WO2008125006A1

WO2008125006A1 - Preparation processes for ivabradine hydrochloride and its stable crystalline form

Info

Publication number: WO2008125006A1
Application number: PCT/CN2008/000699
Authority: WO
Inventors: Junzhi Luo; Yimin Yan; Yongrui Tu
Original assignee: Utopharm (Shanghai) Co., Ltd; Changzhou No.4 Pharmaceutical Factory Co., Ltd
Priority date: 2007-04-12
Filing date: 2008-04-07
Publication date: 2008-10-23

Abstract

A novel preparation process for ivabradine which is the medicine for angina pectoris, wherein compound III is obtained from compound II by catalytic hydrogenation, and then compound III is alkylated with compound IV to obtain compound I. This process is simple and low cost, for the raw materials are cheap. The crystalline form of ivabradine hydrochloride obtained by the process of present application is stable and suitable for long time store. The solvents used are safe, easy to be removed, and suitable for industrial production.

Description

Method for preparing ivabradine hydrochloride and stable crystal thereof

Technical field:

The invention relates to medicinal chemistry, in particular to a novel angina pectoris drug ivabradine (compound I) and a preparation method thereof, and to a stable ivabradine crystal of hydrochloric acid and a preparation method thereof. Background technique:

Ivabradine, chemical name 3-{3-[{[ (7S) -3, 4-dimethoxybicyclo[4.2.0] oct-1, 3, 5-trien-7-yl -methyl}(methyl)amino]propyl-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one, and Pharmaceutically acceptable acid addition salts and hydrates, Compound I of the formula:

Ivabradine, approved by the European Medicines Accreditation Council (EMEA) on November 3, 2005, is available in 27 countries in Europe under the product name Procoralan for the treatment of normal sinus rhythm and beta receptors. Symptomatic treatment of chronic stable angina with contraindications or intolerance.

Developed by Servier, Procoralan is one of the most important advances in cardiovascular therapy over the past 20 years. Procoralan is the first pure heart rate reduction drug that works by selectively suppressing the If channel, which controls the automatic depolarization of the sinus node and regulates heart rate. Procoralan selectively acts on the sinus node and has no effect on intracardiac conduction, myocardial contractility or ventricular repolarization. Unlike the usual drugs for angina, beta-blockers, Procoralan does not cause sexual dysfunction, respiratory adverse reactions due to airway contraction and spasm, and bradycardia or recurrence.

The earliest reported patent for the preparation of this compound is EP05348059, the related patent is US5296482, and the preparation method of the patent is as follows. The compound V is used as a raw material, and reacted with Nal to obtain an iodo compound (compound VI), and then an N-fluorenyl group is formed with the compound IV. The reaction is carried out to obtain the compound VII, and finally the catalytic hydrogenation reaction is carried out to obtain the target ivabradine (reaction formula I):

Reaction formula I:

VII I

The yield of the method is relatively low, especially in the catalytic hydrogenation step, the yield is only 40%, the total yield is 18%, and the product needs to be purified by column chromatography, which is not suitable for industrial production.

Servier subsequently applied for a new preparation method patent CN200510051779 in China, and the related patent has US20050228177. The method uses compound VIII as raw material to obtain compound IX by catalytic hydrogenation, and then reductive amination reaction to obtain the target object. Breiding (reaction formula):

Reaction formula:

VIII IX

The literature reports that the yield of the method is 85%, but the two-step reaction of the method requires expensive metal catalysts, and the amount is large, the cost is extremely expensive, and the raw material compound VIII is not easily obtained, and the preparation process is complicated and high in cost. Therefore, it is not suitable for industrial production.

In addition to the above process patents, the Seville Laboratory has applied for a series of patents involving crystallization methods and crystal forms in China such as CN200510051779. 0 , CN200610058074. 6 , CN200610058076. 5, CN200610058077. X, CN200610058078. 4, CN200610132229. 6 and CN200610132230 . 9, It is summarized as follows:

The method of crystallizing with acetonitrile has been reported in the earlier U.S. Patent No. 5,928, 648 and the European Patent No. EP 0 534 859, but the crystal form is not described in detail. The product prepared by the method is incomplete crystal, has poor stability, is difficult to reproduce, and uses acetonitrile as a solvent, which is highly toxic and unsuitable for medicinal use.

Patent CN200510051779. 0 mentions crystallization from N-methylpyrrolidone and toluene to give the alpha crystal form. The method uses a scented aromatic substance as a solvent, which is highly toxic, has a high boiling point, is difficult to remove, and cannot meet the pharmacopoeia control limit of the drug residual solvent.

Patent CN200610058076. 5 and CN200610058074. 6 respectively describe the use of water or isopropanol plus water to obtain β-crystal form (tetrahydrate), respectively, and then dehydrated to obtain P d-crystal form; patents CN200610058078. 4 and CN200610058077. X respectively describe 2-ethoxyethanol or 2-ethoxyethanol is crystallized with water or ethanol and water to obtain a Y-crystal form (monohydrate), which is then dehydrated to obtain a Y d-crystal form; patents CN 200610132229. 6 and CN200610132230. 9 respectively Desizing δ-crystallization (containing 2.8% water) with acetonitrile or acetonitrile and water is described, followed by dehydration to obtain δ d-crystals. The common point of the preparation of ivabradine hydrochloride by these methods is to select the ivabradine solvate or the ivabradine hydrochloride hydrate, and then remove the solvent or water by heating to obtain the polymorphic ivabradine hydrochloride. . Such a product is difficult to control in a certain crystal form, and exhibits multi-melting point instability, discoloration, and easy degradation to produce impurities in differential thermal analysis and thermal analysis, which is disadvantageous for formulation processing.

