CN103012268A

CN103012268A - Novel preparation method for ivabradine

Info

Publication number: CN103012268A
Application number: CN2013100017493A
Authority: CN
Inventors: 洪承杰; 陈言德; 刘德龙; 朱万里
Original assignee: Jiangsu Yutian Biological Medical Technology Co Ltd
Current assignee: Jiangsu Yutian Pharmaceutical Co., Ltd.
Priority date: 2013-01-05
Filing date: 2013-01-05
Publication date: 2013-04-03
Anticipated expiration: 2033-01-05
Also published as: CN103012268B

Abstract

The invention belongs to the field of pharmaceutical chemical engineering, and relates to a novel synthesis method for ivabradine. The novel synthesis method for ivabradine comprises the following steps of: reacting a compound III with a compound IV in a reaction solvent under the catalysis of an alkali, performing post-treatment to obtain a compound II, and performing hydrogenation reaction under a system containing a catalyst and ammonium formate to obtain a compound I, namely, ivabradine. The method is short in synthesis route, simple to operate, greatly lowered in the difficulty of synthesis for ivabradine, low in cost and high in product yield; and most importantly, the method is good in safety, not involved with high-pressure hydrogenation, free from the use of an inflammable gas, namely, hydrogen, and great in industrialization base and application value.

Description

A kind of new S 16257-2 preparation method

Technical field

The invention belongs to field of medicine and chemical technology, be specifically related to one group suc as formula the preparation of the benzocyclobutane compounds S 16257-2 shown in the I.

Background technology

S 16257-2, suc as formula compound shown in the I, chemical name: 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-yl) methyl]-methylamino-] propyl group)-1,3,4,5-tetrahydro--2 hydrogen-benzazepine-2-ketone can be used for the treatment of various myocardial ischemias clinically, for example stenocardia, myocardial infarction and relevant rhythm disturbance are a kind of boundless cardiovascular drugs of new generation of prospect for the treatment of.

Figure 2013100017493100002DEST_PATH_IMAGE001

I

At present, S 16257-2 synthetic mainly contains following several:

Method one:

Figure 2013100017493100002DEST_PATH_IMAGE002

The R group represents halogen, dioxolane, dioxane etc.

Method two:

Figure 2013100017493100002DEST_PATH_IMAGE003

The R group represents halogen, dioxolane, dioxane etc.

From existing S 16257-2 synthetic method, can find out, which kind of method no matter, the docking reaction yield is all lower, in the building-up process and need to use autoclave, need the multistep recrystallization, solvent-oil ratio is large, cause the preparation manipulation of compound I loaded down with trivial details, preparation cost is high.Caused directly that the preparation cost of hydrochloric acid Ivabradine is high and the preparation difficulty is large, be not suitable for industry's enlarging production.

Summary of the invention

In view of the huge pharmaceutical use of present S 16257-2 with and synthetic larger difficulty, the invention provides a kind of preparation method of new S 16257-2.The method synthetic route is short, and is simple to operate, raw materials used existing detailed preparation method, and the preparation method is simple, and is with low cost, greatly reduces the synthetic difficulty of S 16257-2.

For achieving the above object, the technical scheme that the present invention takes is: a kind of preparation method of new S 16257-2, and synthetic route is as follows:

Figure 2013100017493100002DEST_PATH_IMAGE004

Concrete steps are: compound III is reacted in reaction solvent with compound IV under the catalysis of alkali, obtain compound I I through aftertreatment, compound I I carries out hydrogenation under the system of catalyzer and ammonium formiate, react to get compound I, i.e. S 16257-2.

Described alkali is the mixture of carbonate and iodized salt.

The mol ratio of described compound III and compound IV is: 1:(1-3).

Described aftertreatment is specially: cooling, and water layer is collected in the hydrochloric acid layering of adding 1mol/L, and water layer is adjusted to pH=9-11 with sodium hydroxide, uses ethyl acetate extraction, anhydrous sodium sulfate drying, suction filtration, concentrated filtrate is to doing.

