2-(4-Amino-3-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester → 2-(4-{2-[2-(4-Chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-2-cyclohexyl-acetylamino}-3-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester

HRID 889389ノート

反応式

HRID 889389 の反応式
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])=[C:11]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:10]3=[N:9]2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:44])[C:32]([O:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([F:43])[CH:37]=1)([CH3:34])[CH3:33])[CH3:29]>S(Cl)(Cl)=O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:28]([O:30][C:31](=[O:44])[C:32]([O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:14](=[O:15])[CH:13]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:11]=23)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:38]([F:43])[CH:37]=1)([CH3:34])[CH3:33])[CH3:29]

参加物

6

反応物 2

HCID 671309762-(4-Amino-3-fluoro-phenoxy)-2-methyl-propionic acid ethyl esterHCID 67387113[2-(4-Chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-cyclohexyl-acetic acid

生成物 1

HCID 533903502-(4-{2-[2-(4-Chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-2-cyclohexyl-acetylamino}-3-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester収率 24.3%

試薬・触媒・溶媒 3

HCID 142844-(Dimethylamino)pyridine触媒HCID 6344Dichloromethane溶媒HCID 24386Thionyl Chloride溶媒

実験手順

A solution of [2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-cyclohexyl-acetic acid (40 mg, 103 umol) in thionyl chloride (2 ml) was heated under reflux conditions for 45 min. The solvent was removed under reduced pressure and the resulting crude [2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-cyclohexyl-acetyl chloride was dissolved in CH2Cl2 (1 ml) and added to a solution of 2-(4-amino-3-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester (37 mg, 155 umol) and DMAP (38 mg, 310 umol) in CH2Cl2 (1 ml). The reaction mixture was stirred at ambient temperature for 14 h. Ice water/brine 1/1 was added and the mixture was extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a brown oil which was purified by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water to obtain the title compound (15 mg, 25 umol; 24%) as brown solid. MS: m/e=610.3 [M+H+].

後処理

  1. customThe solvent was removed under reduced pressure
  2. dissolutionthe resulting crude [2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-cyclohexyl-acetyl chloride was dissolved in CH2Cl2 (1 ml)
  3. extractionthe mixture was extracted two times with iPrOAc
  4. washThe combined extracts were washed with ice water/brine 1/1
  5. dry with materialdried over Na2SO4
  6. filtrationAfter filtration the solvent
  7. customwas removed under reduced pressure
  8. customto give a brown oil which
  9. customwas purified by preparative HPLC on reversed phase
  10. washeluting with a gradient of acetonitrile/water

出典と根拠

ORDレコード
ord-83d86381f8634569a2c0046426ce0db7
出典データセット
uspto-grants-2012_08
特許番号
US08252826B2

反応ノート

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