC mode g): column: SHISEIDO CAPCELL PAK C18 MGII(4.6×100 mm) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 80/20 - 30/70 linear concentration gradient elution (25 min) flow rate: 1.0 mL/min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 50℃; | xlv.b Methyl 2-nitro-3-((tetrahydro-2H -pyran-4-yl)amino)benzoate 1126 To a solution of methyl 3-fluoro-2-nitrobenzoate 1125 (100 mg, 0.5 mmol) in MeCN (5 mL) were added tetra hyd ro-2 H-py ra n-4-a m i ne (50 mg, 0.5 mmol) and DIPEA (97 mg, 0.75 mmol). The mixture was heated at 50 C overnight. The solvent was removed and the residue diluted with EtOAc (30 mL). The organic layer was washed with water (30 mL x 2) and brine (30 mL), dried ( a2S04) and concentrated to give the title compound as a brown solid (130 mg, 93%). LCMS-C: RT 2.28 min; m/z 281.1 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; | 36.1 [712] Step 1: synthesis of 4-isocyanatotetrahydro-2H-pyran (54.1) [713] Preparation a solution of tetrahydro-2H-pyran-4-amine (200 mg, 1.98 mmol) and DIPEA (562 mg, 4.35 mmol) in dichloromethane (8 mL). To a solution of triphosgene (217 mg, 0.73 mmol) in dichloromethane (2 mL) was added the solution prepared above with asyringe dropwise. The resulted mixture was stirred at room temperature for 2h to afford a solution of 4-isocyanatotetrahydro-2H-pyran (54.1) in dichloromethane, which can be directly used for next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With benzotriazol-1-ol; 1,2-dichloro-ethane; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 16h; | 3,3,3-trifluoro-N-(tetrahydro-2H-pyran-4-yl)propanamide To a solution of 3,3,3-trifluoropropanoic acid (0.5 g, 3.90 mmol) in THF (20 mL) at Rt was added tetrahydro-2H-pyran-4-amine (0.395 g, 3.90 mmol), followed by EDC (0.749 g, 3.90 mmol), 1-Hydroxybenzotriazole (0.528 g, 3.90 mmol) and Hunig'sBase (1.023 mL, 5.86 mmol). The reaction was stirred at room temperature for 16h. Diluted with EtOAc and IN HCl. Organic was separated and washed with IN NaOH, H20, brine, dried over MgS04, filtered and concentrated to give Intermediate 148A (0.7 g, 3.28 mmol, 84 % yield) as white solid. 1H NMR (400MHz, chloroform-d) δ 5.59 (br. s., 1H), 4.13 - 4.02 (m, 1H), 4.01 - 3.90 (m, 2H), 3.50 (td, J=11.7, 2.3 Hz, 2H), 3.08 (q, J=10.6 Hz, 2H), 2.00 - 1.86 (m, 2H), 1.56 - 1.38 (m, 2H) MS: Anal.Calc'd for C8Hi2N02 211.082, found [M+H] 212.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100℃; for 6h;Inert atmosphere; | Method 10 5-bromo-2-(tetrahydro-2H-pyran-4-ylamino)nicotinonitrile To a solution of oxan-4-amine (243 mg, 2.40 mmol) in NMP (6 mL) was added <strong>[405224-23-9]5-bromo-2-chloropyridine-3-carbonitrile</strong> (475 mg, 2.18 mmol) and DIEA (846 mg, 6.54 mmol) at room temperature. The mixture was stirred for 6 h at 100 C. After cooling to room temperature, the reaction mixture was quenched by the addition of water (10 mL). The resulting mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by reverse phase flash chromatography eluting with acetonitrile in water (0% to 95% gradient in 30 min) to yield 5-bromo-2-[(oxan-4-yl)amino]pyridine-3-carbonitrile as a yellow solid (310 mg, 49%). MS: m/z=282.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 120℃;Inert atmosphere; | 3-fluoro-2-(tetrahydro-2H-pyran-4-ylamino)benzonitrile To a solution of <strong>[21524-39-0]<strong>[21524-39-0]2,3-difluorobenzonitril</strong>e</strong> (2.8 g, 19.99 mmol) in DMSO (40 mL) was added oxan-4-amine (2.0 g, 19.77 mmol) and DIEA (6.5 g, 49.91 mmol) at room temperature. The resulting solution was stirred overnight at 120 C., cooled to room temperature, and treated with water (80 mL). The resulting solution was extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 3-fluoro-2-[(oxan-4-yl)amino]benzonitrile as black solid (3.3 g, 76%). MS: m/z=221.