1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic Acid 5-Methyl-2-oxo-[1,3]-dioxol-4-ylmethyl Ester

HRID 541517Notes

Reaction equation

HRID 541517 reaction equation
CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][C:23]1[O:27][C:26](=[O:28])[O:25][C:24]=1[CH2:29][O:30][C:31](=[O:52])[C@H:32]([OH:51])[CH2:33][N:34]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[F:50])=[CH:39][CH:38]=1)[NH2:35].[CH3:53][O:54][C:55]1[CH:59]=[C:58]([C:60](O)=[O:61])[O:57][N:56]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][C:23]1[O:27][C:26](=[O:28])[O:25][C:24]=1[CH2:29][O:30][C:31](=[O:52])[C@H:32]([OH:51])[CH2:33][N:34]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[F:50])=[CH:41][CH:42]=1)[NH:35][C:60]([C:58]1[O:57][N:56]=[C:55]([O:54][CH3:53])[CH:59]=1)=[O:61]

Participants

7

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 3277173-Methoxy-1,2-oxazole-5-carboxylic acidHCID 86705088(R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester

Product 1

HCID 86705095(R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic Acid 5-Methyl-2-oxo-[1,3]-dioxol-4-ylmethyl EsterYield 23.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

EDCI (169 mg, 880 μmol) and HOBT (119 mg, 880 μmol) were added to a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester (200 mg, 440 μmol) and 3-methoxyisoxazole-5-carboxylic acid (63 mg, 440 μmol) in DMF (10 mL). DIPEA (114 mg, 880 μmol) was added and the mixture was stirred for 5 hours at room temperature. The mixture was washed with saturated aqueous NaCl (2×30 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (hexanes/EtOAc=1:1) to yield the title compound as a white solid (60 mg). LC-MS: 576.1 [M+H]+. 1H-NMR: (DMSO-d6) 2.14 (s, 3H), 3.21-3.19 (m, 2H), 3.91 (s, 3H), 4.17-4.11 (m, 2H), 4.31 (br, 1H), 4.98 (s, 2H), 5.57 (br, 1H), 6.73 (s, 1H), 7.57-7.34 (m, 7H), 10.07 (s, 1H).

Workup

  1. washThe mixture was washed with saturated aqueous NaCl (2×30 mL)
  2. extractionextracted with EtOAc (2×50 mL)
  3. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified by column chromatography (hexanes/EtOAc=1:1)

Sources & evidence

ORD record
ord-26f9872e63db4557a5bab1d378fea0ee
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

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