CN115974835A - Synthesis method of key intermediate of remimazolam - Google Patents

Synthesis method of key intermediate of remimazolam Download PDF

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Publication number
CN115974835A
CN115974835A CN202211627789.4A CN202211627789A CN115974835A CN 115974835 A CN115974835 A CN 115974835A CN 202211627789 A CN202211627789 A CN 202211627789A CN 115974835 A CN115974835 A CN 115974835A
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compound
reaction solvent
reaction
key intermediate
stirring
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沈鑫
鲁光英
周跃辉
罗志希
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Hunan Furui Biomedical Technology Co ltd
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Hunan Furui Biomedical Technology Co ltd
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    • 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

Abstract

The invention provides a synthesis method of a remazolam key intermediate, which is a preparation method of a remazolam Malun, wherein 2- (2-amino-5-bromo-benzoyl) pyridine is used as a raw material to synthesize bromazepam, then protect amide of the bromazepam, then a protected remazol Malun intermediate is obtained by carrying out asymmetric Michael addition reaction with methyl acrylate, and finally a protecting group is removed to obtain the key intermediate.

Description

Synthesis method of key intermediate of remimazolam
Technical Field
The invention relates to the technical field of organic matter synthesis pharmacy, in particular to a method for synthesizing a key intermediate of remimazolam.
Background
The benzenesulfonic acid Rui Ma Lun is officially approved to be marketed in 7 months in 2020 and is used for the fields of painless diagnosis and treatment sedation, general anesthesia, ICU sedation and local anesthesia sedation, etc., rui Malun is a novel ultrashort-effective benzodiazepine anesthetic, and has the characteristics of predictable sedation time and rapid recovery in painless gastrointestinal endoscopy, and the compound 5 is an important intermediate synthesized by Rui Malun, and the structural formula of the compound 5 is as follows:
Figure BDA0004004410220000011
in the prior art, international patents WO0069836 and WO2013029431 take 2- (2-amino-5-bromobenzoyl) pyridine as a starting material, and react with Fmoc-protected glutamic acid, then Fmoc is removed, and finally ring closure is carried out.
Figure BDA0004004410220000012
International patent WO2011032692 also starts from 2- (2-amino-5-bromobenzoyl) pyridine by reaction with Boc-protected glutamic acid, followed by removal of Boc and final ring closure.
Figure BDA0004004410220000021
Chinese patent CN114014839 also uses 2- (2-amino-5-bromobenzoyl) pyridine as starting material, and reacts with trityl protected glutamic acid, then trityl is removed, and finally ring closure is carried out.
Figure BDA0004004410220000022
However, the above patents have the following disadvantages: the total yield is not high, the purity of the product is low, the international patent WO2019/72944 is synthesized by taking Cbz as a protecting group, and although the reported product purity is 99%, no manual data exists; the synthesis difficulty of the starting material, namely trityl protected glutamic acid, in Chinese patent CN114014839 is high, and repeated experiments on Chinese patent CN114014839 show that the chirality is only 96.5%, although the chiral purity can be improved by crystallization and other methods in the later period, the yield is undoubtedly reduced. .
Disclosure of Invention
In view of the above-mentioned drawbacks and problems of the prior art, the present invention provides a method for synthesizing a key intermediate of remimazolam.
