CN101768116A

CN101768116A - Preparation method for Ivabradine

Info

Publication number: CN101768116A
Application number: CN200810246546A
Authority: CN
Inventors: 王春霞; 卢文; 张志强
Original assignee: Beijing Dezhong Wanquan Medicines Technological Development Co Ltd
Current assignee: Beijing Dezhong Wanquan Medicines Technological Development Co Ltd
Priority date: 2008-12-29
Filing date: 2008-12-29
Publication date: 2010-07-07
Anticipated expiration: 2028-12-29
Also published as: CN101768116B

Abstract

The invention discloses a preparation method for Ivabradine. Catalytic hydrogenation is carried out on a formula (II) compound to obtain a formula (III) compound, reaction is carried out between the formula (III) compound and a formula (IV) compound under the action of base catalysis, and a catalyst is removed through filtration and separated to obtain the target compound.

Description

A kind of preparation method of S 16257-2

Technical field

The present invention relates to the S 16257-2 of synthesis type (I), be 3-{3-[{[(7S)-3,4-dimethoxy dicyclo [4.2.0] hot-1,3,5-triolefin-7-yl]-methyl } (methyl) amino] propyl group }-7,8-dimethoxy-1,3,4,5-tetrahydrochysene-2H-3-benzazepine-2-ketone, and the preparation method of the additive salt of pharmaceutically acceptable acid.

Background technology

S 16257-2 and the additive salt that forms with pharmaceutically acceptable acid thereof, more specifically have very valuable pharmacological and treat characteristic, especially decreasing heart rate (bradycardic) characteristic for its hydrochloride, thereby the various clinical settings such as stenocardia, myocardial infarction and the relevant arhythmicity that make these compounds be used for the treatment of or prevent myocardial ischemia, and relate to the various pathologic conditions of arhythmicity, especially supraventricular arhythmicity and heart failure.

Described the preparation method of S 16257-2 and hydrochloride thereof among the European patent specification EP 0534859, its route is as follows:

The aforesaid method shortcoming is that the acquisition of S 16257-2 need pass through column chromatography, and reaction yield is very low, more than all limited its industrialization.

Chinese patent CN200510051779.0 has reported the novel method of synthesis of ivabradine in addition, and its route is as follows:

Above-mentioned route two-step reaction all uses noble metal palladium charcoal to make catalyzer, and all applying pressure still reactions, though total recovery is higher, but considers that from cost and industrialization aspect there is drawback in this route.

Pharmacy value in view of S 16257-2 and salt, particularly its hydrochloride, be necessary to obtain S 16257-2 by more effective synthetic method, but all respects factors such as this method palpus comprehensive cost, yield industrialization, obtain S 16257-2 and salt thereof, particularly hydrochloride with minimum step and satisfied yield.

Summary of the invention

The invention provides the method for preparing S 16257-2, be different from EP 0534859 and CN200510051779.0 institute reported method, it can be by the initial synthetic method with the S 16257-2 that obtains of one step, excellent yield of the salt of formula (IV) compound.

More specifically, the present invention relates to the synthetic method of additive salt of S 16257-2, itself and the pharmaceutically acceptable acid of formula (I), it is characterized in that formula (II) compound

Wherein Y represents halogen, hydroxyl, reaches the hydroxyl to the protection of toluene benzenesulfonyl, obtains formula (III) compound through catalytic hydrogenation:

Wherein Y as above defines, and this compound reacts with formula (IV) compound under base catalysis,

Wherein HX represents pharmaceutically acceptable acid,

After removing by filter catalyzer and separating, directly obtain the additive salt of S 16257-2 and sour HX, when needs obtain the S 16257-2 of free alkali, the optional effect that makes this compound experience alkali.

The feasible salt by formula (IV) compound of this method begins with the yield of one step, excellence and the additive salt of the S 16257-2 that purity directly obtains, and the spy is that its hydrochloride becomes possibility fully.

In formula (II) the hydrogenation of compounds catalyst for reaction, can be palladium, platinum, nickel, rhodium and their compound, the spy be the form or the oxide form of load fully, is preferably the palladium charcoal.

The pressure of formula (II) hydrogenation of compounds reaction is 1-10atm, preferred normal pressure.

The temperature of formula (II) hydrogenation of compounds reaction is 20-60 ℃, preferred 30-40 ℃.

Preferably carry out in alcoholic solvent in the reaction of formula (II) hydrogenation of compounds, this alcoholic solvent comprises methyl alcohol, ethanol and Virahol etc., more preferably methyl alcohol.

More advantageously do not separate purifying formula (III) compound, crude product is directly used in and formula (IV) compound.

The basic catalyst that is used for the reaction of formula (III) compound and formula (IV) compound is an inorganic weak bases, preferred Anhydrous potassium carbonate and anhydrous sodium carbonate, more preferably Anhydrous potassium carbonate.

Be to add the iodination reagent priming reaction, the preferred potassiumiodide of this iodination reagent in the reaction of formula (III) compound and formula (IV) compound.

The solvent that can be used for the reaction of formula (III) compound and formula (IV) compound is nonacid solvent, can be alcoholic solvent, ketones solvent, is preferably acetone.

In the method according to the invention, preferably use the special case of formula (II) compound and formula (III) compound, Y wherein represents halogen, hydroxyl, reaches the hydroxyl to the protection of toluene benzenesulfonyl.

