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Structure of 6011-14-9 * Storage: {[proInfo.prStorage]}
With sodium hydrogencarbonate In tetrahydrofuran; water at 25 - 30℃;
To a solution of hydrochloride salt of amino acetonitrile (50 g 487 mmol) dissolved in water (250 ml) and tetrahydrofuran (250 ml) was added sodium bicarbonate (90.14 g, 1073 mmol) under stirring at 25-30 °C. To this was added di- ie/t-butyldicarbonate (117 g, 536 mmol) drop-wise using addition funnel. The progress of reaction was monitored by thin layer chromatography using a mixture of hexane and acetone as solvent. After complete consumption of starting material, ethyl acetate (500 ml) was added to it and organic layer was separated. The aqueous layer was re-extracted with ethyl acetate (1x250 ml). The organic extracts were combined and dried over anhydrous sodium sulfate, then concentrated to yield 66 g of tert-butyl (cyanomethyl)carbamate as a thick liquid in 86percent yield
66%
With triethylamine In dichloromethane for 16 h; Reflux
Step a: Aminoacetonitrile hydrochloride (5 g, 54 mmol) was added to dichloromethane (30 mL). A solution of di-tert-butyl dicarbonate (11.9 g, 54.6 mmol, 1.01 equiv.) and TEA (24.6 g, 33.7 mL, 243 mmol, 4.5 equiv.) in dichloromethane (25 mL) was also metered in. After completion of the addition the mixture was heated for 16 h under reflux. After the reaction mixture had cooled it was filtered, the filtrate was washed with water (50 mL), dried over magnesium sulphate and freed from solvent under reduced pressure. N-boc-aminoacetonitrile (5.58 g, 66percent yield) remained as a brownish oil, which was used without further purification.
Reference：
[1] Angewandte Chemie - International Edition, 2014, vol. 53, # 39, p. 10510 - 10514[2] Angew. Chem., 2014, vol. 126, # 39, p. 10678 - 10682,5
18
[ 14047-29-1 ]
[ 6011-14-9 ]
[ 1056636-11-3 ]
Yield
Reaction Conditions
Operation in experiment
87%
Stage #1: With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 40℃; for 3.5 h; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 16 h;
To a suspension of 4-carboxyphenylboronic acid (5.0 g, 30 mmol) in DMF (5 mL) and dichloromethane (200 mL) at 0°C was added oxalylchloride (5.9 mL, 66 mmol) dropwise. <n="54"/>When gas evolution slowed, the ice bath was removed and the reaction allowed to warm to room temperature over 30 min. The reaction was then heated at 4O0C for 3 h by which time all solids had dissolved. The dichloromethane was removed by distillation and the DMF solution cooled to 00C. A solution of aminoacetonitrile hydrochloride (3.05 g, 33 mmol) in DMF (80 rnL) and DIPEA (13 mL, 75 mmol) was then added dropwise. After the addition was complete the ice bath was removed and the solution allowed to stir at room temperature for 16 h. Most of the DMF was then removed in vacuo and the reaction was partitioned between ethyl acetate and 2 M aqueous hydrochloric acid. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions dried (Na2SO4) filtered and concentrated under reduced pressure to afford 4-(cyanomethylcarbamoyl)phenylboronic acid as a waxy pale yellow solid (5.34 g, 87percent). 1HNMR (J6-DMSO, 300 MHz) δ 9.18 (IH, br. t, J= 5.1Hz), 7.8-7.9 (4H, m), 4.31 (2H, d, J= 5.4 Hz). LC-MS: rt 0.9 min.; m/z 203.3 [M-H]".