Therefore, the above patent describes the different crystal forms of ivabradine and its hydrochloride and the preparation method thereof, and the preparation process thereof is cumbersome, and the solvent used is not suitable for medicinal use, such as the patent CN200510051779. 0 crystallized with N-methylpyrrolidone and toluene Obtaining α crystal form, the toxicity of toluene used is large, the boiling point of Ν-methylpyrrolidone is high, and it is difficult to remove, etc.; or the obtained crystal form is not stable enough, such as patent CN200610058074; 6 , CN200610058076. 5 , CN200610058077. X, CN200610058078. 4, CN200610132229 6 and CN200610132230. 9 The crystal form is water-containing. The excessive water content of the raw material will affect its stability. It needs to be dried and dehydrated again, which is unfavorable to the integrity and stability of the obtained crystal form, and the preparation process is cumbersome. In addition, there are no reports on the melting point, differential thermal analysis (DSC) and thermogravimetric properties and physical and chemical properties of the crystal forms prepared.

It is very important to obtain a simple and easy-to-use industrialized large-scale production, and at the same time, it is necessary to obtain a compound which is suitable for the preparation of 髙 purity and which can be stored for a long time. Summary of the invention: The technical problem to be solved by the present invention is to overcome the deficiencies of the above preparation method, to study a method for preparing ivabradine and its salt suitable for industrial production, and to obtain stable ivabradine hydrochloride crystal by crystallization.

The invention provides a preparation method of ivabradine (compound I) and a salt thereof, which is 3-(3-substituted propyl)-7,8-dimethoxy-1,3-dihydrogen. -2H-3-Benzazepine-2-one compound II as a starting material, catalyzed hydrogenation reaction at a suitable temperature, solvent and catalyst to give the compound 3-(3-substituted propyl)-7, 8-dimethoxy -1, 3, 4, 5-tetrahydro-2H-3-benzazepine-2-one compound III, then with (lS)-4,5-di at appropriate temperature, solvent and reaction promoter The methoxy-1-(methylaminomethyl)-benzocyclobutane compound IV is subjected to a thiolation reaction to obtain an ivabradine compound I, which is represented by the reaction formula III. The method is easier to carry out, and the reaction conditions are mild. High yield (about 80%).

Reaction III:

Wherein R in the formula or III is a halogen atom such as Cl, Br, I or the like, or a similar leaving group such as a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, a methanesulfonyloxy group or the like, preferably Cl, A halogen atom such as Br or I. The pharmaceutically acceptable acid addition salt is then obtained by reacting with the corresponding hydrochloric acid as needed.

In the above-mentioned synthetic scheme of the reaction formula III, in the catalyst used for the hydrogenation reaction of the compound of the formula (ΠΙ), it may be, but not limited to, palladium, platinum, nickel, rhodium, ruthenium and their compounds, particularly in the form of a load. In the form of an oxide or a catalyst used for the hydrogenation reaction of a compound of the formula (ΠΙ), ruthenium carbon is preferred. The catalyst used for the hydrogenation of the compound of formula (III) is 5% palladium on carbon or 10% ruthenium carbon, more preferably 5% ffi carbon. The amount of the catalyst used for the catalytic hydrogenation of the compound of the formula (III) is from 1% to 30% w/w%, more preferably from 5 to 10% w/w%, based on the compound (Π). 5: 1至1. 1: 1。 The molar ratio of the compound I II to the compound IV is from 1:1 to 1. 5: 1, more preferably 1. 05: 1 to 1. 1: 1.

The temperature for the hydrogenation reaction of the compound of the formula (III) is preferably room temperature to 120 ° C, more preferably 30 to 100 ° C, particularly preferably 40 to 80 ° C.

The hydrogen pressure for the hydrogenation reaction of the compound of the formula (ΠΙ) is from 1 to 150 atm, preferably from 1 to 80 atm, particularly preferably from 1 to 40 atm.

The solvent used for the hydrogenation reaction of the compound of the formula (ΠΙ) is an alcohol such as methanol or ethanol, a ketone such as acetone, butanone or pentanone N-methylpyrrolidone, a nitrile such as acetonitrile or propionitrile, ethyl acetate or acetic acid. An ester such as propyl or butyl acetate; a halogenated hydrocarbon such as chloroform, chloroform, 1,2-dichloroethane or chlorobenzene; an ether such as isopropyl ether or tetrahydrofuran; DMF, DMSO, etc., preferably an alcohol The ketones and the ketones are more preferably alcohols, and most preferably methanol, ethanol or the like.

