CN113956201A - Preparation method of benazepril intermediate - Google Patents
Preparation method of benazepril intermediate Download PDFInfo
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- CN113956201A CN113956201A CN202111327557.2A CN202111327557A CN113956201A CN 113956201 A CN113956201 A CN 113956201A CN 202111327557 A CN202111327557 A CN 202111327557A CN 113956201 A CN113956201 A CN 113956201A
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- 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
Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a benazepril intermediate. Aiming at the problems of low yield and low product purity of the benazepril intermediate BTB synthesized by the existing method, the invention provides the preparation method of the benazepril intermediate BTB, which adopts butyrolactone, benzene, aluminum trichloride and hydrochloric acid as raw materials, prepares tetralone TNK firstly, and then prepares the benazepril intermediate BTB refined product through oximation reaction and rearrangement reaction, wherein the raw materials are easy to obtain, the method is simple to operate, the purity of the prepared benazepril intermediate BTB product reaches 99.5%, the yield is more than 90%, and the method is better than the existing method for preparing the benazepril intermediate BTB and is suitable for popularization and use.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a benazepril intermediate.
Background
Hypertension is a common disease in modern society, and with the improvement of living standard, people eat higher and higher oil and fat, and the risk of hypertension is gradually increased. At present, the drugs for treating hypertension are mainly angiotensin converting enzyme inhibitors. And benazepril, chemical name (3s) -3- { [ ((1s) -1-ethoxycarbonyl) -3-phenylpropyl ] amino } -2,3,4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid, melting point 148-. [ α ] D-159 ° (C ═ 1.2, ethanol). The prodrug is rapidly absorbed, is mainly converted into the active metabolite benazeprilat in the liver to play the role of inhibiting angiotensin, and is a hypertension treatment drug with remarkable effect.
Currently, there are many methods for preparing the drug benazepril, and various benazepril intermediates are involved. Wherein, 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepine-2-ketone (BTB for short) is a common benazepril intermediate, the intermediate can react with phthalimide, then is hydrolyzed, and is resolved by L-tartaric acid to obtain (S) -3-amino-2, 3,4, 5-tetrahydro-1H-benzazepine-2-ketone. It can be seen that BTB is particularly important as an intermediate in the preparation of benazepril, both in terms of yield and purity. The existing method for preparing BTB has low yield and low product purity, limits the preparation of benazepril, and urgently needs to develop a BTB preparation method with higher yield and higher purity.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the benazepril intermediate BTB synthesized by the existing method has the problems of low yield and low product purity.
The technical scheme for solving the technical problems comprises the following steps: a preparation method of benazepril intermediate BTB is provided. The method comprises the following steps:
a. butyrolactone, benzene, aluminum trichloride and hydrochloric acid are used as raw materials to prepare tetralone TNK; the mass ratio of butyrolactone, benzene, aluminum trichloride and hydrochloric acid is respectively 1: 9.6: 6: 5;
b. preparing BTB;
adding 1 part of methanol into a bromine diluting kettle, stirring, cooling saline water to 0 ℃, and dropwise adding 1.33 parts of bromine into the kettle to prepare a bromomethanol solution;
adding 5 parts of methanol into a bromination reaction kettle, then adding 1 part of TNK, cooling to 1.5 ℃, and adding 6kg of hydrobromic acid; slowly dropwise adding a bromomethanol solution, keeping the temperature at 1.5 ℃ after 0.03 part of the bromomethanol solution is added, reacting for 40 minutes, slowly adding the bromomethanol solution after the reaction is started, keeping the temperature in the reaction kettle at 0-2 ℃, and finishing adding the bromomethanol solution after 8 hours;
when the materials in the bromination reaction kettle are completely added, and the detection and sampling are qualified, 0.06 part of anhydrous sodium sulfite is added;
