CN110835319A - Synthesis method of benazepril intermediate and benazepril hydrochloride - Google Patents

Synthesis method of benazepril intermediate and benazepril hydrochloride Download PDF

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Publication number
CN110835319A
CN110835319A CN201810933728.8A CN201810933728A CN110835319A CN 110835319 A CN110835319 A CN 110835319A CN 201810933728 A CN201810933728 A CN 201810933728A CN 110835319 A CN110835319 A CN 110835319A
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compound
benazepril
reaction
benazepril hydrochloride
synthesis
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施李杨
韩宇香
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Hunan Xukang Pharmaceutical Technology Co Ltd
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Hunan Xukang Pharmaceutical Technology Co Ltd
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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

Abstract

The invention relates to a benazepril intermediate and a benazepril hydrochloride synthesis method, wherein the synthesis method comprises the steps of reacting 3-bromo-2, 3,4, 5-tetrahydro-1H- [1] -benzazepine-2-ketone-1-tert-butyl acetate with (S) -homophenylalanine, and obtaining the benazepril intermediate through a dynamic kinetic resolution process; then the refined benazepril hydrochloride is obtained through the steps of esterification reaction and introduction of hydrogen chloride gas. The method utilizes a dynamic kinetic resolution technology to efficiently prepare benazepril hydrochloride, has short steps, simple operation, high total yield, high atom economy and small environmental pollution, and is suitable for industrial production.

