Pivalic acid → Tert-butyl 3-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)-pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}pyrrolidine-1-carboxylate

HRID 2272675Notes

Reaction equation

HRID 2272675 reaction equation
[OH:1][C:2]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3].Br[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=2)[CH:25]=[C:24]([CH3:39])[CH:23]=1.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.C(O)(=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C(=O)C>[OH:1][C:2]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)([C:4]1[S:5][C:6]([C:22]2[CH:23]=[C:24]([CH3:39])[CH:25]=[C:26]([NH:28][C:29]3[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][N:30]=3)[N:27]=2)=[CH:7][N:8]=1)[CH3:3]

Participants

8

Reactant 5

HCID 6417Pivalic acidHCID 11430Potassium CarbonateHCID 11371790Bis(adamantan-1-yl)(butyl)phosphaneHCID 866807956-bromo-4-methyl-N-[4-(trifluoromethyl)pyridine-2-yl]pyridine-2-amineHCID 86715345Tert-butyl 3-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]pyrrolidine-1-carboxylate

Product 1

HCID 86715346Tert-butyl 3-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)-pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}pyrrolidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 31374DimethylacetamideSolvent

Conditions

Temperature
130 °C

Procedure

tert-Butyl 3-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]pyrrolidine-1-carboxylate (100 mg, 0.335 mmol), 6-bromo-4-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (112 mg, 0.337 mmol), butyl di-1-adamantylphosphine (25 mg, 0.070 mmol), tris(dibenzylideneacetone)dipalladium(0) (16.3 mg, 0.018 mmol), pivalic acid (0.018 mL, 0.157 mmol), potassium carbonate (140 mg, 1.013 mmol) and N,N-dimethylacetamide (1 mL) were combined and the mixture was evacuated and purged with nitrogen 3 times then heated to 130° C. for 7 hours. The mixture was filtered then extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to afford tert-butyl 3-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)-pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}pyrrolidine-1-carboxylate, which was used in a subsequent step without further purification. MS ESI calc'd. for C26H30F3N5O3S [M+H]+ 550. found 550.

Workup

  1. customthe mixture was evacuated
  2. custompurged with nitrogen 3 times
  3. filtrationThe mixture was filtered
  4. extractionthen extracted with ethyl acetate
  5. washThe organic phase was washed with water and brine
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-efdfb72df5384e3e96522f795d33ca09
Source dataset
uspto-grants-2015_09
Patent number
US09120785B2

Reaction notes

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