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CN113372274B - Preparation method of ivabradine - Google Patents

Preparation method of ivabradine Download PDF

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Publication number
CN113372274B
CN113372274B CN202010162507.2A CN202010162507A CN113372274B CN 113372274 B CN113372274 B CN 113372274B CN 202010162507 A CN202010162507 A CN 202010162507A CN 113372274 B CN113372274 B CN 113372274B
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ivabradine
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CN113372274A (en
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时江华
霍领雁
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Lunan Pharmaceutical Group Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of ivabradine. The method for preparing ivabradine comprises the following steps: nucleophilic substitution of 7, 8-dimethoxy-1, 3,4, 5-tetrahydro-benzazepin-2-one and (3-chloro-propyl) -methyl-tert-butyl carbamate to generate a compound IV, the compound IV generates a hydrochloride intermediate V under the action of acyl chloride and alcohol, the V and the intermediate compound VI are subjected to nucleophilic substitution to obtain a compound VII, and the compound VII is reduced to obtain the ivabradine. The invention provides a novel preparation method of ivabradine, the whole synthesis method is simple and convenient to operate, the reaction yield is high, the purity of the obtained product is high, and the method is more suitable for industrial production.

Description

Preparation method of ivabradine
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of ivabradine.
Background
Ivabradine (ivabradine) with the chemical name 3- (3- { [ ((7S) -3, 4-dimethoxybicyclo [4.2.0 ]]Octane-1, 3, 5-trien-7-yl) methyl]Methylamino } propyl) -1,3,4, 5-tetrahydro-7, 8-dimethoxy-2H-3-benzazepine
Figure BDA0002406288830000013
2-keto, the first selective specific IF (controlling spontaneous diastolic depolarization in the sinoatrial node and regulating heart rate) inhibitor, has a selective effect on the sinoatrial node and no effect on intracardiac conduction, myocardial contraction or ventricular repolarization; the pharmaceutical composition is approved by European medical evaluation agency (EMA) to be marketed at 25.10.2005, is named Procoralan, and is used for symptomatic treatment of chronic stable angina pectoris accompanied by normal sinus rhythm, contraindication to beta-blockers or intolerance to beta-blockers, and has the following structure:
Figure BDA0002406288830000011
at present, the synthesis method of ivabradine and its related intermediates is becoming one of the hot points of research of various pharmaceutical enterprises, mainly based on the method of the original research company, for example, the early patents EP05348059 and US5296482 report that compound 1 as a raw material reacts with iodine compound which is obtained by refluxing sodium iodide to react with compound 3 to generate N-alkylation reaction, so as to obtain compound 4, and finally the target ivabradine is obtained by catalytic hydrogenation:
Figure BDA0002406288830000012
the method is a main flow route for preparing the ivabradine at present, has the defects of low yield, particularly 40 percent of yield in the step of catalytic hydrogenation and 18 percent of total yield, and is not suitable for industrial production because the product needs to be purified by column chromatography.
Chinese patent application CN103012268A describes a process for preparing ivabradine using the same synthetic route, which improves the hydrogenation reaction, uses palladium-carbon as catalyst, ammonium formate as hydrogen donor, hydrogenates at normal pressure, solves the problem of using autoclave as a special equipment industrially, the process route is as follows:
Figure BDA0002406288830000021
however, ammonium bicarbonate generated when ammonium formate is heated and decomposed can sublimate, so that a condenser is blocked, which is dangerous and not beneficial to industrial safety production; the compound 2 can not react completely in the reaction process, the compound 2 is similar to the compound 3 and the compound 4 in chemical property, the compound is not removed by a post-treatment method of column chromatography, and the purity of the product is only 98.5 percent and is not enough to reach the standard of raw material medicaments.
In order to solve such problems, chinese patent application CN101851204A uses 4,5-dimethoxy-1-nitrile-benzocyclobutane and 7,8-dimethoxy-3- (3-methylamino-propyl) -1,3,4,5-tetrahydro-benzazepin-2-one as raw materials, and reacts in the presence of a transition metal or lanthanide salt, and then performs a reduction reaction to obtain racemic or optically active ivabradine, wherein the reaction formula is as follows:
Figure BDA0002406288830000022
in the reaction, transition metal or lanthanide salt and a metal catalyst are used, so that heavy metal pollution is easily caused, the industrial production is not suitable, and the yield of the ivabradine obtained by the method is only 33 percent.
Therefore, the preparation method of ivabradine has the problems of long route, low yield, low purity, high technical requirement, serious environmental pollution, high production cost and the like; therefore, the problem to be solved at present is to explore a process route for ivabradine synthesis, which is simple and convenient to operate, short in production period, high in yield and more suitable for industrial production.
Disclosure of Invention
Aiming at solving the problems of long route, complex operation, low yield and low purity in the preparation process of ivabradine in the prior art; or the problems of high technical requirement, serious environmental pollution, high production cost and the like, the invention provides a novel method for preparing the ivabradine, and the method has the advantages of short reaction route, simple and convenient operation, milder reaction, economy, environmental protection and high yield, and is suitable for industrial production.
The invention is realized by the following technical scheme:
nucleophilic substitution is carried out on the compound II and the compound III to generate a compound IV, and the compound IV generates a hydrochloride intermediate V under the action of acyl chloride and alcohol; nucleophilic substitution is carried out on the intermediate V and the intermediate compound VI to obtain a compound VII, and the compound VII is reduced to obtain the ivabradine, wherein the synthetic route is as follows:
Figure BDA0002406288830000031
the above steps are described in detail in the following sections:
step 1 preparation of Compound IV
The preparation method of the compound IV comprises the following steps: dissolving a compound II, namely 7, 8-dimethoxy-1, 3,4, 5-tetrahydro-benzazepin-2-ketone, in an organic solvent at room temperature, adding alkali, stirring, and dropwise adding a compound III, namely a mixture of (3-chloro-propyl) -methyl-carbamic acid tert-butyl ester and the organic solvent under ice bath to obtain a compound IV.
In a preferred embodiment, the base is one of or a combination of potassium tert-butoxide, sodium hydride, potassium carbonate, cesium carbonate and lithium diisopropylamide, and potassium tert-butoxide is particularly preferred.
In a preferred embodiment, the feeding molar ratio of the compound II, the compound III and the base is 1.1-2.0.
Preferably, the organic solvent is selected from one or a combination of dimethyl sulfoxide, acetonitrile, tetrahydrofuran, toluene, benzene and xylene.
In a preferred scheme, after the reaction is finished, a post-treatment operation is required, specifically: after the reaction is finished, pouring the mixed solution into pure water, stirring to separate out a solid, performing suction filtration, adding an organic solvent, pulping, performing suction filtration, and drying to obtain a compound IV; the pulping solvent is one or the combination of acetone and diethyl ether.
Step 2 preparation of compound v:
the preparation method of the compound V comprises the following steps: adding acetyl chloride into an alcohol organic solvent at low temperature, adding a compound IV, and continuously stirring at room temperature until the reaction is finished to obtain an intermediate V.
Preferably, the alcohol organic solvent is selected from one or a combination of methanol, ethanol and isopropanol, and ethanol is particularly preferred.
Preferably, the feeding molar ratio of the compound IV to acetyl chloride is as follows: 1, 8.0-12.0, particularly preferably 1.
In a preferable scheme, the temperature of the acetyl chloride dropwise is-5 ℃, and the temperature is particularly preferably 0 ℃.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: decompressing and concentrating the reaction liquid to remove about 3/4 of the volume, adding an organic solvent for extraction while stirring, filtering, washing a filter cake with a small amount of the organic solvent, concentrating the organic solvent, and drying in vacuum to obtain an intermediate V; the organic extraction solvent is: one or the combination of dichloromethane, trichloromethane and ethyl acetate.
Step 3 preparation of compound VII:
the preparation method of the compound VII comprises the following steps: adding the compound V into an organic solvent, adding alkali, adding the compound VI at low temperature, and continuously reacting at room temperature to obtain an intermediate compound VII.
Preferably, the base is one or two selected from sodium hydride, sodium carbonate, potassium carbonate, triethylamine, pyridine and sodium bicarbonate, and sodium carbonate is particularly preferred.
Preferably, the reaction organic solvent is one or a mixture of diethyl ether, tetrahydrofuran, acetonitrile, toluene and 1, 4-dioxane, and tetrahydrofuran is particularly preferred.
In a preferred scheme, the feeding molar ratio of the reaction compounds V and VI to the alkali is as follows: 1.1 to 2.0, and particularly preferably 1.
In a preferred embodiment, the temperature for adding the compound VI is-5 ℃ to 5 ℃, and particularly preferably 0 ℃.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: diluting the reaction solution with deionized water, adding an organic solvent for extraction, washing an organic layer with 2% diluted hydrochloric acid, water and saturated sodium bicarbonate in sequence, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and drying to obtain an intermediate compound VII; the extraction solvent is one or the combination of dichloromethane, trichloromethane and ethyl acetate.
Step 4 preparation of Ivabradine
And (3) under the protection of inert gas, adding the intermediate compound VII into an organic solvent, stirring and dissolving, adding a reducing agent into the reaction solution in batches at a low temperature, and controlling the temperature and stirring to obtain the ivabradine after the addition is finished.
Preferably, the reaction organic solvent is one or a mixture of tetrahydrofuran, acetonitrile, toluene and 1, 4-dioxane, and tetrahydrofuran is particularly preferred.
Preferably, the reducing agent is selected from one or a mixture of potassium borohydride, sodium cyanoborohydride and diethyl (3-pyridyl) -borane, and particularly preferably potassium borohydride.
In a preferred scheme, the feeding molar ratio of the reaction compound V II to the reducing agent is as follows: 1, 3.0 to 6.0, particularly preferably 1.
In a preferred embodiment, the reaction temperature is 35 ℃ to 55 ℃, and particularly preferably 45 ℃.
In a preferred scheme, the temperature of the reducing agent is-10 ℃, and particularly preferably 0 ℃.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: and detecting the reaction of the raw materials by TLC (thin layer chromatography), slowly adding water into the reaction solution to quench the reaction, concentrating under reduced pressure, extracting the residue with ethyl acetate, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the ivabradine.
Compared with the prior art, the invention has the following technical effects:
1. the novel preparation method of ivabradine is provided, the whole synthesis method is simple and convenient to operate, the reaction yield is high, and the purity of the obtained product is high;
2. the new synthesis method takes a new intermediate compound IV as a key intermediate, avoids the generation of traditional nucleophilic substitution dimerization impurities, and has high yield and high purity.
In conclusion, the invention provides a novel compound and a novel method for synthesizing ivabradine by using the compound, the method avoids using dangerous chemical reagents, the synthesized intermediate does not generate dimeric impurities, the traditional catalyst is replaced by a green catalyst, the reaction is milder, the economic and environment-friendly effects are realized, the yield is higher, and the method is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
The structure of the novel compound obtained by the invention is confirmed:
Figure BDA0002406288830000051
high resolution mass spectrum of compound IV: ESI-HRMS: m/z =393.2395[ M + H ]] + , 1 H-NMR(400MHz,CDCl 3 )δ6.47(s,1H),6.38(s,1H),4.33(s,3H)3.83(s,3H),3.82(s,3H),3.73(m,2H),3.56(s,2H),3.37-3.23(m,2H),2.97-3.29(m,2H),2.78(t,J＝4.2Hz,2H),1.85-1.92(m,2H),1.32-1.38(s,9H)； 13 C-NMR(100MHz,CDCl 3 )δ:178.8,174.2,154.5,148.8,147.7,131.4,126.6,116.4,112.4,79.6,56.1,52.2,50.9,48.8,43.3,36.5,35.9,28.6,24.2.
Preparation of Compound IV
Example 1
Dissolving a compound II, namely 7, 8-dimethoxy-1, 3,4, 5-tetrahydro-benzazepin-2-one (44.3 g,0.2 mol) in 250ml of DMSO at room temperature, adding a mixed solution of potassium tert-butoxide (26.9 g, 0.24mol) in batches, stirring for 10min, dropwise adding a compound III, namely a mixed solution of (3-chloro-propyl) -methyl-carbamic acid tert-butyl ester (53.9 g, 0.26mol) and DMSO (120 ml) under ice bath, pouring a reaction solution into pure water (150 ml) after the reaction is finished, stirring to separate out a solid, performing suction filtration, adding 200ml of acetone for pulping, performing suction filtration until no filtrate flows out, and performing vacuum drying at 40 ℃ to obtain a compound IV, wherein the yield is 99.8 percent and the purity is HPLC 99.85 percent.
Example 2
Dissolving a compound II, namely 7, 8-dimethoxy-1, 3,4, 5-tetrahydro-benzazepin-2-one (44.3g, 0.2mol) in 250ml of DMSO at room temperature, adding sodium tert-butoxide (23.1g, 0.24mol) in batches, stirring for 10min, dropwise adding a mixed solution of a compound III, namely (3-chloro-propyl) -methyl-tert-butyl carbamate (45.6 g, 0.22mol) and DMSO (120 ml) in ice bath, pouring a reaction solution into pure water (150 ml) after the reaction is finished, stirring to separate out a solid, performing suction filtration, adding 200ml of acetone for pulping, performing suction filtration until no filtrate flows out, and performing vacuum drying at 40 ℃ to obtain a compound IV, wherein the yield is 94.3 percent and the HPLC purity is 99.81 percent.
Example 3
Dissolving a compound II, namely 7, 8-dimethoxy-1, 3,4, 5-tetrahydro-benzazepin-2-one (44.3g, 0.2 mol) in 250ml of benzene at room temperature, adding potassium carbonate (33.2g, 0.24mol) in batches, stirring for 10min, dropwise adding a mixed solution of a compound III, namely (3-chloro-propyl) -methyl-tert-butyl carbamate (82.9g, 0.40mol) and benzene (120 ml), pouring a reaction solution into pure water (150 ml) after the reaction is finished, stirring to separate out a solid, performing suction filtration, adding 200ml of acetone for pulping, performing suction filtration until no filtrate flows out, and performing vacuum drying at 40 ℃ to obtain a compound IV, wherein the yield is 95.6% and the HPLC purity is 99.76%.
Example 4
Dissolving a compound II, namely 7, 8-dimethoxy-1, 3,4, 5-tetrahydro-benzazepin-2-one (44.3g, 0.2mol) in 250ml of DMSO, adding lithium isopropylamide (25.8g, 0.24mol) in batches, stirring for 10min, dropwise adding a compound III, namely (3-chloro-propyl) -methyl-tert-butyl carbamate (41.5g, 0.20mol) and a mixed solution of DMSO (120 ml), pouring a reaction solution into pure water (150 ml) after the reaction is finished, stirring to separate out a solid, performing suction filtration, adding 200ml of acetone for pulping, performing suction filtration until no filtrate flows out, and performing vacuum drying at 40 ℃ to obtain a compound IV, wherein the yield is 90.2% and the HPLC purity is 99.70%.
Example 5
Dissolving a compound II, namely 7, 8-dimethoxy-1, 3,4, 5-tetrahydro-benzazepin-2-one (44.3g, 0.2mol) in 250ml of DMSO, adding sodium hydride (5.8g, 0.24mol) in batches, stirring for 10min, dropwise adding a mixed solution of a compound III, namely (3-chloro-propyl) -methyl-tert-butyl carbamate (91.1g, 0.44mol) and DMSO (120 ml), pouring a reaction solution into pure water (150 ml) after the reaction is finished, stirring to separate out a solid, performing suction filtration, adding 200ml of acetone for pulping, performing suction filtration until no filtrate flows out, and performing vacuum drying at 40 ℃ to obtain a compound IV, wherein the yield is 89.3% and the HPLC purity is 99.65%.
Example 6
Dissolving a compound II, namely 7, 8-dimethoxy-1, 3,4, 5-tetrahydro-benzazepin-2-one (44.3 g,0.2 mol) in 200ml of acetonitrile at room temperature, adding potassium tert-butoxide (24.7 g, 0.22mol) in batches, stirring for 10min, dropwise adding a mixed solution of a compound III, namely (3-chloro-propyl) -methyl-carbamic acid tert-butyl ester (53.9 g, 0.26mol) and acetonitrile (120 ml), pouring a reaction solution into pure water (150 ml) after the reaction is finished, stirring to separate out a solid, performing suction filtration, adding 200ml of acetone, performing suction filtration until no filtrate flows out, and performing vacuum drying at 40 ℃ to obtain a compound IV, wherein the yield is 93.8 percent and the HPLC purity is 99.78 percent.
Example 7
Dissolving a compound II, namely 7, 8-dimethoxy-1, 3,4, 5-tetrahydro-benzazepin-2-one (44.3 g,0.2 mol) in 230ml of toluene at room temperature, adding potassium tert-butoxide (44.9 g, 0.40mol) in batches, stirring for 10min, dropwise adding a mixed solution of a compound III, namely (3-chloro-propyl) -methyl-carbamic acid tert-butyl ester (53.9 g, 0.26mol) and toluene (120 ml), pouring a reaction solution into pure water (150 ml) after the reaction is finished, stirring to separate out a solid, performing suction filtration, adding 200ml of diethyl ether, performing suction filtration until no filtrate flows out, and performing vacuum drying at 40 ℃ to obtain a compound IV, wherein the yield is 92.4% and the HPLC purity is 99.69%.