Description

Synthesis method of benazepril intermediate and benazepril hydrochloride
Technical Field
The invention relates to a method for synthesizing a benazepril intermediate and benazepril hydrochloride, belonging to the technical field of organic synthesis.
Background
Hypertension is a common disease in modern society. According to statistics, the number of hypertension patients in China reaches 2.7 hundred million, and the market prospect is huge. Angiotensin Converting Enzyme Inhibitor (ACEI) is an important variety of antihypertensive drugs, wherein benazepril is an angiotensin converting enzyme inhibitor which is developed by Ciba-Geigy company of Switzerland and is firstly marketed in 1990, has obvious curative effect on treating hypertension, and has the advantages of less adverse reaction and good safety. Since benazepril was first introduced into the Chinese market in 1994, benazepril has become the first-line drug for the clinical treatment of hypertension in China. It is estimated that in 2006, the market size of benazepril has reached 6.2 billion yuan, and the market of this variety shows a trend of compound growth year by year (annual growth rate 1.2%), while the demand of crude drugs is about 2000 tons per year.
The existing synthetic routes of benazepril hydrochloride raw material medicines can be roughly classified into the following four types:
1. the (R) -ethyl 2-hydroxy-4-phenylbutyrate is prepared by using ethyl 2-oxo-4-phenylbutyrate as a raw material and cinchonidine as a chiral ligand through asymmetric catalytic hydrogenation under high pressure, the intermediate reacts with p-nitrobenzenesulfonyl chloride or trifluoromethanesulfonic anhydride to obtain corresponding sulfonate, and then undergoes nucleophilic substitution and salt hydrolysis with (3S) -3-amino-2, 3,4, 5-tetrahydro-2-oxo-1H-benzazepine-1-tert-butyl acetate to obtain benazepril hydrochloride, as described in documents US4785089, WO02076375, EP206993 and CN 105061312.
2. Benazepril hydrochloride is obtained by using ethyl 2-oxo-4-phenylbutyrate and tert-butyl (3S) -3-amino-2, 34, 5-tetrahydro-2-oxo-1H-benzazepine-1-acetate through reduction ammoniation, recrystallization resolution and hydrolysis to form salt, as described in J.Med.chem.1985,28,1511, US4575503, CN 1844102A.
3. Similar to the method 2, benazepril hydrochloride is obtained by utilizing homophenylalanine ethyl ester and (3S) -3-amino-2, 34, 5-tetrahydro-2-oxo-1H-benzazepine-1-acetic acid tert-butyl ester through reduction ammoniation, recrystallization resolution and hydrolysis to form salt, as described in the document US 4410520.
4. The benazepril hydrochloride is obtained by carrying out Michelal addition, recrystallization resolution and esterification on 4-oxo-4-phenylbutenic acid ethyl ester and (3S) -3-amino-2, 34, 5-tetrahydro-2-oxo-1H-benzazepine-1-acetic acid tert-butyl ester, and finally hydrolyzing into salt, as described in document US 4410520.
The four synthetic routes have the advantages and disadvantages: the preparation method of the route 1 has high synthesis yield, but needs high-pressure catalytic reaction, and uses expensive p-nitrobenzenesulfonyl chloride or trifluoromethanesulfonic anhydride. NaBH used for key reductive amination step in the 2 nd synthetic route3CN is a toxic reagent as a reducing agent; the diastereoisomer ratio obtained is low (95:5), the yield is low (25%), and the marketability is difficult. The raw materials required in route 3 are difficult to obtain and cannot be industrialized. The 4 th route takes Michael addition reaction as a key, and wastes a large amount of the high-cost intermediate (3S) -3-amino-2, 3,4, 5-tetrahydro-2-oxo-1H-benzazepine-1-tert-butyl acetate, and has high cost.
The key intermediate (3S) -3-amino-2, 3,4, 5-tetrahydro-2-oxo-1H-benzazepine, which is used in all three of the above synthetic routes, is mainly prepared by using benzocyclohexanone as a raw material, firstly carrying out Beckman rearrangement to generate a benzazepine intermediate, and then carrying out PCl rearrangement to obtain the benzazepine intermediate (see, for example, U.S. Pat. No. 4,4575503)5/Br2Under the action of (1), the amide is halogenated at α position and then reacts with NaN3Nucleophilic substitution is carried out to generate an azide intermediate, and then the chiral (3S) -3-amino 2,3,4, 5-tetrahydro-2-oxo-1H-benzazepine intermediate is obtained through reduction and resolution. The method for synthesizing the key benzazepine intermediate uses dangerous sodium azide and is not suitable for the requirement of industrial production. In patents GB2103614 and CN1844102, 3-bromo-2, 3,4, 5-tetrahydro-1H-benzazepin-2-one is reacted with phthalimide, followed by hydrolysis and resolution with L-tartaric acid to give (S) -3-amino-2, 3,4, 