Hydrochloric Acid → (S)-3-[(R)-(3-Chloro-2-methylphenoxy)cyclopropylmethyl]pyrrolidine

HRID 1671383Notes

Reaction equation

HRID 1671383 reaction equation
C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([CH:15]2[CH2:17][CH2:16]2)[OH:14])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](F)[C:27]=1[CH3:33].Cl.CCO>>[Cl:25][C:26]1[C:27]([CH3:33])=[C:28]([CH:29]=[CH:30][CH:31]=1)[O:14][C@H:13]([CH:15]1[CH2:16][CH2:17]1)[C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1

Participants

7

Reactant 6

HCID 313Hydrochloric AcidHCID 702EthanolHCID 6228DimethylformamideHCID 99332-Chloro-6-fluorotolueneHCID 24758Sodium hydrideHCID 66891333(S)-3-((R)-cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester

Product 1

HCID 58104598(S)-3-[(R)-(3-Chloro-2-methylphenoxy)cyclopropylmethyl]pyrrolidine

Procedure

(S)-3-((R)-Cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 4.1 mmol) was dissolved in DMF (15 mL, 200 mmol). Washed and dried sodium hydride (298 mg, 12.4 mmol) was added carefully in three separate portions and the resulting mixture was stirred at room temperature for 15 minutes. 2-Chloro-6-fluorotoluene (749 μL, 6.2 mmol) was added, and the mixture was stirred overnight at 70° C. The mixture was concentrated and the BOC-protected intermediate was purified by silica gel chromatography (0-10% EtOAc in hexanes for 10 minutes, 10-50% in 10 minutes) and the desired fractions were isolated and concentrated. The crude material was then treated with 1.25M HCl in EtOH (23.2 mL, 29.0 mmol) and stirred overnight at room temperature. The product was concentrated under vacuum and purified by preparative HPLC to yield the title compound as a mono-TFA salt (240 mg, 99.4% purity). MS m/z: [M+H]+ calcd for C15H20ClNO, 266.12; found 266.0.

Workup

  1. washWashed
  2. customseparate portions
  3. stirringthe mixture was stirred overnight at 70° C
  4. concentrationThe mixture was concentrated
  5. customwas purified by silica gel chromatography (0-10% EtOAc in hexanes for 10 minutes, 10-50% in 10 minutes)
  6. customthe desired fractions were isolated
  7. concentrationconcentrated
  8. stirringstirred overnight at room temperature
  9. concentrationThe product was concentrated under vacuum
  10. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-0dc4e8f794bb4d7cb648ba7799b5de36
Source dataset
uspto-grants-2011_08
Patent number
US07994209B2

Reaction notes

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