Hydrochloric Acid → (3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]-1-[(4-fluorophenyl)carbamoyl]pyrrolidine-3-carboxylic acid hydrochloride

HRID 61391

Reaction equation

HRID 61391 reaction equation
[ClH:1].Cl.[NH2:3][C@:4]1([C:15]([OH:17])=[O:16])[C@@H:8]([CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[CH2:7][NH:6][CH2:5]1.CCN(CC)CC.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1.Cl>CN(C=O)C.O>[ClH:1].[NH2:3][C@:4]1([C:15]([OH:17])=[O:16])[C@@H:8]([CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[CH2:7][N:6]([C:33](=[O:34])[NH:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[CH2:5]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 709554-Fluorophenyl isocyanateHCID 67513430(3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]pyrrolidine-3-carboxylic acid dihydrochloride

Product 1

HCID 67513686(3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]-1-[(4-fluorophenyl)carbamoyl]pyrrolidine-3-carboxylic acid hydrochlorideYield 27%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

While under nitrogen, a stirred mixture of (3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]pyrrolidine-3-carboxylic acid dihydrochloride (0.225 g, 0.623 mmol) in dry DMF (9 mL) was treated with Et3N (0.521 mL, 3.74 mmol) and 4-fluorophenyl isocyanate (92.1 uL, 0.810 mmol). After stirring for 1.5 h, the reaction mixture was diluted with water (5 mL) and acidified to pH˜1 with 3M aqueous HCl (5 mL). The aqueous phase was washed with methylene chloride (2×25 mL) and ethyl acetate (25 mL), concentrated and purified by reverse phase HPLC. Product fractions were pooled, concentrated, re-dissolved in 1M aqueous HCl, concentrated and lyophilized to give (3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]-1-[(4-fluorophenyl)carbamoyl]pyrrolidine-3-carboxylic acid hydrochloride (racemate) (65 mg, 27%) as a white amorphous solid. MS (ESI+) m/z 336 (M−H2O+H+), 3.18 (M−2 H2O+H+) and MS (ESI−) m/z 334 (M−H2O+H+).

Workup

  1. washThe aqueous phase was washed with methylene chloride (2×25 mL) and ethyl acetate (25 mL)
  2. concentrationconcentrated
  3. custompurified by reverse phase HPLC
  4. concentrationconcentrated
  5. dissolutionre-dissolved in 1M aqueous HCl
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-6c94a49428394452ae15b538b46bd1cb
Source dataset
uspto-grants-2016_09
Patent number
US09440995B2

Linked notes

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