Described reaction solvent is any one of acetone, butanone, hexone, ethyl acetate or dehydrated alcohol.

R in the described compound III is fluorine, chlorine, bromine or iodine.

Described catalyzer is the palladium charcoal, does not need any processing and without the moisture requirement.

The hydrogen source of described hydrogenation provides for ammonium formiate, and reaction substrate is that the mol ratio of compound I I is 1:(1-10), preferred 1:(3-7).

The pressure of described hydrogenation is 1-20atm, preferred normal pressure, i.e. 1atm.

The temperature of described hydrogenation is 20-80 ℃, preferred 30-60 ℃.

The solvent of described hydrogenation is alcohols, the preferred lower alcohols of boiling point, more preferably methyl alcohol or ethanol.

The method of the invention synthetic route is short, and is simple to operate, greatly reduces the synthetic difficulty of S 16257-2, and with low cost, and product yield is high, and most importantly security is good, does not relate to high-pressure hydrogenation, has good industrialization basis and using value.

Embodiment

The present invention is described in detail below in conjunction with embodiment.

Embodiment 1:

Get the 2.96g compound III, wherein R is Cl, 2.44g compound IV, 1.38g salt of wormwood and 1.50g sodium iodide back flow reaction 6h in the 50mL hexone, cooling, the hydrochloric acid of the 1N of adding 50mL, layering, collect water layer, water layer is adjusted to pH=10 with sodium hydroxide, uses ethyl acetate extraction, anhydrous sodium sulfate drying, suction filtration, concentrated filtrate to be to do to get intermediate 4.5g, and namely 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-yl) methyl]-methylamino-] propyl group)-1,3 ,-dihydro-2 hydrogen-benzazepine-2-ketone;

In 50 mL reaction flasks, add 2.0 g 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-yl) methyl]-methylamino-] propyl group)-1,3 ,-dihydro-2 hydrogen-benzazepine-2-ketone, 20 mL methyl alcohol, 0.3g ammonium formiate, 0.2g the palladium charcoal, hydrogenation reaction pressure is 1atm, is warming up to 30 ℃ and stirs 4 hours, filter, filtrate is concentrated into dried 2.0g S 16257-2.Yield: 96.2%, HPLC:98.5%.

Embodiment 2:

Get the 3.40g compound III, wherein R is Br, 2.44g compound IV, 0.69g salt of wormwood and 1.50g potassiumiodide back flow reaction 12h in 50mL acetone, filter, concentrated filtrate, residuum adds the hydrochloric acid of the 1N of 50mL, be adjusted to pH=9 with sodium hydroxide, use ethyl acetate extraction, anhydrous sodium sulfate drying, suction filtration, concentrated filtrate is to doing to get intermediate 4.6g, namely 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-yl) methyl]-methylamino-] propyl group)-1,3 ,-dihydro-2 hydrogen-benzazepine-2-ketone;

In 50 mL reaction flasks, add 2.0 g 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-yl) methyl]-methylamino-] propyl group)-1,3 ,-dihydro-2 hydrogen-benzazepine-2-ketone, 20 mL ethanol, 0.6g ammonium formiate, 0.5g the palladium charcoal, hydrogenation reaction pressure is 3atm, is warming up to 60 ℃ and stirs 5 hours, filter, filtrate is concentrated into dried 1.9g S 16257-2.Yield: 93.7%, HPLC:98.8%.

