4-Methylmorpholine → (S)-4,4-difluoro-2-(5-hydroxy-adamantan-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester

HRID 1644804Notes

Reaction equation

HRID 1644804 reaction equation
[NH2:1][CH:2]1[CH:9]2[CH2:10][C:5]3([OH:12])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[CH2:13]([O:20][C:21]([N:23]1[CH2:27][C:26]([F:29])([F:28])[CH2:25][C@H:24]1[C:30](O)=[O:31])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:13]([O:20][C:21]([N:23]1[CH2:27][C:26]([F:29])([F:28])[CH2:25][C@H:24]1[C:30](=[O:31])[NH:1][CH:2]1[CH:3]2[CH2:11][CH:7]3[CH2:6][C:5]([OH:12])([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 28574474-Aminoadamantan-1-olHCID 53909714(S)-1-((Benzyloxy)carbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid

Product 1

HCID 66773599(S)-4,4-difluoro-2-(5-hydroxy-adamantan-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl esterYield 78.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 4-amino-adamantan-1-ol (0.58 g, g, 0.0035 mol) in DMF (12 mL) was added (S)-4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (1.0 g, CAS: 72180-27-9, Journal of Medicinal Chemistry, 2007, 50(20), 4953-4975), NMM (0.9 mL) and HOBT (0.644 g), and the reaction was stirred for 10 minutes. EDCI (0.80 g) was then added and the reaction mixture was stirred at room temperature for 5 h. The reaction was diluted with water (30 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The organic layer was separated and dried over anhydrous Na2SO4. Concentration of the organic layer under reduced pressure using rotary evaporator gave sticky crude material, which was purified through column chromatography (10-20% ethyl acetate:hexane, silica 100-200, Diameter of column—2.5 cm, Height of silica—approx. 7 inch) to give the desired (S)-4,4-difluoro-2-(5-hydroxy-adamantan-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (1.2 g, 78%) as a white solid.

Workup

  1. stirringthe reaction mixture was stirred at room temperature for 5 h
  2. extractionThe aqueous layer was extracted with ethyl acetate (3×10 mL)
  3. customThe organic layer was separated
  4. dry with materialdried over anhydrous Na2SO4
  5. customevaporator
  6. customgave sticky crude material, which
  7. customwas purified through column chromatography (10-20% ethyl acetate:hexane, silica 100-200, Diameter of column—2.5 cm, Height of silica—approx. 7 inch)

Sources & evidence

ORD record
ord-41be34ccfd66492bacbd85b47f408c54
Source dataset
uspto-grants-2012_02
Patent number
US08124636B2

Reaction notes

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