In order to achieve the purpose, the invention provides the following technical scheme:
a synthetic method of a key intermediate of remimazolam comprises the following synthetic route:
Figure BDA0004004410220000031
the method comprises the following steps:
step one, mixing a compound 1: condensing 2- (2-amino-5-bromo-benzoyl) pyridine and glycine to obtain a compound 2, namely adding the compound 1 and the glycine into a reaction solvent, adding a condensing agent for condensation, distilling the reaction solvent under reduced pressure, adding the reaction solvent for redissolution, extracting with saturated salt water, and drying to obtain the compound 2, wherein the reaction solvent comprises one of anhydrous tetrahydrofuran, dichloromethane or ethyl acetate;
step two, protecting Boc on the N group to obtain a compound 3: adding a compound 2 into a reaction solvent, adding dimethyl pyridine and alkali, stirring uniformly, adding BOC-acetic anhydride, stirring at 15-35 ℃ until the reaction is complete, adding water for washing to be neutral, concentrating to be small in volume, cooling and crystallizing to obtain a compound 3; the reaction solvent is: dichloromethane; the alkali is: sodium hydroxide and triethylamine, wherein the addition amount of the alkali is 0-2% of that of the compound 2;
step three, carrying out addition reaction on the compound 3 and methyl acrylate to obtain a compound 4: adding a compound 3 into a reaction solvent, cooling, adding chiral laburnine and lithium diisopropylamide, stirring for 2-4h, adding methyl acrylate, slowly heating to room temperature, adding water and ethyl acetate for extraction after complete reaction, concentrating to a small volume, crystallizing, and drying to obtain a compound 4; the reaction solvent is: anhydrous tetrahydrofuran, dichloromethane;
step four, removing Boc protection from the compound 4 to obtain a compound 5: adding a compound 4 into a reaction solvent, adding hydrochloric acid, cooling to 15-25 ℃, stirring until the reaction is complete, adding a saturated sodium bicarbonate aqueous solution, adjusting the pH value to be neutral, concentrating to a small volume, crystallizing, and drying to obtain a compound 5, wherein the reaction solvent is as follows: acetone, methanol, ethanol.
In the above technical solution, in the first step, the condensing agent includes concentrated sulfuric acid or concentrated sulfuric acid treatment is performed before one or more of HBTU, TBTU, and HOBT is performed.
In the technical scheme, in the second step, the reaction solvent is methanol and ethanol, namely, the compound 2 is added into the reaction solvent, diluted hydrochloric acid is added to adjust the reaction solvent to be neutral, the reaction solvent is concentrated to be dry, ethyl acetate is added to redissolve the reaction solvent, the reaction solvent is concentrated to be small in volume, and the reaction solvent is cooled and crystallized to obtain a compound 3;
in the above technical scheme, in the third step, the compound 3: chiral cytisine =1:0.3-0.8; the compound 3: lithium diisopropylamide =1:0.8-1.5; the compound 3: methyl acrylate =0.1-0.4.
In the above technical scheme, in the fourth step, the compound 4: hydrochloric acid =0.05-0.3.
The invention takes 2- (2-amino-5-bromo-benzoyl) pyridine as a raw material to synthesize bromazepam, protect the amide of the bromazepam, then carry out asymmetric Michael addition reaction with methyl acrylate to obtain a protected Rui Malun intermediate, and finally remove a protecting group to obtain a key intermediate, so that the preparation method of Rui Malun is simple, convenient and stable to operate, easy to separate products in each step, high in yield, environment-friendly and suitable for industrial large-scale production.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The synthetic route of the invention is as follows:
Figure BDA0004004410220000051
according to the technical scheme, 2- (2-amino-5-bromo-benzoyl) pyridine (compound 1) and glycine are condensed to obtain a compound 2. And then the N group is protected by Boc to obtain a compound 3, and the compound 3 is subjected to addition reaction with methyl acrylate to obtain a compound 4, and then the Boc protection is removed to obtain a compound 5.
The method comprises the following specific steps:
step one, mixing a compound 1: condensing 2- (2-amino-5-bromo-benzoyl) pyridine and glycine to obtain a compound 2, namely adding the compound 1 and the glycine into a reaction solvent, adding a condensing agent for condensation, distilling the reaction solvent under reduced pressure, adding the reaction solvent for redissolution, extracting with saturated salt water, and drying to obtain the compound 2, wherein the reaction solvent comprises one of anhydrous tetrahydrofuran, dichloromethane or ethyl acetate; the condensing agent comprises concentrated sulfuric acid or one or more of HBTU, TBTU and HOBT after concentrated sulfuric acid treatment. The reaction avoids glycine condensation under the protection of Boc in the prior art, reduces reaction steps, improves reaction yield and reduces the generation of impurities.