Example 8
Dissolving a compound II, namely 7, 8-dimethoxy-1, 3,4, 5-tetrahydro-benzazepin-2-one (44.3 g,0.2 mol) in 250ml of tetrahydrofuran at room temperature, adding a mixed solution of potassium tert-butoxide (22.5 g,0.2 mol) in batches, stirring for 10min, dropwise adding a compound III, namely (3-chloro-propyl) -methyl-carbamic acid tert-butyl ester (53.9 g, 0.26mol) and tetrahydrofuran (120 ml), pouring a reaction solution into pure water (150 ml) after the reaction is finished, stirring to separate out a solid, performing suction filtration, adding 200ml of diethyl ether for pulping, performing suction filtration until no filtrate flows out, and performing vacuum drying at 40 ℃ to obtain a compound IV, wherein the yield is 86.4% and the purity is 99.70% by HPLC.
Example 9
Dissolving a compound II, namely 7, 8-dimethoxy-1, 3,4, 5-tetrahydro-benzazepin-2-one (44.3 g,0.2 mol) in 220ml of p-xylene at room temperature, adding potassium tert-butoxide (49.4 g, 0.44mol) in batches, stirring for 10min, adding a mixed solution of a compound III, namely (3-chloro-propyl) -methyl-tert-butyl carbamate (53.9g, 0.26mol) and p-xylene (120 ml), pouring a reaction solution into pure water (150 ml) after the reaction is finished, stirring to separate out a solid, performing suction filtration, adding 200ml of diethyl ether, performing suction filtration until no filtrate flows out, and performing vacuum drying at 40 ℃ to obtain a compound IV, wherein the yield is 87.6 percent and the purity is 99.67 percent by HPLC.
Preparation of Compound V
Example 10
Cooling absolute ethyl alcohol (1000 ml) to 0 ℃, slowly dripping acetyl chloride (157.0 g, 2mol), reacting for 10min after dripping, adding compound IV (78.4 g, 0.2mol), naturally heating to room temperature after adding, reacting for about 20h, decompressing and concentrating reaction liquid to remove about 3/4 volume, adding 500ml ethyl acetate while stirring, stirring for about 0.5h after adding, filtering filter cakes, washing with a small amount of ethyl acetate, and vacuum drying to obtain intermediate compound V, wherein the yield is 98.6%, and the HPLC purity is 99.88%.
Example 11
Cooling absolute ethanol (1000 ml) to 0 ℃, slowly dripping acetyl chloride (125.6g, 1.6 mol), reacting for 10min after dripping, adding the compound IV (78.4g, 0.2mol), naturally heating to room temperature after adding, reacting for about 20h, decompressing and concentrating the reaction solution to remove about 3/4 volume, adding 450ml of dichloromethane while stirring, stirring for about 0.5h after adding, filtering a filter cake, washing with a small amount of dichloromethane, and drying in vacuum to obtain an intermediate compound V, wherein the yield is 94.7%, and the HPLC purity is 99.81%.
Example 12
Cooling absolute ethyl alcohol (1000 ml) to-5 ℃, slowly dripping acetyl chloride (188.4 g,2.4 mol), reacting for 10min after dripping, adding the upper compound IV (78.4 g, 0.2mol), naturally heating to room temperature after adding, reacting for about 20h, decompressing and concentrating reaction liquid to remove about 3/4 volume, adding 450ml of dichloromethane while stirring, stirring for about 0.5h after adding, filtering filter cakes, washing with a small amount of dichloromethane, and drying in vacuum to obtain an intermediate compound V, wherein the yield is 95.2% and the HPLC purity is 99.77%.
Example 13
Cooling absolute ethyl alcohol (1000 ml) to 5 ℃, slowly dripping acetyl chloride (109.9g, 1.4mol) into the mixture, reacting for 10min after dripping, adding upper compound IV (78.4g, 0.2mol), naturally heating to room temperature after adding, reacting for about 20h, decompressing and concentrating reaction liquid to remove about 3/4 volume, adding 400ml of trichloromethane while stirring, stirring for about 0.5h after adding, filtering filter cakes, washing with a small amount of trichloromethane, and drying in vacuum to obtain intermediate compound V, wherein the yield is 87.4% and the HPLC purity is 99.71%.