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 15h; | (R)-benzyl 3-((tert-butoxycarbonyl)amino)-4-oxo-4-((tetrahydro-2H-pyran-4- yl)amino)butanoate: [00231] HOBt (240 mg, 1.78 mmol, 1.15 equiv.) was added to a solution of (tf)-4-(benzyloxy)-2- ((ieri-butoxycarbonyl)amino)-4-oxobutanoic acid (500 mg, 1.55 mmol) and tetrahydro-2H-pyran-4- amine (240 mg, 1.55 mmol) in DMF (10 mL). EDC-HCl (296 mg, 1.55 mmol) and N-methylmorpholine (202 mg , 2.00 mmol) were added at 0 C and the reaction mixture was stirred at rt for 15 h. Ethyl acetate was added and the mixture was washed with an aqueous saturated solution of sodium bicarbonate, with brine (2x), dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel using a solution of ethyl acetate in hexanes (10 to 20%) to provide 488 mg (78%) of the title compound as a white solid, m/z (M + H)+ = 407.2; RT = 1.51 min; purity = >95%. HPLC conditions: Column: XBridge CI 8, 3.5muiotaeta, 4.6 x 30mm; Gradient: 5B 0.2 min, 5B - 100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 lOmM Ammonium Formate in Water; Eluent B: Acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 80℃; for 12h;Inert atmosphere; | A mixture of <strong>[22918-01-0]2-bromo-4-chloropyridine</strong> (0.5 g, 2.60 mmol), tetrahydro-2H-pyran-4-amine (0.3 15 g, 3.12 mmol), C52CO3 (1.693 g, 5.20 mmol), and BINAP (1.618 g, 2.60 mmol) in toluene (30 mL) was purged with nitrogen gas for 30 mm and PdOAc2 (0.583 g, 2.60 mmol) was added. The reaction mixture was again purged with nitrogen gas for another 10 mm and heated at 80 C for 12 h. The reaction mixture was cooled to room temperature and was concentrated underreduced pressure. The residue was diluted with water (25 mL) and ethyl acetate (20 mL). The biphasic mixture was filtered through diatomaceous earth. The diatomaceous earth was washed with ethyl acetate (50 mL). The ethyl acetate layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate in petether) to afford 4-chloro-N-(tetrahydro-2H-pyran-4-yl) pyridin-2-amine (150 mg,0.705 mmol, 27% yield) as colorless oil. LCMS (ESI) m/e 213.2 [(M+H), calcd for C10H14C1N2O 213.11; LC/MS retention time (Method Al): tR = 2.48 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | In tetrahydrofuran; at 25℃; for 12h; | j00448j To a solution of N,N-di-CBZ-1H-pyrazole-1-carbamidine (3 g, 7.9mmol) in THF (20 mL) was added tetrahydro-2H-pyran-4-amine (0.9 g, 9.5 mmol) at 25 C.The reaction was stirred for 12 hrs at 25 C. The mixture was concentrated in vacuo to give aresidue. The residue was purified by silica gel column to obtain compound 65 (1.4 g, 38%yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In ethanol; | General procedure: To a solution fo <strong>[579514-75-3]tert-butyl 4-fluoro-3-nitrobenzoate</strong> (560 mg, 2.3 mmol) in 20mL of EtOH were added butan-1-amine (853 mg, 11.6 mmol) and stirred at rt for 2 h.The reaction mixture was concentrated to dryness, and the residue was dissolved inEtOAc (10 x 3 mL) and washed with brine (10 mL). The combined organic layerswere dried over MgSO4, and concentrated in vacuo to afford the product tert-butyl 4-(butylamino)-3-nitrobenzoate (35b) as yellow-orange solid (490 g, 72% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 