Dichloromethane → HCID 68620251, compound

HRID 1807208Notes

Reaction equation

HRID 1807208 reaction equation
[Cl:1][C:2]1[C:3]([F:31])=[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])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN([C:35]([O:39]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC[N:58]([CH:62]([CH3:64])C)[CH:59](C)C.[CH2:65](Cl)Cl>>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[CH:9]([C:28]([N:58]3[CH2:59][C:64]4([CH2:35][O:39][CH2:65]4)[CH2:62]3)=[O:29])[NH:10][CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:12]2([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])[C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 4

HCID 6344Dichloromethane2×HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 666882513-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid

Product 1

HCID 68620251HCID 68620251, compound

Procedure

A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), 2-oxa-6-aza-spiro[3.3]heptane oxylate salt (123 mg, 0.65 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.22 mL, 1.2 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to rac-(2S,3R,4S,5R)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-5-(2-oxa-6-aza-spiro[3.3]heptane-6-carbonyl)-pyrrolidine-3-carbonitrile (78 mg, 33.3%) as an off-white powder. HRMS (ES+) m/z Calcd for C28H29Cl2F2N3O2+H [(M+H)+]: 548.1678. found: 548.1678.

Workup

  1. washwashed with water, brine
  2. customThe organic phase was separated
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationThe mixture was then concentrated
  6. custompurified by reverse phase chromatography (20-95% of ACN/water) to rac-(2S,3R,4S,5R)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-5-(2-oxa-6-aza-spiro[3.3]heptane-6-carbonyl)-pyrrolidine-3-carbonitrile (78 mg, 33.3%) as an off-white powder

Sources & evidence

ORD record
ord-6cdc85e123784d788fd61619be62e191
Source dataset
uspto-grants-2013_01
Patent number
US08354444B2

Reaction notes

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