Acetic Acid → (1R,2S)-2-(3-chloro-4-fluoro-benzylamino)-cyclopentanecarboxylic acid methyl ester

HRID 731261Notes

Reaction equation

HRID 731261 reaction equation
Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH2:11])=[O:5].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[Cl:21].C(O)(=O)C.[BH4-].[Na+]>CO>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([F:12])=[C:14]([Cl:21])[CH:15]=1)=[O:5]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 5938663-Chloro-4-fluorobenzaldehydeHCID 4311764Sodium borohydrideHCID 14698814119993-55-4

Product 1

HCID 57671208(1R,2S)-2-(3-chloro-4-fluoro-benzylamino)-cyclopentanecarboxylic acid methyl ester

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
25 °C

Procedure

(1R,2S)-2-Amino-cyclopentanecarboxylic acid methyl ester hydrochloride (prepared as described in Example 11a, 0.2 g, 1.27 mmol) was dissolved in methanol (5.5 mL), followed by addition of 4-fluoro-3-chlorobenzaldehyde (0.201 g, 1.27 mmol) and stirred at 25° C. for 10 min. After this time, 5.2 M acetic acid (0.245 mL) was added, stirred at 25° C. for 5 min before placing in an ice-bath. Once at 0° C., sodium borohydride (0.203 mg, 3.2 mmol) was added portionwise after which time the mixture was allowed to warm to 25° C. and continued to stir for 17 h. The reaction mixture was quenched by pouring into saturated aqueous sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was concentrated in vacuo and purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-80% ethyl acetate in hexanes) to afford the desired product, (1R,2S)-2-(3-chloro-4-fluoro-benzylamino)-cyclopentanecarboxylic acid methyl ester (256 mg, 0.898 mmol, 70% as a yellow oil, containing residual ethyl acetate. 1H NMR (400 MHz, CDCl3) δ: 1.55-1.97 (m, 6H), 2.86 (dd, 1H, J1=14.2 Hz, J2=7.0 Hz), 3.19 (dd, 1H, J1=13.1 Hz, J2=6.9 Hz), 3.62 (s, 3H), 3.64 (d, 2H, J=6.2 Hz), 6.96 (t, 1H, J=8.5 Hz), 7.04-7.08 (m, 1H), 7.26-7.28 (m, 1H). LC-MS (ESI) calcd for C14H17ClFNO2 285.09, found 286.0 [M+H+].

Workup

  1. stirringstirred at 25° C. for 5 min
  2. custombefore placing in an ice-bath
  3. temperatureto warm to 25° C.
  4. stirringto stir for 17 h
  5. customThe reaction mixture was quenched
  6. additionby pouring into saturated aqueous sodium bicarbonate solution (200 mL)
  7. extractionextracted with ethyl acetate (200 mL)
  8. concentrationThe organic layer was concentrated in vacuo
  9. custompurified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-80% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-e5e3804f3ffb46bdb881ed6b3b4fc55e
Source dataset
uspto-grants-2009_09
Patent number
US07582626B2

Reaction notes

Loading…