Betahistine → n-Methyl-n{(1r)-1-[n-methyl-n-(2-(2-pyridyl)ethyl)carbamoyl]-2-phenylethyl}carbamic acid tert-butyl ester

HRID 413489Notes

Reaction equation

HRID 413489 reaction equation
[C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.[CH3:52][NH:53][CH2:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=1>ClCCl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:9])[C@@H:10]([C:11](=[O:13])[N:53]([CH3:52])[CH2:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 5

HCID 2366BetahistineHCID 81531DiisopropylethylamineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 7015127N-Boc-N-methyl-D-phenylalanine

Product 1

HCID 59063568n-Methyl-n{(1r)-1-[n-methyl-n-(2-(2-pyridyl)ethyl)carbamoyl]-2-phenylethyl}carbamic acid tert-butyl esterYield 68.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-phenylpropionic acid (11.2 g, 40 mmol), 1-hydroxy-7-azabenzotriazole (5.4 g, 40 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.7 g, 40 mmol) were dissolved in dichloromethane (100 mL). The reaction mixture was stirred for 15 min. Ethyidiisopropylamine (6.85 mL, 40 mmol) and 2-(2-methylaminoethyl)pyridine (5.54 mL, 40 mmol) were added. The reaction mixture was stirred for 16 h. The reaction mixture was washed with sat. aqueous sodium hydrogen carbonate solution (3×150 mL). The organic layer was dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using ethyl acetate as eluent, to give 10.9 g of N-methyl-N{(1R)-1-[N-methyl-N-(2-(2-pyridyl)ethyl)carbamoyl]-2-phenylethyl}carbamic acid tert-butyl ester.

Workup

  1. stirringThe reaction mixture was stirred for 16 h
  2. washThe reaction mixture was washed with sat. aqueous sodium hydrogen carbonate solution (3×150 mL)
  3. dry with materialThe organic layer was dried over magnesium sulfate
  4. customThe solvent was removed in vacuo
  5. customThe crude product was purified by flash chromatography on silica (400 g)

Sources & evidence

ORD record
ord-09847c81757d4d2c9cececfcd3ced5ab
Source dataset
uspto-grants-2003_05
Patent number
US06566337B1

Reaction notes

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