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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 1040194
Notes
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Reaction equation

HRID 1040194 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]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

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 ester
Yield 66%

Reagents, catalysts & solvents 2

HCID 44119782Bis(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-5b18c137aca74e3992103bf465b3bc54
Source dataset
uspto-grants-2013_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08551984B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes