Hydrochloric Acid → rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluor O-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide

HRID 909058Notes

Reaction equation

HRID 909058 reaction equation
[Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[CH2:12][N:11]([C:13](Cl)=[O:14])[CH:10]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]2([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1.CC1(C)[O:37][C@@H:36]([CH2:38][CH2:39][NH2:40])[CH2:35][O:34]1.C(N(CC)CC)C.Cl>O1CCCC1>[OH:37][C@H:36]([CH2:35][OH:34])[CH2:38][CH2:39][NH:40][C:13]([N:11]1[CH2:12][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C:9]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]1[CH2:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:14]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 282937772-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethan-1-amineHCID 76707490rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl chloride

Product 1

HCID 86652461rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluor O-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amideYield 28.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl chloride (0.34 g, 0.7 mmol) in tetrahydrofuran (5 mL) was added 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.1 g, 0.71 mmol) and triethylamine (0.15 mL, 1 mmol). The reaction mixture was stirred at room temperature for 30 min. An aqueous HCl solution (1 N, 5 mL, 5 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvents were removed and the residue was partitioned between ethyl acetate and NaHCO3 (sat.) solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (EtOAc) to afford rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.11 g, 28%). HRMS (ES+) m/z Calcd for C27H31Cl2F2N3O3+H [(M+H)+]: 554.1784; Found: 554.1785.

Workup

  1. stirringThe reaction mixture was stirred at room temperature for 1 h
  2. customThe solvents were removed
  3. customthe residue was partitioned between ethyl acetate and NaHCO3 (sat.) solution
  4. customThe organic layer was separated
  5. washwashed with water, brine
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated
  8. customThe residue was purified by column chromatography (EtOAc)

Sources & evidence

ORD record
ord-b2ed9cb60c3248d69e0c19efc7f60eb3
Source dataset
uspto-grants-2011_09
Patent number
US08017607B2

Reaction notes

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