Potassium Carbonate → HCID 90699172, compound

HRID 73607Notes

Reaction equation

HRID 73607 reaction equation
C([O:4][CH:5]1[CH:10]([CH3:11])[CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[N:22]=[C:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[S:24][CH:25]=2)=[O:20])[CH2:7][CH:6]1[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[F:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[C:23]1[S:24][CH:25]=[C:21]([C:19]([NH:18][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:12]=2[CH:8]2[CH2:7][CH:6]([NH:34][C:35](=[O:36])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[CH:5]([OH:4])[CH:10]([CH3:11])[CH2:9]2)=[O:20])[N:22]=1

Participants

4

Reactant 2

HCID 11430Potassium CarbonateHCID 68409699(+/-)-2-(Tert-butoxycarbonylamino)-4-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-6-methylcyclohexyl acetate

Product 1

HCID 90699172HCID 90699172, compoundYield 87%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of (+/−)-2-(tert-butoxycarbonylamino)-4-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-6-methylcyclohexyl acetate in MeOH (0.03 M) was added potassium carbonate (3.0 equiv.) and the reaction was stirred at room temperature for 3 h. Upon completion, the reaction was partitioned between water and ethyl acetate. The aqueous phase was further extracted 3 more times with ethyl acetate. The organics were combined, dried with brine and sodium sulfate, filtered, and concentrated. Isolated tert-butyl(+/−)-5-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate was obtained as an off-white solid in 87% yield. LC/MS=545.2 (M+H), Rt=0.75 min. To a solution of tert-butyl(+/−)-5-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate (1.0 equiv.) in DCM (0.07M) at 0° C. was added DAST (1.0 equiv.) under a nitrogen atmosphere. The reaction was stirred for 1 h, upon which time, 2 more equivalents of DAST were added. After 30 min, the consumption of the starting material was complete. The reaction was quenched by the addition of water, the organic phase was dried with sodium sulfate, and concentrated. The crude material was purified via silica gel column chromatography eluting with ethyl acetate and hexanes (1:1) to afford tert-butyl(+/−)-5-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-2-fluoro-3-methylcyclohexylcarbamate as a clear oil in 60% yield. LC/MS=547.3 (M+H), Rt=0.92 min. The Boc group was removed by treating with 25% TFA in dichloromethane for 2 hours. Upon concentration under vacuo, the crude was purified via semi-prep HPLC. The pure fractions were lyophilized to yield N-(4-((+/−)-3-amino-4-fluoro-5-methylcyclohexyl)pyridin-3-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide as the desired product as the TFA salt in 74% yield. LC/MS=447.0 (M+H), Rt=0.56 min.

Workup

  1. customUpon completion, the reaction was partitioned between water and ethyl acetate
  2. extractionThe aqueous phase was further extracted 3 more times with ethyl acetate
  3. dry with materialdried with brine and sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-d929ef4462964a82847d1ca389b037a8
Source dataset
uspto-grants-2014_09
Patent number
US08829193B2

Reaction notes

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