| 54% |
Stage #1: tert-butyl (R)-1-cyclohexyl-2-(2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-ylamino)-2-oxoethylcarbamate With methanesulfonic acid In tetrahydrofuran at 65℃; for 18 - 24h;
Stage #2: With sodium hydroxide In tetrahydrofuran; water at 15 - 20℃; for 0.0833333h; |
1
Preparation of (2R)-2-amino-2-cyclohexyl-N-(5-(1 -methyl-1 H-pyrazol-4-yl)-1 -oxo-2,6- dihydro-1 H-[1 ,2]diazepino[4,5,6-cd]indol-8-yl)acetamide 12: Methansulfonic acid (44.4 g, 0.46 mol) was added to THF (690 mL) in a 2-L fiask. fert-Butyl (R)-1-cyclohexyl-2-(5-(1 -methyl-1 H- pyrazol-4-yl)-1-oxo-2,6-dihydro-1/-/-[1 ,2]diazepino[4,5,6-cd]indol-8-ylannino)-2-oxoethylcarbamate 11 (30.0 g, 57.74 mmol) was added via powder funnel. THF (60 mL) was used to rinse the funnel and the sides of the flask. The flask was purged with nitrogen, and the reaction was heated to 65 0C and stirred for 18-24h. HPLC analysis revealed that the reaction was complete. The reaction was cooled to room temperature using a water bath. 2M NaOH (255 mL) was added over 30 minutes while maintaining the temperature at 20+5 0C. After stirring for 5 minutes, the mixture was transferred to a 2-L separatory funnel using THF for the rinse. The layers were separated. The aqueous phase was extracted with THF (60 mL). The organic fractions were combined and washed twice with saturated aqueous NaCI (2 x 60 mL). MeOH (80 mL) and MgSO4 (42 g) were added. The mixture was stirred for 75 minutes, and then filtered through celite. The cake was washed with 9:1 THF/MeOH (3 x 50 mL), and the solution was transferred to a 2-L distillation flask. The solution was concentrated to a volume of 300 mL by distillation at 1 atmosphere. EtOH (450 mL) was added slowly, and the solution was cooled to 50 °C to crystallize the product. Once the product had crystallized, the mixture was re-heated and distilled down to a volume of 450 mL. The reaction solvent ratio was monitored by 1H NMR. The distillation was stopped once THF content was reduced to 5 mol%. The resulting yellow suspension was cooled to 25 °C over 60 minutes and vacuum-filtered on paper. The filter cake was washed with EtOH (2 x 75 ml). The solids were transferred to a crystallizing dish and dried under vacuum at 55 0C for 16 hours. 13.55 g of compound 12 (54%) was obtained as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.14(m, 5H), 1.62(m, 6H), 3.10(d, 1 H, J= 5.7 Hz), 3.93(s, 3H), 7.58(s, 1 H), 7.59(s, 1 H), 7.91(s, 1H), 8.11(s, 1H), 8.29(s, 1 H), 10.19(s, 1H), 11.83(s, br, 1H). |
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With sodium hydrogencarbonate In water; ethyl acetate at 22℃; |
4a
Example 4a: Preparation of the first batch of amorphous form of (2R)-2-amino-2- cyclohexyl-N-(5-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2,6-dihydro-1H-[1,2] diazepino[4,5,6- cd]indol-8-yl)acetamide amorphous form:1.3 g of compound 11 (2 HCI) was dissolved in water (200 mL) at 22 0C followed by the addition of a saturated aqueous sodium bicarbonate solution (50 mL) and 500 mL of ethyl acetate. Two more spatulas of sodium bicarbonate were added and another 50 mL of water. After vigorous stirring, the mixture was filtered and the phases separated. The aqueous phase was re- extracted with ethyl acetate (two times 200 mL). The combined organic phase was washed with brine and dried over sodium sulfate. Filtration followed by evaporation of the volatiies up to 10 mL afforded a yellow solid, which was filtered and dried. Total amount of amorphous material obtained was 690 mg. |
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