controlling the temperature of a bromination reaction kettle to be 15-20 ℃, adding 1.1 parts of hydroxylamine hydrochloride, stirring for two hours, and then dropwise adding 1.3 parts of water within 60 minutes; stirring for 10 hours, slowly dripping 0.67 part of water, finishing the addition for 1 hour, keeping the temperature at 15-20 ℃ after the addition is finished, and stirring for reacting for 24 hours; adding 0.67 percent of water, adding the water for 30 minutes, keeping the temperature at 28-30 ℃ after the water is added, and stirring for reacting for 24 hours; adding 1.3 parts of water for 1 hour, keeping the temperature at 28-30 ℃ after the water is added, and stirring for reacting for 24 hours; then adding 2 parts of water, finishing the addition within 2 hours, and stirring for 5 hours; cooling to 5 ℃, carrying out suction filtration, centrifuging and drying to obtain TNK-Br;
c. b, rearranging the material obtained in the step b, and refining to obtain a BTB fine product;
4.5 parts of polyphosphoric acid is put into the rearrangement kettle, the temperature is raised to 80-90 ℃, 1 part of TNK-Br is slowly added, the temperature is controlled within 80-90 ℃, and the temperature is kept for 6-8 hours after the addition; adding 15 parts of water and 2.5 parts of hydrochloric acid into a hydrolysis kettle, slowly dropwise adding the materials in a rearrangement kettle for 2-3 hours, controlling the temperature within 70 ℃, and continuously stirring for 2 hours after adding; centrifuging and washing with water to obtain a BTB crude product;
and adding 10 parts of 70-90% methanol aqueous solution into a refining kettle, pouring the BTB crude product into the kettle, heating to 60 ℃, preserving heat for 2 hours, and carrying out suction filtration and centrifugation to obtain the BTB fine product.
In the preparation method of the benazepril intermediate BTB, the butyrolactone and the benzene in the step a are in industrial grade of more than 99.0%.
Wherein, in the preparation method of the benazepril intermediate BTB, the hydrochloric acid in the step a is industrial grade hydrochloric acid with the purity of more than 31 percent.
Wherein, in the preparation method of the benazepril intermediate BTB, the specific preparation process in the step a comprises the following steps: (1) mixing benzene and anhydrous aluminum trichloride in a synthesis kettle, stirring for 1-5h, dropwise adding butyrolactone at 15-20 ℃ for 2-6h, and stirring for 1-3h after dropwise adding is completed; heating to reflux, refluxing, keeping the temperature for 3-8h, and cooling to room temperature; (2) adding 15 parts of water and 2.5 parts of hydrochloric acid into a hydrolysis kettle, cooling to 0-5 ℃, starting stirring, and slowly dripping the materials in the synthesis kettle into an ice-out kettle at the temperature of less than or equal to 10 ℃ during ice-out; stirring for 1 hour, stopping stirring, standing for half an hour, and removing the lower water layer; adding 7.5 parts of water, stirring for half an hour, standing for half an hour, and removing a water layer; the benzene layer is washed with 5 parts of water again until the pH value is 6-7; (3) and pumping the benzene layer into a desolventizing kettle, heating to 90-100 ℃, recovering benzene, finally, leaving a concentrated material, transferring the concentrated material into a distillation kettle for high vacuum distillation, collecting fractions at the temperature of 110-120 ℃, and preparing the TNK.
Wherein, in the preparation method of the benazepril intermediate BTB, the adding conditions of the polyphosphoric acid in the step c are as follows: the addition is carried out at a rate of 5kg per minute at a temperature of 50-78 ℃.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a preparation method of a benazepril intermediate 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepine-2-ketone, which comprises the steps of firstly preparing tetralone TNK by using butyrolactone, benzene, aluminum trichloride and hydrochloric acid as raw materials, and then preparing a benazepril intermediate BTB refined product through oximation reaction and rearrangement reaction. The benazepril intermediate BTB refined product prepared by the method has the purity of 99.5 percent and the yield of more than 90 percent, and compared with the existing method, the benazepril intermediate BTB refined product has the advantages that the purity and the yield are greatly improved. Moreover, the method is simple to operate, safe and environment-friendly, is suitable for industrial popularization, and has good economic benefit.
