Hydrochloric Acid → 4-Hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxamide

HRID 1040050Notes

Reaction equation

HRID 1040050 reaction equation
[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[O-:31][C:32]#[N:33].[K+].Cl>C1COCC1.O.C([O-])(O)=O.[Na+]>[OH:30][C:24]1([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:25][CH2:26][N:27]([C:32]([NH2:33])=[O:31])[CH2:28][CH2:29]1

Participants

6

Reactant 3

HCID 313Hydrochloric Acid2×HCID 11378442Potassium cyanate2×HCID 584561264-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol

Product 1

HCID 584562314-Hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxamideYield 73.5%

Reagents, catalysts & solvents 2

HCID 516892Sodium BicarbonateSolventHCID 21881883Oxolane--water (1/1)Solvent

Conditions

Temperature
50 °C

Procedure

To 15 mg (0.034 mmol) of 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]piperidin-4-ol in THF/Water (3:1, 1 mL) was added 4.2 mg (0.052 mmol, 1.5 eq) of potassium cyanate and 2N hydrochloric acid (22 μL, 1.3 eq). The mixture was heated at 50° C. for 6 h and then another 1.5 eq of potassium cyanate and 1.5 eq HCl added and the mixture stirred at 50° C. overnight. The reaction was diluted with saturated aqueous NaHCO3 and was partitioned with ethyl acetate. The organic layer was washed with water and dried, filtered and solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes) to give 12 mg (0.025 mmol, 73%) of 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxamide as off-white solid. MS ESI: [M+H]+ m/z 479.2. 1H NMR (600 MHz, CD3OD): δ 8.68 (d, J=4.8 Hz, 1H); 7.99 (s, 1H); 7.87 (s, 1H); 7.40 (s, 1H); 7.10 (m, 2H); 3.91 (m, \2H); 3.28 (m, 2H); 2.34 (s, 3H); 2.16 (m, 2H); 1.83 (m, 2H). rhSYK activity=+++

Workup

  1. customwas partitioned with ethyl acetate
  2. washThe organic layer was washed with water
  3. customdried
  4. filtrationfiltered
  5. customsolvent removed under reduced pressure
  6. customThe residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-a42874266ca747d8953ca0f5de1fbe32
Source dataset
uspto-grants-2013_10
Patent number
US08551984B2

Reaction notes

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