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

HRID 1056197Notes

Reaction equation

HRID 1056197 reaction equation
C([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[C:31]([F:32])=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:34][CH:35]([CH3:37])[CH3:36])[C:26]([CH3:33])=[N:27]4)=[CH:15][C:16]=2C(OCC)=O)[CH2:11][CH2:10]1)=O)(C)(C)C.Cl.NC1(C2NC(C3C(F)=CC=C4C=3N=C(NC(C)C)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:32][C:31]1[C:22]([C:14]2[NH:13][C:12]3[C:9]4([CH2:10][CH2:11]4)[NH:8][C:6](=[O:5])[C:16]=3[CH:15]=2)=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([CH3:33])[C:25]([NH:34][CH:35]([CH3:36])[CH3:37])=[N:24]2

Participants

8

Reactant 5

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 897836712-(1-aminocyclopropyl)-5-(6-fluoro-3-(isopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride2×HCID 89784345ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(6-fluoro-3-(isopropylamino)-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 717302452'-(6-fluoro-3-(isopropylamino)-2-methylquinoxalin-5-yl)-1'H-spiro[cyclopropane-1,6'-pyrrolo[3,4-b]pyrrol]-4'(5'H)-oneYield 59.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

Ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(6-fluoro-3-(isopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (330b) (1.0 g, 1.95 mmol) was converted to 2-(1-aminocyclopropyl)-5-(6-fluoro-3-(isopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (330c: m/z (ESI, +ve) 384.1 (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-(6-fluoro-3-(isopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (330c) (798 mg, 1.9 mmol) in DMF (10 mL) and DCM (10 mL) at 0° C. was treated with DIEA (1.98 mL, 11.40 mmol) followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.29 g, 2.47 mmol). The ice bath was removed and the resulting mixture was stirred at RT for 1 h. The mixture was poured onto 150 G of ice. The insoluble brown solid was filtered, rinsed with 2×5 mL of water followed by 3×10 mL of DCM. The solid was collected, dried in a vacuum oven at 45° C. for 1 h to give 425 mg of 2′-(6-fluoro-3-(isopropylamino)-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (330) as a yellow crystalline solid. The filtrate was transferred to a separatory funnel, extracted with 50 mL of DCM. The organic layer was washed with 10 mL of 1 N NaOH followed by 10 mL of brine, dried over Na2SO4 and concentrated. The residue was stirred in 50 mL of EtOAc for 30 min. The insoluble yellow crystalline solid was filtered to give additional 165 mg of 2′-(6-fluoro-3-(isopropylamino)-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (330). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.12 (1H, br.), 7.68 (2H, m), 7.29 (1H, m), 7.02 (1H, br.), 6.73 (1H, s), 4.26 (1H, m), 2.52 (3H, s) 11.40 (4H, m), 1.29 (6H, m). 19F NMR (377 MHz, DMSO-d6) δ ppm −110.86. m/z (ESI, +ve) 366.2 (M+H)+.

Workup

  1. customThe ice bath was removed
  2. additionThe mixture was poured onto 150 G of ice
  3. filtrationThe insoluble brown solid was filtered
  4. washrinsed with 2×5 mL of water
  5. customThe solid was collected
  6. customdried in a vacuum oven at 45° C. for 1 h

Sources & evidence

ORD record
ord-ac22a1a79e494c8aa0f3aea973050b70
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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