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 410553Notes

Reaction equation

HRID 410553 reaction equation
[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

Participants

9

Reactant 5

HCID 9256ThiazoleHCID 2724682Lithium diisopropylamide2×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×

Product 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 acidYield 428.6%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

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=+++.

Workup

  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)

Sources & evidence

ORD record
ord-19aca8f9b5834af1ba4b532306b801b0
Source dataset
uspto-grants-2014_06
Patent number
US08759366B2

Reaction notes

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