87%
Stage #1: With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 40℃; for 3.5 h; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16 h;
Example 3 - Synthesis of Compound 90; To a suspension of 4-carboxyphenylboronic acid (5.0 g, 30 mmol) in DMF (5 mL) and dichloromethane (200 mL) at 0°C was added oxalylchloride (5.9 mL, 66 mmol) dropwise. When gas evolution slowed, the ice bath was removed and the reaction allowed to warm to room temperature over 30 min. The reaction was then heated at 400C for three hours by which time all solids had dissolved. The dichloromethane was removed by distillation and the DMF solution cooled to 0°C. A solution of aminoacetonitrile hydrochloride (3.05 g, 33 mmol) in DMF (80 mL) and DIPEA (13 mL, 75 mmol) was then added dropwise. After the addition was complete the ice bath was removed and the solution allowed to stir at room temperature for 16 h. Most of the DMF was then removed in vacuo and the reaction was partitioned between ethyl acetate and 2 M aqueous hydrochloric acid. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions dried (Na2SO4) filtered and concentrated under reduced pressure to afford 4-(cyanomethylcarbamoyl)phenylboronic acid as a waxy pale yellow solid (5.34 g, 87percent). 1H NMR (300 MHz, J6-DMSO): 9.18 (br. t, J- 5.1Hz, IH), 7.8-7.9 (m, 4H), 4.31 (d, J= 5.4 Hz, 2H); LC-ESI-MS (method B): rt 0.9 min.; m/z 203.3 [M-H]-.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃;
Et3N (4.1 mL, 30 mmol) was added to a mixture of compound 6(1.88 g, 5.0 mmol) in DMF (20 mL). Then aminoacetonitrile hydrochloride (0.93 g, 10 mmol) was added followed by N-hydroxybenzotriazole (HOBt, 0.81 g, 6.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 1.1 g, 6.0 mmol). The mixture was stirred overnight at room temperature. After removing the solvents under reduced pressure, the residue was dissolved in CH2Cl2 (100 mL) and washed with NaHCO3 aqueous solution. The organic phase was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography on 200–300 mesh silica with EtOAc to afford momelotinib as: Yellow solid; yield 1.86 g (90percent); m.p. 232–234 °C (lit.14 238–243 °C); IR: 3365, 3282, 1660, 1596, 1576, 1512, 1456, 1232 cm–1. Anal. calcd for C23H22N6O2: C, 66.65; H, 5.35; N, 20.28; found: C, 66.78; H, 5.49; N, 20.39percent. ESI-MS: 415.1 [M + H]+, 437.1 [M + Na]+, 413.2 [M – H]–; 1H NMR (300 MHz, DMSO-d6): δ 9.47 (s, 1H), 9.32 (t, J = 5.4 Hz, 1H), 8.54 (d, J = 5.1 Hz, 1H), 8.27 (d,J = 8.1 Hz, 2H), 8.03 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 5.1 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 4.35 (d, J = 5.1 Hz, 2H), 3.74–3.77 (m, 4H), 3.04–3.07 (m, 4H); 13C NMR (75 MHz, DMSO-d6): δ 166.1, 162.4, 160.3, 159.2, 146.2, 139.9, 134.5, 132.8, 127.8, 126.9, 120.3, 117.5, 115.6, 107.6, 66.1, 49.2, 27.7.
90%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃;
To 2g (5.3mmol) C4 was added 4.42 ml (32mmol) triethylamine, 0.98g (10.6mmol) aminoacetonitrile hydrochloride, 1.22g (6.6mmol) EDCI, and 860 ml (6.6mmol) HOBT. It was dissolved in 20mL DMF. After reacting at room temperature overnight, concentrate to dry, by adding dichloromethane, with saturated sodium bicarbonate solution, salt water after washing, concentrating, methanol used for recrystallization to obtain the yellow solid, yield 90percent.
88%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide
To a suspension of 4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzoic acid (theoretically 32.59 g, 86.6 mmol) in DMF (400 mL) was added triethylamine (72.4 mL, 519.6 mmol, 6 eq.) The mixture was sonicated to ensure dissolution. Aminoacetonitrile hydrochloride (16.02 g, 173.2 mmol) was added followed by iV-hydroxybenzotriazole (anhydrous, 14.04 g, 103.8 mmol) and l-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (19.92 g, 103.8 mmol). The suspension was stirred vigorously overnight. The solvent was evaporated under reduced pressure, the residue was diluted with 5percent sodium bicarbonate (400 mL) and water (300 mL), giving a yellow solid, which was broken up and filtered. The solids were washed several times with 100 mL portions of water, triturated with hot methanol/dichloromethane (500 mL, 1:1), concentrated to a volume of approximately 300 mL), cooled and filtered. The solids were washed with cold methanol (3 x 100 mL), ether (200 mL) and hexane (200 mL) prior to drying to afford Compound 3 (31.69 g, 88percent). M.p. 238-243°C. Microanalysis: Found C, 66.52; H, 5.41 ; N, 20.21. C23H26N6O10S2 requires C, 66.65; H, 5.35; N 20.28percent. 13C NMR (75.5MHz, J6-DMSO) δ 166.04, 162.34, 160.26, 159.14, 146.14, 139.87, 134.44, 132.73, 127.80, 126.84, 120.29, 117.49, 115.50, 107.51, 66.06, 49.16, 27.68.
