Dimethylformamide → 3-{5-[(1R)-2-Amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}benzoic acid hydrochloride

HRID 1799207

Reaction equation

HRID 1799207 reaction equation
Br[C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C[O:16][C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)=[O:18].CN(C=[O:32])C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[ClH:8].[NH2:12][CH2:13][C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([C:23]2[CH:24]=[C:19]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:18])=[O:16])[CH:3]=1)[CH2:10][C:11]([OH:14])=[O:32]

Participants

8

Reactant 4

HCID 6228DimethylformamideHCID 62657Potassium Phosphate, TribasicHCID 27347143-(Methoxycarbonyl)benzeneboronic acidHCID 66724952(4R)-4-(3-bromo-4-chlorophenyl)pyrrolidin-2-one

Product 1

HCID 667250703-{5-[(1R)-2-Amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}benzoic acid hydrochloride

Reagents, catalysts & solvents 3

HCID 74236Tetrabutylammonium BromideCatalystHCID 167845palladium(II) acetateCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

(4R)-4-(3-Bromo-4-chlorophenyl)pyrrolidin-2-one (0.5 g, 0.55 mmol) and 3-methoxycarbonylphenyl boronic acid (0.144 g, 0.55 mmol) were mixed with DMF (2 mL). The mixture was degassed by alternately applying a vacuum and flushing with nitrogen. Palladium acetate (0.025 g, 0.11 mmol) and tetrabutylammonium bromide (0.053 g, 0.165 mmol) were added followed by potassium phosphate (0.35 g, 1.65 mmol). The mixture was stirred overnight at 90° C., then cooled to room temperature, diluted with ethyl acetate (30 mL), washed with a 10% aqueous HCl solution then brine, and concentrated in vacuo. The product, 3-[5-((3R)-5-oxopyrrolidin-3-yl)-2-chlorophenyl]benzoic acid, was then treated with HCl as described for the preparation of (3R)-4-amino-3-(3-bromo-4-chlorophenyl)butanoic acid hydrochloride to provide the title compound (25). 1H-NMR (400 MHz, CD3OD): δ8.03-8.06 m, 2H), 7.65-7.68 (m, 2H), 7.55-7.57 (m, 1H), 7.33-7.37 (m, 2H), 3.42-3.49 (m, 1H), 3.2-3.26 (m, 2H), 2.77-2.83 (dd, J=16.8, 6.4 Hz, 1H), 2.63-2.69 (dd, J=16.4, 7.6 Hz, 1H); MS (ESI) m/z 333.98 (M+H)+.

Workup

  1. customThe mixture was degassed
  2. customflushing with nitrogen
  3. temperaturecooled to room temperature
  4. washwashed with a 10% aqueous HCl solution
  5. concentrationbrine, and concentrated in vacuo
  6. additionThe product, 3-[5-((3R)-5-oxopyrrolidin-3-yl)-2-chlorophenyl]benzoic acid, was then treated with HCl
  7. customas described for the preparation of (3R)-4-amino-3-(3-bromo-4-chlorophenyl)butanoic acid hydrochloride

Sources & evidence

ORD record
ord-a8c954e7ca1545b491053e4d53ea3417
Source dataset
uspto-grants-2013_01
Patent number
US08344028B2

Linked notes

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