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Structure of 6011-14-9 * Storage: {[proInfo.prStorage]}
* 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.
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
With sodium nitrite; In diethyl ether; water; at 0 - 20℃; for 2h;
A suspension of aminoacetonitrile hydrochloride (1.56 g, 16.80 mmol) in diethyl ether (20 mL) was cooled to 0C and was treated dropwise with a cold solution of sodium nitrite (1.06 g, 15.3 mmol) in water (4.0 mL). The cooling bath was removed, and the reaction mixture was vigorously stirred at ambient temperature for 2 h. The yellow organic phase containing the diazoacetonitrile was separated, washed with brine, and carefully concentrated to a volume of not less than 10 mL. This solution was then combined with a solution of the ester-nitrile from Step F (1.00 g, 1.5297 mmol) in dichloromethane (4 mL). The reaction mixture was kept at ambient temperature in darkness for 4 weeks. After this time, the entire reaction mixture was loaded onto a silica-gel column, and eluted with a mixture of hexanes and ethyl acetate (gradient, 0 to 80 % of EtOAc). Evaporation of the appropriate fractions afforded the desired product. LCMS for C39H39N309 calculated: 693.27, found 694.60 [M + H]+. 'H NMR (500 MHz, CDCl3) : No. 12.04 (bs, 1H), 8.90 (d, J = 8.0 Hz, 2H), 8.0 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 8.24 Hz, 2H), 7.24 (m, 5H), 7.04 (d, J = 8.0 Hz, 2H), 6.21 (s, 1H), 5.65 (m, 1 H), 5.13 (dd, J = 11.7, 0.4 Hz, 1H), 4.74 (m, 1H), 4.58 (dt, J = 9.2,2.5 Hz, 1H), 2.45 (s, 3H), 2.42 (s, 3H), 2.33 (s, 3H), 1.71 (s, 9H), 1.65 (s, 3H). ¹3C NMR (CDCl3,500 MHz): 8 165.6,165.4, 159.8,144.7, 144.3,144.0, 143.3,130.2, 130.0, 129.7, 129.3, 129.0, 126.7, 126.4, 125.9, 112.9, 84.3, 83.1, 83.0,77.8, 77.2, 77.1, 76.7, 64.1, 31.5, 28.2,22.6, 21.7, 21.7, 21.6,19.5, 14.1.
To a cold (0 oC) solution of aminoacetonitrile hydrochloride (1. 0 g, 10. 8 mmol) in pyridine (10 ML) was added p-toluenesulfonyl chloride (1. 0 g, 5. 2 mmol). The resultant mixture was stirred for 30 minutes at 0 oC. Water was added to the cold reaction mixture. The solids were collected on a filter and washed with cold water. The solids were placed in a flask and azeotroped with methanol to give N (cyanomethyl)-4-methylbenzenesulfonamide (1. 03 g, 94%) as a white SOLID. H NMR (CDC13) : 5 7. 79 (d, J= 8. 4 Hz, 2 H), 7. 37 (d, J=8. 4HZ, 2H), 4. 82 (broad, 1 H), 4. 03 (d, J= 6. 8 Hz, 2 H), 2. 46 (s, 3 H) ; MS m/z 233 (M+Na).
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.
With potassium carbonate; In tetrahydrofuran; water; at 5 - 20℃; for 15h;Inert atmosphere;
To a solution of aminoacetonitrile hydrochloride (25.27 g) and K2C03 (109.80 g) in THF/H20 (200 mL/400 mL) at 5-10C was added benzyl chloroformate (45.22 g) under an atmosphere of nitrogen. The mixture was stirred at room temperature for 15 h and then quenched with NH4C1(aq) (100 mL, 2 M). The resulting mixture was extracted with ethyl acetate (3x200 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to get the crude product S-VI-II (46.88 g, y: 90%).
1.7 g
With sodium hydrogencarbonate; In 1,4-dioxane; water; toluene; at 0 - 20℃; for 12h;
A mixture of <strong>[6011-14-9]2-aminoacetonitrile hydrochloride</strong> (5 g, 54.0 mmol), NaHC03(18.16 g, 216 mmol) and dioxane (50 mL) in H20 (100 mL) was stirred at 0C. Then a solution of benzyl carbonochloridate (1 1.06 g, 64.8 mmol, 9.22 mL) in toluene (10 mL) was added at 0C and stirred at 20C for 12 hours. The mixture was poured into water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mLchi3).The combined organic phases were washed with brine (100 mL), dried with anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give benzyl(cyanomethyl)carbamate (1 .70 g).1H NMR (chloroform-c/400 MHz): 7.40-7.31 (m, 5H), 5.35- 5.13 (m, 3H), 4.16-4.12 (m, 2H).
1.7 g
With sodium hydrogencarbonate; In 1,4-dioxane; water; toluene; at 0 - 20℃; for 12h;
A mixture of <strong>[6011-14-9]2-aminoacetonitrile hydrochloride</strong> (5 g, 54.0 mmol), NaHCC>3 (18.16 g, 216 mmol) and dioxane (50 mL) in H2O (100 mL) was stirred at 0C. Then a solution of benzyl carbonochloridate (11.06 g, 64.8 mmol, 9.22 mL) in toluene (10 mL) was added at 0C and stirred at 20C for 12 hours. The mixture was poured into water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL c 3).The combined organic phases were washed with brine (100 mL), dried with anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give benzyl (cyanomethyl)carbamate (1.70 g). 1H NMR (chloroform-d 400 MHz): 7.40-7.31 (m, 5H), 5.35-5.13 (m, 3H), 4.16-4.12 (m, 2H).
1.7 g
mixture of 214 <strong>[6011-14-9]2-aminoacetonitrile hydrochloride</strong> (5 g, 54.0 mmol), 37 NaHCO3 (18.16 g, 216 mmol) and 136 dioxane (50 mL) in 99 H2O (100 mL) was stirred at 0 C. Then a solution of 215 benzyl carbonochloridate (11.06 g, 64.8 mmol, 9.22 mL) in 119 toluene (10 mL) was added at 0 C. and stirred at 20 C. for 12 hours. The mixture was poured into water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give 216 benzyl (cyanomethyl)carbamate (1.70 g). 1H NMR (chloroform-d 400 MHz): 7.40-7.31 (m, 5H), 5.35-5.13 (m, 3H), 4.16-4.12 (m, 2H).
1.7 g
With sodium hydrogencarbonate; In 1,4-dioxane; water; toluene; at 0 - 20℃; for 12h;
A mixture of <strong>[6011-14-9]2-aminoacetonitrile hydrochloride</strong> (5 g, 54.0 mmol), NaHCC>3 (18.16 g, 216 mmol) and dioxane (50 mL) in H2O (100 mL) was stirred at 0C. Then a solution of benzyl carbonochloridate (11.06 g, 64.8 mmol, 9.22 mL) in toluene (10 mL) was added at 0C and stirred at 20C for 12 hours. The mixture was poured into water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL c 3).The combined organic phases were washed with brine (100 mL), dried with anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give benzyl (cyanomethyl)carbamate (1.70 g). 1H NMR (chloroform-d 400 MHz): 7.40-7.31 (m, 5H), 5.35-5.13 (m, 3H), 4.16-4.12 (m, 2H).
Step c) 2-(Cyanomethyl)-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylic acid methyl ester To a solution of 3-methoxy-1-oxo-1H-2-benzopyran-4-carboxylic acid methyl ester (8.09, 34.19 mmol) in DMF (100 mL) was added aminoacetonitrile hydrochloride (6.32 g, 68.37 mmol) and the suspension was stirred until all the materials have dissolved. Triethylamine (14.3 mL, 102.57 mmol) was added and the mixture was stirred at 100 C. for 30 minutes, and then poured into H2 O, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from acetone/ether/hexane (at -20 C.) gave a yellowish solid (6.5 g, 73.7%); M.P. 169-171 C. IR (KBr, cm-1): 3400 (OH), 1670 (C=O); 1 H NMR (DMSO-d6, 400 MHz): d (3.7, 3.98, s, 3H, --CO2 CH3, rotameric), (4.92, 5.44, s, 2H, --NCH2 CN, rotameric), 7.2-8.4 (m, 4H, Ar--H, rotomeric; MS(m/e): 258 (20, M+), 226 (43, M+ --MeOH), 199 (13, M+ --CO2 Me). Anal. Calcd: C, 60.47; H, 3.90; N, 10.85; Found: C, 60.27; H, 3.77; N, 10.69.