Embodiment 3:

Get the 3.86g compound III, wherein R is I, 2.44g compound IV, 0.69g salt of wormwood and 1.50g potassiumiodide back flow reaction 12h in the 50mL butanone, filter, concentrated filtrate, residuum adds the hydrochloric acid of the 1N of 50mL, be adjusted to pH=11 with sodium hydroxide, use ethyl acetate extraction, anhydrous sodium sulfate drying, suction filtration, concentrated filtrate is to doing to get intermediate 4.4g, namely 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-yl) methyl]-methylamino-] propyl group)-1,3 ,-dihydro-2 hydrogen-benzazepine-2-ketone;

In 50 mL reaction flasks, add 2.3g 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-yl) methyl]-methylamino-] propyl group)-1,3 ,-dihydro-2 hydrogen-benzazepine-2-ketone, 23 mL ethanol, 3.1g ammonium formiate, 2.3g the palladium charcoal, hydrogenation reaction pressure is 1atm, is warming up to 80 ℃ and stirs 1.5 hours, filter, filtrate is concentrated into dried 2.4g S 16257-2.Yield: 94.4%, HPLC:98.6%.

Embodiment 4:

Get the 8.88g compound III, wherein R is Cl, 2.44g compound IV, 1.38g salt of wormwood and 1.50g potassiumiodide back flow reaction 12h in the 50mL ethyl acetate, filter, concentrated filtrate, residuum adds the hydrochloric acid of the 1N of 50mL, be adjusted to pH=10 with sodium hydroxide, use ethyl acetate extraction, anhydrous sodium sulfate drying, suction filtration, concentrated filtrate is to doing to get intermediate 4.6g, namely 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-yl) methyl]-methylamino-] propyl group)-1,3 ,-dihydro-2 hydrogen-benzazepine-2-ketone;

In 50 mL reaction flasks, add 4.6 g 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-yl) methyl]-methylamino-] propyl group)-1,3 ,-dihydro-2 hydrogen-benzazepine-2-ketone, 20 mL methyl alcohol, 1.9g ammonium formiate, 4.6g the palladium charcoal, hydrogenation reaction pressure is 5atm, is warming up to 50 ℃ and stirs 5 hours, filter, filtrate is concentrated into dried 4.5g S 16257-2.Yield: 95.6%, HPLC:98.1%.

Claims

1. the preparation method of a new S 16257-2, step comprises: compound III is reacted in reaction solvent with compound IV under the catalysis of alkali, obtain compound I I through aftertreatment, compound I I carries out hydrogenation under the system of catalyzer and ammonium formiate, react to get compound I, i.e. S 16257-2.

2. the preparation method of S 16257-2 according to claim 1, it is characterized in that: described alkali is the mixture of carbonate and iodized salt.

3. the preparation method of S 16257-2 according to claim 1, it is characterized in that: the mol ratio of described compound III and compound IV is: 1:(1-3).

4. the preparation method of S 16257-2 according to claim 1, it is characterized in that: described aftertreatment is specially: cooling, the hydrochloric acid layering that adds 1mol/L, collect water layer, water layer is adjusted to pH=9-11 with sodium hydroxide, uses ethyl acetate extraction, anhydrous sodium sulfate drying, suction filtration, concentrated filtrate is to doing.

5. the preparation method of S 16257-2 according to claim 1, it is characterized in that: described reaction solvent is any one of acetone, butanone, hexone, ethyl acetate or dehydrated alcohol.

6. the preparation method of S 16257-2 according to claim 1, it is characterized in that: described catalyzer is the palladium charcoal.

7. the preparation method of S 16257-2 according to claim 1, it is characterized in that: the hydrogen source of described hydrogenation provides for ammonium formiate, and reaction substrate is that the mol ratio of compound I I is 1:(1-10), preferred 1:(3-7).

8. according to claim 6 or the preparation method of 7 each described S 16257-2s, it is characterized in that: the pressure of described hydrogenation is 1-20atm, preferred normal pressure, i.e. 1atm.

9. the preparation method of S 16257-2 according to claim 8, it is characterized in that: the temperature of described hydrogenation is 20-80 ℃, preferred 30-60 ℃.

10. the preparation method of S 16257-2 according to claim 8, it is characterized in that: the solvent of described hydrogenation is alcohols, the preferred lower alcohols of boiling point, more preferably methyl alcohol or ethanol.