The reaction temperature described in the synthesis of the compound I is -10-100 ° C, preferably room temperature to 6 (TC,

The reaction solvent described in the synthesis of the compound I is an alcohol such as methanol or ethanol, a ketone such as acetone, butanone or pentanone, a nitrile such as acetonitrile or propionitrile, ethyl acetate, propyl acetate or butyl acetate. Esters, halogenated hydrocarbons such as chloroform, chloroform, 1,2-dichloroacetamidine or chlorobenzene, ethers such as diethyl ether, diisopropyl ether or tetrahydrofuran, DMF, DMSO, etc., preferably alcohols, ketones, Nitriles, more preferably nitriles. '

The reaction accelerator described in the synthesis of the compound I is a basic compound such as an inorganic base such as NaOH or OH>K2C03 Na2C03, or an organic base such as diethylamine, triethylamine, pyridine, potassium t-butoxide or sodium methoxide. Preference is given to diethylamine and triethylamine. 5。 1. The molar ratio of the compound of the reaction promoter to the compound IV is from 1: 1 to 5: 1, preferably from 1: 1 to 2. 5: 1. The ratio of the amount of the basic compound to the compound IV is from 1:1 to 5:1, preferably from 1:1 to 2. 5:1.

Further, the present invention provides a stable ivabradine hydrochloride crystal.

- Stabilized ivabradine hydrochloride crystals of the invention having a DSC pattern having a single endothermic peak in the range of from 100 to 22 (TC range).

The present invention relates to a stable ivabradine hydrochloride crystal having a DSC pattern having a single endothermic peak in the range of 185 to 2 HTC.

The present invention relates to a stable ivabradine hydrochloride crystal having a melting point of 190-210 ° C and decomposition at 200 or 210 ° C or higher.

The invention relates to a stable ivabradine hydrochloride crystal, wherein the thermogravimetric map shows no crystal water or dissolution Agent.

Another object of the present invention is to provide a process for the preparation of stable ivabradine hydrochloride crystals comprising the step of heating and dissolving in a single solvent or a mixed solvent to obtain a pharmaceutically stable ivabradine hydrochloride crystal.

Specifically, the present invention relates to a method for preparing stable ivabradine hydrochloride crystals, wherein a single solvent is a ketone or an ester solvent, and a mixed solvent is obtained by crystallizing N-methylpyrrolidone plus a ketone or an ester solvent. The solvent is safer and easier to remove.

The invention relates to a preparation method of stable ivabradine hydrochloride crystal, the single solvent is methyl ethyl ketone, pentanone; ethyl formate, ethyl acetate, methyl acetate or propyl acetate, and the amount of ivabradine hydrochloride crystal 20 -100 times the amount of w/v, preferably 20-80 times the amount of solvent w/v; using a mixed solvent of N-methylpyrrolidone plus ethyl acetate or methyl ethyl ketone; or N-methylpyrrolidone plus butanone and acetic acid The ethyl ester is used in an amount of from 1 to 10 times the amount of w/v of ivabradine hydrochloride, preferably from 1 to 3 times the amount of w/v.

When preparing a stable ivabradine hydrochloride crystal by using a mixed solvent, a mixture of Ifabridine hydrochloride and N-methylpyrrolidone and ethyl acetate or methyl ethyl ketone; or N-methylpyrrolidone plus butanone The ethyl acetate mixture was dissolved by heating, and then gradually cooled until the crystals were completely precipitated, and the formed crystals were collected by filtration.

Advantageously, the seed crystal of hydrochloric acid & Fabredine can be added during the cooling step.

The present inventors have found that the preparation of stable ivabradine hydrochloride crystals can also be obtained by simply heating ivabradine hydrochloride from a suitable solvent, which is particularly important in that the solvent is small, the treatment is simple, and it is easy to dry. .

Still another object of the present invention is to provide a further preparation method of stable ivabradine hydrochloride crystals, that is, a suspension of ibubradine hydrochloride and a single solvent or a mixed solvent, heated and cooked for a suitable period of time, and then gradually cooled until the crystal The precipitate was completely precipitated, and the formed crystals were collected by filtration to obtain a stable ivabradine hydrochloride crystal.

In the case of heating and cooking, the solvent is preferably a solvent having a low thermal solubility to ifabrex hydrochloride, and is selected from the group consisting of ketones such as methyl ethyl ketone, 2-pentanone and the like, preferably butanone; or an ester solvent such as methyl acetate, acetic acid. Ethyl acetate, propyl acetate or the like is preferably ethyl acetate; or a ketone ester-adding solvent such as methyl ethyl ketone or ethyl acetate.

When preparing a stable ivabradine hydrochloride crystal by a solvent heating cooking method, a solvent of 1-100 times (w/v) of ivabradine hydrochloride is selected, preferably 1 times larger than ivabradine hydrochloride (W/ The solvent of V) is most preferably a solvent of 1-10 times (w/v). When a stable ivabradine hydrochloride crystal is prepared by a heating and cooking method, advantageously, the heating temperature is preferably from 0 ° C to 100 ° C, more preferably from 70 ° C to 100 ° C, and most preferably at a solvent reflux temperature.

When preparing a stable ivabradine hydrochloride crystal by a heating cooking method, advantageously, the cooking time is preferably more than 1 minute, more preferably 1 to 60 minutes, and most preferably 1 to 30 minutes.

