trans-2-Phenyl-1-cyclopropanecarbonyl chloride → HCID 178488229, 화합물

HRID 897691

반응식

HRID 897691 반응식
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[C:33]1([C@@H:39]2[CH2:41][C@H:40]2[C:42](Cl)=[O:43])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:42]([C@H:40]4[CH2:41][C@@H:39]4[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:43])=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12

참가 물질

4

반응물 2

HCID 13656trans-2-Phenyl-1-cyclopropanecarbonyl chloride2회HCID 178488198HCID 178488198, 화합물

생성물 1

HCID 178488229HCID 178488229, 화합물수율 70%

시약·촉매·용매 1

HCID 1049Pyridine용매

반응 조건

온도
0 °C

실험 절차

A solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.162 g, 0.371 mmol) in pyridine (2 mL) at 0° C. was treated with trans-2-phenyl-1-cyclopropylcarbonyl chloride (0.134 g, 0.742 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 20 min at 0° C., the ice bath was removed and the reaction mixture stirred at room temperature for 5 h. Additional trans-2-phenyl-1-cyclopropylcarbonyl chloride (0.034 g, 0.186 mmol) was added and the reaction mixture stirred for 1 h. The organic layer was removed under reduced pressure, and dichloromethane (15 mL) was then added. The layers were separated using an Empore extraction cartridge. The organic layer was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel using 15% methanol in dichloromethane then 20% methanol in dichloromethane as eluent. The column afforded 0.150 g (70%) of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-(1S,2S)-2-phenylcyclopropane-1-carboxamide. A hot solution of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-(1S,2S)-2-phenylcyclopropane-1-carboxamide (0.147, 0.253 mmol) in ethyl acetate was treated with a hot solution of maleic acid (0.088 g, 0.759 mmol) in ethyl acetate. The precipitate formed was filtered under nitrogen and dried under high vacuum to give 0.204 g of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-(1S,2S)-2-phenylcyclopropane-1-carboxamide tris-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 9.64 (s, 1H), 8.23-8.21 (m, 2H), 7.33-7.29 (m, 2H), 7.24-7.17 (m, 4H), 6.16 (s, 6H), 4.69-4.66 (m, 1H), 3.90 (s, 3H), 2.90-2.60 (m, 7H), 2.37-2.35 (m, 2H), 2.10-1.99 (m, 8H), 1.70-1.50 (m, 3H), 1.32 (m, 1H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.346 min (97%).

후처리

  1. customthe ice bath was removed
  2. stirringthe reaction mixture stirred at room temperature for 5 h
  3. stirringthe reaction mixture stirred for 1 h
  4. customThe organic layer was removed under reduced pressure, and dichloromethane (15 mL)
  5. additionwas then added
  6. customThe layers were separated
  7. extractionan Empore extraction cartridge
  8. customThe organic layer was removed under reduced pressure
  9. customThe crude product was purified by flash chromatography on silica gel using 15% methanol in dichloromethane

출처 및 근거

ORD 기록
ord-18fa90a1a8a84aec82c12f6ea3f64993
출처 데이터셋
uspto-grants-2005_07
특허 번호
US06921763B2

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