24%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 20 h; Inert atmosphere
4-(2-(4-(morpholino)phenylamino) pyrimidin-4-yl) benzoic acid (0.500 g, 1.328 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.305 g, 1.594 mmol), 1-hydroxy-phenylpropyl triazole (0.215 g, 1.594 mmol), triethylamine (0.805 g, 7.968 mmol) and N,N-dimethylformamide (5 mL) were added to a flask under nitrogen protection. 2-amino-acetonitrile hydrochloride (0.368 g, 3.985 mmol) was added under stirring, and reacted for 20h under room temperature. Purified water (5mL) and saturated bicarbonate solution (5mL) were added to the reaction mixture, and there was yellow solid precipitated. After stirred for 30 mins, it was filtered and washed by clear water. The crude product was obtained after drying, and was separated and purified by preparative chromatography to obtain yellow solid desired product (0.130 g, PLC purity: 98.3percent, yield: 24percent); MS Calcd.: 414; MS Found: 415 (M+H)+; 1H NMR(400MHz, DMSO-d6) δ 9.63(1H, s), 9.38-9.35(1H, m), 8.57-8.56(1H, d), 8.29-8.27(2H, d), 8.05-8.03(2H, d), 7.74-7.71(2H, d), 7.46-7.44(1H, d), 7.07-7.05(2H, d), 4.37-4.36(2H, d), 3.80-3.78(4H, t), 3.15 ppm(4H, s).
Reference：
[1] Journal of Chemical Research, 2016, vol. 40, # 8, p. 511 - 513
[2] Patent: , 2016, , . Location in patent: Paragraph 0049; 0050; 0051; 0052; 0053; 0054
[3] Patent: WO2008/109943, 2008, A1, . Location in patent: Page/Page column 58
[4] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2902 - 2905
[5] Patent: EP2949647, 2015, A1, . Location in patent: Paragraph 0124
Reference K Synthesis of 1-aminocyclopropanecarbonitrile hydrochloride STEP 1 A mixture of benzophenone imine (25 g, 0. 138 MOL, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 mL) was stirred in a 2L Erlenmeyer flask under nitrogen at room temperature for 5 days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 mL) washed with water (200 mL) and brine. After drying over magnesium sulfate the solution was evaporated to give (BENZHYDRYLIDENEAMINO)-ACETONITRILE (47.89 g).
In dichloromethane; at 20℃; for 120h;
Reference H; Synthesis of 1-aminocyclopropanecarbonitrile hydrochloride; H2N CNDelta -HCI Step lA mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 ml) was stirred in a 2L Erlenmeyer flask under nitrogen at room temperature for 5 days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 ml) washed with water (200 ml) and brine. After drying over magnesium sulfate the solution was evaporated to give (benzhydrylideneamino)- acetonitrile (47.89 g).
In dichloromethane; at 20℃; for 120h;
Reference C Synthesis of 1-aminocyclopropanecarbonitrile hydrochlorideH2N CN Delta -HCIStep 1A mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 mL) was stirred in a 2L Erlenmeyer flask under nitrogen at room temperature for 5 days. The reaction mixture was EPO <DP n="74"/>filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 mL) washed with water (200 mL) and brine. After drying over magnesium sulfate the solution was evaporated to give (benzhydrylideneamino)-acetonitrile (47.89 g).
In dichloromethane; at 20℃; for 120h;
A mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 ml) was stirred in a 2L Erlenmeyer flask under nitrogen at room temperature for 5 days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 ml) washed with water (200 ml) and brine. After drying over magnesium sulfate the solution was evaporated to give (benzhydrylideneamino)-acetonitrile (47.89 g).
In dichloromethane; at 20℃; for 120h;
Reference K; Synthesis of l-aminocyclopropanecarbonitrile hydrochlorideH2N CN Delta -HCIAtty. Docket No. CLOO 1532 PCT 62 EPO <DP n="64"/>Step 1A mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 mL) was stirred in a 2L Erlenmeyer flask under nitrogen at room temperature for 5 days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 mL) washed with water (200 mL) and brine. After drying over magnesium sulfate the solution was evaporated to give (benzhydrylideneamino)acetonitrile (47.89 g).
