Phosgene → rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide

HRID 909108Notes

Reaction equation

HRID 909108 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:35](Cl)(Cl)=[O:36].CC1(C)[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl.CO>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:35]([N:9]1[CH2:10][CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:36]

Participants

8

Reactant 5

HCID 6371PhosgeneHCID 8471TriethylamineHCID 466102Benzenesulfonic acid, 4-methyl-, compd. with pyridine (1:1)HCID 282937772-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethan-1-amineHCID 67095616rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile

Product 1

HCID 86761406rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amideYield 43.8%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

To a mixture of rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (40.5 mg, 0.10 mmol) and triethylamine (TEA, 20.0 mg, 0.20 mmol) in CH2Cl2 (1 mL) was added phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol) by injection, and the reaction mixture was stirred at rt for 20 min. 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (29.4 mg, 0.20 mmol) was then added. The reaction mixture was stirred at rt for another 30 min then concentrated to give the crude product (checked by LCMS) which was diluted with MeOH and treated with PPTS (cat.) at 120° C. for 5 min with CEM microwave reactor. The reaction mixture was concentrated and diluted with CH2Cl2 and washed with water and brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by RP-HPLC to give rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (23.5 mg, 43.8%, 2 steps) as a white amorphous. HRMS (ES+) m/z Calcd for C27H32Cl2FN3O3+H [(M+H)+]: 536.1878; Found: 536.1879.

Workup

  1. stirringThe reaction mixture was stirred at rt for another 30 min
  2. concentrationthen concentrated
  3. customto give the crude product (checked by LCMS) which
  4. concentrationThe reaction mixture was concentrated
  5. additiondiluted with CH2Cl2
  6. washwashed with water and brine
  7. customThe organic phase was separated
  8. filtrationfiltered
  9. dry with materialdried over Na2SO4
  10. concentrationThe mixture was then concentrated
  11. custompurified by RP-HPLC

Sources & evidence

ORD record
ord-2d6bdd92ae6c4915aac848b032c281ee
Source dataset
uspto-grants-2011_09
Patent number
US08017607B2

Reaction notes

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