Example 14
Cooling absolute ethanol (1000 ml) to 6 ℃, slowly dripping acetyl chloride (204.1g, 2.6 mol), reacting for 10min after dripping, adding upper compound IV (78.4g, 0.2mol), naturally heating to room temperature after adding, reacting for about 20h, decompressing and concentrating reaction liquid to remove about 3/4 volume, adding 400ml of trichloromethane while stirring, stirring for about 0.5h after adding, filtering filter cakes, washing with a small amount of trichloromethane, and drying in vacuum to obtain intermediate compound V, wherein the yield is 88.9 percent and the HPLC purity is 99.68 percent.
Preparation of Compound VII
Example 15
Adding the intermediate compound V (65.6 g, 0.20mol) into 500L of diethyl ether solution, stirring, adding sodium carbonate (25.5g, 0.24mol), stirring for 10min, cooling to 0 ℃, adding 200ml of diethyl ether solution of a compound VI (54.3g, 0.24mol) into the solution, after the dropwise addition is finished, stirring at room temperature, finishing TLC detection reaction, adding 300ml of water, extracting by using ethyl acetate, washing an organic layer by using 2% dilute hydrochloric acid, water and saturated sodium bicarbonate in sequence, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, and drying in vacuum at 40 ℃ to obtain a compound VII, wherein the yield is 98.9%, and the HPLC purity is 99.87%.
Example 16
Adding the intermediate compound V (65.6 g, 0.20mol) into 500ml of ether solution, stirring, adding sodium hydride (5.6 g, 0.24mol), stirring for 10min, cooling to 0 ℃, adding 200ml of ether solution of a compound VI (49.8g, 0.22mol), dropwise adding the solution, stirring at room temperature for about 4h after dropwise adding is finished, detecting the reaction by TLC, adding 300ml of water, extracting by ethyl acetate, sequentially washing an organic layer by using 2% of dilute hydrochloric acid, water and saturated sodium bicarbonate, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and drying in vacuum at 40 ℃ to obtain a compound VII, wherein the yield is 95.9%, and the HPLC purity is 99.81%.
Example 17
Adding the intermediate compound V (65.6g, 0.20mol) into 500L of diethyl ether solution, stirring, adding triethylamine (24.3g, 0.24mol), stirring for 10min, cooling to-5 ℃, adding 200ml of diethyl ether solution of the compound VI (90.5g, 0.40mol), dropwise adding the solution, stirring at room temperature for about 4h, finishing TLC detection reaction, adding 300ml of water, extracting by dichloromethane, sequentially washing an organic layer by using 2% of dilute hydrochloric acid, water and saturated sodium bicarbonate, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, and drying in vacuum at 40 ℃ to obtain the compound VII, wherein the yield is 94.4%, and the HPLC purity is 99.75%.
Example 18
Adding the intermediate compound V (65.6 g, 0.20mol) into 500ml of ether solution, stirring, adding pyridine (19.0g, 0.24mol), stirring for 10min, cooling to 5 ℃, adding 200ml of ether solution of a compound VI (45.2g, 0.20mol), dropwise adding the solution, stirring at room temperature for about 4h, detecting by TLC, finishing the reaction, adding 300ml of water, extracting by ethyl acetate, sequentially washing an organic layer by using 2% of dilute hydrochloric acid, water and saturated sodium bicarbonate, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and drying in vacuum at 40 ℃ to obtain a compound VII, wherein the yield is 89.9%, and the HPLC purity is 99.70%.
Example 19
Adding the intermediate compound V (65.6 g, 0.20mol) into 500ml of ether solution, stirring, adding sodium bicarbonate (20.2g, 0.24mol), stirring for 10min, cooling to 6 ℃, adding 200ml of ether solution of a compound VI (99.4g, 0.44mol), dropwise adding the solution, stirring at room temperature for about 4h after dropwise adding is finished, detecting the reaction by TLC, adding 300ml of water, extracting by ethyl acetate, sequentially washing an organic layer by using 2% of dilute hydrochloric acid, water and saturated sodium bicarbonate, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and drying in vacuum at 40 ℃ to obtain a compound VII, wherein the yield is 88.8%, and the HPLC purity is 99.67%.