It has been shown that the stable ivabradine hydrochloride crystals prepared by the method of the present invention are extremely stable to temperature, light and humidity, as shown in the following table:

In the crystallization method of the present invention, ivabradine hydrochloride obtained by any method can be used as a raw material. Since the stable ivabradine hydrochloride crystal prepared by the method of the present invention is extremely stable to temperature, light and humidity, it shows that it has high superiority in the processing and storage of the preparation.

The inventors measured the differential thermal analysis and thermogravimetric diagram of the stable ivabradine hydrochloride solution prepared by the method of the present invention under the following experimental conditions:

Instrument: TGA/SDTA-851 ^e analyzer METTLER TOI^DO company

Test conditions: 600/10/ ₂ 25.0-400.0' C (or 25.0-600.0·C) 10* C/min N ₂ 50.0ml/min

The X-ray powder diffraction spectrum of ivabradine hydrochloride was measured under the following experimental conditions: (There may be a small displacement of the peak position in the figure (±0.2. 2 Θ )

Test instrument model: RIGAKU D/raax 2550VB/PC diffractometer Test Conditions:

SCAN: 3. 0/60. 0/0. 02/0. 15 (sec) , Cu (40Κν, 100mA) , I (cps) =7945

PEAK: 27-pt s/Parabol i c Fi lter, Threshold=10. 0, Cutof f=3. 0%, BG=6/2. 0,

Peak-Top=Summit

NOTE : Intensity=CPS, 2T (0) =0. 0 ( · ) , Wavelength to Compute d- Spacing=l. 54056A (Cu/K— alphal)

Test basis: JY/T009-1996 target multi-crystal X-ray method general rule

Spectral description: expressed as 2- Theta (the position of the ray), d (A) (the interplanar spacing d, denoted by A), Heigt (ray height), Area (radiation area) and FWHM (half height ray width) .

Melting point: Measured with a B-tube, the thermometer is not corrected.

DRAWINGS

Fig. 1: Differential thermal analysis and thermogravimetric analysis of stable ivabradine hydrochloride crystals obtained by crystallization of methyl ethyl ketone. Figure 2: Differential heat of stable ivabradine hydrochloride crystals obtained by heating with methyl ethyl ketone. Analysis and thermogravimetric diagram

Figure 3: Differential thermal analysis and thermogravimetric analysis of stable ivabradine hydrochloride crystals obtained by heating with ethyl acetate

Figure 4: Differential thermal analysis and thermogravimetric diagram of stable ivabradine hydrochloride crystals obtained by crystallization from N-methylpyrrole and ethyl acetate. The method of the invention is simple, the raw materials are easy to obtain, and it is suitable for industrial production. Has a greater application value.

The following examples are presented to illustrate the invention and are not intended to limit the invention. detailed description:

Embodiment 1:

Synthesis of 7, 8-dimethoxy-3-(3-chloropropyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one: 7,8 -Dimethyl-3-(3-chloro)-1,3-dihydro-2-indole-3-benzazepin-2-one (15.0 g, 50.8 tnmol), ethanol (80 ml) and 5°/ . Pd C (0.8g) was added to the autoclave, reacted under hydrogen pressure of 5-10 bar under 60 Torr until hydrogen absorption was stopped, the reaction was terminated, cooled, filtered, concentrated under reduced pressure to about 30 ml, and filtered to obtain 7, 8- Methoxy-3-(3-chloropropyl)-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one, white Solid 13.9g, mp: 93-95 ° C, yield 92.1%

MS: 297 (M+), 299 (M+2), 262 (M-C1)

1H NMR (CDC13): 62.06 (2H, m), 3.07 (2H, t), 3.56 (2H, M), 3.76 (2H, t), 3.81 (2H, t), 3.84 (3H, s), 3.85 (3H) , s), 6.58-6.60 (2H, aryl hydrogen) Example 2:

3-{3-[{[(7S) -3,4-dimethoxybicyclo[4.2.0]octyl-1,3,5-trien-7-yl]-methyl} (methyl)amino Synthesis of propyl-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (Compound I, ivabradine):

7, 8-Dimethoxy-3-(3-chloropropyl)-1, 3, 4, 5-tetrahydro-2H-3-benzazepine-2-one

(10.0 g. 33.7 mmol), (1 S>4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane (Compound IV, 7.0 g, 33.8 mmol), triethylamine (10 ml) and acetonitrile (50 ml) were added to a three-necked flask, and the mixture was stirred at room temperature for 20 hr, then concentrated under reduced pressure, and then water (200 ml), ethyl acetate (150 ml*3), dried over anhydrous magnesium sulfate Concentration by pressure gave a yellow oil, ie, 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0] oct-1,3,5-trien-7-yl] -Methyl}(methyl)amino]propyl-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine weed-2-one, about 13.5 g .

The sample for analysis was obtained by silica gel column chromatography, which was obtained as a pale yellow oil.