4-aminotetrahydropyran; N-tert-butyloxycarbonylpiperidin-4-one In 1,2-dichloro-ethane at 20℃; for 0.166667h; Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; | 97 Synthesis of Int-97-3 A mixture of Int-97-1 (1.37 g, 6.89 mmol) and tetrahydro-2H-pyran-4- amine Int-97-2 (1.395 g, 13.79 mmol) in 1,2-dichloroethane (20 mL) was stirred at RT for 10 min. To the mixture NaBH(OAc)3 (2.92 g, 3.79 mmol) and AcOH (0.78 mL, 13.79 mmol)) were added. The reaction mixture was stirred at RT overnight. The solvent was evaporated under reduced pressure, and the residue was partitioned between saturated aqueous solution of Na2CO3 and EtOAc. The organic phase was separated, and the aqueous layer was extracted with EtOAc (2 x 40 mL). The combined organic phase was dried over Na2SO4 and evaporated under reduced pressure. The product was purified by column chromatography (CH2Cl2: MeOH = 97:3) to afford Int- 97-3 as yellow oil (1.716 g, 88% yield). LC-MS: (M+1) m/z = 285. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.2% | With N-ethyl-N,N-diisopropylamine; In ethanol; at 90℃; for 18h;Sealed tube; | To a 75 ml sealed flask with teflon screw cap was added <strong>[31872-62-5]4-methoxy-3-nitropyridine</strong> (6.86 g, 44.5 mmol), tetrahydro-2H-pyran-4-amine (3.07 ml, 29.7 mmol), absolute EtOH (49.4 ml) and Hunig's Base (7.77 ml, 44.5 mmol) then the vessel was tightly sealed and heated in a 90 °C oil bath for 18 h. The reaction was cooled to 0 °C and the yellow precipitate was collected and washed with hexanes. The solid was dried in vacuo (2.0 g, 8.96 mmol, 30.2percent yield). 1H NMR (600 MHz, DMSO-d6) delta 9.03 (s, 1H), 8.27 (dd, J = 6.2, 0.8 Hz, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 6.3 Hz, 1H), 3.96 - 3.90 (m, 1H), 3.87 (ddd, J = 12.1, 4.2, 2.7 Hz, 2H), 3.47 (td, J = 11.6, 2.2 Hz, 2H), 1.89 (ddd, J = 12.6, 4.5, 2.2 Hz, 2H), 1.71 - 1.59 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: 4-aminotetrahydropyran With 3,5-di-tert-butyl-o-benzoquinone In methanol at 25℃; Stage #2: trimethylsilyl cyanide In methanol at 0 - 25℃; for 24h; Stage #3: With periodic acid In methanol; water; acetonitrile at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In methanol for 3h; Reflux; | Synthesis of 2-amino-3-((tetrahydro-2H-pyran-4-ylimino)methyl)-4H-chromen-4-one (H2chpr) A solution of tetrahydro-2H-pyran-4-amine (0.20 g; 1.98 mmol) in 20 cm3 of methanol was added drop wise to a stirring methanolic solution (20 cm3) of 2-amino-3-formylchromone (0.37 g; 1.98 mmol). The resultant reaction mixture was refluxed for 3 hours and then reduced down to 5 cm3, cooled in an ice bath which resulted in the formation of yellow crystals of the titled compound. These crystals was washed with anhydrous petroleum ether and dried under vacuum. Yield = 86%, M.P. = 165 - 167 °C. IR (νmax/cm-1): ν(N-H) 3074 (m), ν(C=O) 1661 (s), ν(C=N) 1602 (vs), ν(C-O-C)chromone 1566, 1490 (s), ν(C-O-C)tetrahydropyran 1139 (s). 1H NMR (295K/ppm, see Fig. S4): 8.93 (br, s, 2H, NH2), 8.76 (s, 1H, H10), 8.00 (d, 1H, H3), 7.67 (t, 1H, H4), 7.42 - 7.35 (m, 2H, H5, H6), 3.92 - 3.84 (m, 2H, H12, H12’), 3.39 - 3.53 (m, 2H, H15, H15’), 1.77 - 1.56 (m, 4H, H13, H13’, H14, H14’). UV-Vis (DMF, (λmax (ε, M-1cm-1))): 236 nm (19312); 267 nm (sh, 12843); 301 nm (sh, 9134); 334 nm (7979); 350 nm (9253); 364 nm (sh, 7890). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 3h;Inert atmosphere; | To a solution of 5- bromo-2 -methyl-pyrimidine (700 mg, 4.05 mmol) and tetrahydropyran-4-amine (818 mg, 8.09 mmol) in toluene (12 ml) was added BINAP (504 mg, 0.81 mmol), Pd(OAc)2 (91 mg, 0.40 mmol) and Cs2C03 (2.64 g, 8.09 mmol). The mixture was stirred under N2 at 100 °C for 3 h. (1528) The mixture was poured into ethyl acetate (100 ml) and washed with 10: 1 H20 / methanol (4 x 100 ml). The EtOAc phase was concentrated in vacuo. The residue was purified by FCC (33 - 100 percent EtOAc in petroleum ether) to give the title compound as a white solid (Y = 45 percent). H NMR (400 MHz, chloroform-J) d ppm 8.07 (s, 2H), 4.05 - 3.95 (m, 2H), 3.57 - 3.48 (m, 3H), 2.61 (s, 3H), 2.06 - 2.00 (m, 2H), 1.55 - 1.44 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120℃; for 3h;Inert atmosphere; | To a solution of tetrahydropyran-4- amine (1.35 g, 13.4 mmol) in toluene (5 ml) was added 5-bromo-2,4- dimethyl-pyrimidine (500 mg, 2.67 mmol), BINAP (333 mg, 0.53 mmol), Cs2C03 (1.74 g, 5.35 mmol) and Pd(OAc)2 (60 mg, 0.27 mmol) at rt under N2. The mixture was heated at 120 C for 3 h under a N2 atmosphere. H20 (10 ml) was added and the mixture was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by FCC (0 - 50 % MeOH in EtOAc) to give the title compound as a brown solid (Y = (1619) 90 %). H NMR (400 MHz, methanol-^) d ppm 7.98 (s, 1H), 4.02 - 3.99 (m, 2H), 3.62 - 3.54 (m, 3H), 2.51 (s, 3H), 2.39 (s, 3H), 2.05 - 1.92 (m, 2H), 1.66 - 1.56 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a stirred solution of HATU (724 mg, 1.9 mmol) in DMF (1 mL) was added DIPEA (363 pL, 2.08 mmol) and <strong>[13509-19-8]4-nitropyridine-2-carboxylic acid</strong> (320 mg, 1.9 mmol) and the mixture was stirred for 15 mins. Tetrahydropyran-4-amine (0.18 mL, 1.73 mmol) was added in one portion and the mixture was stirred at room temperature for 1 hour. The resulting mixture was washed with water (10 mL), NaHCO3 (10 mL) and extracted with EtOAc (2 x 10 mL).The combined organic extracts were dried over Na2504 and concentrated in vacuo to afford the titled compound as a pale orange solid. H NMR (500 MHz, DMSO-d6) delta = 1.70- 1.75 (m, 4H), 3.37- 3.44 (m, 2H), 3.88 (dt, J=11.2, 3.2, 2H), 4.05 (s, 1H), 8.33 (dd, J=5.3, 2.3, 1H), 8.53 (dd, J=2.3, 0.5, 1H), 8.92 (d, J=8.2, 1H), 9.02 (dd, J=5.3, 0.5, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-hydroxy-4-nitro-benzoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 4-aminotetrahydropyran In N,N-dimethyl-formamide for 12h; | 1.2.4 General procedure for the preparation of intermediates c1-c14 General procedure: Dissolved 4 (3-Hydroxy-4-nitrobenzoic acid, 1.0 equiv) in DMF, followed by HBTU (1.2 equiv), Et3N (1.3 equiv), and the mixture was stirred for 1 h at room temperature, then amine (R1NH2, 3.0 equiv) was added. The resultant was stirred overnight. The mixture was washed by brine and extracted by ethyl acetate. Combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by chromatography on a silica gel column to give corresponding product c1-c14. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | General procedure: To a solutionof the corresponding aldehyde (1.2 eq.; unless stated otherwise) in DMF (2 inL per 0.3 mmol of aldehyde; unless stated otherwise) was added the corresponding amine (2.5 eq.; unless stated otherwise) and the resulting solution was stirred at 25 C to form the corresponding inline. Then, the corresponding isocyano(tosyl)methyl)arene reagent (1 eq.; unless stated otherwise) and K2CO3 (1.5 eq.; unless stated otherwise*) were added and the reaction mixture was stirred at 25 C (unless stated otherwise). The reaction was stopped after the time indicated for each particular reaction. The