Example 20
Adding the intermediate compound V (65.6g, 0.20mol) into 500ml tetrahydrofuran solution, stirring, adding sodium carbonate (23.4g, 0.22mol), stirring for 10min, cooling to 0 ℃, adding 200ml diethyl ether solution of the compound VI (54.3g, 0.24mol), dropwise adding the solution, stirring at room temperature for about 4h, detecting by TLC, finishing the reaction, concentrating the solvent under reduced pressure, adding 300ml of water, extracting by trichloromethane, sequentially washing an organic layer by using 2% dilute hydrochloric acid, water and saturated sodium bicarbonate, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, and drying in vacuum at 40 ℃ to obtain the compound VII, wherein the yield is 94.3%, and the HPLC purity is 99.78%.
Example 21
Adding the intermediate compound V (65.6g, 0.20mol) into 500ml of acetonitrile solution, stirring, adding sodium carbonate (42.4g, 0.40mol), stirring for 10min, cooling to-6 ℃, adding 200ml of ether solution of the compound VI (54.3g, 0.24mol), dropwise adding the solution, stirring at room temperature for about 4h, finishing TLC detection reaction, concentrating the solvent under reduced pressure, adding 300ml of water, extracting with ethyl acetate, sequentially washing an organic layer with 2% of dilute hydrochloric acid, water and saturated sodium bicarbonate, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and drying under vacuum at 40 ℃ to obtain the compound VII, wherein the yield is 93.8%, and the HPLC purity is 99.74%.
Example 22
Adding the intermediate compound V (65.6 g, 0.20mol) into 500ml of toluene solution, stirring, adding sodium carbonate (10.6 g, 0.20mol), stirring for 10min, cooling to-5 ℃, adding 200ml of ether solution of a compound VI (54.3g, 0.24mol), dropwise adding the solution, stirring at room temperature for about 4h, finishing TLC detection reaction, adding 300ml of water, extracting by ethyl acetate, sequentially washing an organic layer by using 2% dilute hydrochloric acid, water and saturated sodium bicarbonate, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and drying in vacuum at 40 ℃ to obtain a compound VII, wherein the yield is 86.3%, and the HPLC purity is 99.70%.
Example 23
Adding the intermediate compound V (65.6 g, 0.20mol) into 500ml of 1.4-dioxane solution, stirring, adding sodium carbonate (46.6 g, 0.44mol), stirring for 10min, cooling to 0 ℃, adding 200ml of ether solution of a compound VI (54.3 g, 0.24mol), dropwise adding the solution, stirring for about 4h at room temperature, finishing TLC detection reaction, concentrating the solvent under reduced pressure, adding 300ml of water, extracting by using ethyl acetate, washing an organic layer by using 2% of dilute hydrochloric acid, water and saturated sodium bicarbonate in sequence, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, and drying in vacuum at 40 ℃ to obtain a compound VII, wherein the yield is 87.7%, and the HPLC purity is 99.66%.
Preparation of ivabradine
Example 24
Adding 200ml of anhydrous tetrahydrofuran into a 500ml reaction flask under the protection of nitrogen gas, adding an intermediate compound VII (48.3 g, 0.1mol), stirring for dissolving, cooling to 0 ℃, adding potassium borohydride (21.6 g,0.4 mol) into the reaction solution in batches, stirring for reaction at 45 ℃, detecting that the raw material is completely reacted by TLC, slowly adding 100ml of water into the reaction solution for quenching reaction, concentrating under reduced pressure, extracting with ethyl acetate (250 ml multiplied by 2), drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain ivabradine, wherein the yield is 97.7%, and the HPLC purity is 99.86%.
Example 25
Adding 200ml of anhydrous acetonitrile into a 500ml reaction bottle under the protection of nitrogen gas, adding an intermediate compound VII (48.3 g,0.1 mol), stirring for dissolving, cooling to-10 ℃, adding potassium borohydride (16.2 g,0.3 mol) into the reaction solution in batches, stirring for reaction at 35 ℃, detecting that the raw material is completely reacted by TLC, slowly adding 100ml of water into the reaction solution for quenching reaction, concentrating under reduced pressure, extracting by dichloromethane (250 ml multiplied by 2), drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain ivabradine, wherein the yield is 94.2%, and the HPLC purity is 99.77%.
Example 26
Adding 200ml of anhydrous toluene in a 500ml reaction flask under the protection of nitrogen gas, adding an intermediate compound VII (48.3g, 0.1mol), stirring for dissolving, cooling to-5 ℃, adding potassium borohydride (32.4g, 0.6 mol) into the reaction solution in batches, stirring for reaction at 55 ℃, detecting that the raw material reaction is complete by TLC, slowly adding 100ml of water into the reaction solution for quenching reaction, concentrating under reduced pressure, extracting by trichloromethane (250 ml multiplied by 2), drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain ivabradine, wherein the yield is 93.4 percent and the HPLC purity is 99.70 percent.
