4-Methylmorpholine → (1S,3aR,6aS)-ethyl 2-(2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylate

HRID 424971Notes

Reaction equation

HRID 424971 reaction equation
[CH:1]1([CH:7]([NH:22][C:23]([C:25]2[CH:30]=[N:29][CH:28]=[CH:27][N:26]=2)=[O:24])[CH:8]([NH:13][CH:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15](O)=[O:16])[C:9]([F:12])([F:11])[F:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C@@H:32]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C@H:36]2[CH2:37][CH2:38][CH2:39][C@H:35]2[CH2:34][NH:33]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH:1]1([CH:7]([NH:22][C:23]([C:25]2[CH:30]=[N:29][CH:28]=[CH:27][N:26]=2)=[O:24])[CH:8]([NH:13][CH:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([N:33]2[CH2:34][C@@H:35]3[CH2:39][CH2:38][CH2:37][C@@H:36]3[C@H:32]2[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:16])[C:9]([F:10])([F:11])[F:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

8

Reactant 4

HCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 667048352-(3-Cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoic acidHCID 72183111(1S,3aR,6aS)-Octahydrocyclopenta[c]pyrrole-1-carboxylic acid ethyl ester hydrochloride

Product 1

HCID 86635382(1S,3aR,6aS)-ethyl 2-(2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylate

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

The stereoisomer of 2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoic acid designated as 8A1-isomerA (crude product from above), (1S,3aR,6aS)-ethyl octahydrocyclopenta[c]pyrrole-1-carboxylate (9) (1 eq), N-methylmorpholine (0.106 mL, 2.5 eq) and O-(7-azabenzotriazole-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (101 mgm, 1 eq) in a mixture of N,N-dimethylformamide (1.2 mL) and tetrahydrofuran (0.2 mL) was stirred at room temperature for 18 hours. The reaction mixture was then diluted with ethyl acetate and washed successively with 1N hydrochloric acid, water, brine and then dried over anhydrous sodium sulfate. Evaporation to dryness under reduced pressure gave crude product, which was purified by silica gel column chromatography. Elution with a solvent gradient from hexane to 20% ethyl acetate/hexane gave pure (1S,3aR,6aS)-ethyl 2-(2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoyl)octahydrocyclopenta-[c]pyrrole-1-carboxylate, designated as 10A1-isomer A.

Workup

  1. washwashed successively with 1N hydrochloric acid, water, brine
  2. dry with materialdried over anhydrous sodium sulfate
  3. customEvaporation to dryness under reduced pressure
  4. customgave crude product, which
  5. customwas purified by silica gel column chromatography
  6. washElution with a solvent gradient from hexane to 20% ethyl acetate/hexane

Sources & evidence

ORD record
ord-cc2e82c7a2ea4407831ebb356d707049
Source dataset
uspto-grants-2012_01
Patent number
US08106059B2

Reaction notes

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