4-Methylmorpholine → (1S,3aR,6aS)-2-(2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide

HRID 424972Notes

Reaction equation

HRID 424972 reaction equation
[CH:1]1([CH:7]([NH:34][C:35](C2C=NC=CN=2)=[O:36])[CH:8]([NH:13][CH:14]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:15]([N:17]2[CH2:21][C@@H:20]3[CH2:22][CH2:23][CH2:24][C@@H:19]3[C@H:18]2C(OCC)=O)=[O:16])[C:9]([F:12])([F:11])[F:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C1(C(NC([C:79]2[CH:84]=[N:83][CH:82]=[CH:81][N:80]=2)=O)C(NC(C(C)(C)C)C(N2C[C@@H]3CCC[C@@H]3[C@H]2C(O)=O)=O)C(F)(F)F)CCCCC1.CN1CC[O:89][CH2:88]C1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl.[NH2:114][C@@H:115]([CH2:124][CH2:125][CH3:126])[CH:116]([OH:123])[C:117]([NH:119][CH:120]1[CH2:122][CH2:121]1)=[O:118]>C(O)C.C(OCC)(=O)C.O1CCCC1.ClCCl>[CH:1]1([CH:7]([NH:34][C:35]([C:84]2[CH:79]=[N:80][CH:81]=[CH:82][N:83]=2)=[O:36])[CH:8]([NH:13][CH:14]([C:30]([CH3:32])([CH3:33])[CH3:31])[C:15]([N:17]2[CH2:21][C@@H:20]3[CH2:22][CH2:23][CH2:24][C@@H:19]3[C@H:18]2[C:88]([NH:114][C@@H:115]([CH2:124][CH2:125][CH3:126])[CH:116]([OH:123])[C:117]([NH:119][CH:120]2[CH2:121][CH2:122]2)=[O:118])=[O:89])=[O:16])[C:9]([F:11])([F:10])[F:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

12

Reactant 7

HCID 79724-MethylmorpholineHCID 14798Sodium HydroxideHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 66656935Hexanamide, 3-amino-N-cyclopropyl-2-hydroxy-, hydrochloride (1:1), (3S)-HCID 66704743(1S,3aR,6aS)-2-(2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acidHCID 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

Product 1

HCID 66704750(1S,3aR,6aS)-2-(2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

The stereoisomer of (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 (85 mg) was dissolved in ethanol (3 mL) and treated with 2N aqueous sodium hydroxide solution (0.665 mL) at 65° C. for 2 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 the crude acid, designated as 11A1-isomer A, an isomer of (1S,3aR,6aS)-2-(2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid. The crude compound of formula 11A1-isomer A was mixed with N-methylmorpholine (0.078 mL, 5 eq), 1-hydroxybenzotriazole (38.6 mgm, 2 eq), 1-ethyl-3-(3′-dimethylaminopropyl)carbodimide (55 mgm, 2 eq), and (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride (12) (123 mgm, 4 eq) and dissolved in a mixture of tetrahydrofuran and dichloromethane, and stirred at room temperature for 18 hours. The reaction mixture was then diluted with ethyl acetate, washed successively with 1N hydrochloric acid, water, brine and then dried over anhydrous sodium sulfate. Evaporation to dryness under reduced pressure gave crude product (13A1-isomer A), an isomer of (1S,3aR,6aS)-2-(2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide.

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 the crude acid
  5. washwashed successively with 1N hydrochloric acid, water, brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. customEvaporation to dryness under reduced pressure

Sources & evidence

ORD record
ord-edcb747f589149808530c68a1bfe2484
Source dataset
uspto-grants-2012_01
Patent number
US08106059B2

Reaction notes

Loading…