Example 27
Adding 200ml of anhydrous 1.4-dioxane into a 500ml reaction bottle under the protection of nitrogen gas, adding an intermediate compound VII (48.3 g,0.1 mol), stirring for dissolving, cooling to-15 ℃, adding diethyl (3-pyridyl) -borane (36.8 g, 0.25mol) into the reaction liquid in batches, stirring for reaction at 30 ℃ after the addition is finished, detecting that the raw materials are completely reacted by TLC, slowly adding 100ml of water into the reaction liquid for quenching reaction, concentrating under reduced pressure, extracting by using ethyl acetate (250 ml multiplied by 2), drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain ivabradine, wherein the yield is 87.5 percent, and the HPLC purity is 99.65 percent.
Example 28
Adding 200ml of anhydrous tetrahydrofuran into a 500ml reaction bottle under the protection of nitrogen gas, adding an intermediate compound VIII (48.3 g, 0.1mol), stirring for dissolving, cooling to 10 ℃, adding sodium cyanoborohydride (40.8g, 0.65mol) into the reaction liquid in batches, stirring for reaction at 60 ℃, detecting that the raw materials completely react by TLC, slowly adding 100ml of water into the reaction liquid for quenching reaction, concentrating under reduced pressure, extracting by dichloromethane (250 ml multiplied by 2), drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain ivabradine, wherein the yield is 88.2%, and the HPLC purity is 98.70%.

Claims (10)

1. The preparation method of ivabradine is characterized in that a compound II and a compound III are subjected to nucleophilic substitution to generate a compound IV, and the compound IV generates a hydrochloride intermediate V under the action of acyl chloride and alcohol; nucleophilic substitution is carried out on the intermediate V and the intermediate compound VI to obtain a compound VII, and the compound VII is reduced to obtain the ivabradine, wherein the synthetic route is as follows:
Figure FDA0003985856040000011
the reducing agent for reducing the compound VII is selected from one of potassium borohydride, sodium borohydride, nitrile sodium borohydride and diethyl (3-pyridyl) -borane or the combination thereof.
2. The method of claim 1, comprising the steps of:
(1) Dissolving the compound II in an organic solvent at room temperature, adding alkali, stirring, and dripping the compound III, namely (3-chloro-propyl) -methyl-tert-butyl carbamate, into the solution to continue to react to obtain a compound IV;
(2) Adding acetyl chloride into an alcohol organic solvent at low temperature, adding a compound IV, heating to room temperature, and continuously stirring until the reaction is finished to obtain an intermediate V;
(3) Adding the compound V into an organic solvent, adding alkali, adding the compound VI at low temperature, and continuously reacting at room temperature to obtain an intermediate compound VII;
(4) And under the protection of inert gas, adding the intermediate compound VII into an organic solvent, stirring and dissolving, controlling the temperature, adding a reducing agent into the reaction liquid in batches, and controlling the temperature and stirring to obtain the ivabradine.
3. The method according to claim 2, wherein the base in step (1) is one of potassium tert-butoxide, sodium hydride, potassium carbonate, cesium carbonate, lithium diisopropylamide, or a combination thereof.
4. The production method according to claim 2, wherein the compound II, the compound III, and the base are fed at a molar ratio of 1.
5. The preparation method according to claim 2, wherein the compound IV and acetyl chloride are fed in the step (2) in a molar ratio of: 1, 8.0-12.0.
6. The preparation method according to claim 2, wherein the alcoholic organic solvent in step (2) is selected from one or a combination of methanol, ethanol, isopropanol; the temperature of acetyl chloride addition is-5 ℃ to 5 ℃.
7. The preparation method according to claim 2, wherein the base in step (3) is one or two selected from sodium hydride, sodium carbonate, potassium carbonate, triethylamine, pyridine, and sodium bicarbonate; the temperature for adding the compound VI is-5 ℃ to 5 ℃.
8. The method according to claim 2, wherein the molar ratio of the compounds V and VI and the base in step (3) is: 1.1-2.0.
9. The method according to claim 2, wherein the temperature of the reducing agent added in the step (4) is-10 to 10 ℃.
10. The preparation method according to claim 2, wherein the compound v II and the reducing agent are fed in the step (4) in a molar ratio of: 1, 3.0-6.0.
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