1-Hydroxybenzotriazole → 2'-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1'H-spiro[cyclopropane-1,6'-pyrrolo[3,4-b]pyrrol]-4'(5'H)-one

HRID 1056195Notes

Reaction equation

HRID 1056195 reaction equation
C(OC([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][C:34]3([CH3:37])[CH2:36][CH2:35]3)[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19]CC)=O)[CH2:11][CH2:10]1)=O)(C)(C)C.Cl.NC1(C2NC(C3C=CC=C4C=3N=C(NC3(C)CC3)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.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH3:32][C:26]1[C:25]([NH:33][C:34]2([CH3:37])[CH2:35][CH2:36]2)=[N:24][C:23]2[C:28](=[CH:29][CH:30]=[CH:31][C:22]=2[C:14]2[NH:13][C:12]3[C:9]4([CH2:11][CH2:10]4)[NH:8][C:17](=[O:19])[C:16]=3[CH:15]=2)[N:27]=1

Participants

9

Reactant 6

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 897832462-(1-aminocyclopropyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride2×HCID 89783550ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-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 717302442'-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1'H-spiro[cyclopropane-1,6'-pyrrolo[3,4-b]pyrrol]-4'(5'H)-oneYield 30%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

Ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate (329b) (925 mg, 1.829 mmol) was converted to 2-(1-aminocyclopropyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (329c: m/z (ESI, +ve) 378.1 (M+H)+) in a fashion similar to that described for Intermediate 324c. This material was used as crude. At RT, to a suspension of 2-(1-aminocyclopropyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)-quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (329c) in 10 mL of DMF and 10 mL of DCM was sequentially added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (619 mg, 3.23 mmol), 1-hydroxybenzotriazole (436 mg, 3.23 mmol) and DIEA (1.77 mL, 10.20 mmol). The homogeneous reaction mixture was stirred at RT for 18 h. It was diluted with 80 mL of DCM, washed sequentially with 5 mL of water, 5 mL of 1 N NaOH and 5 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (50-100% EtOAc in DCM followed by 1-5% MeOH in DCM) twice to give 2′-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (329) (192 mg, 30% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.28 (1H, br.), 8.00 (1H, d, J=7.4 Hz), 7.73 (1H, s), 7.54-7.68 (2H, m), 7.36 (1H, t, J=7.8 Hz), 7.22 (1H, s), 2.52 (3H, s), 1.50 (3H, s), 1.48 (2H, m), 1.31 (2H, m), 0.94 (2H, m), 0.74 (2H, m). m/z (ESI, +ve) 360.2 (M+H)+.

Workup

  1. washwashed sequentially with 5 mL of water, 5 mL of 1 N NaOH and 5 mL of brine
  2. dry with materialdried over Na2SO4
  3. concentrationconcentrated
  4. customThe residue was purified by silica gel chromatography (50-100% EtOAc in DCM followed by 1-5% MeOH in DCM) twice

Sources & evidence

ORD record
ord-587bf32048234551a484a5bfd978c02a
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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