In dichloromethane; at 20℃; for 120h;Inert atmosphere;
A mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 mL) was stirred in a 2L Erlenmeyer flask under nitrogen at room temperature for five days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 mL) and washed with <n="40"/>water (200 niL) and brine. After drying over magnesium sulfate, the solution was evaporated to give (benzhydrylideneamino)-acetonitrile (47.89 g).
In dichloromethane; at 20℃; for 120h;
A mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 mL) was stirred in a 2L Erlenmeyer flask under nitrogen at room temperature for 5 days. The reaction mixture was filtered to remove the precipitated aminonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 mL) washed with water (200 mL) and brine. After drying over magnesium sulfate the solution was evaporated to give (benzhydrylideneamino)-acetonitrile (47.89 g).
In dichloromethane; at 20℃; for 120h;
Synthesis Example 1 Synthesis of 1-aminocyclo?ropanecarbonitrile hydrochlorideH2N CN ? HCIA mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 mL) was stirred in a 2L Erlenmeyer flask under nitrogen at room temperature for five days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 mL) and washed with water (200 mL) and brine. After drying over magnesium sulfate, the solution was evaporated to give (benzhydrylideneamino)-acetonitrile (47.89 g).
In dichloromethane; at 20℃; for 120h;
Step 1 A mixture of benzophenone imine (25 g, 0. 138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 mL) was stirred in a 2L Erlenmeyer flask under nitrogen at room temperature for 5 days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 mL) washed with water (200 mL) and brine. After drying over magnesium sulfate the solution was evaporated to give (benzhydrylideneamino) acetonitrile (47.89 g).
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 25 - 30℃;
To a solution of hydrochloride salt of amino acetonitrile (50 g 487 mmol) dissolved in water (250 ml) and tetrahydrofuran (250 ml) was added sodium bicarbonate (90.14 g, 1073 mmol) under stirring at 25-30 C. To this was added di- ie/t-butyldicarbonate (117 g, 536 mmol) drop-wise using addition funnel. The progress of reaction was monitored by thin layer chromatography using a mixture of hexane and acetone as solvent. After complete consumption of starting material, ethyl acetate (500 ml) was added to it and organic layer was separated. The aqueous layer was re-extracted with ethyl acetate (1x250 ml). The organic extracts were combined and dried over anhydrous sodium sulfate, then concentrated to yield 66 g of tert-butyl (cyanomethyl)carbamate as a thick liquid in 86% yield
66%
With triethylamine; In dichloromethane; for 16h;Reflux;Product distribution / selectivity;
Step a: Aminoacetonitrile hydrochloride (5 g, 54 mmol) was added to dichloromethane (30 mL). A solution of di-tert-butyl dicarbonate (11.9 g, 54.6 mmol, 1.01 equiv.) and TEA (24.6 g, 33.7 mL, 243 mmol, 4.5 equiv.) in dichloromethane (25 mL) was also metered in. After completion of the addition the mixture was heated for 16 h under reflux. After the reaction mixture had cooled it was filtered, the filtrate was washed with water (50 mL), dried over magnesium sulphate and freed from solvent under reduced pressure. N-boc-aminoacetonitrile (5.58 g, 66% yield) remained as a brownish oil, which was used without further purification.
With triethylamine; In tetrahydrofuran;
Example 6 N-(BOC) amino Acetonitrile To a stirred suspension of aminoacetonitrile hydrochloride (0.1 mol) and triethyl amine (0.25 mol) in THF (150 ml) is added a solution of di-t-butyldicarbonate in THF (75 ml) at room temperature under argon. After stirring overnight, the reaction mixture is filtered and concentrated to give the title compound as an oil.