5-tetrahydro-1H-benzazepin-2-one. The method has poor atom economy, produces a large amount of phthalic acid as a by-product and has high cost. In Chinese patent CN101538242A, 3-bromo-2, 3,4, 5-tetrahydro-1H-benzazepin-2-one reacts with ammonia under the condition of pressurization, and then (S) -3-amino is obtained by resolution-2,3,4, 5-tetrahydro-1H-benzazepin-2-one. In patent GB2103614, an analogous method is adopted, and expensive chiral raw materials are adopted, and after alkylation, carbonyl reduction and Boc (tert-butyloxycarbonyl) removal, (S) -3-amino-2, 3,4, 5-tetrahydro-1H-benzazepin-2-ketone is obtained. The above routes all use resolution, which not only consumes expensive resolution reagents, but also loses half of the substrate, and is not economical and environment-friendly enough. The synthesis route of the key intermediate (3S) -3-amino-2, 34, 5-tetrahydro-2-oxo-1H-benzazepine is as follows:
therefore, the improvement, development and research on the benazepril hydrochloride synthesis technology can find a suitable green chemical process route, and has important economic value and practical requirements.
Disclosure of Invention
The invention solves the technical problems that the synthetic route of benazepril hydrochloride has poor comprehensive effect, for example, one or more technical problems of longer synthetic route, lower yield, higher pollution, higher cost and the like exist.
The technical scheme of the invention is to provide a preparation method of benazepril hydrochloride and an intermediate thereof.
The invention provides a synthesis method of a benazepril intermediate, which takes a compound 18 as a precursor to react with a compound 6, and obtains a compound 19 through a dynamic kinetic resolution process;
wherein compound 18 isCompound 18 includes both the R and S configurations, whereint-Bu represents a tert-butyl group; compound 6 isCompound 19 isThe synthetic route is as follows:
the compound 19 obtained in the above process consists of a mixture of S, S and S, R diastereoisomers. The proportions of the S, S and S, R diastereoisomers depend mainly on the reaction conditions employed, the most influential being the reaction solvent, and there is also a certain relationship with the reaction time, the concentration of compound 18, the temperature and the additives, and there is also a certain influence on the reaction yield.
The reaction time of the above process is preferably 15 to 40 hours, preferably 20 to 30 hours.
The process is further characterized in that the S, S isomer is less soluble and the S, R isomer is more soluble in a suitable solvent, so that the S, S isomer precipitates out, while the S, R isomer remains in solution and can be separated by simple filtration.
The dynamic kinetic resolution is characterized in that: (1) the theoretical yield can reach 100 percent; (2) Ka/Kb >20, Kinv > Ka; (3) the two configurations of the substrate or the product can be mutually converted under the reaction conditions. Based on the principle, the invention finds out the optimal reaction condition for realizing the process through screening a large number of reaction conditions.
Preferably, the reaction is carried out in an organic solvent or water, more preferably in an alcoholic solvent or water, most preferably in isopropanol.
Because the compound 18 contains both R configuration and S configuration, the synthesis of the target product of a single isomer is very difficult, and the synthesis method of the invention can obtain the target product with higher purity without chiral resolution of the compound 18.
Preferably, the reaction temperature is from 25 to 100 ℃, more preferably, the reaction is carried out at from 40 to 90 ℃, most preferably, the reaction is carried out at from 50 to 70 ℃.
Preferably, the molar ratio of compound 18 to compound 6 is 0.5 to 2, more preferably, the molar ratio is 0.9 to 1.2.
Preferably, the reaction is carried out under alkaline conditions, i.e. a base as an additive to the reaction. The base is an organic base, preferably triethylamine; the base is an inorganic base, preferably sodium carbonate. The amount of the base to be added is 0.9 to 2.0 equivalents (generally, compound 18 based on the molar amount of the minor reactants), preferably 1.5 equivalents.
The invention also provides a method for synthesizing benazepril, which comprises the step of carrying out esterification reaction on the compound 19 obtained by the synthesis method and ethanol to obtain a compound 20. Compound 20 is (S, S) -3- [ [1- (ethoxycarbonyl) -3-phenyl-propyl ] -amino ] -1-tert-butoxycarbonylmethyl-2, 3,4, 5-tetrahydro-1H-benzazepin-2-one.
Preferably, the esterification reaction is carried out in the presence of a condensing agent.
The condensing agent is carbonyldiimidazole, thionyl chloride, dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, etc.