MS: 468 (M+), 469 (M+1), 353 (468-CH3), 305 (M-163), 262 (M-206),

1H NMR (CDC13): 6l.79 (2H, m), 2.33 (3H, s), 2.44 (2H, t), 2.44 (2H, t), 2.5 (1H, M), 2.74 (2H, dd), 3.04 (2H,t), 3.25(1 H,dd),3.5((3H,m), 3.7(2H, t), 3.8-3.9(14H,4-OCH3 and -CH2-), 6.5-6.70(4H, Aromatic hydrogen) Example 3:

3-{3-[{[(7S) -3,4-dimethoxybicyclo[4.2.0]octyl-1,3,5-trien-7-yl]-methyl} (methyl)amino Preparation of propyl-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one hydrochloride: Compound 3-{3- [{[(7S) -3,4-dimethoxybicyclo[4.2.0]octyl-1,3,5-trien-7-ylmethyl} (methyl)amino]propyl-7, 8 -dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one (Iwa Braiding) (13.5g,) dissolved in acetonitrile (40ml), then heated to 70'C, and passed to dry HCl gas with stirring to a pH of about 2-3, add 1g of activated carbon, reflux for 10 minutes, heat Filtration, cooling, filtration, vacuum drying at 60 ° C to obtain 12.4 g of an off-white powder, mp: ° C, yield 73.1% (based on compound III), the crude product was recrystallized from acetonitrile to give white powder 10.6 g, yield 85.5 %, HPLC>99.0%, [a] 7.2 (DMSO, 1%)

MS: 468 (M+), 469 (M+1), 453 (M-CH3), 305 (M-163), 262 (M-206). Embodiment 4:

A mixture of 5 mg of ivabradine hydrochloride and 400 ral of butanone was dissolved by heating, and then slowly cooled to the next day until the crystallization was completed. The crystals were filtered under vacuum and dried under vacuum at 60 Torr to give an off-white crystal, m _P: 193-196 V , began to decompose above 210 °C. Embodiment 5:

350 ml of methyl ethyl ketone was heated to 70 ° C, then 5 g of ivabradine hydrochloride was added in portions, stirred under reflux to dissolve, and then slowly cooled to the next day until the crystallization was complete, and the crystals were filtered under vacuum at 70 ° C. Drying under vacuum gave an off-white crystal, i.e., 192-195 Torr, which began to decompose above 210 °C.

Crystalline product of butanone X-ray powder diffraction pattern data (1)

[F762. raw] YFBLD (DT)

- 2-Theta d(A) Height Area FWHM

1 4.02 21.959 1224 20893 0.29

2 7.69 11.474 1402 25906 0.314

3 8.03 10.989 1525 17758 0.198

4 9.13 9.67 260 2466 0.152

5 10.37 8.516 1818 17352 0.162

6 11.81 7.481 1665 18944 0.193

7 12.09 7.309 495 13166 0.452

8 13.10 6.752 1479 21939 0.252

9 13.72 6.448 1259 13833 0.187 10 14.77 5.99 216 854 0.063

11 15.24 5.808 471 5835 0.211

12 15.64 5.661 360 4399 0.196

13 16.41 5.394 7116 109787 0.262

14 17.32 5.115 2721 37576 0.235

15 18.12 4.891 1364 20466 0.255

16 19.38 4.576 701 29597 0.718

17 20.02 4.431 6163 153874 0.424

18 20.52 4.324 1848 26637 0.245

19 21.30 4.168 1788 40361 0.384

20 21.86 4.062 3514 47178 0.228

21 22.28 3.986 1415 26947 0.324

22 22.94 3.873 591 7911 0.214

23 23.25 3.821 627 5562 0.151

24 24.22 3.671 936 14715 0.267

25 24.95 3.564 853 26526 0.529

26 25.72 3.46 3044 86420 0.483

27 26.42 3.37 4756 87441 0.313

28 26.74 3.331 1382 38801 0.477

29 27.66 3.222 1038 19019 0.311

30 28.38 3.142 1237 71159 0.978 Example 6:

6 g of ivabradine hydrochloride and 15 ml of N-methylpyrrolidone were dissolved by heating, and then, while stirring, 30 ml of ethyl acetate was slowly added dropwise, and the mixture was stirred uniformly, and then slowly cooled until the crystallization was completed, and the crystals were filtered under vacuum with ethyl acetate. Washing, drying under vacuum at 70 Torr gave colorless crystals, mp: 193-196. Decomposition begins above 210'C. X-ray powder diffraction pattern data of crystallized product with N-methylpyrrolidone and ethyl acetate

N3/X3d 900SZT/800Z OAV 27 26. 44 3. 368 5855 101302 0. 294

28 26. 75 3. 328 1827 46395 0. 432

29 27. 68 3. 22 1410 20496 0, 247

30 28. 42 3. 137 1823 93182 0. 869

O C Example 7:

The suspension of 5 g of ivabradine hydrochloride and 30 ml of butanone was heated to reflux, then stirred at this temperature for a few minutes, then cooled to room temperature, and the crystals were filtered under vacuum and dried in vacuo at 70 ° C to give colorless crystals. -194 °C, decomposition begins above 210 °C.