α-amino-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
157.6 g
With hydrogenchloride; aluminum (III) chloride; water; In nitromethane; at 10 - 20℃; for 16.0h;
Add to a 1000 mL reaction flask300 mL of nitromethane,Adding 203 g of anhydrous aluminum trichloride in portions, After cooling to room temperature, add 114g aminoacetonitrile hydrochloride; to a temperature below 20 C, 150 g of intermediate III (<strong>[123664-84-6]4-phenoxy-3-methanesulfonamidoanisole</strong>) was added; after stirring for 10 minutes, a dry hydrogen chloride gas was introduced, Ventilation for about 15h, the end of the reaction. The reaction solution was slowly added to 1200 g of 2 mol / L dilute hydrochloric acid at a controlled temperature of 10 C or less, for stirring 1h, filter, solid with a small amount of water (about 80mL) washing, drying; and then 150mL ethyl acetate beating, filter dry,Dry; then the solid and then twice the volume of 95% (volume percentage) of ethanol reflux lh cooling, filtration, solid bake to moisture qualified,157.6 g of the final product (alpha-amino-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone hydrochloride), 105.07% by weight, and a purity of 99.49% For 168.8 to 17.1.4 C.
Boc-1-aminocyclohexane carboxylic acid (40 mmol), HOBt (40 mmol) and WSCD (42 mmol) are dissolved in dimethylformamide (75 ml) and stirred for 15 min. at RT. 2-aminoacetonitrile hydrochloride (40 mmol) and triethylamine (40 mmol) are suspended in DMF (25 ml) and added to the reaction mixture which is stirred at 25 C. over night. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, 10% citric acid, brine, sodium bicarbonate, brine and dried over magnesium sulfate and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). 7.35 g of a white powder with mp. 160-162 C., Rf=0.28 (n-hexane:ethyl acetate=1:1) is obtained.
To a suspension of 4-carboxyphenylboronic acid (5.0 g, 30 mmol) in DMF (5 mL) and dichloromethane (200 mL) at 0C was added oxalylchloride (5.9 mL, 66 mmol) dropwise. <n="54"/>When gas evolution slowed, the ice bath was removed and the reaction allowed to warm to room temperature over 30 min. The reaction was then heated at 4O0C for 3 h by which time all solids had dissolved. The dichloromethane was removed by distillation and the DMF solution cooled to 00C. A solution of aminoacetonitrile hydrochloride (3.05 g, 33 mmol) in DMF (80 rnL) and DIPEA (13 mL, 75 mmol) was then added dropwise. After the addition was complete the ice bath was removed and the solution allowed to stir at room temperature for 16 h. Most of the DMF was then removed in vacuo and the reaction was partitioned between ethyl acetate and 2 M aqueous hydrochloric acid. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions dried (Na2SO4) filtered and concentrated under reduced pressure to afford 4-(cyanomethylcarbamoyl)phenylboronic acid as a waxy pale yellow solid (5.34 g, 87%). 1HNMR (J6-DMSO, 300 MHz) delta 9.18 (IH, br. t, J= 5.1Hz), 7.8-7.9 (4H, m), 4.31 (2H, d, J= 5.4 Hz). LC-MS: rt 0.9 min.; m/z 203.3 [M-H]".
87%
Example 3 - Synthesis of Compound 90; To a suspension of 4-carboxyphenylboronic acid (5.0 g, 30 mmol) in DMF (5 mL) and dichloromethane (200 mL) at 0C was added oxalylchloride (5.9 mL, 66 mmol) dropwise. When gas evolution slowed, the ice bath was removed and the reaction allowed to warm to room temperature over 30 min. The reaction was then heated at 400C for three hours by which time all solids had dissolved. The dichloromethane was removed by distillation and the DMF solution cooled to 0C. A solution of aminoacetonitrile hydrochloride (3.05 g, 33 mmol) in DMF (80 mL) and DIPEA (13 mL, 75 mmol) was then added dropwise. After the addition was complete the ice bath was removed and the solution allowed to stir at room temperature for 16 h. Most of the DMF was then removed in vacuo and the reaction was partitioned between ethyl acetate and 2 M aqueous hydrochloric acid. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions dried (Na2SO4) filtered and concentrated under reduced pressure to afford 4-(cyanomethylcarbamoyl)phenylboronic acid as a waxy pale yellow solid (5.34 g, 87%). 1H NMR (300 MHz, J6-DMSO): 9.18 (br. t, J- 5.1Hz, IH), 7.8-7.9 (m, 4H), 4.31 (d, J= 5.4 Hz, 2H); LC-ESI-MS (method B): rt 0.9 min.; m/z 203.3 [M-H]-.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;
