Potassium Carbonate → 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 924142Notes

Reaction equation

Cl[C:2]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:34]1[CH:38]2[CH2:39][NH:40][CH2:41][CH:37]2[CH2:36][N:35]1C(OC(C)(C)C)=O>CN(C=O)C>[CH2:34]1[CH:38]2[CH2:39][NH:40][CH2:41][CH:37]2[CH2:36][N:35]1[C:2]1[C:21]([C:22]2[CH:27]=[N:26][CH:25]=[N:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1

Participants

Conditions

Temperature: 110 °C

Procedure

To a solution of 6-chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 223.1, 100 mg, 0.253 mmol) in DMF (2 mL) were added K2CO3 (105 mg, 0.760 mmol) and tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (81 mg, 0.380 mmol). The RM was stirred at 110° C. for 4 h and then at 130° C. for 5 h. After removal of solvent under reduced pressure, the crude intermediate was treated with a mixture of TFA/DCM (1 mL/2 mL) at RT for 5 h. The solvent was evaporated off under reduced pressure to afford 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, a portion of which (100 mg, 0.213 mmol) was dissolved in anhydrous THF (2 mL) and was treated with KOtBu (71.6 mg, 0.638 mmol) and 2-bromoethanol (0.1 mL, 1.435 mmol). The RM was stirred at 70° C. overnight, the solvent was evaporated off under reduced pressure and the crude material was purified by preparative HPLC. The compound was lyophilized in water/MeCN to afford the title product. UPLC-MS (Condition 3), tR=0.77 min, m/z=515.2 [M+H]+.

Workup

waitat 130° C. for 5 h
customAfter removal of solvent under reduced pressure
additionthe crude intermediate was treated with a mixture of TFA/DCM (1 mL/2 mL) at RT for 5 h
customThe solvent was evaporated off under reduced pressure

Sources & evidence

ORD record: ord-520119264a7a46aa95fcdb43a728ac01
Source dataset: uspto-grants-2016_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09278981B2

Reaction notes

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