reaction progress was monitored by TLC. (0083) A saturated aqueous solution of NH4CI (10 mL per 1 mmol of aldehyde) was added to the reaction mixture, which was then extracted with EtOAc (2 x 30 mL per 1 mmol of aldehyde). The combined organic extracts were washed with H2O (2 x 25 mL per 1 mmol of aldehyde), dried over MgSCC, filtered, and the solvent was evaporated in vacuo to provide the crude product. The residue obtained after the workup was purified using column chromatography or preparative TLC (unless stated otherwise). (0084) * note: in cases when the amine was used as HC1 salt, 4 eq. of K2CO3 were used |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine; In ethanol; at 20℃;Cooling with ice; | In a round bottom flask was added <strong>[1780-36-5]2,4,6-trichloro-5-methylpyrimidine</strong> (7.75 g, 39.3 mmol),100 mL of ethanol was dissolved, and triethylamine (11 mL, 78.6 mmol) was added.4-amino-tetrahydropyran (3.77g, 37.3mmol) under ice-cooling,The temperature was slowly raised to room temperature and the reaction was performed overnight. The sample was directly spin-dried and mixed on the column. The intermediate a was obtained by column chromatography as a white solid product 6.92 g with a yield of 70% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine; In tetrahydrofuran; at 80℃; for 4h; | To a solution of 5-bromo-l,3-difluoro-2-nitrobenzene (033, 500 mg, 2.101 mmol) in THF (lOmL, 0.2 M) at rt were added tetrahydro-2H-pyran-4-amine (034, 202 mg, 1.996 mmol) and triethylamine (0.359 ml, 2.521 mmol). The reaction mixture was stirred at 80 C for 4 hrs. The reaction mixture was concentrated and applied to ISCO on a gradient 0-20% Hex:EtOAc to give N-(5-bromo-3-fluoro-2- nitrophenyl)tetrahydro-2H-pyran-4-amine (035, 540 mg, 1.692 mmol, 81 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Stage #1: 4-acetyloxy-benzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 0.5h; Cooling with ice; Stage #2: 4-aminotetrahydropyran In dichloromethane; N,N-dimethyl-formamide at 20℃; for 5h; | 29.I Step I: Preparation of 4-((tetrahydro-2H-pyran-4-yl)aminoformyl)phenyl acetate(29-1) 4-acetoxybenzoic acid (500 mg, 2.78 mmol) was dissolved in anhydrous dichloromethane (10 mL) and DMF (10 mL), and in ice bath, added with oxalyl chloride (1.06 g, 8.34 mmol), and the mixture was reacted for half an hour. The reaction solution was then concentrated for further use. 4-aminotetrahydro-2H-pyran (336 mg, 3.33 mmol) was dissolved in DMF and added with the above prepared acyl chloride solution, and the mixture was reacted at room temperature. LCMS was used to monitor the reaction. After 5 hours, the reaction solution was added with water and extracted with ethyl acetate. The organic phase was dried and concentrated, then subject to column chromatography separation to afford the title compound, which was a brown liquid (225 mg, 31%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | Stage #1: bis(trichloromethyl) carbonate; 6-bromo-1H-pyrrolo[3,2-b]pyrridine With triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #2: 4-aminotetrahydropyran In dichloromethane Inert atmosphere; | 21.1 Step 1: 6-bromo-N-tetrahydropyran-4-yl-pyrrolo[3,2-b]pyridine-1- carboxamide;methane (C21-1) To a solution of 6-bromo-1H-pyrrolo[3,2-b]pyridine (150 mg, 0.76 mmol) and Et3N in anhydrous CH2Cl2 (10 mL) under N2 was added triphosgene (BTC) (90 mg, 0.30 mmol), and the mixture was stirred at room temperature for 2 h. A61-2 (521 mg, 3.80 mmol) was added. After the reaction was complete, the mixture was partitioned between a saturated aqueous NaHCO3 solution (2 mL) and EtOAc (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EtOAc) to provide the title compound C21-1 as a yellow solid (70 mg, 29%). 