The special case of formula (II) compound and formula (III) compound, Y wherein represents halogen, hydroxyl, reaches the hydroxyl to the protection of toluene benzenesulfonyl.Be new compound, they in chemistry or pharmaceutical industry, particularly S 16257-2 and with the additive salt of pharmaceutically acceptable acid synthetic in, can be used as intermediate, they have constituted integral part of the present invention thus.

Use formula (IV) compound according to preferable methods of the present invention, HX wherein represents the special case of formula (IV) compound of hydrochloride, thereby the hydrochloride of production (I) S 16257-2, this salt is recrystallization in the mixed solvent of methyl alcohol and methylene dichloride, can be used as the activeconstituents of pharmaceutical preparation, as the purposes in the medicine of bradycardic.

Figure of description

Fig. 1: 3-(3-hydroxypropyl)-7, the 8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-2 (3H)-ketone, nuclear-magnetism figure,

Fig. 2: the hydrochloride of S 16257-2, nuclear-magnetism figure.

Embodiment

Embodiment 1:3-(3-hydroxypropyl)-7, the 8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-2 (3H)-ketone 2.3g3-(3-hydroxypropyl)-7,8-dimethoxy-1H-benzazepine-2 (3H)-ketone and 1.8g 10%Pd/C join in the 20mL methyl alcohol, slowly feed H then in system ₂, make the interior bubbling of system even.Heating systems makes it react 24h down at 40 ℃.Suction filtration reclaims Pd/C, filtrate revolving steam white solid 1.97g, yield: 85%, 102.5 ℃ of fusing points.1H-NMR(CDCl ₃，400MHz)，δ1.72-1.75(t，2H)，3.05-3.08(t，2H)，3.48-3.51(t，2H)，3.58-3.61(t，2H)，3.71-3.74(q，2H)，3.84-3.85(d，8H)，6.57-6.60(d，2H)。Nuclear-magnetism figure sees accompanying drawing 1

Embodiment 2: the hydrochloride preparation of S 16257-2

0.4g 3-(3-hydroxypropyl)-7, the 8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-2 (3H)-ketone and 0.3g (S)-(4,5-dimethoxy-1,2-dihydrobenzo cyclobutyl-1-yl)-N-methyl methylamine joins among the 10mL in the acetone, and then adds 0.2g KI and 0.5g K ₂CO ₃, begin to stir and be heated to backflow.Stopped reaction behind the reaction 24h.Suction filtration, filtrate be spin-dried for sticky solid, in water, suction filtration gets filter cake with solid dispersed, filtrate discards.With dissolving in the ethyl acetate, the HCl solution washing of 3N is in harmonious proportion to pH to 7-8 with sodium hydroxide solution then then, anhydrous magnesium sulfate drying, and vacuum rotary steam gets oily matter.Oily matter is dispersed in becomes mono-hydrochloric salts in the ethyl acetate, obtain the 0.5g white crystalline powder with methyl alcohol and acetone recrystallization, yield 75%, 196.3 ℃ of fusing points. ¹H-NMR (D ₂O, 500MHz), δ 2.15 (s, 2H), 2.66-2.70 (d, 2H), 2.91 (s, 3H), 3.00-3.03 (t, 2H), 3.12-3.14 (t, 2H), 3.16-3.18 (t, 1H), 3.23-3.29 (t, 1H), 3.41-3.44 (t, 1H), 3.56-3.60 (t, 1H), 3.62-3.66 (d, 6H), 3.68-3.75 (m, 3H), and 3.81-3.84 (d, 6H), 3.86-3.90 (q, 2H), 3.93-3.96 (t, 1H), (q, 4H), nuclear-magnetism figure sees accompanying drawing 2 to 6.64-6.80.

Claims

1. the preparation method of a S 16257-2 pharmaceutically acceptable acid additive salt, it is characterized in that formula (II) compound obtains formula (III) compound through catalytic hydrogenation, under base catalysis with formula (IV) compound reaction, after removing by filter catalyzer and separating, obtain the additive salt of S 16257-2 and sour HX

Wherein Y represents halogen, hydroxyl, reaches the hydroxyl to the protection of toluene benzenesulfonyl, and HX represents pharmaceutically acceptable acid.

2. according to the preparation method of claim 1, the catalyzer of its Chinese style (II) compound is the palladium charcoal.

3. according to the preparation method of claim 1, the pressure of its Chinese style (II) hydrogenation of compounds reaction is 1-10atm, preferred normal pressure, and temperature is 20-60 ℃, preferred 30-40 ℃.

4. according to the preparation method of claim 1, wherein do not separate purifying formula (III) compound.

5. according to the preparation method of claim 1, the basic catalyst of its Chinese style (III) compound and the reaction of formula (IV) compound is an inorganic weak bases, preferred Anhydrous potassium carbonate and anhydrous sodium carbonate, more preferably Anhydrous potassium carbonate.

6. according to the preparation method of claim 1, need add the iodination reagent priming reaction, the preferred potassiumiodide of this iodination reagent in its Chinese style (III) compound and the reaction of formula (IV) compound.

7. according to the preparation method of claim 1, the solvent of its Chinese style (III) compound and the reaction of formula (IV) compound is an acetone.

8. according to the preparation method of claim 1, wherein use Y in formula (II) compound and formula (III) chemical combination to represent halogen, hydroxyl or to the hydroxyl of toluene benzenesulfonyl protection.

9. according to the preparation method of claim 1, the HX in its Chinese style (IV) compound represents hydrochloride.

10. according to the preparation method of claim 9, wherein obtain hydrochloride recrystallization in the mixed solvent of acetone and methyl alcohol of S 16257-2.