Formaldehyde → 1-(Tert-butoxycarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-3-carboxylic acid

HRID 1867755노트

반응식

HRID 1867755 반응식
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:17][CH2:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][C:28]=2[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]3[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([N:17]([CH2:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][C:28]=2[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]3[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])[CH3:42])([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

참가 물질

7

반응물 4

HCID 712FormaldehydeHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydride2회HCID 690457921-(Tert-butoxycarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]piperidine-3-carboxylic acid

생성물 1

HCID 690457481-(Tert-butoxycarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-3-carboxylic acid수율 89.3%

시약·촉매·용매 2

HCID 176Acetic Acid용매HCID 6344Dichloromethane용매

실험 절차

1-(tert-Butoxycarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]piperidine-3-carboxylic acid (Isomer 1) (400 mg, 0.71 mmol) was dissolved in 5% acetic acid in dichloromethane (25 ml) and 37% aqueous formaldehyde (5 ml) added. The mixture was stirred rapidly and sodium triacetoxyborohydride (151 mg, 0.71 mmol) added. Over a period of 5 hours a further 3 equivalents of sodium triacetoxyborohydride were added. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate, the layers separated and the organic phased dried (MgSO4) and concentrated under reduced pressure. Column chromatography on silica, eluting with 10% ammonia in methanol/dichloromethane gave 1-(tert-butoxycarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-3-carboxylic acid (Isomer 1) (364 mg, 85%) as a white solid; 1H NMR Spectrum: (DMSO d6 100° C.) 1.27 (s, 9H); 1.47 (m, 1H); 1.86 (m, 1H); 2.01 (m, 2H); 2.30 (s, 3H); 3.30 (m, 1H); 3.44 (m, 1H); 3.63 (d, 1H); 3.74 (d, 1H); 3.81 (d, 1H); 3.88 (d, 1H); 3.96 (s, 3H); 7.19 (s, 1H); 7.25 (t, 1H); 7.40 (t, 1H); 7.65 (m, 1H); 8.22 (s, 1H); 8.41 (s, 1H); Mass Spectrum: (M+H)+ 574.5.

후처리

  1. customthe layers separated
  2. dry with materialthe organic phased dried (MgSO4)
  3. concentrationconcentrated under reduced pressure
  4. washColumn chromatography on silica, eluting with 10% ammonia in methanol/dichloromethane

출처 및 근거

ORD 기록
ord-cd2d0860462b491dba66535e2e5e828e
출처 데이터셋
uspto-grants-2009_12
특허 번호
US07632840B2

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