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CN108003102A - A kind of synthetic method of Ivabradine - Google Patents

A kind of synthetic method of Ivabradine Download PDF

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Publication number
CN108003102A
CN108003102A CN201710760174.1A CN201710760174A CN108003102A CN 108003102 A CN108003102 A CN 108003102A CN 201710760174 A CN201710760174 A CN 201710760174A CN 108003102 A CN108003102 A CN 108003102A
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CN
China
Prior art keywords
compound
synthetic method
ivabradine
reaction
solvent
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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CN201710760174.1A
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Chinese (zh)
Inventor
袁金桥
竺来发
刘虎
陈舟
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HARVEST (HUNAN) PHARMACEUTICAL TECHNOLOGY Co Ltd
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HARVEST (HUNAN) PHARMACEUTICAL TECHNOLOGY Co Ltd
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Priority to CN201710760174.1A priority Critical patent/CN108003102A/en
Publication of CN108003102A publication Critical patent/CN108003102A/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D223/00Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16Benzazepines; Hydrogenated benzazepines

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention provides a kind of synthetic method of Ivabradine, and specific reactions steps are as follows:Step 1:Compound (II) is alkylated reaction with bromo-chloropropane under the catalysis of the first alkali and obtains compound (III);Step 2:Compound (III) carries out hydrogenation under palladium carbon and ammonium formate system and obtains compound (IV);Step 3:Compound (IV) carries out iodination reaction with iodo reagent, obtains compound (V);Step 4:Compound (V) carries out condensation reaction with compound (VI) under the catalysis of the second alkali, obtains compound (I).This method is easy to operate, mild condition, raw materials used to have been commercialized, and synthetic method is simple, of low cost, greatly reduces the synthesis difficulty of Ivabradine.