73.7%
With triethylamine; In N,N-dimethyl-formamide;
Step c) 2-(Cyanomethyl)-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylic Acid Methyl Ester To a solution of 3-methoxy-1-oxo-1H-2-benzopyran-4-carboxylic acid methyl ester (8.09 g, 34.19 mmol) in DMF (100 mL) was added aminoacetonitrile hydrochloride (6.32 g, 68.37 mmol) and the suspension was stirred until all the materials had dissolved. Triethylamine (14.3 mL, 102.57 mmol) was added and the mixture was stirred at 100 C. for 30 minutes, and then poured into H2 O, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from acetone/ether/hexane (at -20 C.) gave a yellowish solid (6.5 g, 73.7%). 1 H NMR (DMSO-d6, 400 MHz): delta (3.7, s, 3.98, s, 3H, --CO2 CH3, rotameric), (4.92, s, 5.44, s, 2H, --NCH2 CN, rotameric), 7.2-8.4 (m, 4H, Ar--H, rotomeric; IR (KBr, cm-1): 3400 (OH), 1670 (C=O); MS (m/e): 258 (20, M+), 226 (43, M+ --MeOH), 199 (13, M+ --CO2 Me). Anal. Calcd.: C, 60.47; H, 3.90; N, 10.85. Found: C, 60.27; H, 3.77; N, 10.69.
73.7%
With triethylamine; In N,N-dimethyl-formamide;
Step c 2-(Cyanomethyl)-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylic Acid Methyl Ester To a solution of 3-methoxy-1-oxo-1H-2-benzopyran-4-carboxylic acid methyl ester (8.0 g, 34.19 mmol) in DMF (100 mL) was added aminoacetonitrile hydrochloride (6.32 g, 68.37 mmol) and the suspension was stirred until all the materials have dissolved. Triethylamine (14.3 mL, 102.57 mmol) was added and the mixture was stirred at 100 C. for 30 minutes, and then poured into H2 O, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from acetone/ether/hexane (at -20 C.) gave a yellowish solid (6.5 g, 73.7%). 1 H NMR (DMSO-d6, 400 MHz): delta [3.7 (s), 3.98 (s), 3H, --CO2 CH3, rotameric], [4.92 (s), 5.44 (s), 2H, --NCH2 CN, rotameric], 7.2-8.4 (m, 4H, Ar-H, rotameric). IR (KBr, cm-1): 3400 (OH), 1670, (C=O). MS (m/e): 258 (20, M+), 226 (43, M+ --MeOH), 199 (13, M+ --CO2 Me). Anal. Calcd.: C, 60.47; H, 3.90; N, 10.85. Found: C, 60.27; H, 3.77; N, 10.69.
73.7%
With triethylamine; In N,N-dimethyl-formamide;
Step H) 2-(Cyanomethyl)-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinoline carboxylic Acid Methyl Ester To a solution of 3-methoxy-1-oxo-1H-2-benzopyran-4-carboxylic acid methyl ester (8.0 g, 34.19 mmol) in DMF (100 mL) was added aminoacetonitrile hydrochloride (6.32 g, 68.37 mmol) and the suspension was stirred until all the materials have dissolved. Triethylamine (14.3 mL, 102.57 mmol) was added and the mixture was stirred at 100 C. for 30 minutes, and then poured into H2 O, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from acetone/ether/hexane (at -20 C.) gave a yellowish solid (6.5 g, 73.7%). 1 H NMR (DMSO-d6, 400 MHz): delta[3.7 (s), 3.98 (s), 3H, --CO2 CH3, rotameric], [4.92 (s), 5.44 (s), 2H, --NCH2 CN, rotameric], 7.2-8.4 (m, 4H, Ar-H, rotameric). IR (KBr, cm-1): 3400 (OH), 1670 (C=O). MS (m/e): 258 (20, M+), 226 (43, M+ --MeOH), 199 (13, M+ --CO2 Me). Anal. Calcd.: C, 60.47; H, 3.90; N, 10.85; Found: C, 60.27; H, 3.77; N, 10.69.
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.
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;
To a DMF (200 mL) solution of the acid from Step 7 (9 g) was added benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (11.6 g), aminoacetonitrile hydrochloride (3.94 g) and the mixture was cooled to 00C. Triethylamine (9.9 mL) was added dropwise and the mixture warmed to room temperature and stirred for 16 hours. It was poured into ice and saturated aqueous sodium bicarbonate and extracted with diethyl ether (3 X 100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes (1:1). The title compound was then stirred in diethyl ether for 16 hours, filtered and dried (mp 140.50C).1H NMR (CD3COCD3) delta 8.0(2H, d), 7.95(2H, d), 7.8(2H, d), 7.65(2H, d), 4.35-4.45(1H, m), 4.1-4.2(2H, m), 3.45-3.55(lH, m), 3.15(3H, s), 2.65-2.7(1H, m), 1.85-1.95(1H, m), 1.4-1.6(2H, m), 0.85-0.95(6H, m)
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In acetonitrile; at 0 - 20℃; for 16h;
To a DMF (200 mL) solution of the acid from Step 7 (9 g) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (11.6 g), aminoacetonitrile hydrochloride (3.94 g) and the mixture was cooled to 0 C. Triethylamine (9.9 mL) was added dropwise and the mixture warmed to room temperature and stirred for 16 hours. It was poured into ice and saturated aqueous sodium bicarbonate and extracted with diethyl ether (3×100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes (1:1). The title compound was then stirred in diethyl ether for 16 hours, filtered and dried (mp 140.5 C.).
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 16h;
Step 7 : Preparation of N1(cyanomethyl)-N2{(1S)-2,2,2-trifluoro-1-[4'-(methylsulfonyl)-1,1'- BIPHENYLLETHYL}-L-LEUCINAMIDE; To a DMF (200 ML) solution of the acid from Step 7 (9 g) was added benzotriazol-1- yloxytris (dimethylamino) phosphonium hexafluorophosphate (11.6 g), aminoacetonitrile hydrochloride (3.94 g) and the mixture was cooled to 0 C. Triethylamine (9.9 ML) was added dropwise and the mixture warmed to room temperature and stirred for 16 hours. It was poured into ice and saturated aqueous sodium bicarbonate and extracted with diethyl ether (3 X 100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on SIO2USING ethyl acetate and hexanes (1: 1). The title compound was then stirred in diethyl ether for 16 hours, filtered and dried (mp 140.5 C). 1H NMR (CD3COCD3) 6 8.0 (2H, d), 7.95 (2H, d), 7.8 (2H, d), 7.65 (2H, d), 4.35-4. 45 (1H, m), 4.1-4. 2 (2H, m), 3.45-3. 55 (1H, m), 3.15 (3H, s), 2.65-2. 7 (1H, m), 1.85-1. 95 (1H, m), 1.4-1. 6 (2H, m), 0. 85-0. 95 (6H, m).
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; at 0 - 20℃; for 16h;
Step 7: Preparation of NL (CYANOMETHYL)-N2T (1 S)-2. 2. 2-TRIFLUORO-1-F4 -(METHYLSULFONYL)-1. 1 - BIPHENYL-4-VLLETHYL}-L-LEUCINAMIDE; To a DMF (200 mL) solution of the acid from Step 7 (9 g) was added benzotriazol-1- yloxytris (dimethylamino) phosphonium hexafluorophosphate (11.6 g), aminoacetonitrile hydrochloride (3.94 g) and the mixture was cooled to 0 C. Triethylamine (9.9 mL) was added dropwise and the mixture warmed to room temperature and stirred for 16 hours. It was poured into ice and saturated aqueous sodium bicarbonate and extracted with diethyl ether (3 X 100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on SIO2USING ethyl acetate and hexanes (1: 1). The title compound was then stirred in diethyl ether for 16 hours, filtered and dried (mp 140.5 C). 1H NMR (CD3COCD3) 8 8.0 (2H, d), 7.95 (2H, d), 7.8 (2H, d), 7.65 (2H, d), 4.35-4. 45 (1H, m), 4.1-4. 2 (2H, m), 3.45-3. 55 (1H, m), 3.15 (3H, s), 2.65-2. 7 (1H, m), 1.85-1. 95 (1H, m), 1.4-1. 6 (2H, m), 0.85-0. 95 (6H, m).
With benzotriazol-1-ol; In DMF (N,N-dimethyl-formamide); at 0 - 25℃;
Fmoc-Leucine (0.27 mmol) and aminoacetonitrile hydrochloride (32.4 mmol) are dissolved in dimethylformamide (300 ml) and cooled with ice-salt. HOBt (32.4 mmol) and WSCD (32.4 mmol) are added, and the reaction mixture is stirred at 4-25 C. over night. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with saturated sodium bicarbonate, 1N hydrochloric acid and brine, dried over magnesium sulfate and the solvent is evaporated. Chromatography on silica gel using n-hexane/ethyl acetate=1/1 (v/v) gives the product in 90% yield. mp. 173-175 C., Rf=0.68 (chloroform:methanol:acetic acid=90:10:1).
