Thiazole → (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid

HRID 410553ノート

反応式

HRID 410553 の反応式
[Li].[CH3:2][C:3]1[CH:4]=[C:5]([NH:14][C:15]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)[CH:6]=[C:7]([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH:8]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:33][C:34]1([CH3:44])[CH2:39][C:38](=[O:40])[CH2:37][CH2:36][CH:35]1[C:41]([OH:43])=[O:42].S1C=CN=C1>C1COCC1.O.CO>[OH:40][C@:38]1([C:12]2[S:13][C:9]([C:7]3[CH:6]=[C:5]([NH:14][C:15]4[N:20]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:18]=[CH:17][N:16]=4)[CH:4]=[C:3]([CH3:2])[CH:8]=3)=[CH:10][N:11]=2)[CH2:37][CH2:36][C@H:35]([C:41]([OH:43])=[O:42])[C:34]([CH3:44])([CH3:33])[CH2:39]1

参加物

9

反応物 5

HCID 9256ThiazoleHCID 2724682Lithium diisopropylamide2 回HCID 3028194LithiumHCID 529112052,2-Dimethyl-4-oxocyclohexane-1-carboxylic acidHCID 58456403N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine2 回

生成物 1

HCID 53251506(1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid収率 428.6%

試薬・触媒・溶媒 3

HCID 887Methanol溶媒HCID 962Water溶媒HCID 8028Tetrahydrofuran溶媒2 回

反応条件

温度
-78 °C

実験手順

Lithium diispropylamide (1.31 M, 10.0 mL, 13.1 mmol) was cooled to −78° C. and N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 4, 2.0 g, 5.95 mmol) in THF (20 mL) was added portionwise. While stirring at −78° C. additional lithium diisopropylamide (1.31 M, 4.55 mL, 5.95 mmol) was added. In a separate flask, lithium diisopropylamide (1.31 M, 10.0 mL, 13.1 mmol) was cooled to 0° C. and 2,2-dimethyl-4-oxo-cyclohexanecarboxylic acid (2.02 g, 11.9 mmol) in THF (20 mL) was added. The resulting solution of the carboxylate anion was transferred via cannula to the previously prepared thiazole anion solution, maintaining an internal reaction temperature below −68° C. The resultant mixture was stirred at −78° C. for 1 h, then methanol (5 mL) was added and the reaction mixture allowed to warm to room temperature. The reaction mixture was poured into water (200 mL) and extracted with MTBE (2×). The layers were separated and the aqueous portion was acidified to pH=3 with 2 N aqueous HCl then extracted with ethyl acetate (2×). The combined organic portions were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide a yellow foam. The foam was then purified and the enantiomers separated via supercritical fluid chromatography (30% MeOH:CO2) to give (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (Example 42(1), 12.9 g, 25.5 mmol, 21%) as a yellow solid. MS ESI: [M+H]+ m/z 507.1. 1H NMR (500 MHz, DMSO-d6) δ 12.13-11.86 (br s, 1H), 10.24 (s, 1H), 8.82 (m, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.46 (s, 1H), 7.27 (m, 1H), 7.14 (s, 1H), 5.89 (s, 1H), 2.31 (s, 3H), 2.16 (d, J=12.7, 1H), 2.02 (m, 1H), 1.86 (m, 3H), 1.64 (d, J=13.8, 1H), 1.57 (d, J=13.1, 1H), 1.11 (s, 3H), 0.99 (s, 3H). rhSYK activity=+++.

後処理

  1. additionwas added
  2. temperaturemaintaining an internal reaction temperature below −68° C
  3. temperatureto warm to room temperature
  4. extractionextracted with MTBE (2×)
  5. customThe layers were separated
  6. extractionthen extracted with ethyl acetate (2×)
  7. dry with materialThe combined organic portions were dried over anhydrous Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customto provide a yellow foam
  11. customThe foam was then purified
  12. customthe enantiomers separated via supercritical fluid chromatography (30% MeOH:CO2)

出典と根拠

ORDレコード
ord-19aca8f9b5834af1ba4b532306b801b0
出典データセット
uspto-grants-2014_06
特許番号
US08759366B2

反応ノート

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