Description

A kind of synthetic method of Ivabradine
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of synthetic method of Ivabradine.
Background technology
Ivabradine, the compound as shown in formula (I), chemical name:7,8- dimethoxys -3- (3- [[(1S) (4,5- bis- Methoxyl group benzocyclobutane -1- bases) methyl]-methylamino] propyl group) -2 hydrogen of -1,3,4,5- tetrahydros-benzazepine -2- ketone:
Ivabradine (Ivabradine), the approval of the medical evaluation office (EMEA) in Europe is obtained on November 3rd, 2005 In the country's listing of 27, Europe, name of product Procoralan, for treating with normal sinus rhythm, to beta-blocker Taboo or the symptomatic treatment of intolerable chronic stable angina pectoris.
Procoralan is researched and developed by Shi Weiya company, and the cardiovascular treatment field in 20 years that becomes history obtain it is most important One of progress.Procoralan is that the 1st pure heart rate lowers medicine, is responsible for controlling sinoatrial node automatic by selective depression The If passages of depolarising and adjusting heart rate play a role.Procoralan selectively actings are in sinoatrial node, to intracardiac conduction, cardiac muscle Convergent force or ventricular repolarisation do not influence.Different from anginal common medicine beta-blocker, Procoralan does not cause sexual function Obstacle, respiratory system adverse reaction and bradycardia or rebound phenomenon caused by airway contraction and spasm.
Report has EP05348059 in relation to the patent for preparing the compound earliest, its related patents is US5296482, this is special Sharp synthetic method is as follows:
This method yield is relatively low, and particularly chiral starting material is expensive, and catalytic hydrogenation this step, yield only 40%, Total recovery is 18%, and product need to be purified through column chromatography, greatly improve manufacturing cost, be not suitable for industrialized production.
In addition Chinese patent CN20051005779 reports the new method of synthesis of ivabradine, its route is as follows:
Each step of this method uses palladium-carbon catalyst, and is high-pressure hydrogenation, although total recovery is higher, from cost and work There are larger drawback for this route from the aspect of industry.
The content of the invention
In order to solve the above technical problems, the present invention provides a kind of synthetic method of Ivabradine, this method is easy to operate, Mild condition, raw materials used to have been commercialized, synthetic method is simple, of low cost, greatly reduces the synthesis of Ivabradine Difficulty.
To reach above-mentioned purpose, the present invention provides a kind of synthetic method of Ivabradine, and specific reactions steps are as follows:
Step 1:Compound (II) is alkylated reaction under the catalysis of the first alkali with bromo-chloropropane and obtains compound (III);
Step 2:Compound (III) carries out hydrogenation under palladium carbon and ammonium formate system and obtains compound (IV);
Step 3:Compound (IV) carries out iodination reaction with iodo reagent, obtains compound (V);
Step 4:Compound (V) carries out condensation reaction with compound (VI) under the catalysis of the second alkali, obtains compound (I)。
Further, the present invention provides a kind of synthetic method of Ivabradine, and first alkali is sodium hydroxide, hydrogen-oxygen Change potassium, potassium tert-butoxide etc., more preferably potassium tert-butoxide.
Further, the present invention provides a kind of synthetic method of Ivabradine, and the alkylated reaction is in the first solvent Middle progress, first solvent for tetrahydrofuran, n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl sulfoxide (DMSO) etc., It is preferred that N,N-dimethylformamide.
Further, the present invention provides a kind of synthetic method of Ivabradine, the compound (III) and ammonium formate Molar ratio is 1:(1~20), preferably 1:(8~15).
Further, the present invention provides a kind of synthetic method of Ivabradine, and the hydrogenation carries out under normal pressure.
Further, the present invention provides a kind of synthetic method of Ivabradine, and the temperature of the hydrogenation is 10- 100 DEG C, preferably 40-70 DEG C.
Further, the present invention provides a kind of synthetic method of Ivabradine, and the hydrogenation is in the second solvent Carry out, second solvent is methanol, ethanol, isopropanol, propane diols etc., more preferably methanol.
Further, the present invention provides a kind of synthetic method of Ivabradine, and the iodo reagent is sodium iodide, iodate Potassium, magnesium iodide etc., more preferably sodium iodide.
Further, the present invention provides a kind of synthetic method of Ivabradine, and the iodination reaction is in the 3rd solvent Carry out, the 3rd solvent is acetone, butanone, methyl ethyl ketone, hexone etc., more preferably acetone.
Further, the present invention provides a kind of synthetic method of Ivabradine, the temperature of the iodide reaction for 30~ 80 DEG C, preferably 50~60 DEG C.
Further, the present invention provides a kind of synthetic method of Ivabradine, and second alkali is anhydrous magnesium carbonate, nothing Aqueous sodium carbonate, Anhydrous potassium carbonate etc., more preferably Anhydrous potassium carbonate.
Further, the present invention provides a kind of synthetic method of Ivabradine, the compound (V) and compound (VI) Molar ratio be (1.0~1.3):1, it is preferably 1.2:1.
Further, the present invention provides a kind of synthetic method of Ivabradine, and the condensation reaction is in the 4th solvent Carry out, the 4th solvent is tetrahydrofuran, n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl sulfoxide (DMSO) etc., more Preferably N,N-dimethylformamide.
