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 410553노트

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HRID 410553 반응식
[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

참가 물질

9

반응물 5

HCID 9256ThiazoleHCID 2724682Lithium diisopropylamide2회HCID 3028194LithiumHCID 529112052,2-Dimethyl-4-oxocyclohexane-1-carboxylic acidHCID 58456403N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine2회

생성물 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 acid수율 428.6%

시약·촉매·용매 3

HCID 887Methanol용매HCID 962Water용매HCID 8028Tetrahydrofuran용매2회

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온도
-78 °C

실험 절차

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=+++.

후처리

  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)

출처 및 근거

ORD 기록
ord-19aca8f9b5834af1ba4b532306b801b0
출처 데이터셋
uspto-grants-2014_06
특허 번호
US08759366B2

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