tert-Butanol → (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 242319Notes

Reaction equation

HRID 242319 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:26]=[C:27]([C:33]([F:36])([F:35])[F:34])[C:28]([O:31][CH3:32])=[N:29][CH:30]=1.CC(C)([O-])C.[Na+].C(O)(C)(C)C>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].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1N(C)C)(C)(C)C.CCOC(C)=O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][N:22]([C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

8

Reactant 4

HCID 6386tert-ButanolHCID 23676156Sodium t-butoxideHCID 533931825-Bromo-2-methoxy-3-(trifluoromethyl)pyridine2×HCID 57495324Tert-butyl (S)-3-((5,6,7,8-tetrahydropyrido[4,3-D]pyrimidin-4-YL)amino)pyrrolidine-1-carboxylate2×

Product 1

HCID 57495325(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl esterYield 74%

Reagents, catalysts & solvents 3

HCID 27349362-Di-tert-butylphosphino-2'-(N,N-dimethylamino)biphenylCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 21584119Ethylacetate methanolSolvent

Conditions

Temperature
100 °C

Procedure

To a glass vial was added (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 23) (3.5 g, 10.96 mmol), 5-bromo-2-methoxy-3-(trifluoromethyl)pyridine (intermediate 1) (3.09 g, 12.05 mmol), sodium tert-butoxide (1.58 g, 16.44 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.502 g, 0.548 mmol), 2-di-t-butylphosphino-2′-(N,N-dimethylamino)biphenyl (0.225 g, 0.657 mmol) and anhydrous tert-butanol (6 mL). The vial was flushed with a stream of argon for 15 sec and capped. The mixture was heated with stirring for 5 h at 100° C. Allowed to cool and partitioned between EtOAc (100 mL) and water (20 mL) and filtered the biphasic mixture through a celite pad. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. Purified by flash column chromatography through Biotage® amino silica gel eluting with heptane/EtOAc, 100/0 to 0/100 then EtOAc/MeOH (90/10) to give (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow foam (4.00 g, 74% yield). LCMS: [M+H]+=495.2, Rt(3)=1.59 min.

Workup

  1. customThe vial was flushed with a stream of argon for 15 sec
  2. customcapped
  3. temperatureThe mixture was heated
  4. temperatureAllowed to cool
  5. custompartitioned between EtOAc (100 mL) and water (20 mL)
  6. filtrationfiltered the biphasic mixture through a celite pad
  7. customThe organic layer was separated
  8. dry with materialdried (MgSO4)
  9. concentrationconcentrated in vacuo
  10. customPurified by flash column chromatography through Biotage® amino silica gel eluting with heptane/EtOAc, 100/0 to 0/100

Sources & evidence

ORD record
ord-2e380c3e6dab4be59480cd54b811d32c
Source dataset
uspto-grants-2014_02
Patent number
US08653092B2

Reaction notes

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