X-ray powder diffraction pattern data of the product obtained by heating and boiling with methyl ethyl ketone

F679. YFBLD (DT - ZZ)

2-Theta d (A) Height Area FWHM

1 3. 99 22. 09 2950 39272 0. 226

2 7. 65 11. 533 2113 31730 0. 255

3 8. 00 11. 041 3776 30637 0. 138

4 10. 33 8. 549 3579 38331 0. 182

5 11. 78 7. 506 1485 19569 0. 224

6 12. 01 7. 357 938 8844 0. 16

7 6. 763 1667 14890 0. 152

8 13. 69 6. 459 1763 17708 0. 171

9 15. 22 5. 816 704 -5305 0. 02

10 16. 06 5. 513 2959 90819 0. 522

11 16. 38 5. 407 6298 88729 0. 24

12 17. 32 5. 115 3725 48063 0. 219

13 18. 07 4. 903 1135 7435 0. I l l

14 19. 33 4. 586 395 1832 0. 074

15 20. 10 4. 413 7753 141989 0. 311 16 20. 50 4. 328 1344 17525 0. 222

17 21. 00 4. 226 1171 28711 0. 392

18 21. 27 4. 172 1555 26702 0. 292

19 21. 83 4. 066 3880 46348 0. 203

20 22. 25 3. 99 1205 20609 0. 291

21 22. 92 3. 877 557 3438 0. 099

22 23. 21 3. 827 646 4878 0. 128

23 24. 17 3. 677 1200 15692 0. 222

24 24. 88 3. 575 1064 23967 0. 383

25 25. 69 3. 463 3052 53694 0. 299

26 26. 39 3. 373 5312 84213 0. 27

27 26. 69 3. 336 1718 34987 0. 346

28 27. 63 3. 224 1191 18187 0. 26

29 28. 35 3. 144 1683 49265 0. 498

30 29. 12 3. 064 1041 34813 0. 569 Example 8:

A suspension of 5 g of ivabradine hydrochloride and 50 ml of ethyl acetate was heated to reflux, then stirred at this temperature for 10 minutes, then cooled to room temperature, and the crystals were filtered under vacuum and dried under vacuum at 60 ° C to give colorless crystals. Mp: 193-196 ° C, starting to decompose above 210 ° C.

X-ray powder diffraction pattern data obtained by heating and cooking ethyl acetate

[F680. raw] YFBLD (YSYZ- ZZ)

2-Theta d (A) Height Area FWHM

1 4. 00 22. 065 2334 34593 0. 252

2 7. 67 11. 505 1844 30891 0. 285

3 8. 00 11. 04 3047 28525 0. 159

4 10. 35 8. 533 2685 32327 0. 205

Claims

Rights request

A method for preparing ivabradine, characterized in that the method comprises the following steps:

(1) using 3-(3-substituted propyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one compound II as a starting material in a solvent Catalytic hydrogenation in the presence of a catalyst to give 3-(3-substituted propyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2 - ketone compound III;

(2) Compound III is then thiolated with (lS)-4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane compound IV in a solvent and a reaction accelerator. Reaction to obtain ivabradine compound I;

Wherein R in the formula II or formula III is a Cl, Br or I halogen atom or is a benzenesulfonyloxy group, a p-toluenesulfonyloxy group or a methanesulfonyloxy group; preferably a Cl, Br or a halogen atom.

The method for preparing ivabradine according to claim 1, wherein the catalyst used in the catalytic hydrogenation in the step (1) is palladium, platinum, nickel, ruthenium or osmium or a compound thereof, preferably Palladium carbon; ^ Palladium carbon catalyst is 5% palladium carbon or 10% palladium carbon, preferably 5% palladium carbon; catalytic hydrogenation catalyst is used in an amount of 1% - 30% w / w%, preferably 5 10% of the compound of formula II w/w%o

3. The ivabradine preparation method according to claim 1, wherein the step (1), the catalytic hydrogenation reaction is carried out at a temperature of from room temperature to 120 ° C, preferably 30-100 °. C, particularly preferably 40-80 °C.

The method for preparing ivabradine according to claim 1, characterized in that the hydrogen pressure of the catalytic hydrogenation reaction in the step (1) is from 1 to 150 atm, preferably from 1 to 80 atm, particularly preferably from 140 atm.

The method for preparing ivabradine according to claim 1, wherein the solvent for the catalytic hydrogenation in the step (1) is methanol or ethanol; acetone, butanone, pentanone or N-methylpyrrolidone Acetonitrile or Acetonitrile; ethyl acetate, propyl acetate or butyl acetate; chloroform, chloroform, ί, 2-dichloroethane or chlorobenzene; isopropyl ether or tetrahydrofuran or DMF or DMSO; preferably alcohol or ketone; An alcohol is preferred; methanol or ethanol is particularly preferred.

And a molar ratio of the hydrazine to the compound IV of the step (2) is from 1:1 to 1.5:1. Preferably, it is 1. 05: 1 to 1. 1 : 1.

The method for preparing ivabradine according to claim 1, wherein the reaction solvent in the step (2) is methanol or ethanol; acetone, butanone or pentanone; acetonitrile or propionitrile; ethyl acetate, acetic acid Propyl or butyl acetate; chloroform, chloroform, 1,2-dichloroethane or chlorobenzene; diethyl ether, diisopropyl ether or tetrahydrofuran; DMF or DMSO; preferably an alcohol, a ketone or a nitrile, more preferably a nitrile.

The method for preparing ivabradine according to claim 1, wherein the reaction accelerator of the step (2) is NaOH, KOH, K ₂ C0 ₃ or Na ₂ C0 _{3 ;} or diethylamine, Triethylamine, pyridine, potassium t-butoxide or sodium methoxide; preferably diethylamine, triethylamine or NaOH.