The reaction conditions of the reaction can be selected from the methods disclosed in the prior art. The reaction is carried out in an organic solvent, for example selected from aromatic solvents, preferably toluene; halogenated solvents, preferably dichloromethane; esters, preferably ethyl acetate; cyanogen, preferably acetonitrile; ethers, preferably tetrahydrofuran; ketones, preferably acetone and the like (except water, alcohols), at a reaction temperature of-10 to 80 ℃, preferably 0 ℃ to 25 ℃, according to a preferred embodiment of the invention the solvent is isopropyl acetate.
The invention also provides the benazepril intermediate (compound 19) which has the structural formula as follows:
compound 19
The invention also provides a synthesis method of benazepril hydrochloride, which comprises the following steps:
(1) compound 19 was prepared according to the above synthesis;
(2) compound 20 (benazepril) was prepared according to the synthetic method described above;
(3) introducing hydrogen chloride gas into the solution containing the compound 20 to obtain a crude benazepril hydrochloride product, washing the crude benazepril hydrochloride product with a proper amount of isopropyl acetate at the temperature of 10 ℃, and filtering the crude benazepril hydrochloride product to obtain a refined benazepril hydrochloride product.
The detailed synthetic route for benazepril hydrochloride is:
step (3) can be carried out by conventional methods, and the present invention preferably dissolves the crude product from step (2) in isopropyl acetate, bubbles hydrogen chloride gas thereinto at a temperature ranging from-10 to 10 ℃, removes the remaining hydrochloride by conventional methods after precipitation of benazepril hydrochloride is completed, and then washes the product with isopropyl acetate or acetone to obtain benazepril hydrochloride, or benazepril hydrochloride (i.e. compound 1), with diastereomeric purity higher than 99%. In the step (4), recrystallization can be used, or the solvent can be directly used for washing.
The method of the invention has the following beneficial effects: short steps, simple operation, high total yield, high atom economy and little environmental pollution, and is suitable for industrial production.
The core advantage of the present invention is embodied in the first step, 1) preparation of chiral compound 19 from racemic compound 18 using dynamic kinetic resolution technique without the need of other catalysts; 2) the compound 19(S, S) isomer has low solubility in a solvent, is directly precipitated from a reaction system, and can be directly filtered and washed to obtain a product.
Detailed Description
The present invention will be further described with reference to the following examples.
Related study of the Synthesis of Compound 19 (Benazepril intermediate)
Example 1: influence of solvent
100g (0.34mol) of tert-butyl 3-bromo-2, 3,4, 5-tetrahydro-1H- [1] -benzazepin-2-one-1-acetate (Compound 18) and 53g of (S) -homophenylalanine were dissolved in alcohol or water (1.7L), 42g of triethylamine was added thereto, and the mixture was heated to 60 ℃ with stirring to react for 24 hours. The batch was cooled to room temperature, the insoluble material was filtered off and washed with an appropriate amount of alcohol, dried in vacuo, weighed and analyzed by HPLC for the proportion of (S, S)/(S, R) isomer.
As shown in Table 2, better results were obtained with isopropanol as solvent;
TABLE 1 solvent-diastereomer ratio Table
Note: the concentration is as follows: 0.2M (concentration of Compound 18) and a reaction time of 24 hours
Example 2:
100g (0.34mol) of tert-butyl 3-bromo-2, 3,4, 5-tetrahydro-1H- [1] -benzazepin-2-one-1-acetate (Compound 18) and 53g of (S) -homophenylalanine were dissolved in an appropriate amount of isopropanol (3.4L,1.7L,850mL), 42g of triethylamine was added thereto, and the mixture was heated to 60 ℃ with stirring to react for 24 hours. The batch was cooled to room temperature, the insoluble material was filtered off and washed with an appropriate amount of isopropanol, dried in vacuo, weighed and analysed by HPLC for the ratio of (S, S)/(S, R) isomers.
As shown in Table 2, better results were obtained at a concentration of 0.2mol/L of Compound 18;
TABLE 2 reaction concentration-diastereomer ratio Table
Note: the additive was triethylamine (1.2 equivalents) and the reaction time was 24 hours
Example 3:
100g (0.34mol) of tert-butyl 3-bromo-2, 3,4, 5-tetrahydro-1H- [1] -benzazepin-2-one-1-acetate (Compound 18) and 53g of (S) -homophenylalanine were dissolved in an appropriate amount of isopropanol (1.7L), 42g of triethylamine was added thereto, and the mixture was heated to a specific temperature with stirring and reacted for 24 hours. The batch was cooled to room temperature, the insoluble material was filtered off and washed with an appropriate amount of isopropanol, dried in vacuo, weighed and analysed by HPLC for the ratio of (S, S)/(S, R) isomers.
