Sodium Iodide → (S)-2-Methoxycarbonylamino-3-methylbutyric Acid (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)hydrazino]-2-hydroxypropionyloxymethyl Ester

HRID 541536Notes

Reaction equation

HRID 541536 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:16][C:17]([C:19]3[NH:23][C:22](=[O:24])[N:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.Cl[CH2:39][O:40][C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:45])[CH3:44].[Na+].[I-].CC1C=CC=C(C)N=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([O:35][CH2:39][O:40][C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:45])[CH3:44])=[O:34])[NH:16][C:17]([C:19]3[NH:23][C:22](=[O:24])[N:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]=3)=[O:18])=[CH:12][CH:13]=2)[CH:7]=1

Participants

7

Reactant 4

HCID 5238Sodium IodideHCID 79372,6-LutidineHCID 86669865(S)-chloromethyl 2-((methoxycarbonyl)amino)-3-methylbutanoateHCID 136344432(R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)hydrazino]-2-hydroxypropionic acid

Product 1

HCID 136344441(S)-2-Methoxycarbonylamino-3-methylbutyric Acid (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)hydrazino]-2-hydroxypropionyloxymethyl EsterYield 3.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)hydrazino]-2-hydroxypropionic acid (200 mg, 335 μmol) in dry DMF (6 mL) was added (S)-2-methoxycarbonylamino-3-methylbutyric acid chloromethyl ester (112 mg, 503 μmol), NaI (101 mg, 670 μmol), 2,6-dimethylpyridine (143 mg, 1.3 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 8 hours. Water (12 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=3:1) to yield the title compound as a white solid (8.4 mg). LC-MS: 712.9 [M+H]+. 1H NMR: (MeOD, 400 MHz) δ 0.85 (dd, J=14.1, 6.8 Hz, 6H), 2.01-2.17 (m, 1H), 3.42-3.51 (m, 2H), 3.69 (s, 3H), 4.00 (d, J=5.9 Hz, 1H), 4.23 (br, 2H), 4.42 (t, J=4.7 Hz, 1H), 5.83 (dd, J=31.5, 5.6 Hz, 2H), 7.19 (t, J=9.4 Hz, 1H), 7.32-7.39 (m, 3H), 7.47-7.51 (m, 4H), 7.56-7.58 (m, 2H), 7.91 (d, J=8.0 Hz, 2H).

Workup

  1. extractionthe mixture was extracted with EtOAc (3×20 mL)
  2. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  3. concentrationconcentrated in vacuo
  4. customThe residue was purified by column chromatography (PE:EtOAc=3:1)

Sources & evidence

ORD record
ord-5f0fddc1a5e346c68d576791f6b85a61
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

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