2-tert-Butyloxycarbonylamino-3-methyl-pentanoic acid cyanomethyl-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With benzotriazol-1-ol; In DMF (N,N-dimethyl-formamide); water; at 20℃; for 1h;
A. 2-tert-Butyloxycarbonylamino-3-methyl-pentanoic acid cyanomethyl-amide N-Tertbutyloxycarbonyl-isoleucine semihydrate (3 g, 12.5 mmol), HOBt (3.71 g, 27.5 mmol, 2.2 eq.) and aminoacetonitrile hydrochloride (1.27 g, 13.7 mmol, 1.1 eq.) are dissolved in dimethylformamide (36 ml) and WSCD (2.5 ml, 13.7 mmol, 1.1 eq.) is added.. After stiring for 1 hour at rt, 4% sodium bicarbonate solution is added and the mixture is extracted with ethyl acetate.. The organic layer is washed with sodium bicarbonate and dilute hydrochloric acid, dried over magnesium sulfate and evaporated, to give the product in quantitative yield. mp. 125-133.5 C., Rf=0.44 (hexanes:ethyl acetate=1:1)
[2-(cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃;
To a solution of (10.33 g, 42.46 mmol) acid in DMF (85 ml) were added aminoacetonitrile HCl salt (4.32 g, 46.70 mmol), EDCI (8.95 g, 46.70 mmol), HOBT (6.31 g (46.70 mmol), and N-methylmorpholine (14.0 ml, 127.38 mmol). The reaction mixture was stirred at room temperature overnight, partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated. Recrystallization in ethyl acetate:hexane (1:15), provided [2-(cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (8.05 g, 70%).
2-[(benzenesulfonyliminomethyl)amino]-3-cyclohexyl-propionic acid[ No CAS ]
[ 6011-14-9 ]
N-cyanomethyl-2(S)-[(benzenesulfonyliminomethyl)amino]-3-cyclohexylpropionamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0℃; for 2h;
A mixture of ethyl dimethylaminopropylcarbodiimide hydrochloride (0.270 g, 1.14mmol), hydroybenzotriazole (0.184 g, 1.2 mmol) and aminoacetonitrile hydrochloride (0.130 g,1.4 mmol) in methylene chloride (2.5 mL) was cooled in an ice bath and then treated with 2-[(benzenesulfonylimino-methyl)amino]-3-cyclohexyl-propionic acid (0.386 g, 1.14 mmol) inmethylene chloride (3 mL). JV-methylmorpholine (0.155 g, 1.55 mmol) was added to thereaction mixture was then stirred at room temperature for 2 h. The reaction mixture was dilutedwith ice water and the product extracted with ethyl acetate. The extracts were washed withaqueous sodium bicarbonate, then brine, then dried over magnesium sulfate and evaporated.The resulting oil was crystallized from methylene chloride to give JV-cyanomethyl-2iS'-[(benzenesulfonyliminomethyl)-amino]-3-cyclohexyl-propionamide (0.218 g, 51%)..H NMR (DMSO-d6): 6 9.24 (dd, J=7Hz, 5 Hz, 1H), 8.97 (t, J=5Hz, 1H), 8.15 (d, J= 5Hz, 1H), 7.73 (m, 2H), 7.56 (m, 3H), 4.5 (m, 1H), 4.14 (d, J=5Hz, 2H), 1.53 (m, 7H), 1.1 (m,3H), 0.94 (m, 3H): Exact mass 376.16. Found: M+H = 376.8, M+Na = 399.2, M-H = 375.0.
With (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 0.166667h;
Preparation Example E-1 Quinoline-6-carboxylic acid cyanomethyl-amide To a solution of quinoline-6-carboxylic acid (500mg, 2.9mmol) and amino acetonitrile hydrochloride (320mg, 3.4mmol) in N,N-dimethylformamide (10mL) were added benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (1.5g, 3.48mmol) and triethylamine (1.2mL, 8.7mmol), and the solution was stirred at 60C for 10 minutes. Ethyl acetate and water was added to the reaction solution, which was then partitioned, the organic layer was washed twice with water. Silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, purified by NH silica gel column chromatography (ethyl acetate), and the title compound (420mg, 2.0mmol, 68.9%) was obtained as a light brown solid. 1H-NMR Spectrum (DMSO-d6) delta (ppm): 4.43 (2H, d, J=5.6Hz), 7.65 (1H, dd, J=4.0, 8.4Hz), 8.14 (1H, d, J=8.8Hz), 8.18-8.22 (1H, m), 8.30-8.35 (1H, m), 8.58 (1H, d, J=1.2Hz), 9.02-9.05 (1 H, m), 9.49 (1 H, t, J=5.6Hz).
68.9%
With (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 0.166667h;
To a solution of quinoline-6-carboxylic acid (500mg, 2.9mmol) and amino acetonitrile hydrochloride (320mg, 3.4mmol) in N,N-dimethylformamide (10mL) were added benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (1.5g, 3.48mmol) and triethylamine (1.2mL, 8.7mmol), and the solution was stirred at 60C for 10 minutes. Ethyl acetate and water was added to the reaction solution, which was then partitioned, the organic layer was washed twice with water. Silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, purified by NH silica gel column chromatography (ethyl acetate), and the title compound (420mg, 2.0mmol, 68.9%) was obtained as a light brown solid. 1H-NMR Spectrum (DMSO-d6) delta(ppm) : 4.43 (2H, d, J=5.6Hz), 7.65 (1H, dd, J=4.0, 8.4Hz), 8.14 (1H, d, J=8.8Hz), 8.18-8.22 (1H, m), 8.30-8.35 (1H, m), 8.58 (1H, d, J=1.2Hz), 9.02-9.05 (1H, m), 9.49 (1H, t, J=5.6Hz).
EXAMPLE 6 Preparation of 5-methyl-1-oxypyrazin-2-amine Isonitrosoacetone (18.7 g; 0.21 mol) and methylmorpholine (22.0 g; 0.213 mol) were charged initially with chloroform (200 ml) into a flask under argon. At 65 C., aminoacetonitrile hydrochloride (24.35 g; 0.257 mol) was added a little at a time over 2 hours, and stirring was continued for a further 2 hours at this temperature. At 20 C., water (80 ml) and HCl (32 percent strength; 12.9 g) were then added. The crude solution was filtered through celite and the phases were then separated. The aqueous phase was adjusted to pH 11 using NaOH (30 percent strength; 71.0 g). The product was extracted with 2-methyl-2-butanol (4 times 60 ml each time) at 40 C. The organic phase was completely removed by distillation. 7.68 g of the product, corresponding to a yield of 30 percent, was obtain. Other data concerning the product was: NMR (DMSO-d6) (400 MHz): 2.24 (s, 3H); 6.70 (s, 2H); 8.02 (s, 2H).
EXAMPLE X17 2H-(5-Methyl-1,3-dihydroisoindole)-2-acetonitrile The title compound was prepared from 16 g (84 mmole) of <strong>[2735-06-0]1,2-bischloromethyl-4-methylbenzene</strong>, 10 g (100 mmole) of aminoacetonitrile hydrochloride and 44 ml (322 mmole) of triethylamine by an analogous method to that described in Example X1. 1 H-nmr delta (CDCl3):
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).
<strong>[6011-14-9]2-aminoacetonitrile hydrochloride</strong> salt (3.67 g, 39.7 mmol) was added to a solution of 2-nitrobenzaldehyde (5.00 g, 33.1 mmol) dissolved in anhydrous MeOH (30 mL). The reaction was stirred at room temperature for 5 minutes to achieve solution. NaCNBH3 (2.08 g, 33.1) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, then diluted with EtOAc (50 mL). The organics phase was washed with saturated NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated to give 4.20 g (22.0 mmol, 66% yield) of 2-(2-nitrobenzylamino)acetonitrile (1) as a tan oil 4.20 g (22.0 mmol, 66% yield). The material was used without purification in the next step.
To a solution of compound 8 (40mg, O. lmmol) in THF (3mL) and methonal (I mL) was added water (1 mL) and lithium hydroxide (8mg, 0.3mmol). The reaction was stirred at rt 17 h, then ~5mL of 5% aq. citric acid added and the methanol and THF removed. The precipitate that formed was collected by filtration and washed with water to afford the acid as a yellow solid (37.5mg, 98%). To a suspension of the acid (37mg, O.lmmol) in DCM (2mL) and DMF (ImL) was added triethylamine (72muL, 0.52mmol) and HATU (59mg, 0.16mmol). The reaction was sonicated for one minute then aminoacetonitrile hydrochloride (19.3mg, 0.2mmol) WAS added and the reaction allowed to stir at room temperature 16 h. The reaction was diluted with EtOAc and saturated aq. NaHCO3, the layers partitioned and the aqueous layer extracted twice further with EtOAc. The combined aqueous fractions were washed with water and brine, dried (Na2SO4) filtered and evaporated to afford compound 17 as a yellow solid (35mg, 86%).
4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-benzoic acid[ No CAS ]
[ 6011-14-9 ]
N-cyanomethyl-4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 24 - 48h;
Step E. N-Cyanomethyl-4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-benzamide. Isomer 1 4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-benzoic acid, isomer 1 (220 mg, 0.47 mmol) is mixed with dichloromethane (5 mL). Triethylamine (0.20 mL, 1.4 mmol), DMAP (5 mg), aminoacetonitrile hydrochloride (65 mg, 0.70 mmol), and EDCI (270 mg, 1.4 mmol) are added and the reaction stirred at room temperature for 24-48 h. The reaction mixture is loaded onto a silica gel column and eluted with hexanes using a gradient of 0-100% ethyl acetate to provide 160 mg (68%) of the titled compound.
