Methyl 4-aminobenzoate → rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzoic acid methyl ester

HRID 909053Notes

Reaction equation

HRID 909053 reaction equation
[Cl:1][C:2]1[C:3]([F:32])=[C:4]([C@H:8]2[CH2:12][N:11]([CH2:13][C:14](O)=[O:15])[C@@H:10]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C@@:9]2([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1.[NH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:41][O:40][C:38](=[O:39])[C:37]1[CH:36]=[CH:35][C:34]([NH:33][C:14](=[O:15])[CH2:13][N:11]2[CH2:12][C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:32])[C@:9]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[F:31])([C:22]#[N:23])[C@@H:10]2[CH2:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:43][CH:42]=1

Participants

6

Reactant 4

HCID 12082Methyl 4-aminobenzoateHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 51355303rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid

Product 1

HCID 51355304rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzoic acid methyl esterYield 81%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A mixture of rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid (0.5 g, 1.04 mmol), methyl 4-aminobenzoate (Aldrich) (0.3 g, 1.99 mmol), HATU (0.4 g, 1.05 mmol) and iPr2NEt (0.3 g, 2.33 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 20 h. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by chromatography (EtOAc:hexanes=1:5) to give rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzoic acid methyl ester as a white solid (0.5 g, 81%).

Workup

  1. washwashed with water, brine
  2. customThe organic phase was separated
  3. filtrationfiltered
  4. dry with materialdried over Na2SO4
  5. concentrationThe mixture was then concentrated
  6. custompurified by chromatography (EtOAc:hexanes=1:5)

Sources & evidence

ORD record
ord-2bc5ddd193fa421d84e9480248956cae
Source dataset
uspto-grants-2011_09
Patent number
US08017607B2

Reaction notes

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