Potassium Carbonate → 2-[3,5-bis(trifluoromethyl)phenyl]-N-(4-(4-fluoro-2-methylphenyl)-6-{[(2S)-2-pyrrolidinylmethyl]amino}-3-pyridinyl)-N,2-dimethylpropanamide

HRID 421204ノート

反応式

HRID 421204 の反応式
[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:37][CH2:38][C@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1C(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:37][CH2:38][C@@H:39]3[CH2:43][CH2:42][CH2:41][NH:40]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

参加物

6

反応物 3

HCID 11430Potassium CarbonateHCID 1512534tert-butyl (2R)-2-(aminomethyl)pyrrolidine-1-carboxylateHCID 235027842-(3,5-Bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyrid-3-yl)-N,2-dimethylpropanamide

生成物 1

HCID 592157702-[3,5-bis(trifluoromethyl)phenyl]-N-(4-(4-fluoro-2-methylphenyl)-6-{[(2S)-2-pyrrolidinylmethyl]amino}-3-pyridinyl)-N,2-dimethylpropanamide収率 24.5%

試薬・触媒・溶媒 2

HCID 679Dimethyl Sulfoxide溶媒HCID 6344Dichloromethane溶媒

反応条件

温度
138 °C

実験手順

A suspension of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (1.5 g, 2.81 mmol) 1,1-dimethylethyl (2R)-2-(aminomethyl)-1-pyrrolidinecarboxylate (N-Boc prolinamine) (1.41 g, 7.025 mmol) and potassium carbonate (777 mg, 5.62 mmol) in 6 mL of DMSO was heated for 18 h at 150° C. (temperature detected 138° C.). A HPLC/MS check showed a 50% conversion with partial loss of the Boc protecting group. The reaction was heated under microwave irradiation to 160° C. for 1 h and to 180° C. for two cycles of 1 h and 1.5 h, respectively. The suspension was diluted with dichloromethane and extracted with sat. NaHCO3 and the organics were dried (Na2SO4) and the solution was loaded on a SCX cartridge, washed with dichloromethane (100 mL) and methanol (200 mL, this wash allowed the recovery of the unreacted chloropyridine) and eluted with 2M NH3 in MeOH. The crude thus obtained, which contained both the Boc-protected and unprotected compounds, was purified by flash chromatography (silica, cyclohexane:EtOAc 80:20 to EtOAc). Isolated 350 mg of Boc-protected amine and 410 mg of the title compound. This last compound was purified further by a boc-protection, flash chromatography, TFA deprotection and SCX isolation procedure. Final yield: 165 mg.

後処理

  1. temperatureThe reaction was heated under microwave irradiation to 160° C. for 1 h and to 180° C. for two cycles of 1 h and 1.5 h
  2. extractionextracted with sat. NaHCO3
  3. dry with materialthe organics were dried (Na2SO4)
  4. washwashed with dichloromethane (100 mL) and methanol (200 mL
  5. washeluted with 2M NH3 in MeOH
  6. customThe crude thus obtained
  7. customwas purified by flash chromatography (silica, cyclohexane:EtOAc 80:20 to EtOAc)

出典と根拠

ORDレコード
ord-710d728345114dbb8b88daa47ec63aa9
出典データセット
uspto-grants-2012_01
特許番号
US08097618B2

反応ノート

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