Et3N (4.1 mL, 30 mmol) was added to a mixture of compound 6(1.88 g, 5.0 mmol) in DMF (20 mL). Then aminoacetonitrile hydrochloride (0.93 g, 10 mmol) was added followed by N-hydroxybenzotriazole (HOBt, 0.81 g, 6.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 1.1 g, 6.0 mmol). The mixture was stirred overnight at room temperature. After removing the solvents under reduced pressure, the residue was dissolved in CH2Cl2 (100 mL) and washed with NaHCO3 aqueous solution. The organic phase was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography on 200-300 mesh silica with EtOAc to afford momelotinib as: Yellow solid; yield 1.86 g (90%); m.p. 232-234 C (lit.14 238-243 C); IR: 3365, 3282, 1660, 1596, 1576, 1512, 1456, 1232 cm-1. Anal. calcd for C23H22N6O2: C, 66.65; H, 5.35; N, 20.28; found: C, 66.78; H, 5.49; N, 20.39%. ESI-MS: 415.1 [M + H]+, 437.1 [M + Na]+, 413.2 [M - H]-; 1H NMR (300 MHz, DMSO-d6): delta 9.47 (s, 1H), 9.32 (t, J = 5.4 Hz, 1H), 8.54 (d, J = 5.1 Hz, 1H), 8.27 (d,J = 8.1 Hz, 2H), 8.03 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 5.1 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 4.35 (d, J = 5.1 Hz, 2H), 3.74-3.77 (m, 4H), 3.04-3.07 (m, 4H); 13C NMR (75 MHz, DMSO-d6): delta 166.1, 162.4, 160.3, 159.2, 146.2, 139.9, 134.5, 132.8, 127.8, 126.9, 120.3, 117.5, 115.6, 107.6, 66.1, 49.2, 27.7.
90%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;
To 2g (5.3mmol) C4 was added 4.42 ml (32mmol) triethylamine, 0.98g (10.6mmol) aminoacetonitrile hydrochloride, 1.22g (6.6mmol) EDCI, and 860 ml (6.6mmol) HOBT. It was dissolved in 20mL DMF. After reacting at room temperature overnight, concentrate to dry, by adding dichloromethane, with saturated sodium bicarbonate solution, salt water after washing, concentrating, methanol used for recrystallization to obtain the yellow solid, yield 90%.
88%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide;
To a suspension of 4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzoic acid (theoretically 32.59 g, 86.6 mmol) in DMF (400 mL) was added triethylamine (72.4 mL, 519.6 mmol, 6 eq.) The mixture was sonicated to ensure dissolution. Aminoacetonitrile hydrochloride (16.02 g, 173.2 mmol) was added followed by iV-hydroxybenzotriazole (anhydrous, 14.04 g, 103.8 mmol) and l-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (19.92 g, 103.8 mmol). The suspension was stirred vigorously overnight. The solvent was evaporated under reduced pressure, the residue was diluted with 5% sodium bicarbonate (400 mL) and water (300 mL), giving a yellow solid, which was broken up and filtered. The solids were washed several times with 100 mL portions of water, triturated with hot methanol/dichloromethane (500 mL, 1:1), concentrated to a volume of approximately 300 mL), cooled and filtered. The solids were washed with cold methanol (3 x 100 mL), ether (200 mL) and hexane (200 mL) prior to drying to afford Compound 3 (31.69 g, 88%). M.p. 238-243C. Microanalysis: Found C, 66.52; H, 5.41 ; N, 20.21. C23H26N6O10S2 requires C, 66.65; H, 5.35; N 20.28%. 13C NMR (75.5MHz, J6-DMSO) delta 166.04, 162.34, 160.26, 159.14, 146.14, 139.87, 134.44, 132.73, 127.80, 126.84, 120.29, 117.49, 115.50, 107.51, 66.06, 49.16, 27.68.