Detailed Description
Specifically, the invention provides a preparation method of a benazepril intermediate BTB, which comprises the following steps:
a. butyrolactone, benzene, aluminum trichloride and hydrochloric acid are used as raw materials to prepare tetralone TNK; the specific preparation process comprises the following steps: (1) mixing 500ml of benzene and 300g of anhydrous aluminum trichloride in a synthesis reactor, stirring for 1-5h, dropwise adding 52g of butyrolactone at the temperature of 15-20 ℃ for 2-6h, and stirring for 1-3h after dropwise adding is finished; heating to reflux, refluxing, keeping the temperature for 3-8h, and cooling to room temperature; (2) adding 1500ml of water and 200g of hydrochloric acid into an ice separation kettle, cooling to 0-5 ℃, starting stirring, and slowly dripping the materials in the synthesis kettle into the ice separation kettle at the ice separation temperature of less than or equal to 10 ℃; stirring for 1 hour, stopping stirring, standing for half an hour, and removing the lower water layer; adding 750ml of water, stirring for half an hour, standing for half an hour, and removing a water layer; the benzene layer is repeatedly washed by 500ml of water until the pH value is 6-7; (3) pumping the benzene layer into a desolventizing kettle, heating to 90-100 ℃, recovering benzene, finally, leaving a concentrated material, transferring the concentrated material into a distillation kettle for high vacuum distillation, collecting fractions at the temperature of 110-120 ℃, and preparing to obtain TNK;
in the step a, the butyrolactone and the benzene are industrial grade hydrochloric acid with the purity of more than 31 percent, and the hydrochloric acid is industrial grade hydrochloric acid with the purity of more than 99.0 percent.
Specifically, the chemical reaction equation in step a is as follows:
b. preparing BTB;
adding 150g of methanol into a synthesis reactor, stirring, cooling saline water to 0 ℃, and dropwise adding 200g of bromine into the reactor to prepare a bromomethanol solution;
adding 750g of methanol into a bromination reactor, then adding 142g of TNK, cooling to 1.5 ℃, and adding 3g of hydrobromic acid; slowly dropwise adding a bromomethanol solution, keeping the temperature at 1.5 ℃ after adding 5g of the bromomethanol solution, reacting for 40 minutes, slowly adding the bromomethanol solution after the reaction is started, keeping the temperature in the reaction kettle at 0-2 ℃, and finishing adding the bromomethanol solution after 8 hours;
when the materials in the bromination reactor are completely added, 10g of anhydrous sodium sulfite is added after the materials are detected and sampled to be qualified;
controlling the temperature of a bromination reaction kettle to be 15-20 ℃, adding 165g of hydroxylamine hydrochloride, stirring for two hours, and then dropwise adding 200g of water within 60 minutes; stirring for 10 hours, slowly dripping 100g of water, finishing the addition for 1 hour, keeping the temperature at 15-20 ℃, and stirring for reaction for 24 hours; adding 100g of water, finishing the addition in 30 minutes, keeping the temperature at 28-30 ℃ after the addition, and stirring for reacting for 24 hours; adding 200g of water, finishing the addition for 1 hour, keeping the temperature at 28-30 ℃ after the addition is finished, and stirring for reacting for 24 hours; adding 300g of water, finishing the addition within 2 hours, and stirring for 5 hours; cooling to 5 ℃, filtering, centrifuging and drying;
specifically, the chemical reaction equation in step b is:
c. b, rearranging the material obtained in the step b, and refining to obtain a BTB fine product;
under the condition of 50-78 ℃, 450g of polyphosphoric acid is put into the rearrangement kettle at the speed of 2.5g per minute, the temperature is increased to 80-90 ℃, 100g of TNK-Br is slowly added, the temperature is controlled within 80-90 ℃, and the temperature is kept for 6-8 hours after the addition; adding 1500ml of water into the hydrolysis kettle, slowly dropwise adding the materials in the rearrangement kettle for 2-3 hours, controlling the temperature within 70 ℃, and continuing stirring for 2 hours after adding; centrifuging and washing with water to obtain a BTB crude product;
and adding 1000ml of 70-90% methanol aqueous solution into a refining kettle, pouring the BTB crude product into the kettle, heating to 60 ℃, preserving heat for 2 hours, and carrying out suction filtration and centrifugation to obtain the BTB fine product.