Further, the present invention provides a kind of synthetic method of Ivabradine, and the reaction temperature of the condensation reaction is Room temperature, is preferably 20~30 DEG C.
Further, the present invention provides a kind of synthetic method of Ivabradine, needed after the completion of the condensation reaction into Row post processing, the process of the post processing are as follows:Add water quenching to go out reaction, add concentrated hydrochloric acid and adjust pH < 2, water phase is collected in liquid separation; Water is added ammonium hydroxide and adjusts pH > 8, and after being extracted with ethyl acetate, with purifying water washing organic phase, organic phase, which is concentrated to dryness, to be changed Compound (I).
Beneficial effect
A kind of synthetic method of Ivabradine of the present invention, the synthetic method is easy to operate, and reaction condition is gentle, yield Height, total recovery reach 60%, and wherein catalytic hydrogenation high income thoroughly solves hydrogenation operation with high pressure danger, yield is low up to 90% Drawback, has good Industry Foundation and actual application value.
The experimentation of the preparation method is succinct, and route is clear and definite, irredundant operation, and end-product is post-processed without column layer Analysis, simplification of flowsheet, reaction condition is gentle, reduces the three wastes and produces, is easy to industrial applications, to drug quality control and clinic Curative effect is of great significance.
Embodiment
In order to make those skilled in the art more fully understand technical scheme, it is non-that some are disclosed further below Limiting embodiment, the present invention is described in further detail.
Embodiment 1
At room temperature, 10g compounds (II) are taken, 100ml n,N-Dimethylformamide stirs evenly, and adds the 6.2g tert-butyl alcohols Gone to after potassium activation 30min in the container for filling 8.6g bromo-chloropropane dilutions, 25 ± 5 DEG C of temperature control, reacts 30min, instead It should finish to go in 1L frozen water and crystallization 5h is quenched, filter, crude product is in acetone/water (volume ratio 1:6) recrystallization, obtains white in Solid 9.8g.
In reaction bulb, 8g compounds (III), 80ml methanol, 14g ammonium formates, 1.6g palladium carbons are added, normal pressure is warming up to 60 DEG C reaction 6h, filtering, filtrate is concentrated to dryness to obtain compound (IV).
Take 7g compounds (IV), 40ml acetone, 18g sodium iodides, temperature rising reflux 24h, cold filtration, be concentrated under reduced pressure into it is dry, 50ml dichloromethane stirring and dissolvings are added at room temperature, and filtering removes excessive sodium iodide, and filtrate decompression is concentrated to dryness to obtain chemical combination Thing (V) 8.1g.
In reaction bulb, 3.0g compounds (VI), 50ml n,N-Dimethylformamide, 12g Anhydrous potassium carbonate room temperatures are added 1h is stirred, adds 5.7g compounds (V), reaction 6h is stirred at room temperature, reaction finishes, and adds 100ml frozen water that reaction is quenched, and adds hydrochloric acid PH < 2 are adjusted, add ethyl acetate to extract (100ml × 3), discard organic phase, collect water phase, water is added concentrated ammonia liquor and adjusts pH > 8, Ethyl acetate extracts (100ml × 3), merges organic phase, adds purifying water washing (200ml × 3) organic phase, and organic phase is concentrated under reduced pressure It is extremely dry to obtain 5.4g Ivabradines, yield 94.1%, HPLC:99.5%.
Embodiment 2:
At room temperature, 20g compounds (II) are taken, 200mlN, dinethylformamide stirs evenly, and adds the 12.4g tert-butyl alcohols Gone to after potassium activation 30min in the container for filling 17.2g bromo-chloropropane dilutions, 25 ± 5 DEG C of temperature control, reacts 30min, instead It should finish to go in 1L frozen water and crystallization 5h is quenched, filter, crude product is in acetone/water (volume ratio 1:6) recrystallization, obtains white in Solid 20.1g.
In reaction bulb, 15g compounds (III), 200ml methanol, 32g ammonium formates, 3.0g palladium carbons are added, normal pressure is warming up to 60 DEG C of reaction 6h, filtering, filtrate are concentrated to dryness to obtain compound (IV).
12g compounds (IV), 80ml acetone, 30, g sodium iodides are taken, temperature rising reflux 24h, cold filtration, is concentrated under reduced pressure into It is dry, 150ml dichloromethane stirring and dissolvings are added at room temperature, and filtering removes excessive sodium iodide, and filtrate decompression is concentrated to dryness to obtain Compound (V) 14.3g.
In reaction bulb, 5.0g compounds (VI), 50ml n,N-Dimethylformamide, 20g Anhydrous potassium carbonate room temperatures are added 1h is stirred, adds 9.6g compounds (V), reaction 6h is stirred at room temperature, reaction finishes, and adds 100ml frozen water that reaction is quenched, and adds hydrochloric acid PH < 2 are adjusted, add ethyl acetate to extract (100ml × 3), discard organic phase, collect water phase, water is added concentrated ammonia liquor and adjusts pH > 8, Ethyl acetate extracts (100ml × 3), merges organic phase, adds purifying water washing (200ml × 3) organic phase, and organic phase is concentrated under reduced pressure It is extremely dry to obtain 9.2g Ivabradines.Yield 95.8%, HPLC:99.1%.
The foregoing is only a preferred embodiment of the present invention, is not intended to limit the invention, for the skill of this area For art personnel, the invention may be variously modified and varied.Within the spirit and principles of the invention, that is made any repaiies Change, equivalent substitution, improvement etc., should all be included in the protection scope of the present invention.