24%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 20.0h;Inert atmosphere;
4-(2-(4-(morpholino)phenylamino) pyrimidin-4-yl) benzoic acid (0.500 g, 1.328 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.305 g, 1.594 mmol), 1-hydroxy-phenylpropyl triazole (0.215 g, 1.594 mmol), triethylamine (0.805 g, 7.968 mmol) and N,N-dimethylformamide (5 mL) were added to a flask under nitrogen protection. 2-amino-acetonitrile hydrochloride (0.368 g, 3.985 mmol) was added under stirring, and reacted for 20h under room temperature. Purified water (5mL) and saturated bicarbonate solution (5mL) were added to the reaction mixture, and there was yellow solid precipitated. After stirred for 30 mins, it was filtered and washed by clear water. The crude product was obtained after drying, and was separated and purified by preparative chromatography to obtain yellow solid desired product (0.130 g, PLC purity: 98.3%, yield: 24%); MS Calcd.: 414; MS Found: 415 (M+H)+; 1H NMR(400MHz, DMSO-d6) delta 9.63(1H, s), 9.38-9.35(1H, m), 8.57-8.56(1H, d), 8.29-8.27(2H, d), 8.05-8.03(2H, d), 7.74-7.71(2H, d), 7.46-7.44(1H, d), 7.07-7.05(2H, d), 4.37-4.36(2H, d), 3.80-3.78(4H, t), 3.15 ppm(4H, s).
Step 1: 2-Chloro-5-(3-(cyanomethyl)triaz-l-en-l-yl)benzonitrile 2a [00151] <strong>[35747-58-1]5-amino-2-chloro-benzonitrile</strong> (800 mg, 5.243 mmol) was dissolved in hydrochloric acid (12.06 mL of 2 M, 24.12 mmol) and diluted with water (16 mL) and cooled to 0C. Sodium nitrite (362 mg, 167 mu,, 5.24 mmol) was added and the reaction was stirred at 0C for 20 min and then a solution of 2-aminoacetonitrile monohydrochloride (485 mg, 5.24 mmol) in water (6 mL) was slowly added. The mixture was stirred for 10 min at 0C and sodium acetate (6.04 g, 73.61 mmol) was then added and the mixture allowed to warm to room temperature and stirred for 1 h. The precipitate was collected by filtration and washed with water to afford the title compound 2a as a tan colored solid. MS m/z: 220.1 (M + H)+.
General procedure: For the aryl alpha-iminonitriles, a suspension of aminoacetonitrile hydrochloride (0.37 g, 4.0 mmol) and Et3N (1.0 mL, 7.2 mmol) in ethanol (10 mL) was stirred at room temperature for 0.5 h. To the resulting solution was added the corresponding aldehyde (2.0 mmol). After the reaction mixture was stirred for 1-2 h, the solvent was removed in vacuo. The residue was then diluted with EtOAc and washed with brine, dried over MgSO4, filtered and concentrated under in vacuo. The crude alpha-iminonitrile was used in next step without further purification.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 25℃; for 2.5h;
<strong>[131747-43-8]2-trifluoromethylpyridine-3-carboxylic acid</strong> (0.191 g, 1.0 mmol)And aminoacetonitrile hydrochloride (0.081 g, 1.0 mmol)Dissolved in 25 mL of dichloromethane,Add triethylamine (0.202 g, 2.0 mmol),Then EDCI (0.287 mg, 1.5 mmol) was added.HOBt (0.20g, 1.5mmol),Reaction at 25 C for 2.5 h,TLC detects the reaction completely,The reaction solution was washed with water (20 ml*2),Saturated saline solution (20ml*1),Dry over anhydrous sodium sulfate,Desolvent, get crude,Crude column chromatography gave an off-white solid.M.p. 90-93 C, yield: 79.5%.
With sodium carbonate; In water; toluene; at 10 - 30℃; for 5h;
In a 1000 ml four-necked flask equipped with a thermometer and a dropping funnel, 33.3 g (0.314 mol) of sodium carbonate and 133.2 g of tap water were charged, and after stirring for 10 minutes, 120 ml of toluene was added, and aminoacetonitrile hydrochloride was 21.79 g (0.235). Mol), then the temperature is lowered to 10 C under stirring, and the dropwise addition of <strong>[81565-19-7]4-(trifluoromethyl)nicotinyl chloride</strong> solution is started. The addition is completed in about 3 hours, the temperature is maintained at 10-15 C, and the addition is completed. After incubation at 30 C for 2 hours, the reaction was completed, filtered, and the product was washed with 30 ml of water to obtain a white solid product, N-cyanomethyl-4-(trifluoromethyl)nicotinamide.The purity was 99.8%, and the yield was 93.2% based on 4-(trifluoromethyl)nicotinic acid.
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