Step two, protecting Boc on the N group to obtain a compound 3: when the reaction solvent is dichloromethane, adding the compound 2, dimethyl pyridine and alkali into the reaction solvent, stirring uniformly, adding BOC-acetic anhydride, stirring at 15-35 ℃ until the reaction is complete, adding water to wash the mixture to be neutral, concentrating the mixture to be small in volume, and cooling and crystallizing the mixture to obtain a compound 3; the alkali is: sodium hydroxide and triethylamine, wherein the addition amount of the alkali is 0-2% of that of the compound 2;
when the reaction solvent in the second step is changed into methanol or ethanol, adding a compound 2 into the reaction solvent, adding diluted hydrochloric acid to adjust to be neutral, concentrating to be dry, adding ethyl acetate to redissolve, concentrating to be small in volume, cooling and crystallizing to obtain a compound 3;
step three, carrying out addition reaction on the compound 3 and methyl acrylate to obtain a compound 4: adding a compound 3 into a reaction solvent, cooling, adding chiral laburnine and lithium diisopropylamide, stirring for 2-4h, adding methyl acrylate, slowly heating to room temperature, adding water and ethyl acetate for extraction after the reaction is completed, concentrating to a small volume, crystallizing, and drying to obtain a compound 4; the reaction solvent is: anhydrous tetrahydrofuran, dichloromethane; the compound 3: chiral cytisine =1:0.3-0.8; the compound 3: lithium diisopropylamide =1:0.8-1.5; the compound 3: methyl acrylate =0.1-0.4.
Step four, removing Boc protection from the compound 4 to obtain a compound 5: adding a compound 4 into a reaction solvent, adding hydrochloric acid, cooling to 15-25 ℃, stirring until the reaction is complete, adding a saturated sodium bicarbonate aqueous solution, adjusting the pH value to be neutral, concentrating to a small volume, crystallizing, and drying to obtain a compound 5, wherein the reaction solvent is as follows: acetone, methanol, ethanol.
The specific implementation case is as follows:
example 1:
adding 500ml of anhydrous tetrahydrofuran, 46.7g of compound 1 and 37.1g of glycine into a reaction kettle, adding 3.6g of concentrated sulfuric acid, cooling to 0 ℃, stirring for 30min, heating to 20 ℃, adding 4g of TBTU, continuously stirring for 5h, heating to reflux for 30min, concentrating under reduced pressure to a small volume, adding dichloromethane for dissolving, washing with 300ml of saturated saline solution for three times, drying with 300g of anhydrous magnesium sulfate overnight, concentrating to a small volume, and crystallizing to obtain 31.6g of compound 2.
Adding 31.6g of compound 2 and 12.2g of lutidine into a reaction kettle, dissolving with 500g of dichloromethane, adding triethylamine to adjust the pH value to 8.5, slowly dropwise adding 100 ml of dichloromethane solution of 21.8g of Boc-anhydride at 20-25 ℃, stirring until the HPLC detection compound 2 completely reacts, adding purified water to wash, drying and concentrating to obtain 3.5 g of compound.
Adding 40.5g of the compound 3 into a reaction kettle, adding 500g of anhydrous tetrahydrofuran, cooling to minus 78 ℃, dropwise adding 19g of chiral laburnine and 70g of lithium diisopropylamide, stirring for 2-4 hours at the temperature, then slowly dropwise adding 8.6g of methyl acrylate, and slowly heating to room temperature within 6-8 hours after the addition is finished. After the HPLC detection reaction, purified water was added, extracted with ethyl acetate, concentrated to a small volume, crystallized and dried to obtain 42.1g of Boc protected compound 4.
Adding 42.1g of compound 4 and 500g of acetone into a reaction kettle, dropwise adding 50ml of 6N hydrochloric acid, stirring at 20-25 ℃ until HPLC shows that the raw materials disappear, slowly adding a saturated sodium bicarbonate aqueous solution, adjusting the pH value to be neutral, concentrating, precipitating a large amount of solid, filtering, washing with purified water, and drying to obtain 32.2g of compound 5.