Claims (10)

1. a kind of synthetic method of Ivabradine, it is characterised in that specific reactions steps are as follows:
Step 1:Compound (II) is alkylated reaction with bromo-chloropropane under the catalysis of the first alkali and obtains compound (III);
Step 2:Compound (III) carries out hydrogenation under palladium carbon and ammonium formate system and obtains compound (IV);
Step 3:Compound (IV) carries out iodination reaction with iodo reagent, obtains compound (V);
Step 4:Compound (V) carries out condensation reaction with compound (VI) under the catalysis of the second alkali, obtains compound (I).
2. the synthetic method of Ivabradine according to claim 1, it is characterised in that first alkali is hydroxide Sodium, potassium hydroxide, potassium tert-butoxide.
3. the synthetic method of Ivabradine according to claim 1, it is characterised in that the alkylated reaction is first Carried out in solvent, first solvent is tetrahydrofuran, n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl are sub- Sulfone.
4. the synthetic method of Ivabradine according to claim 1, it is characterised in that the compound (III) and first The molar ratio of sour ammonium is 1:(1~20).
5. the synthetic method of Ivabradine according to claim 1, it is characterised in that the hydrogenation is under normal pressure Carry out;The temperature of the hydrogenation is 10-100 DEG C.
6. the synthetic method of Ivabradine according to claim 1, it is characterised in that the hydrogenation is molten second Carried out in agent, second solvent is methanol, ethanol, isopropanol, propane diols.
7. the synthetic method of Ivabradine according to claim 1, it is characterised in that the iodo reagent is iodate Sodium, potassium iodide, magnesium iodide;The iodination reaction carries out in the 3rd solvent, and the 3rd solvent is acetone, butanone, methyl second Base ketone, hexone;The temperature of the iodide reaction is 30~80 DEG C.
8. the synthetic method of Ivabradine according to claim 1, it is characterised in that second alkali is Carbon Dioxide Magnesium, natrium carbonicum calcinatum, Anhydrous potassium carbonate;The compound (V) and the molar ratio of compound (VI) are (1.0~1.3):1.
9. the synthetic method of Ivabradine according to claim 1, it is characterised in that the condensation reaction is molten the 4th Carried out in agent, the 4th solvent is tetrahydrofuran, n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl sulfoxide (DMSO); The reaction temperature of the condensation reaction is room temperature.
10. the synthetic method of Ivabradine according to claim 1, it is characterised in that after the completion of the condensation reaction Need to be post-processed, the process of the post processing is as follows:Add water quenching to go out reaction, add concentrated hydrochloric acid and adjust pH < 2, liquid separation is collected Water phase;Water is added ammonium hydroxide and adjusts pH > 8, and after being extracted with ethyl acetate, with purifying water washing organic phase, organic phase is concentrated to dryness Obtain compound (I).
CN201710760174.1A 2017-08-30 2017-08-30 A kind of synthetic method of Ivabradine Pending CN108003102A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111187211A (en) * 2020-01-19 2020-05-22 北京鑫开元医药科技有限公司海南分公司 Preparation method of dimer impurity in ivabradine hydrochloride intermediate
CN115286577A (en) * 2022-08-25 2022-11-04 江苏永安制药有限公司 Preparation method of ivabradine hydrochloride and intermediate thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5296482A (en) * 1991-09-27 1994-03-22 Adir Et Compagnie (Benzocycloalkyl) alkylamines
CN101284813A (en) * 2007-04-12 2008-10-15 上海优拓医药科技有限公司 Preparation method of ivabradine
CN101544605A (en) * 2008-03-24 2009-09-30 北京深蓝海生物医药科技有限公司 Ivabradine and method for preparing pharmaceutically acceptable addition salt thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5296482A (en) * 1991-09-27 1994-03-22 Adir Et Compagnie (Benzocycloalkyl) alkylamines
CN101284813A (en) * 2007-04-12 2008-10-15 上海优拓医药科技有限公司 Preparation method of ivabradine
CN101544605A (en) * 2008-03-24 2009-09-30 北京深蓝海生物医药科技有限公司 Ivabradine and method for preparing pharmaceutically acceptable addition salt thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
海莉 等: "3-(3-氯丙基)-1, 3, 4, 5-四氢-7, 8-二甲氧基-2H-3-苯并氮杂卓-2-酮合成工艺的改进", 《华西药学杂志》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111187211A (en) * 2020-01-19 2020-05-22 北京鑫开元医药科技有限公司海南分公司 Preparation method of dimer impurity in ivabradine hydrochloride intermediate
CN115286577A (en) * 2022-08-25 2022-11-04 江苏永安制药有限公司 Preparation method of ivabradine hydrochloride and intermediate thereof
CN115286577B (en) * 2022-08-25 2023-10-20 江苏永安制药有限公司 Preparation method of ivabradine hydrochloride and intermediate thereof

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