The ratio of the reaction accelerator to the compound IV is from 1:1 to 5:1, preferably from 1:1 to 2. 5:1. .

The method for producing ivabradine according to claim 1, wherein the reaction temperature in the step (2) is from -10 to 100 ° C, preferably from room temperature to 60 ° C.

11. A stable ivabradine hydrochloride crystal of the formula la, characterized in that the DSC pattern is a single endothermic peak in the range of 100 to 220 'C.

12. A stable ivabradine hydrochloride crystal of the formula l a characterized in that the DSC pattern is a single endothermic peak in the range of 185 to 210 Torr.

The stable ivabradine hydrochloride crystal according to claim 11 or 12, which has a melting point of 190-210 ° C and decomposes above 200 or 210 ° C; the thermogravimetric map shows no crystal water Or solvent.

A method for preparing a stable ivabradine hydrochloride crystal according to claim 11 or 12, characterized in that the method is a heating dissolution method, that is, heating and dissolving ibubradine hydrochloride and a single solvent or a mixed solvent. Then, the crystals were gradually cooled, and the formed crystals were collected by filtration.

The method for preparing stabilized ivabradine hydrochloride crystal according to claim 14, characterized in that the stable ivabradine crystal of hydrochloric acid is prepared by a heating dissolution method, and the single solvent used is methyl ethyl ketone and pentanone; Ester, ethyl acetate, methyl acetate or propyl acetate, in an amount of 20-100 times w/v of ivabradine hydrochloride, preferably 20-80 times the amount of solvent w/v; using a mixed solvent for N-methyl Pyrrolidone plus ethyl acetate or methyl ethyl ketone; or N-methylpyrrolidone plus butanone and ethyl acetate, the mixed solvent is 1-10 times the amount of ivabradine hydrochloride w / v, preferably 1-3 Multiplier w/v.

The method for preparing stable ivabradine hydrochloride hydrochloride according to claim 14, wherein the stable HCl is prepared by heating and dissolving the stable ivabradine crystals using methyl ethyl ketone as a solvent. The ivabradine crystals have the following powder X-ray diffraction pattern:

[F762. raw] YFBLD (DT)

2-Theta d(A) Height Area FWHM

1 4.02 21.959 1224 20893 0.29

2 7.69 11.474 1402 25906 0.314,

3 8.03 10.989 1525 17758 0.198

9.13 9.67 260 2466 0.152

5 10.37 8.516 1818 17352 0.162

6 11.81 7.481 1665 18944 0.193

7 12.09 7.309 495 13166 0.452

8 13.10 6.752 1479 21939 0.252

9 13.72 6.448 1259 13833 0.187

10 14.77 5.99 216 854 0.063

11 15.24 5.808 471 5835 0.211

12 15.64 5.661 360 4399 0.196

13 16.41 5.394 7116 109787 0.262

14 17.32 5.115 2721 37576 0.235

15 18.12 4.891 1364 20466 0.255

16 19.38 4.576 701 29597 0.718

17 20.02 4.431 6163 153874 0.424

18 20.52 4.324 1848 26637 0.245

19 21.30 4.168 1788 40361 0.384

20 21.86 4.062 3514 47178 0.228

21 22.28 3.986 1415 26947 0.324

22 22.94 3.873 591 7911 0.214

23 23.25 3.821 627 5562 0.151

24 24.22 3.671 936 14715 0.267

25 24.95 3.564 853 26526 0.529

26 25.72 3.46 3044 86420 0.483

27 26.42 3.37 4756 87441 0.313

28 26.74 3.331 1382 38801 0.477

29 27.66 3.222 1038 19019 0.311

30 28.38 3.142 1237 71159 0.978

The method for preparing stable ivabradine hydrochloride according to claim 14, characterized in that the stable ivabradine crystal of hydrochloric acid is prepared by heating and dissolving, and the mixture is mixed with N-methylpyrrolidone and ethyl acetate. The solvent is crystallized, and the obtained stable ivabradine hydrochloride has the following powder X-ray diffraction pattern:

[D349. raw] YFBLD

2-Theta d (A) Height Area FWHM

1 4. 04 21. 847 2704 50317 0. 316

2 7. 70 11. 470 1949 36371 0. 317

3 8. 06 10. 960 3612 41501 0. 195

4 . 10. 38 8. 515 2907 35028 0. 205

5 11. 83 7. 468 2017 32125 0. 271

6 12. 09 7. 310 1152 21663 0. 301

7 . 13. 12 6. 741 1853 28290 0. 260

8 13. 74 6. 439 1963 23190 0. 201

9 15. 25 5. 802 870 6864 0. 126

10 16. 14 5. 486 3725 132834 0. 606

11 16. 43 5. 387 8110 119466 0. 250

12 17. 37 5. 098 3925 58601 0. 254

13 18. 10 4. 896 1528 15192 0. 159

14 19. 36 4. 581 985 17311 0. 281

15 20. 15 4. 401 8417 197524 0. 399

16 20. 54 4. 320 2088 42634 0. 347

17 21. 08 4. 210 1907 79192 0. 664

18 21. 30 4. 167 2208 51441 0. 396

19 21. 87 4. 058 4994 65414 0. 223

20 22. 33 3. 976 1767 28236 0. 272

21 22. 94 3. 873 399 2909 0. 117

22 23. 26 3. 820 665 5598 0. 135

23 24. 24 3. 668 1332 15223 0. 183

24 24. 94 3. 567 1377 20841 0. 257

25 25. 22 3. 528 978 22974 0. 376

26 25. 77 3. 453 4673 81344 0. 296

27 26. 44 3. 368 5855 101302 0. 294

28 26. 75 3. 328 1827 46395 0. 432

29 27. 68 3. 22 1410 20496 0. 247

30 28. 42 3. 137 1823 93182 0. 869

18. A method for preparing a stable ivabradine hydrochloride crystal according to claim 11 or 12, characterized in that the method is a heating and cooking method, that is, suspending of a mixture of efabride hydrochloride and a single solvent or a mixed solvent. The product was heated and cooked, and then the crystals were gradually cooled, and the formed crystals were collected by filtration.

19. A process for the preparation of stable ivabradine hydrochloride crystals according to claim 18, characterized in that the single solvent used is methyl ethyl ketone or pentanone; ethyl formate, ethyl acetate, methyl acetate or acrylic acid The ester is used in an amount of 20-100 times the amount of ivabradine hydrochloride νν/ν, preferably 20-80 times the amount of solvent w/v: using a mixed solvent of Ν-methylpyrrolidone plus ethyl acetate or methyl ethyl ketone; Or Ν-methylpyrrolidone plus butanone and ethyl acetate, The mixed solvent is used in an amount of from 1 to 10 times w/V, preferably from 1 to 3 times M w/v, of ivabradine hydrochloride.

The method for preparing stable ivabradine hydrochloride hydrochloride according to claim 18, wherein when the stable ivabradine hydrochloride crystal is prepared by heating and cooking, the solvent used is methyl ethyl ketone or 2-pentanone, preferably butanone; or methyl acetate, ethyl acetate or propyl acetate, preferably ethyl acetate; or a mixed solvent of methyl ethyl ketone and ethyl acetate, in an amount of 1-100 times ivabradine hydrochloride W/v solvent, preferably 1-10 times the amount of w/v solvent; heating cooking temperature (TC-10 (TC, preferably 7 (rC-I00 ° C, most preferably at the solvent reflux temperature; heating cooking time 1-60) Minutes or longer, preferably 1-30 minutes.

The method for preparing stable ivabradine hydrochloride hydrochloride according to claim 18, characterized in that the stabilized ivabradine crystal obtained by heating and cooking with ethyl acetate as a solvent has the following powder X-ray. Diffraction pattern -

[F680. raw] YFBLD (YSYZ-ZZ)

. 2-Theta d (A) Height' Area FWHM

1 4. 00 22. 065 2334 34593 0. 252

2 7. 67 11. 505 1844 30891 0. 285

3 8. 00 11. 04 3047 28525 0, 159

4 10. 35 8. 533 2685 32327 0. 205

5 11. 79 7. 494 1910 25056 0. 223

6 12. 03 7. 345 843 11374 0. 216

7 13. 08 6. 762 1661 26300 0. 269

8 13. 73 6. 44 1666 22052 0. 225

9 15. 22 5. 816 770 13890 0. 307

10 16. 08 5. 506 2853 141603 0. 844

11 16. 40 5. 4 7334 101008 0. 234

12 17. 35 5. 104 3540 47643 0. 229

13 18. 08 4. 902 1231 13476 0. 186

14 19. 36 4. 581 867 14326 0. 281

15 20. 13 4. 405 6925 162626 0. 399

16 20. 53 4. 32 1728 28359 0. 279

17 21. 06 4. 215 1445 45880 0. 508

18 21. 28 4. 171 1769 32805 0. 315

19 21. 85 4. 062 4321 53648 0. 211

20 22. 28 3. 986 1473 22166 0. 256

21 22. 88 3. 882 456 1156 0. 041

22 23. 26 3. 821 732 4971 0. 116

23 24. 25 3. 666 1193 18797 0. 268

24 24. 92 3. 57 1166 27140 0. 396

25 25. 72 3. 46 3355 68623 0. 348

26 26. 41 3. 37 4988 85776 0. 292

27 26. 71 3. 333 1427 37917 0. 452

28 27. 66 3. 222 1084 16744 0. 263

29 28. 39 3. 14 1718 69329 0. 686

30 28. 58 3. 12 1514 75929 0. 802

The method for preparing stable ivabradine hydrochloride hydrochloride according to claim 18, characterized in that the X-ray powder diffraction pattern of the stabilized hydrochloric acid ivabradine crystal is obtained by heating and cooking with methyl ethyl ketone as a solvent: :

[F679. raw] YFBLD (DT- ZZ)

2-Theta d (A) Height Area FWHM

1 3. 99 22. 09 2950 39272 0. 226

2 7. 65 11. 533 2113 31730 0. 255

3 8. 00 11. 041 3776 30637 0. 138

4 10. 33 8. 549 3579 38331 0. 182

5 11. 78 7. 506 1485 19569 0. 224

6 12. 01 7. 357 938 8844 0. 160 Tz

0IN3/X3d 900SZ: T/800Z OAV