Tetrahydrofuran → 2-(3-Chloro-4-fluorophenyl)-N5-(3,3-difluoro-1-methylcyclobutyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide

HRID 920776ノート

反応式

HRID 920776 の反応式
[F:1][C:2]1([F:10])[CH2:5][C:4]([CH3:9])(C(O)=O)[CH2:3]1.C1C=CC(P([N:25]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[C:44]([C:45]([NH2:47])=[O:46])=[C:39]3[CH2:40][NH:41][CH2:42][CH2:43][N:38]3[N:37]=2)[CH:32]=[CH:33][C:34]=1[F:35].C1[CH2:52][O:51]CC1>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[C:44]([C:45]([NH2:47])=[O:46])=[C:39]3[CH2:40][N:41]([C:52]([NH:25][C:4]4([CH3:9])[CH2:3][C:2]([F:1])([F:10])[CH2:5]4)=[O:51])[CH2:42][CH2:43][N:38]3[N:37]=2)[CH:32]=[CH:33][C:34]=1[F:35]

参加物

6

反応物 4

HCID 8028TetrahydrofuranHCID 199401P,P-Diphenylphosphinic azideHCID 234468533,3-Difluoro-1-methylcyclobutane-1-carboxylic acidHCID 1180616272-(3-Chloro-4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

生成物 1

HCID 1180614842-(3-Chloro-4-fluorophenyl)-N5-(3,3-difluoro-1-methylcyclobutyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide収率 34.8%

試薬・触媒・溶媒 1

HCID 1140Toluene溶媒

反応条件

温度
85 °C

実験手順

To a solution of Intermediate 296B (30.6 mg, 0.204 mmol) in toluene (6 mL) was added TEA (0.071 mL, 0.509 mmol), DPPA (0.047 mL, 0.204 mmol) and the reaction mixture was heated to 85° C. and stirred for 1 h. The reaction mass was cooled to RT and to it was added a solution of Intermediate 185B (30 mg, 0.102 mmol) in THF (1 mL) and stirred for 12 h. The reaction mixture was concentrated and the residue was extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with water, dried over sodium sulfate, filtered and the filtrate concentrated. The crude product was purified by preparative HPLC to afford Compound 296 as an off-white solid (16 mg, 34.8%). HPLC retention time 1.33 min. and 1.35 min. (Methods J and K respectively). MS(ES): m/z=442 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.82-7.89 (m, 1H), 7.66-7.73 (m, 1H), 7.43-7.51 (m, 1H), 7.09-7.33 (m, 1H), 4.73 (s, 2H), 4.12-4.18 (m, 2H), 3.78-3.88 (m, 2H), 2.80-2.94 (m, 2H), 2.55-2.65 (m, 2H), 1.45 (s, 3H).

後処理

  1. temperatureThe reaction mass was cooled to RT and to it
  2. stirringstirred for 12 h
  3. concentrationThe reaction mixture was concentrated
  4. extractionthe residue was extracted with ethyl acetate (3×10 mL)
  5. washThe combined organic layer was washed with water
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationthe filtrate concentrated
  9. customThe crude product was purified by preparative HPLC

出典と根拠

ORDレコード
ord-6b342d5c815b43259f100480efd4314f
出典データセット
uspto-grants-2016_03
特許番号
US09273058B2

反応ノート

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