4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid[ No CAS ]
[ 6011-14-9 ]
4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-N-cyanomethyl-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine; In tetrahydrofuran; at 20℃; for 24h;
Step C: 4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-N-cyanomethyl-benzamide, Isomer 1 4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid (1.00 g, 2.25 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (593 mg, 3.38 mmol) is stirred in THF (25 mL) under nitrogen. N-Methyl morpholine (0.37 mL, 3.38 mmol) is added followed by addition of aminoacetonitrile hydrochloride (229 mg, 2.48 mmol) and the mixture stirred at room temperature for 24 h. The reaction is filtered and the resulting filtrate concentrated and purified by silica gel chromatography, eluding with hexanes using a gradient of 0-100% ethyl acetate to provide 806 mg (74%) of the titled compound as a white solid. 1H NMR.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 2h;
To a solution of 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid (350 mg, 1.08 mmol) in DMF (10 mL) is added DIPEA (0.94 mL, 5.4 mmol) and HATU (490 mg, 1.29 mmol). After being stirred at 25 C., aminoacetonitrile hydrochloride (19 mg, 1.29 mmol) is added. The mixture is stirred for 2 h, and diluted with EtOAc (20 mL) and washed with H2O (3×10 mL). The organic layer is dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography (CH2Cl2/MeOH: 97%/3%) to give 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid cyanomethyl-amide (280 mg, 72%).1H-NMR (400 MHz, CDCl3) delta=1.97 (4H, m), 2.25 (3H, s), 2.36 (3H, s), 2.58 (1H, m), 3.07 (2H, t), 3.67 (2H, d), 4.12 (2H, d), 4.44 (2H, s), 7.14 (2H, d), 7.31 (3H, m).MS (m/z, MH+) meas. 364.3.
General procedure: 2-Aminoacetonitrile hydrochloride 2 (7.0 mmol) and sodium acetate (8.0 mmol) were dissolved in 35 mL of methanol. Aldehyde 1 (7.0 mmol) was added to the grey solution, and the reaction mixture was stirred at room temperature. A solid suspension was formed after a few minutes (for compounds 3a, 3c, 3f and 3g). The suspension was stirred for 2 h and the solid filtered and washed with cold methanol, leading to the pure product 3. A second crop was isolated from the mother liquor after complete removal of methanol in the rotary evaporator, addition of dichloromethane (40 mL) and dry flash chromatography of the solution using dichloromethane (4×10 mL) as eluent. The solution was concentrated in the rotary evaporator and the yellow oil was kept at 0 C leading to the product 3 that was filtered and washed with cold diethyl ether. For compounds 3b, 3d, 3e and 3h-k, the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in the rotary evaporator and dichloromethane (40 mL) was added to the mixture. Dry flash chromatography of this mixture was performed using 20 mL of dichloromethane as eluent. The solvent was removed in the rotary evaporator leading to a solid product. Cold diethyl ether was added to the suspension, kept for a few minutes in an ice bath. The solid was filtered and washed with cold diethyl ether, leading to the pure (arylideneamino)acetonitrile 3.
General procedure: 2-Aminoacetonitrile hydrochloride 2 (7.0 mmol) and sodium acetate (8.0 mmol) were dissolved in 35 mL of methanol. Aldehyde 1 (7.0 mmol) was added to the grey solution, and the reaction mixture was stirred at room temperature. A solid suspension was formed after a few minutes (for compounds 3a, 3c, 3f and 3g). The suspension was stirred for 2 h and the solid filtered and washed with cold methanol, leading to the pure product 3. A second crop was isolated from the mother liquor after complete removal of methanol in the rotary evaporator, addition of dichloromethane (40 mL) and dry flash chromatography of the solution using dichloromethane (4×10 mL) as eluent. The solution was concentrated in the rotary evaporator and the yellow oil was kept at 0 C leading to the product 3 that was filtered and washed with cold diethyl ether. For compounds 3b, 3d, 3e and 3h-k, the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in the rotary evaporator and dichloromethane (40 mL) was added to the mixture. Dry flash chromatography of this mixture was performed using 20 mL of dichloromethane as eluent. The solvent was removed in the rotary evaporator leading to a solid product. Cold diethyl ether was added to the suspension, kept for a few minutes in an ice bath. The solid was filtered and washed with cold diethyl ether, leading to the pure (arylideneamino)acetonitrile 3.
General procedure: 2-Aminoacetonitrile hydrochloride 2 (7.0 mmol) and sodium acetate (8.0 mmol) were dissolved in 35 mL of methanol. Aldehyde 1 (7.0 mmol) was added to the grey solution, and the reaction mixture was stirred at room temperature. A solid suspension was formed after a few minutes (for compounds 3a, 3c, 3f and 3g). The suspension was stirred for 2 h and the solid filtered and washed with cold methanol, leading to the pure product 3. A second crop was isolated from the mother liquor after complete removal of methanol in the rotary evaporator, addition of dichloromethane (40 mL) and dry flash chromatography of the solution using dichloromethane (4×10 mL) as eluent. The solution was concentrated in the rotary evaporator and the yellow oil was kept at 0 C leading to the product 3 that was filtered and washed with cold diethyl ether. For compounds 3b, 3d, 3e and 3h-k, the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in the rotary evaporator and dichloromethane (40 mL) was added to the mixture. Dry flash chromatography of this mixture was performed using 20 mL of dichloromethane as eluent. The solvent was removed in the rotary evaporator leading to a solid product. Cold diethyl ether was added to the suspension, kept for a few minutes in an ice bath. The solid was filtered and washed with cold diethyl ether, leading to the pure (arylideneamino)acetonitrile 3.
General procedure: 2-Aminoacetonitrile hydrochloride 2 (7.0 mmol) and sodium acetate (8.0 mmol) were dissolved in 35 mL of methanol. Aldehyde 1 (7.0 mmol) was added to the grey solution, and the reaction mixture was stirred at room temperature. A solid suspension was formed after a few minutes (for compounds 3a, 3c, 3f and 3g). The suspension was stirred for 2 h and the solid filtered and washed with cold methanol, leading to the pure product 3. A second crop was isolated from the mother liquor after complete removal of methanol in the rotary evaporator, addition of dichloromethane (40 mL) and dry flash chromatography of the solution using dichloromethane (4×10 mL) as eluent. The solution was concentrated in the rotary evaporator and the yellow oil was kept at 0 C leading to the product 3 that was filtered and washed with cold diethyl ether. For compounds 3b, 3d, 3e and 3h-k, the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in the rotary evaporator and dichloromethane (40 mL) was added to the mixture. Dry flash chromatography of this mixture was performed using 20 mL of dichloromethane as eluent. The solvent was removed in the rotary evaporator leading to a solid product. Cold diethyl ether was added to the suspension, kept for a few minutes in an ice bath. The solid was filtered and washed with cold diethyl ether, leading to the pure (arylideneamino)acetonitrile 3.
General procedure: 2-Aminoacetonitrile hydrochloride 2 (7.0 mmol) and sodium acetate (8.0 mmol) were dissolved in 35 mL of methanol. Aldehyde 1 (7.0 mmol) was added to the grey solution, and the reaction mixture was stirred at room temperature. A solid suspension was formed after a few minutes (for compounds 3a, 3c, 3f and 3g). The suspension was stirred for 2 h and the solid filtered and washed with cold methanol, leading to the pure product 3. A second crop was isolated from the mother liquor after complete removal of methanol in the rotary evaporator, addition of dichloromethane (40 mL) and dry flash chromatography of the solution using dichloromethane (4×10 mL) as eluent. The solution was concentrated in the rotary evaporator and the yellow oil was kept at 0 C leading to the product 3 that was filtered and washed with cold diethyl ether. For compounds 3b, 3d, 3e and 3h-k, the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in the rotary evaporator and dichloromethane (40 mL) was added to the mixture. Dry flash chromatography of this mixture was performed using 20 mL of dichloromethane as eluent. The solvent was removed in the rotary evaporator leading to a solid product. Cold diethyl ether was added to the suspension, kept for a few minutes in an ice bath. The solid was filtered and washed with cold diethyl ether, leading to the pure (arylideneamino)acetonitrile 3.
General procedure: 2-Aminoacetonitrile hydrochloride 2 (7.0 mmol) and sodium acetate (8.0 mmol) were dissolved in 35 mL of methanol. Aldehyde 1 (7.0 mmol) was added to the grey solution, and the reaction mixture was stirred at room temperature. A solid suspension was formed after a few minutes (for compounds 3a, 3c, 3f and 3g). The suspension was stirred for 2 h and the solid filtered and washed with cold methanol, leading to the pure product 3. A second crop was isolated from the mother liquor after complete removal of methanol in the rotary evaporator, addition of dichloromethane (40 mL) and dry flash chromatography of the solution using dichloromethane (4×10 mL) as eluent. The solution was concentrated in the rotary evaporator and the yellow oil was kept at 0 C leading to the product 3 that was filtered and washed with cold diethyl ether. For compounds 3b, 3d, 3e and 3h-k, the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in the rotary evaporator and dichloromethane (40 mL) was added to the mixture. Dry flash chromatography of this mixture was performed using 20 mL of dichloromethane as eluent. The solvent was removed in the rotary evaporator leading to a solid product. Cold diethyl ether was added to the suspension, kept for a few minutes in an ice bath. The solid was filtered and washed with cold diethyl ether, leading to the pure (arylideneamino)acetonitrile 3.
