Sodium Iodide → (R)-3-{N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic Acid Ethoxycarbonyloxymethyl Ester

HRID 541515Notes

Reaction equation

HRID 541515 reaction equation
N1C(C)=CC=CC=1C.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([F:45])=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:39][C@@H:40]([OH:44])[C:41]([OH:43])=[O:42])[NH:24][C:25]([C:27]3[O:31][N:30]=[C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[F:38])[CH:28]=3)=[O:26])=[CH:18][CH:17]=2)[CH:15]=1.[CH2:46]([O:48][C:49](=[O:53])[O:50][CH2:51]Cl)[CH3:47].[Na+].[I-]>CN(C=O)C.O>[CH2:46]([O:48][C:49]([O:50][CH2:51][O:42][C:41](=[O:43])[C@H:40]([OH:44])[CH2:39][N:23]([CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[CH:15]=[C:10]([Cl:9])[CH:11]=[CH:12][C:13]=2[F:45])=[CH:17][CH:18]=1)[NH:24][C:25]([C:27]1[O:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[CH:28]=1)=[O:26])=[O:53])[CH3:47]

Participants

7

Reactant 4

HCID 5238Sodium IodideHCID 79372,6-LutidineHCID 5325479Chloromethyl Ethyl CarbonateHCID 67973214(R)-3-{N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid

Product 1

HCID 86705094(R)-3-{N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic Acid Ethoxycarbonyloxymethyl EsterYield 11.7%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

2,6-Lutidine (407 mg, 3.8 mmol) was added to a solution of (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (200 mg, 380 mmol), carbonic acid chloromethyl ester ethyl ester (105 mg, 760 μmol) and NaI (114 mg, 760 μmol) in DMF (10 mL). The mixture was stirred overnight at room temperature. Water (30 mL) was added and the mixture was extracted with EtOAc (3×40 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (MeCN—H2O (0.1% TFA); Gradient 60-70) to yield the title compound as a white solid (56 mg). LC-MS: 630.1 [M+H]+. 1H-NMR: (CD3OD-d4, 400 MHz) δ 1.24 (t, J=5.9 Hz, 3H), 3.30-3.33 (m, 2H), 4.17-4.32 (m, 4H), 4.45 (t, J=4.2 Hz, 1H), 5.78 (br, 2H), 7.20-7.28 (m, 1H), 7.57-7.29 (m, 10H), 7.92-7.95 (m, 1H).

Workup

  1. extractionthe mixture was extracted with EtOAc (3×40 mL)
  2. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  3. concentrationconcentrated in vacuo
  4. customThe residue was purified by preparative HPLC (MeCN—H2O (0.1% TFA); Gradient 60-70)

Sources & evidence

ORD record
ord-66aeefae8dd74906b15e4035ef1a3e90
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

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