Example 2:
adding 500g of dichloromethane, 46.7g of compound 1 and 37.1g of glycine into a reaction kettle, adding 4.3g of concentrated sulfuric acid, cooling to 5 ℃, stirring for 30min, heating to 20 ℃, keeping the temperature and stirring for 5h, heating to reflux for 30min, concentrating under reduced pressure to a small volume, adding dichloromethane for dissolving, washing with 300ml of saturated saline solution for three times, drying with 300g of anhydrous magnesium sulfate to be overnight, concentrating to a small volume, and crystallizing to obtain 29.7g of compound 2.
Adding 29.7g of compound 2g and 11.6g of lutidine into a reaction kettle, dissolving with 500g of methanol, adding triethylamine to adjust the pH value to 8.5, slowly dropwise adding 100 ml of methanol solution of 20.6g of Boc-anhydride at 20-25 ℃, and stirring until the compound 2 is completely reacted by HPLC detection after the addition is finished. And (3) adding diluted hydrochloric acid to adjust the pH value to be neutral, concentrating to a small volume, adding 300g of ethyl acetate to redissolve, concentrating to a small volume, stirring for crystallization, and drying to obtain 36.8g of a compound 3.
Adding 36.8g of the compound 3 into a reaction kettle, adding 500g of dichloromethane, cooling to minus 78 ℃, dropwise adding 21.3g of chiral cytisine and 71.4g of lithium diisopropylamide, stirring at the temperature for 2-4 hours, slowly dropwise adding 8.9g of methyl acrylate, and slowly heating to room temperature within 6-8 hours after the addition is finished. After the HPLC detection reaction, purified water is added, ethyl acetate is used for extraction, the mixture is concentrated to a small volume, and crystallization and drying are carried out to obtain 36.7g of the Boc protected compound 4.
Adding 36.7g of compound 4 and 500g of methanol into a reaction kettle, dropwise adding 50ml of 6N hydrochloric acid, stirring at 20-25 ℃ until HPLC shows that the raw materials disappear, slowly adding a saturated sodium bicarbonate aqueous solution, adjusting the pH value to be neutral, concentrating, precipitating a large amount of solid, filtering, washing with purified water, and drying to obtain 5.1g of compound.
Example 3:
500g of ethyl acetate, 50g of compound 1 and 39g of glycine are added into a reaction kettle, 4.3g of concentrated sulfuric acid is added, the temperature is reduced to 0 ℃, the mixture is stirred for 30min, the temperature is increased to 20 ℃, 6g of HOBT is added, the mixture is stirred for 5h, heated to reflux for 30min, then concentrated to a small volume under reduced pressure, ethyl acetate is added for redissolution, the mixture is washed with 300ml of saturated saline solution for three times, dried with 300g of anhydrous magnesium sulfate overnight, concentrated to a small volume, and 39.4g of compound 2 is crystallized.
39.4g of the compound 2 and 13.2g of lutidine are added into a reaction kettle, 500g of ethanol is used for dissolving, the pH value is adjusted to 8.5 by adding sodium hydroxide, 100 ml of ethanol solution of 21.8g of Boc-anhydride is slowly dripped at 20-25 ℃, and after the addition is finished, the mixture is stirred until the compound 2 is completely reacted by HPLC detection. And (3) adding diluted hydrochloric acid to adjust the pH value to be neutral, concentrating to a small volume, adding 300g of ethyl acetate to redissolve, concentrating to a small volume, stirring for crystallization, and drying to obtain 34.5g of a compound 3.
34.5g of the compound 3 is added into a reaction kettle, 500g of anhydrous tetrahydrofuran is added, the mixture is cooled to minus 78 ℃, 20.1g of chiral laburnine and 73.1g of lithium diisopropylamide are added dropwise, the mixture is stirred for 2 to 4 hours at the temperature, 9.1g of methyl acrylate is slowly added dropwise, and the temperature is slowly raised to room temperature (6 to 8 hours) after the addition. After the HPLC detection reaction, purified water is added, ethyl acetate is used for extraction, the mixture is concentrated to a small volume, and crystallization and drying are carried out to obtain 35.1g of the Boc protected compound 4.