Specifically, the chemical reaction equation in step c is:
the invention provides a new preparation method for benazepril intermediate BTB, butyrolactone, benzene, aluminum trichloride and hydrochloric acid are used as raw materials, tetralone TNK is prepared firstly, then benazepril intermediate BTB refined product is prepared through oximation reaction and rearrangement reaction, the raw materials are easy to obtain, the method is simple to operate, the purity of the prepared benazepril intermediate BTB product reaches 99.5%, the yield is more than 90%, and the method is better than the existing method for preparing benazepril intermediate BTB and has obvious progress.
Specifically, in the step a, benzene and anhydrous aluminum trichloride are mixed, the temperature is controlled to be 10-20 ℃, then gamma-butyrolactone is dripped for about 1-4 hours, then the temperature is increased to 80 ℃ in a gradient manner after being increased to 40 ℃ and 50 ℃ for half an hour, and the temperature is maintained and refluxed for 5-10 hours. The slow dripping can control the reaction speed, the reaction is very violent when the dripping is too fast, side reactions are more, the yield is very low, the process of slow temperature rise is also used for fully dissolving materials, the reaction speed is controlled, and the conversion rate and the selectivity of products are improved. By adopting the reaction method of the invention, the yield can be improved.
Specifically, in the step b, 1-10 g of hydrogen bromide is added besides the alpha-tetralone and the methanol, and the hydrogen bromide is used as an initiator of the bromination reaction, so that the bromination reaction is started more quickly. In addition, the invention adopts the hydroxylamine hydrochloride, the market supply amount of the hydroxylamine hydrochloride is large, the price is low, the reaction is mild, and the reaction of the hydroxylamine sulfate can release heat, so the yield can be further improved by adopting the hydroxylamine hydrochloride.
In addition, in the step b, the invention also adopts a mode of adding water in batches in a time period. The main reasons for adding water in batches at different time intervals are: if water is added at one time, the reaction speed is reduced and more impurities are generated due to low material concentration, and the direct result is that the conversion rate and the yield of the materials are lower. In order to further improve the conversion rate and the yield, a sectional water adding mode is finally determined through a large number of experiments, the method can keep the concentration of the materials within a reasonable range in the reaction process of the materials at different time periods, the materials are promoted to react orderly, the reaction time is short, the impurities are few, and the conversion rate and the yield are high.
The following examples are intended to illustrate specific embodiments of the present invention without limiting the scope of the invention to the examples.
Example 1 preparation of a BTB Fine product by the method of the present invention
The specific operation steps are as follows:
a. butyrolactone, benzene, aluminum trichloride and hydrochloric acid are used as raw materials to prepare tetralone TNK; the specific preparation process comprises the following steps: (1) mixing 500ml of benzene and 300g of anhydrous aluminum trichloride in a synthesis kettle, stirring for 1h, dropwise adding 52g of butyrolactone, wherein the dropwise adding temperature is 15 ℃, the dropwise adding time is 2h, and stirring for 1h after the dropwise adding is finished; heating to reflux, refluxing, keeping the temperature for 3h, and cooling to room temperature; (2) adding 1500ml of water and 250g of hydrochloric acid into an ice separation kettle, cooling to 0 ℃, starting stirring, and slowly dripping the materials in the synthesis kettle into the ice separation kettle at the ice separation temperature of less than or equal to 10 ℃; stirring for 1 hour, stopping stirring, standing for half an hour, and removing the lower water layer; adding 750ml of water, stirring for half an hour, standing for half an hour, and removing a water layer; the benzene layer is repeatedly washed by 500ml of water until the pH value is 6-7; (3) pumping the benzene layer into a desolventizing kettle, heating to 90 ℃, recovering benzene, finally, leaving a concentrated material, transferring the concentrated material into a distillation kettle for high vacuum distillation, collecting fractions at 110 ℃, and preparing to obtain TNK;
b. preparing BTB;
adding 150g of methanol into a bromine diluting kettle, stirring, cooling saline water to 0 ℃, and dropwise adding 200g of bromine into the kettle to prepare a bromomethanol solution;
adding 750g of methanol into a bromination reaction kettle, then adding 142g of TNK, cooling to 1.5 ℃, and adding 3g of hydrobromic acid; slowly dropwise adding a bromomethanol solution, keeping the temperature at 1.5 ℃ after adding 5g of the bromomethanol solution, reacting for 40 minutes, slowly adding the bromomethanol solution after the reaction is started, keeping the temperature in the reaction kettle at 0 ℃, and finishing adding the bromomethanol solution after 8 hours;
when the materials in the bromination reaction kettle are completely added, 10g of anhydrous sodium sulfite is added after the detection and sampling are qualified;
controlling the temperature of a bromination reaction kettle to be 15 ℃, adding 165g of hydroxylamine hydrochloride, stirring for two hours, and then dropwise adding 200g of water within 60 minutes; stirring for 10 hours, slowly dropwise adding 100g of water, finishing the adding for 1 hour, keeping the temperature at 15 ℃ after the adding is finished, and stirring for reacting for 24 hours; adding 100g of water, finishing the addition in 30 minutes, keeping the temperature at 28 ℃ after the addition is finished, and stirring for reacting for 24 hours; adding 200g of water, finishing the addition for 1 hour, keeping the temperature at 28 ℃ after the addition is finished, and stirring for reacting for 24 hours; adding 300g of water, finishing the addition within 2 hours, and stirring for 5 hours; cooling to 5 ℃, filtering, centrifuging and drying;
c. rearranging the material obtained in the step b to obtain a BTB fine product;
at the temperature of 50 ℃, 450g of polyphosphoric acid is put into a rearrangement kettle at the speed of 2.5g per minute, the temperature is raised to 80 ℃, 100g of TNK-Br is slowly added, the temperature is controlled within 80 ℃, and the temperature is kept for 6 hours after the addition; adding 1500ml of water into the hydrolysis kettle, slowly dropwise adding the materials in the rearrangement kettle for 2 hours, controlling the temperature within 70 ℃, and continuing stirring for 2 hours after adding; centrifuging and washing with water to obtain a BTB crude product;
adding 1000ml of 70% methanol aqueous solution into a refining kettle, pouring the BTB crude product into the kettle, heating to 60 ℃, preserving the temperature for 2 hours, and carrying out suction filtration and centrifugation to obtain the BTB fine product.
The purity of the BTB refined product prepared in example 1 was 99.72%, the yield was 92%, and the impurity content was less than 0.03%.