As shown in Table 3, better results were obtained using a reaction temperature of 60 ℃.
TABLE 3 temperature-diastereomer ratio Table
Note: the reaction time was 24 hours
Example 4:
100g (0.34mol) of tert-butyl 3-bromo-2, 3,4, 5-tetrahydro-1H- [1] -benzazepin-2-one-1-acetate (compound 18), and (S) -homophenylalanine were dissolved in an appropriate amount of isopropanol (1.7L), 42g of triethylamine was added thereto, and the mixture was heated to 60 ℃ with stirring to react. The reaction was allowed to cool to room temperature for the appropriate time, the insoluble material was filtered off and washed with an appropriate amount of isopropanol, dried in vacuo, weighed and analyzed by HPLC for the ratio of (S, S)/(S, R) isomers.
As shown in Table 4, better results were obtained at 24 hours of reaction.
TABLE 4 reaction time-diastereomer ratio Table
Example 5:
100g (0.34mol) of 3-bromo-2, 3,4, 5-tetrahydro-1H- [1] -benzazepin-2-one-1-acetic acid tert-butyl ester (compound 18) and a certain amount of (S) -homophenylalanine were dissolved in isopropanol (1.7L), 42g of triethylamine was added thereto, and the mixture was heated to 60 ℃ with stirring to react. The batch was cooled to room temperature, the insoluble material was filtered off and washed with an appropriate amount of isopropanol, dried in vacuo, weighed and analysed by HPLC for the ratio of (S, S)/(S, R) isomers.
As shown in table 4, compound 18: better results were obtained with a 1:1.2 molar ratio of compound 6.
TABLE 4 reactant ratio-diastereomer ratio Table
Note: the reaction time was 24 hours
Synthesis of benazepril hydrochloride
Example 6
100g (0.34mol) of tert-butyl 3-bromo-2, 3,4, 5-tetrahydro-1H- [1] -benzazepin-2-one-1-acetate (18) and 53g of (S) -homophenylalanine were dissolved in isopropanol (1.7L), 42g of triethylamine was added thereto, and the mixture was heated to 60 ℃ with stirring to react for 24 hours. The material was cooled to room temperature, the insoluble material was filtered off and the filter cake was washed with an appropriate amount of isopropanol.
The filter cake from the previous step was dried and suspended in 250mL of isopropyl acetate and carbonyldiimidazole was added and the mixture was stirred at room temperature for 4 hours, then 100mL of ethanol was added. After 4 hours of reaction, the solvent was evaporated, 300mL of isopropyl acetate and 100mL of water were added to the mixture, the phases were separated, the organic phase was washed twice with water, the solvent was evaporated, 100mL of isopropyl acetate was added to the mixture, the mixture was cooled to below 10 ℃, hydrogen chloride gas was introduced until saturation of absorption was achieved, and a solid precipitated. And (4) carrying out suction filtration, and washing a filter cake by using a proper amount of recovered isopropyl acetate. The resulting wet crude was added to 500ml of isopropyl acetate, heated to 75 ℃ and stirred for 4 h. Slowly cooling to about 10 ℃, filtering, and washing a filter cake by using a proper amount of isopropyl acetate. After vacuum drying at 60 ℃, about 99.6g of white benazepril hydrochloride refined product is obtained, and the total yield is 63%. Purity by HPLC was 99.3%.
Example 7
100g (0.34mol) of tert-butyl 3-bromo-2, 3,4, 5-tetrahydro-1H- [1] -benzazepin-2-one-1-acetate (18) and 53g of (S) -homophenylalanine were dissolved in isopropanol (1.7L), 42g of triethylamine was added thereto, and the mixture was heated to 60 ℃ with stirring to react for 24 hours. The material was cooled to room temperature, the insoluble material was filtered off and the filter cake was washed with an appropriate amount of isopropanol.
And drying the filter cake in the previous step, adding the filter cake into 600mL of ethanol (50g) and isopropyl acetate, cooling to below 10 ℃, slowly dropwise adding 100g of thionyl chloride, monitoring by TLC (thin layer chromatography), and recovering isopropyl acetate by normal pressure distillation until the volume of the residual feed liquid is about 500 mL. Cooling to below 10 deg.C, introducing hydrogen chloride gas until absorption saturation, and separating out solid. And (4) carrying out suction filtration, and washing a filter cake by using a proper amount of recovered isopropyl acetate. The resulting wet crude was added to 400ml of acetone, heated to 75 ℃ and stirred for 4 h. Slowly cooling to about 10 ℃, filtering, and washing a filter cake by using a proper amount of acetone. After vacuum drying at 60 ℃, about 82.2g of white benazepril hydrochloride refined product is obtained, and the total yield is 52%. Purity by HPLC 98.5%.

