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 1056195ノート

反応式

HRID 1056195 の反応式
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

参加物

9

反応物 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 回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

生成物 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)-one収率 30%

試薬・触媒・溶媒 2

HCID 6228Dimethylformamide溶媒HCID 6344Dichloromethane溶媒2 回

実験手順

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)+.

後処理

  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

出典と根拠

ORDレコード
ord-587bf32048234551a484a5bfd978c02a
出典データセット
uspto-grants-2016_07
特許番号
US09394297B2

反応ノート

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