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.
General procedure: 2-Aminoacetonitrile hydrochloride 2 (7.0 mmol) and sodium acetate (8.0 mmol) were dissolved in 35 mL of methanol. Aldehyde 1 (7.0 mmol) was added to the grey solution, and the reaction mixture was stirred at room temperature. A solid suspension was formed after a few minutes (for compounds 3a, 3c, 3f and 3g). The suspension was stirred for 2 h and the solid filtered and washed with cold methanol, leading to the pure product 3. A second crop was isolated from the mother liquor after complete removal of methanol in the rotary evaporator, addition of dichloromethane (40 mL) and dry flash chromatography of the solution using dichloromethane (4×10 mL) as eluent. The solution was concentrated in the rotary evaporator and the yellow oil was kept at 0 C leading to the product 3 that was filtered and washed with cold diethyl ether. For compounds 3b, 3d, 3e and 3h-k, the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in the rotary evaporator and dichloromethane (40 mL) was added to the mixture. Dry flash chromatography of this mixture was performed using 20 mL of dichloromethane as eluent. The solvent was removed in the rotary evaporator leading to a solid product. Cold diethyl ether was added to the suspension, kept for a few minutes in an ice bath. The solid was filtered and washed with cold diethyl ether, leading to the pure (arylideneamino)acetonitrile 3.
General procedure: 2-Aminoacetonitrile hydrochloride 2 (7.0 mmol) and sodium acetate (8.0 mmol) were dissolved in 35 mL of methanol. Aldehyde 1 (7.0 mmol) was added to the grey solution, and the reaction mixture was stirred at room temperature. A solid suspension was formed after a few minutes (for compounds 3a, 3c, 3f and 3g). The suspension was stirred for 2 h and the solid filtered and washed with cold methanol, leading to the pure product 3. A second crop was isolated from the mother liquor after complete removal of methanol in the rotary evaporator, addition of dichloromethane (40 mL) and dry flash chromatography of the solution using dichloromethane (4×10 mL) as eluent. The solution was concentrated in the rotary evaporator and the yellow oil was kept at 0 C leading to the product 3 that was filtered and washed with cold diethyl ether. For compounds 3b, 3d, 3e and 3h-k, the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in the rotary evaporator and dichloromethane (40 mL) was added to the mixture. Dry flash chromatography of this mixture was performed using 20 mL of dichloromethane as eluent. The solvent was removed in the rotary evaporator leading to a solid product. Cold diethyl ether was added to the suspension, kept for a few minutes in an ice bath. The solid was filtered and washed with cold diethyl ether, leading to the pure (arylideneamino)acetonitrile 3.
General procedure: 2-Aminoacetonitrile hydrochloride 2 (7.0 mmol) and sodium acetate (8.0 mmol) were dissolved in 35 mL of methanol. Aldehyde 1 (7.0 mmol) was added to the grey solution, and the reaction mixture was stirred at room temperature. A solid suspension was formed after a few minutes (for compounds 3a, 3c, 3f and 3g). The suspension was stirred for 2 h and the solid filtered and washed with cold methanol, leading to the pure product 3. A second crop was isolated from the mother liquor after complete removal of methanol in the rotary evaporator, addition of dichloromethane (40 mL) and dry flash chromatography of the solution using dichloromethane (4×10 mL) as eluent. The solution was concentrated in the rotary evaporator and the yellow oil was kept at 0 C leading to the product 3 that was filtered and washed with cold diethyl ether. For compounds 3b, 3d, 3e and 3h-k, the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in the rotary evaporator and dichloromethane (40 mL) was added to the mixture. Dry flash chromatography of this mixture was performed using 20 mL of dichloromethane as eluent. The solvent was removed in the rotary evaporator leading to a solid product. Cold diethyl ether was added to the suspension, kept for a few minutes in an ice bath. The solid was filtered and washed with cold diethyl ether, leading to the pure (arylideneamino)acetonitrile 3.
General procedure: 2-Aminoacetonitrile hydrochloride 2 (7.0 mmol) and sodium acetate (8.0 mmol) were dissolved in 35 mL of methanol. Aldehyde 1 (7.0 mmol) was added to the grey solution, and the reaction mixture was stirred at room temperature. A solid suspension was formed after a few minutes (for compounds 3a, 3c, 3f and 3g). The suspension was stirred for 2 h and the solid filtered and washed with cold methanol, leading to the pure product 3. A second crop was isolated from the mother liquor after complete removal of methanol in the rotary evaporator, addition of dichloromethane (40 mL) and dry flash chromatography of the solution using dichloromethane (4×10 mL) as eluent. The solution was concentrated in the rotary evaporator and the yellow oil was kept at 0 C leading to the product 3 that was filtered and washed with cold diethyl ether. For compounds 3b, 3d, 3e and 3h-k, the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in the rotary evaporator and dichloromethane (40 mL) was added to the mixture. Dry flash chromatography of this mixture was performed using 20 mL of dichloromethane as eluent. The solvent was removed in the rotary evaporator leading to a solid product. Cold diethyl ether was added to the suspension, kept for a few minutes in an ice bath. The solid was filtered and washed with cold diethyl ether, leading to the pure (arylideneamino)acetonitrile 3.
General procedure: 2-Aminoacetonitrile hydrochloride 2 (7.0 mmol) and sodium acetate (8.0 mmol) were dissolved in 35 mL of methanol. Aldehyde 1 (7.0 mmol) was added to the grey solution, and the reaction mixture was stirred at room temperature. A solid suspension was formed after a few minutes (for compounds 3a, 3c, 3f and 3g). The suspension was stirred for 2 h and the solid filtered and washed with cold methanol, leading to the pure product 3. A second crop was isolated from the mother liquor after complete removal of methanol in the rotary evaporator, addition of dichloromethane (40 mL) and dry flash chromatography of the solution using dichloromethane (4×10 mL) as eluent. The solution was concentrated in the rotary evaporator and the yellow oil was kept at 0 C leading to the product 3 that was filtered and washed with cold diethyl ether. For compounds 3b, 3d, 3e and 3h-k, the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in the rotary evaporator and dichloromethane (40 mL) was added to the mixture. Dry flash chromatography of this mixture was performed using 20 mL of dichloromethane as eluent. The solvent was removed in the rotary evaporator leading to a solid product. Cold diethyl ether was added to the suspension, kept for a few minutes in an ice bath. The solid was filtered and washed with cold diethyl ether, leading to the pure (arylideneamino)acetonitrile 3.
(a) 4-t-Butoxycarbonylamino-2-methylpyrrole-3-carboxylic acid ethyl ester ; Triethylamine (8.25 mL, 59.17 mmol) was added to a solution of amino acetonitrile hydrochloride (7.00 g, 53.79 mmol) in ethanol (23 mL), and the obtained mixture was then stirred at room temperature for 10 minutes. Thereafter, ethyl acetoacetate (5.47 g, 59.17 mmol) was added to the reaction solution, and the obtained mixture was then stirred at 70C for 1 hour. Thereafter, the solvent was distilled away, and ice water (50 mL) was then added to the reaction solution, followed by stirring at 0C. The generated precipitate was collected by filtration to obtain an enamine compound (7.35 g, yield: 81%) in the form of a colorless powder. The obtained enamine compound (7.35 g, 43.7 mmol) was added to a solution of sodium ethoxide in ethanol prepared from sodium metal (1.11 g, 48.1 mmol), and the obtained mixture was then stirred at room temperature for 18 hours. Thereafter, a 4 M-hydrochloric acid-ethyl acetate solution was added to the reaction solution to neutralize it (pH = 6), and the solvent was then distilled away. The generated precipitate was collected by filtration to obtain an aminopyrrole compound in the form of a brown solid. Triethylamine (4.74 mL, 34.0 mmol), Boc2O (7.42 g, 34.0 mmol), and DMAP (3.12 g, 25.5 mmol) were added to a solution of the obtained aminopyrrole compound in dichloromethane (150 mL). The obtained mixture was stirred at room temperature for 4 hours. Thereafter, water was added to the reaction solution, and it was then extracted with ethyl acetate twice, washed with a saturated saline, and then dried over anhydrous sodium sulfate, followed by concentration. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain the title compound (1.84 g, yield in two steps: 20%) in the form of a colorless oily substance. 1H NMR (400 MHz, CDCl3): delta (ppm) = 8.49 (1H, brs), 7.90 (1H, brs), 7.01 (1H, d, J = 1.9 Hz), 4.31 (2H, q, J = 7.2 Hz), 2.45 (3H, s), 1.49 (9H, s), 1.37 (3H, t, J = 7.2 Hz).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 10 - 35℃; for 15h;
To a solution of {2-[5-[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (65 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), aminoacetonitrile hydrochloride (52 mg), and triethylamine (120 muL), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (methanol:ethyl acetate:hexane = 0:0:100 to 10:90:0, volume ratio), and crystallized from acetonitrile to give the title compound (103 mg, yield 64%) as white crystals. MS 570 (MH+). 1H NMR (DMSO-d6) delta1.60 - 1.80 (2 H, m), 1.87 - 2.03 (2 H, m), 2.52 - 2.75 (2 H, m), 3.24 (3 H, s), 3.38 - 3.60 (2 H, m), 3.87 - 4.04 (2 H, m), 4.17 (2 H, d, J=5.7 Hz), 4.20 - 4.47 (3 H, m), 4.63 - 4.84 (1 H, m), 6.79 (1 H, d, J=1.9 Hz), 6.86 (1 H, d, J=1.9 Hz), 7.01 (1 H, d, J=1.9 Hz), 7.45 (1 H, dd, J=8.7, 2.6 Hz), 7.99 (1 H, d, J=8.7 Hz), 8.52 (1 H, d, J=2.6 Hz), 8.72 (1 H, t, J=5.7Hz), 11.94 (1 H, s).