Claims (10)

1. A synthetic method of benazepril intermediate is characterized in that compound 18 and compound 6 are reacted, and compound 19 is obtained through dynamic kinetic resolution process;
wherein compound 18 isCompound 18 includes both the R and S configurations, whereint-Bu represents a tert-butyl group; compound 6 isCompound 19 isThe synthetic route is as follows:
2. the method of claim 1, wherein the reaction is carried out in water or an alcoholic solvent.
3. The method of synthesis according to claim 1, wherein the reaction is carried out in isopropanol.
4. The method of synthesis according to claim 1, wherein the reaction temperature is 25-100 ℃.
5. The method of claim 1, wherein the molar ratio of compound 18 to compound 6 is 0.5 to 2.
6. The method of claim 1, wherein the reaction is carried out under basic conditions.
7. A process for the synthesis of benazepril, characterized by preparing compound 19 according to the synthesis process of any one of claims 1-6, and subjecting compound 19 to esterification with ethanol to obtain benazepril.
8. The benazepril intermediate is characterized by having a structural formula
9. A synthetic method of benazepril hydrochloride is characterized by comprising the following steps:
(1) compound 19 is prepared according to the synthetic method of any one of claims 1-6;
(2) compound 20 prepared according to the synthetic method of claim 7;
(3) and (3) introducing hydrogen chloride gas into the solution containing the compound 20 to obtain a crude benazepril hydrochloride product, washing with isopropyl acetate or acetone, and filtering to obtain a refined benazepril hydrochloride product.
10. The method of claim 1, wherein in step (3), the washing is performed at 5-25 ℃.
CN201810933728.8A 2018-08-16 2018-08-16 Synthesis method of benazepril intermediate and benazepril hydrochloride Pending CN110835319A (en)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
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CN1844102A (en) * 2006-05-19 2006-10-11 大道隆达(北京)医药科技发展有限公司 Process for preparing Benazepril hydrochloride materials
WO2007089745A2 (en) * 2003-07-29 2007-08-09 Signature R & D Holdings, Llc Novel compounds with high therapeutic index
CN101538141A (en) * 2009-04-20 2009-09-23 沈金良 Composite board for fire and smoke exhaust pipe

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001079176A1 (en) * 2000-04-18 2001-10-25 Scinopharm Singapore Pte Ltd Process for preparation of 3-[(1'-(alkoxycarbonyl)-3'-phenylpropyl)amino]-2-oxo-[1]-benzazepine and its derivatives
WO2007089745A2 (en) * 2003-07-29 2007-08-09 Signature R & D Holdings, Llc Novel compounds with high therapeutic index
CN1844102A (en) * 2006-05-19 2006-10-11 大道隆达(北京)医药科技发展有限公司 Process for preparing Benazepril hydrochloride materials
CN101538141A (en) * 2009-04-20 2009-09-23 沈金良 Composite board for fire and smoke exhaust pipe

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KAFSSI HASSAN等: "3-[(1-乙氧羰基-3-苯基丙基)氨基]-2, 3, 4, 5-四氢-2-氧代-1-H-1-苯并氮杂卓-1-乙酸叔丁酯的制备研究", 《化学试剂》 *

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