Diisopropylethylamine → 2'-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1'H-spiro[cyclopropane-1,6'-pyrrolo[3,4-b]pyrrol]-4'(5'H)-one

HRID 1056199Notes

Reaction equation

HRID 1056199 reaction equation
C(O[C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][CH2:34][CH:35]([F:37])[F:36])[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2C(OCC)=O)[CH2:11][CH2:10]1)=[O:7])(C)(C)C.Cl.NC1(C2NC(C3C=CC=C4C=3N=C(NCC(F)F)C(C)=N4)=CC=2C(O)=O)CC1.Cl.NC1(C2NC(C3C=CC=C4C=3N=C(NC(C)(C)C)C(C)=N4)=CC=2C(O)=O)CC1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[F:36][CH:35]([F:37])[CH2:34][NH:33][C:25]1[C:26]([CH3:32])=[N:27][C:28]2[C:23]([N:24]=1)=[C:22]([C:14]1[NH:13][C:12]3[C:9]4([CH2:10][CH2:11]4)[NH:8][C:6](=[O:7])[C:16]=3[CH:15]=1)[CH:31]=[CH:30][CH:29]=2

Participants

8

Reactant 5

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 897835332-(1-aminocyclopropyl)-5-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride2×HCID 89783739ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylateHCID 897846002-(1-aminocyclopropyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride

Product 1

HCID 717303652'-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1'H-spiro[cyclopropane-1,6'-pyrrolo[3,4-b]pyrrol]-4'(5'H)-oneYield 66%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

Ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(34(2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (331b) (378 mg, 0.73 mmol) was converted to 2-(1-aminocyclopropyl)-5-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (331c: m/z (ESI, +ve) 388.1 (M+H)+) in a fashion similar to that described for Intermediate 324c. This material was used as crude. A suspension of 2-(1-aminocyclopropyl)-5-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (331c) in DMF (5 mL) and DCM (5 mL) at 0° C. was treated with DIEA (0.76 mL, 4.38 mmol) followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (456 mg, 0.87 mmol). The ice bath was removed and the resulting mixture was stirred at RT for 18 h. It was treated with 20 G of ice, the yellow solid was filtered, washed sequentially with 5 mL of water, 5 mL of 0.5 N NaOH, 5 mL of water and 2×5 mL of DCM. The yellow solid was dried in a vacuum oven at 45° C. for 5 h to give 2′-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (331) (179 mg, 0.48 mmol, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.59 (1H, br.), 7.83 (1H, d, J=8.0 Hz), 7.65 (2H, m), 7.58 (1H, br.), 7.40 (1H, t, J=7.5 Hz), 6.85 (1H, s), 6.43 (0.25; H, m), 6.29 (0.5; H, m), 6.14 (0.25; H, m), 3.92 (2H, m), 2.57 (3H, s), 1.42 (2H, m), 1.38 (2H, m). 19F NMR (376 MHz, DMSO-d6) δ ppm −120.48. m/z (ESI, +ve) 370.1 (M+H)+.

Workup

  1. customThe ice bath was removed
  2. additionIt was treated with 20 G of ice
  3. filtrationthe yellow solid was filtered
  4. washwashed sequentially with 5 mL of water, 5 mL of 0.5 N NaOH, 5 mL of water and 2×5 mL of DCM
  5. customThe yellow solid was dried in a vacuum oven at 45° C. for 5 h

Sources & evidence

ORD record
ord-21ddd1ff9b154f0fa2a5bc74bfddff62
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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