Tetrahydrofuran → methyl(2R)-2-methyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propanoate

HRID 410604Notes

Reaction equation

HRID 410604 reaction equation
Br[C:2]1[S:3][C:4]([C:7]2[CH:8]=[C:9]([NH:14][C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=3)[CH:10]=[C:11]([CH3:13])[CH:12]=2)=[CH:5][N:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C1COCC1.[Br-].[CH3:60][O:61][C:62](=[O:67])[C@H:63]([CH3:66])[CH2:64][Zn+]>[NH4+].[Cl-].O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:64][C@H:63]([CH2:66][C:2]1[S:3][C:4]([C:7]2[CH:8]=[C:9]([NH:14][C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=3)[CH:10]=[C:11]([CH3:13])[CH:12]=2)=[CH:5][N:6]=1)[C:62]([O:61][CH3:60])=[O:67]

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 58456233N-[3-(2-bromo-1,3-thiazol-5-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine2×HCID 178501470HCID 178501470, compound

Product 1

HCID 58456198methyl(2R)-2-methyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propanoateYield 87%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 25517Ammonium ChlorideSolvent

Procedure

N-[3-(2-Bromo-1,3-thiazol-5-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 9, 1.50 g, 3.61 mmol), Pd(OAc)2 (81 mg, 0.361 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (297 mg, 0.722 mmol) were combined in a vial, sealed, and purged with nitrogen (2×). Degassed THF (15 mL) and (S)-(−)-3-methoxy-2-methyl-3-oxopropylzinc bromide (0.5 M in THF, 28.9 mL, 14.45 mmol) were added, and the reaction was stirred at room temperature overnight. The reaction was diluted with saturated aqueous NH4Cl and water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Flash chromatography (0-50% ethyl acetate in hexanes) afforded methyl (2R)-2-methyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propanoate (1.37 g, 87%) as a yellow gum. MS ESI: [M+H]+ m/z 437.0. 1H NMR (600 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.80 (d, J=4.8, 1H), 7.93 (s, 2H), 7.43 (s, 1H), 7.25 (d, J=4.9, 1H), 7.12 (s, 1H), 3.58 (s, 3H), 3.25 (dd, J=7.8, 15.2, 1H), 3.09 (dd, J=6.2, 15.2, 1H), 3.00-2.91 (m, 1H), 2.29 (s, 3H), 1.15 (d, J=7.0, 3H). rhSYK activity=+++

Workup

  1. customsealed
  2. custompurged with nitrogen (2×)
  3. extractionextracted with ethyl acetate (2×)
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. customevaporated

Sources & evidence

ORD record
ord-79ca3d21d9ac4e59899149f343037537
Source dataset
uspto-grants-2014_06
Patent number
US08759366B2

Reaction notes

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