Sodium t-butoxide → (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 242320Notes

Reaction equation

HRID 242320 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+]>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=1C)(C)(C)C.C(O)(C)(C)C>[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

7

Reactant 3

HCID 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 95.1%

Reagents, catalysts & solvents 3

HCID 27349372-(Di-tert-butylphosphino)-2'-methyl-1,1'-biphenylCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6386tert-ButanolSolvent

Procedure

To a glass flask 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) (6.331 g, 15.86 mmol), 5-bromo-2-methoxy-3-(trifluoromethyl)pyridine (intermediate 1) (4.465 g, 17.442 mmol), sodium tert-butoxide (2.29 g, 23.78 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.726 g, 0.793 mmol), di-tert-butyl(2′-methylbiphenyl-2-yl)phosphine (0.297 g, 0.951 mmol) and anhydrous tert-butanol (30 mL). The flask was flushed with a stream of nitrogen for 15 sec and capped. The mixture was heated with stirring for 4 h under reflux. The mixture was allowed to cool to rt and partitioned between EtOAc (100 mL) and water (20 mL). The biphasic mixture was filtered the through a celite pad. The organic layer was separated and concentrated in vacuo to give crude (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 (7.46 g, 95% yield).

Workup

  1. customThe flask was flushed with a stream of nitrogen for 15 sec
  2. customcapped
  3. temperatureThe mixture was heated
  4. temperatureunder reflux
  5. custompartitioned between EtOAc (100 mL) and water (20 mL)
  6. filtrationThe biphasic mixture was filtered the through a celite pad
  7. customThe organic layer was separated
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-cf71baaa6db94a4ea3f4d7da0a738977
Source dataset
uspto-grants-2014_02
Patent number
US08653092B2

Reaction notes

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