Acetone → (S)-2-Amino-3-methylbutyric Acid 3-Acetyl-5-[N'-((R)-2-carboxy-2-hydroxyethyl)-N'-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)hydrazinocarbonyl]pyrazol-1-ylmethyl Ester

HRID 541544Notes

Reaction equation

HRID 541544 reaction equation
[C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][N:12]([CH2:28][C@@H:29]([OH:33])[C:30]([OH:32])=[O:31])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[NH:7][N:8]=1)(=[O:3])[CH3:2].CC(C)=O.CCN(CC)CC.Cl[CH2:46][O:47][C:48](=[O:61])[C@@H:49]([NH:53]C(OC(C)(C)C)=O)[CH:50]([CH3:52])[CH3:51].CC#N.Cl.O1CCOCC1>>[C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][N:12]([CH2:28][C@H:29]([C:30]([OH:32])=[O:31])[OH:33])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[N:7]([CH2:46][O:47][C:48](=[O:61])[C@@H:49]([NH2:53])[CH:50]([CH3:52])[CH3:51])[N:8]=1)(=[O:3])[CH3:2]

Participants

8

Reactant 7

HCID 180AcetoneHCID 313Hydrochloric AcidHCID 6342AcetonitrileHCID 8471TriethylamineHCID 312751,4-DioxaneHCID 54112037chloromethyl (2S)-2-(((tert-butoxy)carbonyl)amino)-3-methylbutanoateHCID 86705116(R)-3-[N'-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid

Product 1

HCID 117669070(S)-2-Amino-3-methylbutyric Acid 3-Acetyl-5-[N'-((R)-2-carboxy-2-hydroxyethyl)-N'-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)hydrazinocarbonyl]pyrazol-1-ylmethyl EsterYield 74.5%

Conditions

Temperature
60 °C

Procedure

(R)-3-[N′-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (95.5 mg, 0.2 mmol) was dissolved in acetone (886 μL, 12.1 mmol). Et3N (70 μL, 503 μmol) and (S)-2-t-butoxycarbonylamino-3-methyl-butyric acid chloromethyl ester (56.1 mg, 211 μmol) were added, and the resulting mixture was stirred at 60° C. for 6 hours. The solvent was removed in vacuo and the residue was purified using flashy chromatography (normal phase; MeOH:EtOAc=0:50). The pure fractions were collected, concentrated, then dissolved in MeCN (630 μL, 12.1 mmol). A solution of 4.0 M HCl in 1,4-dioxane (503 μL, 2.0 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo to yield the title compound (90 mg).

Workup

  1. customThe solvent was removed in vacuo
  2. customthe residue was purified
  3. customThe pure fractions were collected
  4. concentrationconcentrated
  5. stirringthe resulting mixture was stirred at room temperature for 2 hours
  6. customThe solvent was removed in vacuo

Sources & evidence

ORD record
ord-11fd5fa702484629a2c41e46a5d35af7
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

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