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

HRID 61390Notes

Reaction equation

HRID 61390 reaction equation
[F:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][CH2:14][CH2:15][B:16]3[O:20]C(C)(C)C(C)(C)[O:17]3)[C@:10]([NH:29]C(=O)C(F)(F)F)([C:25]([O:27]C)=[O:26])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.O.[OH-].[Li+].[ClH:41]>C1COCC1.O>[ClH:41].[NH2:29][C:10]1([C:25]([OH:27])=[O:26])[CH:11]([CH2:13][CH2:14][CH2:15][B:16]([OH:20])[OH:17])[CH2:12][N:8]([C:6](=[O:7])[C:5]2[CH:36]=[CH:37][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9]1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 168937Lithium hydroxide, monohydrate2×HCID 123559287racemic methyl (3R,4S)-1-(4-fluorobenzoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]-3-[(trifluoroacetyl)amino]pyrrolidine-3-carboxylate

Product 1

HCID 77305148racemic (3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]-1-(4-fluorobenzoyl)pyrrolidine-3-carboxylic acid hydrochlorideYield 30%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

A stirred solution of racemic methyl (3R,4S)-1-(4-fluorobenzoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]-3-[(trifluoroacetyl)amino]pyrrolidine-3-carboxylate (200 mg, 0.377 mmol) in THF 94.2 mL) and water (3.7 mL) was sparged with nitrogen for 5 min. Lithium hydroxide monohydrate (33.2 mg, 0.792 mmol) was added, and the mixture was sparged with nitrogen for 10 min and stirred under nitrogen at room temperature for 4 days, during which additional lithium hydroxide monohydrate (39.6 mg, 0.943 mmol) was added. The mixture was diluted with water (5 mL) and acidified to pH<1 with 3 M aqueous HCl. The resulting solution was washed with ethyl acetate (2×20 mL) and methylene chloride (2×20 mL). The aqueous phase was concentrated under reduced pressure and purified by reverse phase HPLC. Product fractions were pooled, concentrated, re-dissolved in 1M aqueous HCl, concentrated and lyophilized to give racemic (3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]-1-(4-fluorobenzoyl)pyrrolidine-3-carboxylic acid hydrochloride (42 mg, 30%) as a white amorphous solid. MS (ESI+) m/z 321 (M−H2O+H+), 303 (M−2 H2O+H+) and MS (ESI−) m/z 319 (M−H2O−H+).

Workup

  1. customthe mixture was sparged with nitrogen for 10 min
  2. additionwas added
  3. washThe resulting solution was washed with ethyl acetate (2×20 mL) and methylene chloride (2×20 mL)
  4. concentrationThe aqueous phase was concentrated under reduced pressure
  5. custompurified by reverse phase HPLC
  6. concentrationconcentrated
  7. dissolutionre-dissolved in 1M aqueous HCl
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-20653aeb25754ccc9ce202d091f2649f
Source dataset
uspto-grants-2016_09
Patent number
US09440995B2

Reaction notes

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