Adding 35.1g of compound 4 and 500g of methanol into a reaction kettle, dropwise adding 50ml of 6N hydrochloric acid, stirring at 20-25 ℃ until HPLC shows that the raw materials disappear, slowly adding a saturated sodium bicarbonate aqueous solution, adjusting the pH value to be neutral, concentrating, precipitating a large amount of solid, filtering, washing with purified water, and drying to obtain 30.6g of compound 5.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily think of the changes or substitutions within the technical scope of the present invention, and shall cover the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (5)

1. A synthetic method of a key intermediate of remazolam is characterized by comprising the following steps: the synthetic route is as follows:
Figure FDA0004004410210000011
the method comprises the following steps:
step one, mixing a compound 1: condensing 2- (2-amino-5-bromo-benzoyl) pyridine and glycine to obtain a compound 2, namely adding the compound 1 and the glycine into a reaction solvent, adding a condensing agent for condensation, distilling the reaction solvent under reduced pressure, adding the reaction solvent for redissolution, extracting with saturated salt water, and drying to obtain the compound 2, wherein the reaction solvent comprises one of anhydrous tetrahydrofuran, dichloromethane or ethyl acetate;
step two, protecting Boc on the N group to obtain a compound 3: adding a compound 2 into a reaction solvent, adding lutidine and alkali, uniformly stirring, adding BOC-acetic anhydride, stirring at 15-35 ℃ until the reaction is complete, adding water for washing to be neutral, concentrating to be small in volume, cooling and crystallizing to obtain a compound 3; the reaction solvent is: dichloromethane; the alkali is: sodium hydroxide and triethylamine, wherein the addition amount of the alkali is 0-2% of that of the compound 2;
step three, carrying out addition reaction on the compound 3 and methyl acrylate to obtain a compound 4: adding a compound 3 into a reaction solvent, cooling, adding chiral laburnine and lithium diisopropylamide, stirring for 2-4h, adding methyl acrylate, slowly heating to room temperature, adding water and ethyl acetate for extraction after complete reaction, concentrating to a small volume, crystallizing, and drying to obtain a compound 4; the reaction solvent is: anhydrous tetrahydrofuran, dichloromethane;
step four, removing Boc protection from the compound 4 to obtain a compound 5: adding a compound 4 into a reaction solvent, adding hydrochloric acid, cooling to 15-25 ℃, stirring until the reaction is complete, adding a saturated sodium bicarbonate aqueous solution, adjusting the pH value to be neutral, concentrating to a small volume, crystallizing, and drying to obtain a compound 5, wherein the reaction solvent is as follows: acetone, methanol, ethanol.
2. The method for synthesizing the key intermediate of the remimazolam according to claim 1, wherein: in the second step, the reaction solvent is methanol and ethanol, namely, the compound 2 is added into the reaction solvent, diluted hydrochloric acid is added to adjust the reaction solvent to be neutral, the reaction solvent is concentrated to be dry, ethyl acetate is added to redissolve the reaction solvent, the reaction solvent is concentrated to be small in volume, and the compound 3 is obtained by cooling and crystallization.
3. A process for the synthesis of a key intermediate of remozolam according to claims 1 or 2, characterized in that: in the first step, the condensing agent comprises concentrated sulfuric acid or one or more of HBTU, TBTU and HOBT after concentrated sulfuric acid treatment.
4. The method for synthesizing the key intermediate of the remimazolam according to claim 3, wherein: in the third step, the weight ratio of the compound 3: chiral cytisine =1:0.3-0.8; the compound 3: lithium diisopropylamide =1:0.8-1.5; the compound 3: methyl acrylate =0.1-0.4.
5. The method for synthesizing the key intermediate of the remimazolam according to claim 4, wherein: in the fourth step, the compound 4: hydrochloric acid =0.05-0.3.
CN202211627789.4A 2022-12-16 2022-12-16 Synthesis method of key intermediate of remimazolam Pending CN115974835A (en)

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