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;Cooling with ice;
To a solution of Compound (I-1-2) (1.33 g, 3.79 mmol) in dimethylformamide were successively added <strong>[6011-14-9]2-aminoacetonitrile hydrochloride</strong> (0.525 g, 5.68 mmol), HATU (2.159 g, 5.68 mmol) and Et3N (1.049 mL, 7.57 mmol) with ice-cooling, then the reaction mixture was stirred at room temperature for 3 hours. To the reaction solution were added 0.1M hydrochloric acid and ethyl acetate, then the reaction solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure. The obtained residue was purified by column chromatography to give Compound (I-1-3) (1.23 g, 83%) as a yellow solid.Compound (I-1-3); 1H-NMR (CDCl3) delta: 3.97 (s, 2H), 4.24 (d, J=5.6 Hz, 2H), 4.76 (s, 2H), 7.39 (t, J=7.4 Hz, 1H), 7.48 (t, J=7.4 Hz, 2H), 7.63 (d, J=7.1 Hz, 2H), 7.74 (dd, J=8.6, 1.5 Hz, 1H), 8.02-8.07 (m, 3H).
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.
4-(2-(4-(3', 3', 5', 5'-d<SUB>4</SUB>-morpholino)phenylamino) pyrimidin-4-yl) benzoate[ No CAS ]
[ 6011-14-9 ]
[ 1619927-64-8 ]
Yield
Reaction Conditions
Operation in experiment
55%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 20h;Inert atmosphere;
4-(2-(4-(3', 3', 5', 5' -d4-morpholino)phenylamino) pyrimidin-4-yl) benzoic acid (0.100 g, 0.263 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.061 g, 0.316 mmol), 1-hydroxy-phenylpropyl triazole (0.043 g, 0.316 mmol), triethylamine (0.159 g, 1.578 mmol) and N,N-dimethylformamide (2 mL) were added to a flask under nitrogen protection. 2-amino-acetonitrile hydrochloride (0.073 g, 0.789 mmol) was added under stirring, and reacted for 20h under room temperature. Purified water (2 mL) and saturated bicarbonate solution (2 mL) 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 (0.060 g, HPLC purity: 98.4%, yield: 55%); MS Calcd.: 418; MS Found: 419 (M+H)+. 1H NMR (400MHz, DMSO-d6) delta 9.62(1H, s), 9.38-9.35(1H, m), 8.57-8.56(1H, d), 8.29-8.27(2H, d), 8.04-8.02(2H, d), 7.73-7.70(2H, d), 7.45-7.44(1H, d), 7.05(2H, s), 4.37-4.36(2H, d), 3.14 ppm(4H, s).
trans-4-(3-cyclopropyl-4-oxo-7-[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexanecarbaldehyde[ No CAS ]
[ 6011-14-9 ]
2-([trans-4-(3-cyclopropyl-4-oxo-7-[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexyl]methyl}amino)acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With 2-picoline borane complex; acetic acid; In methanol; at 20℃; for 24h;
REFERENCE SYNTHETIC EXAMPLE 86 2-([trans-4-(3-Cyclopropyl-4-oxo-7-[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexyl]methyl}amino)acetonitrile (0315) (0316) To a solution of trans-4-(3-cyclopropyl-4-oxo-7-[2-(trimethylsilyl)ethoxy]methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexanecarbaldehyde (24.0 mg, 51.2 mumol) obtained in Reference Synthetic Example 74 in a mixed solvent of methanol (1.0 mL) and acetic acid (0.10 mL), aminoacetonitrile hydrochloride (23.7 mg, 0.256 mmol) and 2-picoline borane (11.0 mg, 0.102 mmol) were added, and the mixture was stirred at room temperature for 1 day. The reaction mixture was mixed with 1 M hydrochloric acid and separated with ethyl acetate. The aqueous layer was basified with 1 M aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 (v/v)?ethyl acetate?ethyl acetate/methanol=10/1 (v/v)) to obtain the title compound as a colorless oil (20.6 mg, yield: 79%).
3-bromo-N-(cyanomethyl)-2-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
A solution of 3-bromo-2-methylbenzoic acid (0.500 g, 2.33 mmol), EDC (0.669 g, 3.49 mmol), HOBT (0.534 g, 3.49 mmol), and DIEA (1.22 mL, 6.98 mmol) in THF (14.5 mL) and DCM (14.5 mL) was stirred at room temperature for 30 min, then was treated with <strong>[6011-14-9]2-aminoacetonitrile hydrochloride</strong> (0.237 g, 2.56 mmol). The mixture was stirred at room temperature for 5 h, then was partitioned between saturated aqueous NaHCO3 and EtOAc. The organic phase was dried and concentrated, and the residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 20-40%) to provide 3-bromo-N-(cyanomethyl)-2-methylbenzamide as a white solid (0.554 g, 94% yield). Mass spectrum m/z 253, 255 (M+H)+. 1H NMR (400 MHz, CDCl3) delta 7.67 (dd, J=8.0, 1.0 Hz, 1H), 7.30 (dd, J=7.7, 0.9 Hz, 1H), 7.14-7.08 (m, 1H), 6.14 (br. s., 1H), 4.38 (d, J=5.9 Hz, 2H), 2.48 (s, 3H).
With aluminum (III) chloride; In dichloromethane; at 20℃; for 5h;
300 mL of dichloromethane, 107 g (0.8 mol) of anhydrous aluminum trichloride, 37.4 g (0.404 mol) of aminoacetonitrile hydrochloride and 37.6 g (0.4 mol) of phenol were added to the reaction flask in that order, Stir at room temperature for 5 h. Stop the reaction, recovery of methylene chloride under reduced pressure, and then add water to the reaction flask 300mL, stirring filter, dried to a yellow solid, p-hydroxy acetophenone amine hydrochloride, M.p. 244-240C. HPLC purity was determined.
Under nitrogen protection100 g (523 mmol) of 4-trifluoromethylnicotinic acid and 600 mL of toluene were placed in a three-neck reaction flask with a reflux condenser and a constant pressure dropping funnel, and 125 g (1.05 mol) of SOCl2 was slowly added to the reaction flask at 0 C. It was refluxed at 120 C for 2.5 hours. The contents of the reaction flask were concentrated, and after cooling, 600 mL of THF was added. 100 g (1.08 mol) of aminoacetonitrile hydrochloride and 600 mL of toluene were placed in the previous reaction flask, and the reaction flask was cooled to 0 C to maintain the temperature, and 190 g (1.88 mol) of Et 3 N was slowly added. The reaction flask was reacted at 25 C for 10 hours, and then most of the THF solution was removed under reduced pressure, and water and ethyl acetate were added for extraction.After drying and concentrating the organic phase, 112 g (488 mmol) of the solid of flonicamid was obtained.The yield was 93.4%.
91.6%
With phosgene; triethylamine; In toluene; at -10 - 5℃; for 4h;
In a mechanical stirrer,Thermometer and vent tube in a 500 mL three-necked flask,40.2 g (200 mmol)95% 4-trifluoromethylnicotinic acid,18. 7 g (200 mmol)Aminoacetonitrile hydrochloride,61.2 g (600 mmol) of triethylamine and 140 mL of toluene,When cooling to -10 ~ 5 C,To the reaction mixture was introduced 20.0 g (200 mmol) of phosgene,About 4 hours through the end,After completion of phosgene sampling after liquid chromatography detection,When the peak area ratio of 4-trifluoromethylnicotinic acid is less than 1%The product was washed with 30 mL of water and dried to obtain 42.4 g of white product. The quantitative determination of the product by HPLC was 98.9%, and the product was treated with 4-trifluoromethylnicotinic acid The yield was 91.6%.