Example 2 preparation of a BTB Fine product by the method of the present invention
The specific operation steps are as follows:
a. butyrolactone, benzene, aluminum trichloride and hydrochloric acid are used as raw materials to prepare tetralone TNK; the specific preparation process comprises the following steps: (1) mixing 500ml of benzene and 300g of anhydrous aluminum trichloride in a synthesis kettle, stirring for 5 hours, dropwise adding 52g of butyrolactone, wherein the dropwise adding temperature is 20 ℃, the dropwise adding time is 6 hours, and stirring for 3 hours after the dropwise adding is finished; heating to reflux, refluxing, keeping the temperature for 8h, and cooling to room temperature; (2) adding 1500ml of water and 250g of hydrochloric acid into an ice separation kettle, cooling to 5 ℃, starting stirring, and slowly dripping the materials in the synthesis kettle into the ice separation kettle at the ice separation temperature of less than or equal to 10 ℃; stirring for 1 hour, stopping stirring, standing for half an hour, and removing the lower water layer; adding 750ml of water, stirring for half an hour, standing for half an hour, and removing a water layer; the benzene layer is repeatedly washed by 500ml of water until the pH value is 6-7; (3) pumping the benzene layer into a desolventizing kettle, heating to 100 ℃, recovering benzene, finally, leaving a concentrated material, transferring the concentrated material into a distillation kettle for high vacuum distillation, collecting fractions at 120 ℃, and preparing to obtain TNK;
b. preparing BTB;
adding 150g of methanol into a bromine diluting kettle, stirring, cooling saline water to 0 ℃, and dropwise adding 200g of bromine into the kettle to prepare a bromomethanol solution;
adding 750g of methanol into a bromination reaction kettle, then adding 142g of TNK, cooling to 1.5 ℃, and adding 3g of hydrobromic acid; slowly dropwise adding a bromomethanol solution, keeping the temperature at 1.5 ℃ after adding 5g of the bromomethanol solution, reacting for 40 minutes, slowly adding the bromomethanol solution after the reaction is started, keeping the temperature in the reaction kettle at 2 ℃, and finishing adding the bromomethanol solution after 8 hours;
when the materials in the bromination reaction kettle are completely added, 10g of anhydrous sodium sulfite is added after the detection and sampling are qualified;
controlling the temperature of a bromination reaction kettle to be 20 ℃, adding 165g of hydroxylamine hydrochloride, stirring for two hours, and then dropwise adding 200g of water within 60 minutes; stirring for 10 hours, slowly dropwise adding 100g of water, finishing the adding for 1 hour, keeping the temperature at 20 ℃ after the adding is finished, and stirring for reacting for 24 hours; adding 100g of water, finishing the addition in 30 minutes, keeping the temperature at 30 ℃ after the addition is finished, and stirring for reacting for 24 hours; adding 200g of water, finishing the addition for 1 hour, keeping the temperature at 30 ℃ after the addition is finished, and stirring for reacting for 24 hours; adding 300g of water, finishing the addition within 2 hours, and stirring for 5 hours; cooling to 5 ℃, filtering, centrifuging and drying;
c. rearranging the material obtained in the step b to obtain a BTB fine product;
at 78 ℃, adding 450g of polyphosphoric acid into the rearrangement kettle at the speed of 2.5g per minute, heating to 90 ℃, slowly adding 100g of TNK-Br, controlling the temperature within 90 ℃, and preserving heat for 8 hours after the addition; adding 1500ml of water into the hydrolysis kettle, slowly dropwise adding the materials in the rearrangement kettle, finishing the adding within 3 hours, controlling the temperature within 70 ℃, and continuing to stir for 2 hours after finishing the adding; centrifuging and washing with water to obtain a BTB crude product;
adding 1000ml of 90% methanol aqueous solution into a refining kettle, pouring the BTB crude product into the kettle, heating to 60 ℃, preserving the temperature for 2 hours, and carrying out suction filtration and centrifugation to obtain the BTB fine product.
The purity of the BTB refined product prepared in example 2 was 99.75%, the yield was 93%, and the impurity content was less than 0.03%.
