Hydrochloric Acid → HCID 69669579, compound

HRID 590749Notes

Reaction equation

HRID 590749 reaction equation
[NH2:1][C@:2]1([C:41]([OH:43])=[O:42])[C@@H:6]([CH2:7][CH2:8][CH2:9][B:10]2[O:14]C(C)(C)C(C)(C)[O:11]2)[CH2:5][N:4]([C:19](=[O:40])[C@H:20]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[NH:21]C(OC(C)(C)C)=O)[CH2:3]1.[ClH:44]>C1COCC1.O1CCOCC1.O>[ClH:44].[ClH:44].[NH2:1][C@:2]1([C:41]([OH:43])=[O:42])[C@@H:6]([CH2:7][CH2:8][CH2:9][B:10]([OH:14])[OH:11])[CH2:5][N:4]([C:19](=[O:40])[C@H:20]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:32][CH:31]=2)[NH2:21])[CH2:3]1

Participants

6

Reactant 2

HCID 313Hydrochloric Acid2×HCID 67517051HCID 67517051, compound

Product 1

HCID 69669579HCID 69669579, compound

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 312751,4-DioxaneSolvent

Procedure

A solution of the crude (3R,4S)-3-amino-1-[N-(tert-butoxycarbonyl)-4-(trifluoromethyl)phenylalanyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxylic acid (Step 2, 242 mg) in anhydrous THF (6 mL) under nitrogen was treated with 4 N HCl in 1,4-dioxane (6 mL). After stirring for 2 h at room temperature, 1M aqueous HCl (6 mL) was added and stirring was continued for an additional 1.5 h. The reaction mixture was diluted with water (15 mL) and washed successively with ethyl acetate (25 mL) and methylene chloride (25 mL). The aqueous phase was concentrated and the residue was purified by reverse phase HPLC. Product fractions (mixture of diastereomers) were pooled and concentrated. The residue was reconstituted in 1 M HCl and re-concentrated. The resulting residue was diluted with deionized water and lyophilized to give (3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]-1-[4-(trifluoromethyl)phenylalanyl]-pyrrolidine-3-carboxylic acid dihydrochloride (mixture of two diastereomers, each a racemate) (43 mg, 12% overall for 3 steps) as a pale yellow amorphous solid. MS (ESI+) m/z 414 (M−H2O+H+), 396 (M−2H2O+H+); MS (ESI−) m/z 412 (M−H2O−H+).

Workup

  1. stirringstirring
  2. waitwas continued for an additional 1.5 h
  3. washwashed successively with ethyl acetate (25 mL) and methylene chloride (25 mL)
  4. concentrationThe aqueous phase was concentrated
  5. customthe residue was purified by reverse phase HPLC
  6. additionProduct fractions (mixture of diastereomers)
  7. concentrationconcentrated
  8. concentrationre-concentrated
  9. additionThe resulting residue was diluted with deionized water

Sources & evidence

ORD record
ord-e756decd13944c95b1a51a8cb11d35f9
Source dataset
uspto-grants-2016_01
Patent number
US09233985B2

Reaction notes

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