1-p-fluoro-azidophenyl-3-nitrilemethyltriazene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
fluoroaniline 1.1 g, 0.01 mol dissolved in 30 ml 2M hydrochloric acid, add 40 ml of water diluted, then sodium nitrite 0.7 g, 0.01 mol dissolved in a small amount of water, 0 C under the reaction of diazonium salt solution, To this temperature was added dropwise a solution of 1.0 g of aminoacetoacetonitrile hydrochloride, 0.01 ml of a 30 ml aqueous solution, and the reaction was stirred for 2 hours;A-2, add excess sodium acetate 25-30 grams dissolved after standing overnight, petroleum ether extraction crude, and then recrystallized in petroleum ether 1-p-fluoro-azidophenyl-3-nitrile-triazene (A) 1.9 grams, the melting point of 95-96 C, the yield of 95%;
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
Step 1. 4-Bromo-N-(cyanomethyl)benzamide (0943) [00303] A solution of 4-bromobenzoic acid (5 g, 24.87 mmol), <strong>[6011-14-9]2-aminoacetonitrile hydrochloride</strong> (3.47 g, 37.50 mmol), HBTU (14 g, 36.92 mmol) and DIEA (6.42 g, 49.67 mmol) in DMF (100 mL) was stirred for 16 h at ambient temperature, then was poured into water (300 mL) and was extracted with EtOAc (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with a gradient of 0-100% EtOAc/PE) to afford 4 g (67%) of 4-bromo-N-(cyanomethyl)benzamide as a white solid. 1H MR (400 MHz, CD3OD) delta 7.82-7.72 (m, 2H), 7.75-7.63 (m, 2H), 4.34 (s, 2H).
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 dichloromethane; at 0 - 20℃; for 2h;
General procedure: The coupling of a Cbz-protected amino acid to an amine is described and is referred to as General Method 4. To a solution of Compound 101-G (3.5 g, 4.9 mmol) and (5)- 2-(((benzyloxy)carbonyl)amino)-6-((tert-butoxycarbonyl)amino)hexanoic acid (2.4 g, 6.4 mmol)in DCM (30 mL) at 0 C, HATU (3.7 g, 9.8 mmol) and DIPEA (1.9 g, 14.7 mmol) was added. The resulting mixture was allowed to gradually warm up to room temperature and stirred for 2 h. The reaction mixture was diluted with DCM (100 mL), which was washed with brine (100 mL x 3). The organic layer was dried over Na2504, concentrated and the residue was purified by silica column chromatography to afford Compound 101-H (5.3 g, 99% yield) as a whitesolid. [Starting from Compound 331-H (50.0 mg, 0.04 mmol) and <strong>[6011-14-9]2-aminoacetonitrile hydrochloride</strong> (39.7 mg, 0.43 mmol), General Method HATU (Example 5) was used to prepare Compound 331-1(30 mg, 58.2% yield) as a white solid. LCMS (5-95AB_1.Smin): tR = 1.103 mi [M+Hj 1204.1.
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 dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 1h;
The coupling of an aminonitrile to a carboxylic acid and subsequentBoc-deprotection is described and is referred to as General Method 6. To a solution ofCompound 101-N (180 mg, 0.15 mmol), aminoacetonitrile hydrochloride (31 mg, 0.33 mmol) and DIPEA (38 mg, 0.29 mmol) in DCM/DMF (3 mL, 2:1) at 0C, HATU (56 mg, 0.15 mmol) was added while stirring. The resulting mixture was stirred at room temperature for lh. Most DCM was removed under reduced pressure and the residue was poured into water (10 mL),which was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2504, concentrated to the residue, which was purified by flash chromatography column to afford Compound 101-0 (140 mg, 76%) as a white solid.
In a 250 mL three-necked flask, 10 g of maleic anhydride, 9.5 g of aminoacetonitrile hydrochloride, 50 ml of acetonitrile was added, and triethylamine was added dropwise at a temperature of 0 to 10 C.Thereafter, the reaction solution was cooled to room temperature, and then the acetonitrile was distilled off under reduced pressure.Thereafter, 30 ml of ethyl acetate and 25 ml of water were added to the residue. After the stirring, the liquid separation operation was carried outAnd then the water layer is removed.To the organic layer, 25 ml of a saturated aqueous solution of sodium chloride was added, followed by a liquid separation operation after stirring, and then the aqueous layer was removed. There will be several layers of distillation under reduced pressure.To give 12.8 g of an oil (compound 2) in 81% yield, volume 1 (purity: 99.21%).
With potassium hydroxide; In propan-1-ol; at 97 - 110℃; for 5h;
At 1000 mL equipped with condensing reflux tube, the reactor of the thermometer was charged with 89.3 g (0.5 mol) of propyl 4-chloroacetoacetate, propanol 700 mL, aminoacetonitrile hydrochloride 46.3 g (0.5 mol), potassium hydroxide (56.1 g, 1.0 mol), heated to 97 to 110 C, the reaction was complete at 97 to 110 C for 5 hours and the reaction was complete. Filtered, washed with 50 mL of ethanol, and evaporated to dryness under reduced pressure to give the crude product of the oxalcetam intermediate compound (I). To the crude oxazetam intermediate compound (I), 660 mL of ethyl acetate was added thereto, followed by stirring for about 1 hour. Filtered, washed with 30 mL of ethyl acetate, and the solvent was removed by distillation under reduced pressure to give about 51 g of oxalcetam intermediate compound (I) as a solid. Total yield: 73.9%.
4-(2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)aniline[ No CAS ]
[ 6011-14-9 ]
1-(cyanomethyl)-3-(4-(2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.8%
Toluene (5 mL)(2,3-b] pyrazin-7-yl) aniline (36 mg, 0.12 mmol) was added to a solution of 4- (2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [Triphosgene (33 mg, 0.11 mmol)Add two drops of triethylamine,110 reflux reaction 5h,The reaction solution was cooled to room temperature,Aminoacetonitrile hydrochloride (28 mg, 0.30 mmol) was added,Triethylamine (100 mg, 0.10 mmol)Stirred at room temperature for 12 h,Reaction by adding silica gel, direct spin dry mix,Column separation (dichloromethane / methanol (v / v) = 15/1)35 mg of a white solid was obtained in a yield of 75.8%.
N-cyanomethyl-N,N-bis(4-trifluoromethylnicotinoyl)amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.7%
General procedure: The aminoacetonitrile hydrochloride was added to a solution of xylene in triethylamine,Heated to 40 for 15 min,Preparation of amino acetonitrile solution;4-trifluoromethylnicotinic acid was dissolved in xylene,Added to the above amino acetonitrile solution,Cooling to -10 C, slowly dropping oxalyl chloride in xylene solution,To be added dropwise,Heated to 45 reaction 1h,Then continue to raise the temperature to 100 reaction 2 h;among them,Aminoacetonitrile hydrochloride and triethylamine in a molar ratio of 1: 2.5; 4-trifluoromethylnicotinic acid and aminoacetonitrile hydrochlorideReaction molar ratio of 1: 0.5; 4-trifluoromethyl nicotinic acid and oxalyl chloride reaction molar ratio of 1: 1.05.After the reaction was completed, the temperature was lowered to 85 C and hot filtration was performed to obtain a filtrate 1 and an organic salt. The resulting filtrate1 slowly cooled to room temperature, transferred to a cryogenic tank, -5 crystallization, filtration,The filtrate 2 (in which N-cyanomethylbis (trifluoromethyl) nicotinamide, flonicamid, 4-trifluoromethylnicotinic acid, xylene and triethylamine was included in the filtrate 2)The filter cake is washed with water,And the volume ratio of 82:18 methyl tert-butyl ether and ethyl acetate solution was recrystallized,A white N-cyanomethylbis (trifluoromethyl) nicotinamide solid powder was obtained,The yield was 71.1% and the purity after purification was 99.9%. Examples 2-5 are respectively a preparation method of N-cyanomethylbis (trifluoromethyl) nicotinamide and N-cyanomethylbisMethyl) nicotinamide, which is similar to the preparation method and application described in Example 1, except that the amount of raw materials involved, the technical parameters involved in the preparation method and the application are different, as follows Table shows:
benzyl (S)-(1-((cyanomethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
General procedure: N-protected amino acid was dissolved in dichloromethane (DCM). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl, 1.3 eq.) and hydroxybenzotriazole (HOBt ·xH2O, 1.3 eq.) were added at 0 C and the mixture was stirred for 50 min, after which thecorresponding amine (1.3 eq.) and N,N-Diisopropylethylamine (DIPEA, 1.3 eq.) were added at 0C. After stirring overnight, the mixture was washed with a 5% potassium sulfate solution(KHSO4), a 5% sodium bicarbonate solution (NaHCO3) and with water. After drying over sodiumsulfate (Na2SO4) and evaporation of the solvent, the residue was purified via columnchromatography.
2-(((2-chlorothiazol-5-yl)methyl)amino)acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With triethylamine; In ethanol; at 0 - 40℃; for 6h;
At room temperature, 9.3 g (0.1 mol) of aminoacetonitrile hydrochloride and 22 g (0.2 mol) of triethylamine are successively added to 30 mlIn 95% ethanol, cool to 0C. 8.5 g (0.05 mol) of 2-chloro-5-chloromethylthiazole was added dropwise to the above solution, the temperature was controlled below 5 C., and the addition time was 1 h. After the addition, stirring was continued for 1 h at 0 C. Gradually warm up to 40C and continue stirring for 5h. TLC test, the reaction of raw materials is completed. The reaction solution was concentrated under reduced pressure, and the residue was added with 50 ml of water and extracted with ethyl acetate (3×30 ml). The combined extracts were washed with 50 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 6.6 g of the product. 71%.