Example 3 preparation of a BTB Fine product by the method of the present invention
The specific operation steps are as follows:
a. butyrolactone, benzene, aluminum trichloride and hydrochloric acid are used as raw materials to prepare tetralone TNK; the specific preparation process comprises the following steps: (1) mixing 500ml of benzene and 300g of anhydrous aluminum trichloride in a synthesis kettle, stirring for 3 hours, dropwise adding 52g of butyrolactone, wherein the dropwise adding temperature is 18 ℃, the dropwise adding time is 5 hours, and stirring for 2 hours after the dropwise adding is finished; heating to reflux, refluxing, keeping the temperature for 5h, and cooling to room temperature; (2) adding 1500ml of water and 250g of hydrochloric acid into an ice separation kettle, cooling to 3 ℃, starting stirring, and slowly dripping the materials in the synthesis kettle into the ice separation kettle at the ice separation temperature of less than or equal to 10 ℃; stirring for 1 hour, stopping stirring, standing for half an hour, and removing the lower water layer; adding 750ml of water, stirring for half an hour, standing for half an hour, and removing a water layer; the benzene layer is repeatedly washed by 500ml of water until the pH value is 6-7; (3) pumping the benzene layer into a desolventizing kettle, heating to 95 ℃ to recover benzene, finally, leaving a concentrated material, transferring the concentrated material into a distillation kettle for high vacuum distillation, collecting 115 ℃ fractions, and preparing to obtain TNK;
b. preparing BTB;
adding 150g of methanol into a bromine diluting kettle, stirring, cooling saline water to 0 ℃, and dropwise adding 200g of bromine into the kettle to prepare a bromomethanol solution;
adding 750g of methanol into a bromination reaction kettle, then adding 142g of TNK, cooling to 1.5 ℃, and adding 3g of hydrobromic acid; slowly dropwise adding a bromomethanol solution, keeping the temperature at 1.5 ℃ after adding 5g of the bromomethanol solution, reacting for 40 minutes, slowly adding the bromomethanol solution after the reaction is started, keeping the temperature in the reaction kettle at 1 ℃, and finishing adding the bromomethanol solution after 8 hours;
when the materials in the bromination reaction kettle are completely added, 10g of anhydrous sodium sulfite is added after the detection and sampling are qualified;
controlling the temperature of a bromination reaction kettle to be 18 ℃, adding 165g of hydroxylamine hydrochloride, stirring for two hours, and then dropwise adding 200g of water within 60 minutes; stirring for 10 hours, slowly dropwise adding 100g of water, finishing the adding for 1 hour, keeping the temperature at 18 ℃ after the adding is finished, and stirring for reacting for 24 hours; adding 100g of water, finishing the addition in 30 minutes, keeping the temperature at 29 ℃ after the addition is finished, and stirring for reacting for 24 hours; adding 200g of water, finishing the addition for 1 hour, keeping the temperature at 29 ℃ after the addition is finished, and stirring for reacting for 24 hours; adding 300g of water, finishing the addition within 2 hours, and stirring for 5 hours; cooling to 5 ℃, filtering, centrifuging and drying;
c. rearranging the material obtained in the step b to obtain a BTB fine product;
at the temperature of 60 ℃, 450g of polyphosphoric acid is put into a rearrangement kettle at the speed of 5kg per minute, the temperature is raised to 85 ℃, 100g of TNK-Br is slowly added, the temperature is controlled within 85 ℃, and the temperature is kept for 7 hours after the addition; adding 1500ml of water into the hydrolysis kettle, slowly dropwise adding the materials in the rearrangement kettle, finishing the adding within 3 hours, controlling the temperature within 70 ℃, and continuing to stir for 2 hours after finishing the adding; centrifuging and washing with water to obtain a BTB crude product;
adding 1000ml of 80% methanol aqueous solution into a refining kettle, pouring the BTB crude product into the kettle, heating to 60 ℃, preserving the temperature for 2 hours, and carrying out suction filtration and centrifugation to obtain the BTB fine product.
The purity of the BTB refined product prepared in example 3 was 99.78%, the yield was 92%, and the impurity content was less than 0.03%.
