Water → (R)-methyl 1-(3-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-ylcarbamoyl)benzoyl)pyrrolidine-2-carboxylate

HRID 2071192Notes

Reaction equation

HRID 2071192 reaction equation
O.[OH:2][C@H:3]([CH2:24][NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:32]=1)[C@@H:4]([NH:12][C:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:49][O:50][C:51]([C@H:53]1[CH2:57][CH2:56][CH2:55][NH:54]1)=[O:52].CCN(C(C)C)C(C)C.O1C2C=CC=CC=2C=C1CNC(=O)OC(C)(C)C>C(Cl)Cl.CN(C=O)C>[OH:2][C@H:3]([CH2:24][NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([CH:33]([CH3:34])[CH3:35])[CH:32]=1)[C@@H:4]([NH:12][C:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([N:54]1[CH2:55][CH2:56][CH2:57][C@@H:53]1[C:51]([O:50][CH3:49])=[O:52])=[O:19])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1

Participants

9

Reactant 6

HCID 962WaterHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 44629857Methyl D-prolinate hydrochlorideHCID 686712363-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-ylcarbamoyl)benzoic acidHCID 68671575Tert-butyl benzofuran-2-ylmethylcarbamate

Product 1

HCID 68671264(R)-methyl 1-(3-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-ylcarbamoyl)benzoyl)pyrrolidine-2-carboxylateYield 31%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

H2O (0.0177 g, 0.131 mmol, 1.1 eq) was added to a stirred solution of 3-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-ylcarbamoyl)benzoic acid (0.055 g, 0.119 mmol, 1 eq) in 2 ml anhydrous CH2Cl2 at 0° C. under Ar. After 30 min EDCI.HCl (0.0197 g, 0.119 mmol, 1.1 eq) was added. After 30 min 1 ml anhydrous DMF was added. In a separate flask (R)-methylpyrrolidine-2-carboxylate hydrochloride (Bachem, 0.0197 g, 0.119 mmol, 1 eq) in 2 ml anhydrous CH2Cl2 under Ar was treated with DIPEA (0.083 ml, 0.062 g, 0.476 mmol, 4 eq). After both solutions had stirred for 1 h, the active ester was treated with the free-base amine. The reaction was stirred at 0° C. to room temperature overnight. The solvent was removed in vacuo. The residue was partitioned between EtOAc/H2O and the layers were separated. The organic layer was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent removed in vacuo. Purification via flash chromatography yielded 0.0208 g (0.036 mmol, 31% yield) of (R)-methyl 1-(3-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-ylcarbamoyl)benzoyl)pyrrolidine-2-carboxylate, which was treated under hydrolysis conditions as described herein to generate (R)-1-(3-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-ylcarbamoyl)benzoyl)pyrrolidine-2-carboxylic acid.

Workup

  1. stirringThe reaction was stirred at 0° C. to room temperature overnight
  2. customThe solvent was removed in vacuo
  3. customThe residue was partitioned between EtOAc/H2O
  4. customthe layers were separated
  5. washThe organic layer was washed with water (×3), brine (×1)
  6. dry with materialdried over Na2SO4
  7. filtrationThe inorganics were filtered off
  8. customthe solvent removed in vacuo
  9. customPurification via flash chromatography

Sources & evidence

ORD record
ord-1a7613061d7b4433b5087a5e883b6858
Source dataset
uspto-grants-2012_10
Patent number
US08299267B2

Reaction notes

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