Sodium Carbonate → (1S,4R)-4-hydroxy-2,2-dimethyl-4-{5-[3-methyl-5-(4-methyl-pyrimidin-2-ylamino)-phenyl]-1,3-thiazol-2-yl}-cyclohexanecarboxylic acid methyl ester

HRID 410694Notes

Reaction equation

HRID 410694 reaction equation
[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:12]=[C:11]([CH3:24])[CH:10]=2)[N:3]=1.[CH3:25][O:26][C:27]([C@H:29]1[CH2:34][CH2:33][C@@:32]([C:36]2[S:37][C:38](Br)=[CH:39][N:40]=2)([OH:35])[CH2:31][C:30]1([CH3:43])[CH3:42])=[O:28].C(=O)([O-])[O-].[Na+].[Na+]>CC1CCCO1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:25][O:26][C:27]([C@H:29]1[CH2:34][CH2:33][C@:32]([OH:35])([C:36]2[S:37][C:38]([C:13]3[CH:14]=[C:9]([NH:8][C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=4)[CH:10]=[C:11]([CH3:24])[CH:12]=3)=[CH:39][N:40]=2)[CH2:31][C:30]1([CH3:43])[CH3:42])=[O:28]

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 584562194-methyl-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amineHCID 58456350(1S,4R)-4-(5-Bromo-thiazol-2-yl)-4-hydroxy-2,2-dimethyl-cyclohexanecarboxylic acid methyl ester

Product 1

HCID 67250092(1S,4R)-4-hydroxy-2,2-dimethyl-4-{5-[3-methyl-5-(4-methyl-pyrimidin-2-ylamino)-phenyl]-1,3-thiazol-2-yl}-cyclohexanecarboxylic acid methyl esterYield 66%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 73012-MethyltetrahydrofuranSolvent

Conditions

Temperature
70 °C

Procedure

To a mixture of (4-methyl-pyrimidin-2-yl)-[3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amine (20.0 g, 56.9 mmol), (1S,4R)-4-(5-Bromo-thiazol-2-yl)-4-hydroxy-2,2-dimethyl-cyclohexanecarboxylic acid methyl ester (19.8 g, 56.9 mmol), and PdCl2(dppf)2 (2.33 g, 2.85 mmol) in degassed 2-methyltetrahydrofuran (237 mL), was added sodium carbonate (2 M in H2O, 56.9 mL, 114 mmol). The reaction flask was purged with nitrogen and then heated to 70° C. for 5 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and filtered over celite. The solution was washed with water, dried over MgSO4, filtered and concentrated in vacuo. Purification by chromatography on silica gel (Isco CombiFlash 100:0 to 40:60, hexanes:ethyl acetate), then by Chromatography on silica gel (2:98, methanol:dichloromethane) provided 17.5 g (37.4 mmol 66%) of (1S,4R)-4-hydroxy-2,2-dimethyl-4-{5-[3-methyl-5-(4-methyl-pyrimidin-2-ylamino)-phenyl]-1,3-thiazol-2-yl}-cyclohexanecarboxylic acid methyl ester as a light tan foam.

Workup

  1. customThe reaction flask was purged with nitrogen
  2. temperatureThe mixture was cooled to room temperature
  3. additiondiluted with ethyl acetate (100 mL)
  4. filtrationfiltered over celite
  5. washThe solution was washed with water
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customPurification by chromatography on silica gel (Isco CombiFlash 100:0 to 40:60, hexanes:ethyl acetate)

Sources & evidence

ORD record
ord-42d09c24def441bcb2fd1b622d7e91e1
Source dataset
uspto-grants-2014_06
Patent number
US08759366B2

Reaction notes

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