ChemicalBook CAS DataBase List Ivabradine Impurity 1 Hydrochloride

Ivabradine Impurity 1 Hydrochloride synthesis

4synthesis methods

Product Name:Ivabradine Impurity 1 Hydrochloride
CAS Number:85175-77-5
Molecular formula:C16H24N2O3
Molecular Weight:292.37

3H-3-Benzazepine-3-propanal, 1,2,4,5-tetrahydro-7,8-dimethoxy-2-oxo-

85175-82-2
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74-89-5 Synthesis

74-89-5
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85175-77-5
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Yield:85175-77-5 80%

Reaction Conditions:

Stage #1: 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)propanal;methylamine in methanol;water at 0; for 1 h;
Stage #2: with methanol;sodium tetrahydroborate in water at 0 - 20; for 12.5 h;

Steps:

1 7,8-dimethoxy-3-[3-(methylamino)propyl]-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

EXAMPLE 1 7,8-Dimethoxy-3-[3-(methylamino)propyl]-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one Dissolve 50 g (0.18 mol) of 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)propanal in 625 ml of methanol. Cool the resulting solution to 0° C. and then add 62.5 ml (0.81 mol; 4.5 equivalents) of an aqueous 40% methylamine solution. Stir for one hour at 0° C. and then add 7.5 g (0.2 mol; 1.1 equivalent) of NaBH₄. Stir for 30 minutes at 0° C. and then stir for 12 hours at ambient temperature. Evaporate off the methanol. The residue is taken up in aqueous hydrochloric acid solution (1N), and washed with ethyl acetate. The aqueous phase is then adjusted to pH=8 by adding 20% sodium hydroxide solution and extracted with dichloromethane. The organic phase is washed with water, dried over MgSO₄, filtered and then evaporated to dryness to obtain 52 g of an oil, which is purified by flash chromatography on 1.5 kg of silica (eluant=dichloromethane/-ethanol/NH₄OH:80/20/2). 42 g of the expected product are obtained in the form of a white solid. Yield=80% M.p. (KB)=68-70° C.

References:

US2010/160628,2010,A1 Location in patent:Page/Page column 3