Methanol → Methyl 5-{1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}pyridine-2-carboxylate

HRID 1040189Notes

Reaction equation

HRID 1040189 reaction equation
Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([NH:22][C:23]4[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=4)[CH:19]=[C:18]([CH3:33])[CH:17]=3)=[CH:14][N:15]=2)([OH:10])[CH3:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:63][OH:64].C(N(CC)CC)C.CN([CH:75]=[O:76])C>[NH4+].[Cl-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:10][C:8]([C:5]1[CH:4]=[CH:3][C:2]([C:63]([O:76][CH3:75])=[O:64])=[N:7][CH:6]=1)([C:11]1[S:12][C:13]([C:16]2[CH:21]=[C:20]([NH:22][C:23]3[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=3)[CH:19]=[C:18]([CH3:33])[CH:17]=2)=[CH:14][N:15]=1)[CH3:9]

Participants

8

Reactant 5

HCID 887MethanolHCID 6228DimethylformamideHCID 8471TriethylamineHCID 812191,3-Bis(diphenylphosphino)propaneHCID 866582581-(6-Bromopyridin-3-yl)-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethanol

Product 1

HCID 67430690Methyl 5-{1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}pyridine-2-carboxylateYield 66%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
70 °C

Procedure

The product of Step 1 (175 mg, 0.326 mmol), palladium (II) acetate (7.32 mg, 0.033 mmol), and 1,3-bis(diphenylphosphino)propane (13.46 mg, 0.033 mmol) were combined in a 5 ml microwave vial, sealed, and taken up in DMF (3 ml)/MeOH (1.5 ml). CO was bubbled through the reaction mixture for 5 min. Triethylamine (0.091 ml, 0.653 mmol) was added, a CO balloon was attached, and the reaction was stirred at 70° C. overnight. The reaction was diluted with saturated NH4Cl solution and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. The crude material was purified by chromatography on silica gel (Biotage 25 g SNAP, 50-100% EtOAc/hexanes, 50-100% EtOAc/toluene) followed by reverse phase HPLC (45-80% MeCN/water w/0.1% TFA). The fractions containing the desired product were combined, partially concentrated to remove MeCN, diluted with saturated NaHCO3, and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to provide methyl 5-{1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}pyridine-2-carboxylate (111 mg, 0.215 mmol, 66% yield) as a colorless foam. MS ESI: [M+H]+ m/z 516.1.

Workup

  1. customsealed
  2. customCO was bubbled through the reaction mixture for 5 min
  3. extractionextracted with EtOAc (2×)
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried (MgSO4)
  6. customevaporated
  7. customThe crude material was purified by chromatography on silica gel (Biotage 25 g SNAP, 50-100% EtOAc/hexanes, 50-100% EtOAc/toluene)
  8. additionThe fractions containing the desired product
  9. concentrationpartially concentrated
  10. customto remove MeCN
  11. additiondiluted with saturated NaHCO3
  12. extractionextracted with CH2Cl2 (2×)
  13. washThe combined organic layers were washed with brine
  14. dry with materialdried (MgSO4)
  15. filtrationfiltered
  16. customevaporated

Sources & evidence

ORD record
ord-ea9328a707034b1e907e248435e50e2b
Source dataset
uspto-grants-2013_10
Patent number
US08551984B2

Reaction notes

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