1H NMR (400 MHz, DMSO-d6) d 8.66 (s, 1H), 8.54 (s, 1H), 8.26-8.23 (m, 2H), 3.92-3.89 (m, 3H), 3.43-3.35 (m, 2H), 1.87-1.83 (m, 2H), 1.65-1.57 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.7% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With 1,4-diaza-bicyclo[2.2.2]octane; tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; Co<SUP>III</SUP>(dimethylglyoximate)<SUB>2</SUB>(4-NMe<SUB>2</SUB>-C<SUB>5</SUB>H<SUB>4</SUB>N)Cl; acetic acid In acetonitrile at 70℃; for 36h; Inert atmosphere; Irradiation; | 1-(Tetrahydro-2H-pyran-4-yl)indolin-2-one (3) Following GP1 using [Ru(bpy)3](PF6)2 (2 mol%) as the photocatalyst,ethyl 2-(2-oxocyclohexyl)acetate (54 L, 0.3 mmol, 1.0 equiv.), and 4-aminotetrahydropyran (47 L, 0.45 mmol, 1.5 equiv.) gave 3 (41 mg,63%) as an oil; Rf (hexane/EtOAc 1:1) = 0.27.1H NMR (CDCl3, 400 MHz): = 7.30-7.18 (m, 2 H), 7.11 (d, 1 H, J = 7.8Hz), 7.03 (t, 1 H, J = 7.9 Hz), 4.55 (tt, 1 H, J = 12.5, 4.4 Hz), 4.12 (dd, 2 H,J = 11.6, 4.9 Hz), 3.58-3.48 (m, 4 H), 2.51 (qd, 2 H, J = 12.5, 4.8 Hz),1.66 (dd, 2 H, J = 13.0, 2.2 Hz).13C NMR (CDCl3, 100 MHz): = 175.0, 143.6, 127.8, 125.0, 124.8,122.1, 110.2, 67.7, 48.7, 36.0, 29.1.HRMS (ESI+): m/z [M]+ calcd for C13H15NO2: 217.1091; found:217.1103. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 1,4-diaza-bicyclo[2.2.2]octane / dimethyl sulfoxide / 16 h / 100 °C / Inert atmosphere 2: triethylamine / dichloromethane / 22 °C 3: nickel(II) bromide dimethoxyethane; 1,4-diaza-bicyclo[2.2.2]octane; tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate / dimethyl sulfoxide / 0.5 h / 50 °C / Inert atmosphere; Irradiation; Flow reactor 4: dichloromethane / 0 - 22 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1: 1,4-diaza-bicyclo[2.2.2]octane / dimethyl sulfoxide / 16 h / 100 °C / Inert atmosphere 2: triethylamine / dichloromethane / 22 °C 3: nickel(II) bromide dimethoxyethane; 1,4-diaza-bicyclo[2.2.2]octane; tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate / dimethyl sulfoxide / 1 h / 50 °C / Inert atmosphere; Irradiation; Flow reactor 4: dichloromethane / 0 - 22 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: 3-bromo-5-(trifluoromethoxy)benzoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 4-aminotetrahydropyran In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 18h; | 16 Preparation of 3-bromo-N-tetrahydropyran-4-yl-5-(trifluoromethoxy)benzamide A mixture of 3-bromo-5-(trifluoromethoxy)benzoic acid (500 mg, 1.753 mmol), HATU (1.33 g, 3.506 mmol) and DIPEA (1.131 g, 8.771 mmol) in DMF (8 mL) was stirred at r.t. for 30 min. Tetrahydropyran-4-amine (0.355 g, 3.506 mmol) was added. The resulting mixture was stirred at r.t. for 18 h and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (3X). The combined organic phase was washed with sat. NaHCO3 and brine, dried(MgSO4), filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 0-50% EtOAc/hexane to afford the title compound (0.399 g, Yield 62%). |
Tags: 38041-19-9 synthesis path| 38041-19-9 SDS| 38041-19-9 COA| 38041-19-9 purity| 38041-19-9 application| 38041-19-9 NMR| 38041-19-9 COA| 38041-19-9 structure
[ 33024-60-1 ]
Tetrahydro-2H-pyran-4-amine hydrochloride
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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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