Claims (5)
1. The preparation method of the benazepril intermediate BTB is characterized by comprising the following steps:
a. butyrolactone, benzene, aluminum trichloride and hydrochloric acid are used as raw materials to prepare tetralone TNK; the mass ratio of butyrolactone, benzene, aluminum trichloride and hydrochloric acid is respectively 1: 9.6: 6: 5;
b. preparing BTB;
adding 1 part of methanol into a bromine diluting kettle, stirring, cooling saline water to 0 ℃, and dropwise adding 1.33 parts of bromine into the kettle to prepare a bromomethanol solution;
adding 5 parts of methanol into a bromination reaction kettle, then adding 1 part of TNK, cooling to 1.5 ℃, and adding 6kg of hydrobromic acid; slowly dropwise adding a bromomethanol solution, keeping the temperature at 1.5 ℃ after 0.03 part of the bromomethanol solution is added, reacting for 40 minutes, slowly adding the bromomethanol solution after the reaction is started, keeping the temperature in the reaction kettle at 0-2 ℃, and finishing adding the bromomethanol solution after 8 hours;
when the materials in the bromination reaction kettle are completely added, and the detection and sampling are qualified, 0.06 part of anhydrous sodium sulfite is added;
controlling the temperature of a bromination reaction kettle to be 15-20 ℃, adding 1.1 parts of hydroxylamine hydrochloride, stirring for two hours, and then dropwise adding 1.3 parts of water within 60 minutes; stirring for 10 hours, slowly dripping 0.67 part of water, finishing the addition for 1 hour, keeping the temperature at 15-20 ℃ after the addition is finished, and stirring for reacting for 24 hours; adding 0.67 percent of water, adding the water for 30 minutes, keeping the temperature at 28-30 ℃ after the water is added, and stirring for reacting for 24 hours; adding 1.3 parts of water for 1 hour, keeping the temperature at 28-30 ℃ after the water is added, and stirring for reacting for 24 hours; then adding 2 parts of water, finishing the addition within 2 hours, and stirring for 5 hours; cooling to 5 ℃, carrying out suction filtration, centrifuging and drying to obtain TNK-Br;
c. b, rearranging the material obtained in the step b, and refining to obtain a BTB fine product;
4.5 parts of polyphosphoric acid is put into the rearrangement kettle, the temperature is raised to 80-90 ℃, 1 part of TNK-Br is slowly added, the temperature is controlled within 80-90 ℃, and the temperature is kept for 6-8 hours after the addition; adding 15 parts of water and 2.5 parts of hydrochloric acid into a hydrolysis kettle, slowly dropwise adding the materials in a rearrangement kettle for 2-3 hours, controlling the temperature within 70 ℃, and continuously stirring for 2 hours after adding; centrifuging and washing with water to obtain a BTB crude product;
and adding 10 parts of 70-90% methanol aqueous solution into a refining kettle, pouring the BTB crude product into the kettle, heating to 60 ℃, preserving heat for 2 hours, and carrying out suction filtration and centrifugation to obtain the BTB fine product.
2. A process for the preparation of benazepril intermediate BTB according to claim 1, characterized in that: the butyrolactone and benzene described in step a are of technical grade > 99.0%.
3. A process for the preparation of benazepril intermediate BTB according to claim 1, characterized in that: the hydrochloric acid in the step a is industrial grade hydrochloric acid with the purity of more than 31 percent.
4. A process for the preparation of benazepril intermediate BTB according to claim 1, characterized in that: the specific preparation process of the step a comprises the following steps: (1) mixing benzene and anhydrous aluminum trichloride in a synthesis kettle, stirring for 1-5h, dropwise adding butyrolactone at 15-20 ℃ for 2-6h, and stirring for 1-3h after dropwise adding is completed; heating to reflux, refluxing, keeping the temperature for 3-8h, and cooling to room temperature; (2) adding 15 parts of water and 2.5 parts of hydrochloric acid into an ice separation kettle, cooling to 0-5 ℃, starting stirring, and slowly dripping the materials in the synthesis kettle into the ice separation kettle at the temperature of less than or equal to 10 ℃ during ice separation; stirring for 1 hour, stopping stirring, standing for half an hour, and removing the lower water layer; adding 7.5 parts of water, stirring for half an hour, standing for half an hour, and removing a water layer; the benzene layer is washed by 5 parts of water again until the PH value is 6-7; (3) and pumping the benzene layer into a desolventizing kettle, heating to 90-100 ℃, recovering benzene, finally, leaving a concentrated material, transferring the concentrated material into a distillation kettle for high vacuum distillation, collecting fractions at the temperature of 110-120 ℃, and preparing the TNK.
5. A process for the preparation of benazepril intermediate BTB according to claim 1, characterized in that: the adding conditions of the polyphosphoric acid in the step c are as follows: the addition is carried out at a rate of 5kg per minute at a temperature of 50-78 ℃.
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