Triethylamine (18 mL, 0.133 mol) and1-hydroxybenzotriazole (HOBt) (9.7 g, 0.071 mol) were added to a stirred solution of 4-acetylbenzoicacid (16) (10 g, 0.061 mol) in DMF (100 mL) at room temperature and the reaction solution was stirredfor 30 min. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) (13.8 g, 0.071mol) was then added and the reaction solution was stirred at room temperature for another 30 min.Aminoacetonitrile hydrochloride (6.16 g, 0.067 mol) was added and the reaction mixture was stirred atroom temperature for 4 h. The resulting suspension was poured into cooled 5% hydrochloric acid (300mL) and was stirred for 30 min. The resulting solid was collected by suction filtration, washed with H2O(50 mL × 2), dried at 40 C for 6 h to afford 16 (11.7 g, 95%) as a colorless solid; mp 140.2-142.5 C. 1H NMR (500 MHz, DMSO-d6): delta 2.64 (s, 3H), 4.36 (d, J = 5.4 Hz, 2H), 8.00 (d, J = 8.3 Hz, 2H), 8.07 (d, J= 8.3 Hz, 2H), 9.40 (t, J = 5.3 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): delta 27.5, 28.3, 118.0, 128.2, 128.8,137.0, 139.7, 166.4, 198.2. MS (ESI): m/z = 203.1 [M + H]+.HPLC Conditions: Column: Acclaim C18 (150 mm × 2.1 mm × 5 mum); Detection: 254 nm; Flow rate: 0.8mL/min; Temperature: 35 C; Injection load: 1 muL; Solvent: MeOH; Run time: 20 min; Mobile phase:MeOH/H2O = 70/30, tR: 3.921 min, purity: 99.97%.
95%
4-Acetylbenzoic acid (10 g, 0.061 mol) was added to a 500 mL eggplant-shaped bottle. Add N,N-dimethylformamide (150 mL), triethylamine (18 mL, 13.5 g), HOBt (9.7 g, 0.071 mol), and stirred at room temperature for 10 min. After the solid was substantially dissolved, EDCI (13.8 g, 0.071 mol) was added and stirring was continued for 1 h. Aminoacetonitrile hydrochloride (6.16 g, 0.067 mol) was added to react at room temperature, and the reaction was followed by thin layer chromatography (TLC). After 4 h, TLC showed the reaction was completed. A large amount of solid is formed, and the reaction solution is poured into dilute hydrochloric acid (concentration: 12 to 18% by weight), stirred for 30 minutes, and the solid is precipitated, suction filtered, washed with water, and dried to obtain 4-acetyl-N-(cyanomethyl)benzoamide 11.7 g, yield 95%.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 25℃; for 3h;
2-trifluoromethylpyridine-5-carboxylic acid (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 EDC (0.287 mg, 1.5 mmol) was added.HOBt (0.20g, 1.5mmol),Reaction at 25 C for 3 h,After TLC detects the reaction,The reaction solution was first washed with water (20 mL*2).Wash with saturated brine (20ml*1),After drying with anhydrous sodium sulfate,Desolvent, get crude,The crude product was purified by column chromatography to give a white solid.M.p. 83-85 C, yield: 88%.
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.
1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indole-3-carboxylic acid[ No CAS ]
[ 6011-14-9 ]
N-(cyanomethyl)-1-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;
To compound 112c 1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indole-3-carboxylic acid(100mg, 0.3mmol)To a mixture of DIPEA (155 mg, 1.2 mmol) in DMF (8 mL) was added compound 112d, <strong>[6011-14-9]2-aminoacetonitrile hydrochloride</strong> (55 mg, 0.6 mmol) and HATU (126 mg, 0.33 mmol). Stir at room temperature for 18 hours.After the reaction was completed, the reaction solution was poured into water, and the precipitated solid was collected by filtration. Solid with EtOAc / MeOH (about 4: 1)Beating to obtain off-white solid compound 112,N-(cyanomethyl)-1-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indole-3-carboxamide(95.3 mg, converted to 85%).
1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazole-4-carboxylic acid[ No CAS ]
[ 6011-14-9 ]
N-(cyanomethyl)-1-(2(-(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59.4%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
Compound 9f (45 mg, 0.157 mmol)And N, N-dimethylformamide (5mL) into a three-necked flask,Then 9g of compound (16.78mg, 0.181mmol) was added in order while stirring,N, N-diisopropylethylamine (70.2 mg, 0.544 mmol) and2- (7-benzotriazole) -N, N, N ', N'-TetramethylureaHexafluorophosphate(68.9mg, 0.181mmol),Stir overnight at room temperature,The reaction solution was poured into ice water (20 mL),Then filtered and dried,Compound 9 was obtained as a yellow solidN- (cyanomethyl) -1 (2 (-(1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazole-4-carboxamide(30.3 mg, yield 59.4%).
Compound III-2 aminoacetonitrile hydrochloride (1 mmol) was added to 200 mul of water, sodium nitrite (1 mmol) was added under ice bath for 1 h, and then tetrahydrofuran and 1,4-dioxane were added Ring mixed solution (1mL: 3mL) 4mL, compound II-28 (0.3mmol), trisodium phosphate (0.45mmol), silver oxide (0.45mmol), reaction at room temperature for 3h, TCL detection reaction was complete, 5ml saturated ammonium chloride solution Quench, extract twice with ethyl acetate (5mL × 2), filter, extract organic phase, concentrate under reduced pressure, and purify by column chromatography (ethyl acetate: petroleum ether = 30: 1, v: v) to obtain white Solid, yield 55% (40mg).
4-(2-((6-carboxy-2-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)benzo[d]thiazol-4-yl)oxy)ethyl)morpholin-4-ium chloride[ No CAS ]
[ 6011-14-9 ]
4-(2-((6-((cyanomethyl)carbamoyl)-2-(3,4-dichloro-5-methyl-1H-pyrrole-2- carboxamido)benzo[d]thiazol-4-yl)oxy)ethyl)morpholin-4-ium chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
A solution of 4-(2-((6-carboxy-2-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)benzo[d]thiazol-4- yl)oxy)ethyl)morpholin-4-ium chloride (Example 10) (19 mg, 0.035 mmol) in N,N-dimethylformamide (4 mL) was cooled to 0 C and then EDC (8 mg, 0.042 mmol), HOBt (6 mg, 0.046 mmol) and N- methylmorpholine (12 muL, 0.106 mmol) were added and the reaction mixture stirred for 20 min at 0 C. Then aminoacetonitrile hydrochloride (5 mg, 0.053 mmol) was added and reaction mixture stirred overnight at room temperature. The solvent was evaporated in vacuo, to the residue ethyl acetate (10 mL) and 1M HCl (10 mL) were added after which the precipitate formed. The solid was filtered off and dried. Yield: 14 mg (68.0%); beige solid. (0686) 1H NMR (400 MHz, DMSO-d6) d 2.29 (s, 3H), 3.25-3.34 (m, 2H), 3.62-3.73 (m, 4H), 3.76-3.88 (m, 2H), 4.01-4.10 (m, 2H), 4.36 (d, J = 5.4 Hz, 2H), 4.71 (t, 2H), 7.62 (d, J = 1.5 Hz, 1H), 8.21 (d, J = 0.5 Hz, 1H), 9.40 (t, J = 5.5 Hz, 1H), 10.93 (s, 1H), 12.20 (s, 1H), 12.78 (s, 1H). (0687) HRMS (ESI+) m/z for C22H23Cl2N6O4S ([M+H]+): calculated 537.0873, found 537.0861.HPLC: tr 4.313 min (96.9 % at 254 nm, 97.7 % at 280 nm), method A
N-(aminomethyl)-4-{2-cyclopropaneamido-[1,2,4]triazolo[1,5-a]pyridin-5-yl}benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
0.1g (0.3mmol) intermediate VI, 0.03g (0.4mmol) aminoacetonitrile hydrochloride, 0.16g (0.45mmol) HATU and 0.2mL (7mmol) DIPEA were added to 2mL DMF, the reaction at room temperature for 4-5h. After the reaction was completed, 5 mL of DCM was added to the reaction solution for dilution, and the DCM layer was washed 3 times with water. Distilling off part of the solvent, and purifying by column chromatography to obtain the target compound I-1 white solid 0.08g, the yield was 72%;
10 mmol of 3,5-dichlorobenzaldehyde was added to 20 ml of an aqueous solution in which 20 mmol of potassium hydroxide and 10 mmol of aminoacetonitrile hydrochloride were dissolved, then 20 ml of ethanol was added and stirred for one hour. Then, 12 mmol of sodium borohydride was added, and the mixture was stirred overnight at room temperature. After adding hydrochloric acid, the reaction was adjusted to be acidic, extracted with ethyl acetate, the organic phase was separated, washed with saturated brine, separated the organic phase, dried over anhydrous sodium sulfate, and suspending the solvent to obtain the product. (80% yield, yellow solid).
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