A method for synthesizing a key intermediate of remazolam

Abstract

The invention provides a method for synthesizing a key intermediate of remimazolam. The method comprises the following steps: firstly synthesizing bromazepam with 2-(2-amino-5-bromo-benzoyl)pyridine as a raw material, then protecting the amide of bromazepam, and then performing an asymmetric Michael addition reaction with methyl acrylate to obtain a protected remimazolam intermediate, and finally removing the protecting group to obtain the key intermediate. The method is simple and stable to operate, the products of each step are easily separated, the yield is high, the method is environmentally friendly, and the method is suitable for industrial-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthetic pharmaceuticals, and more specifically, to a method for synthesizing a key intermediate of remazolam. Background Art

[0002] Remimazolam besylate was officially approved for marketing in July 2020. It is used in the fields of painless diagnosis and treatment sedation, general anesthesia, ICU sedation, and local anesthesia sedation. Remimazolam is a new type of ultra-short-acting benzodiazepine anesthetic, which has the characteristics of predictable sedation time and rapid recovery in painless gastrointestinal endoscopy. Compound 5 is an important intermediate in the synthesis of remimazolam. The structural formula of compound 5 is as follows:

[0003]

[0004] In the prior art, international patents WO0069836 and WO2013029431 use 2-(2-amino-5-bromobenzoyl)pyridine as a starting material, react with Fmoc-protected glutamic acid, then remove Fmoc, and finally close the ring.

[0005]

[0006] International patent WO2011032692 also uses 2-(2-amino-5-bromobenzoyl)pyridine as a starting material, reacts with Boc-protected glutamic acid, then removes Boc and finally closes the ring.

[0007]

[0008] Chinese patent CN114014839 also uses 2-(2-amino-5-bromobenzoyl)pyridine as a starting material, reacts with trityl-protected glutamic acid, then removes the trityl group, and finally closes the ring.

[0009]

[0010] However, the above patents have defects: the total yield is not high, the purity of the product is low, the international patent WO2019 / 72944 uses Cbz as a protective group for synthesis, and although the product purity is reported to be 99%, there is no chirality data; the starting material of the Chinese patent CN114014839, trityl-protected glutamic acid, is difficult to synthesize, and repeated experiments on the Chinese patent CN114014839 found that the chirality is only 96.5%. Although the chiral purity can be improved by crystallization and other methods in the later stage, it will undoubtedly reduce the yield. . Summary of the invention

[0011] In view of the above-mentioned defects and problems in the prior art, the present invention provides a method for synthesizing a key intermediate of remazolam.

[0012] In order to achieve the above object, the present invention provides the following technical solutions:

[0013] A method for synthesizing a key intermediate of remazolam, the synthetic route is:

[0014]

[0015] Includes steps:

[0016] Step 1, condensing compound 1: 2-(2-amino-5-bromo-benzoyl)pyridine and glycine to obtain compound 2, that is, adding compound 1 and glycine in a reaction solvent, adding a condensing agent for condensation, distilling the reaction solvent under reduced pressure, adding a reaction solvent for redissolution, extracting with saturated brine, and drying to obtain compound 2, wherein the reaction solvent includes one of anhydrous tetrahydrofuran, dichloromethane or ethyl acetate;

[0017] Step 2, protecting Boc on the N group to obtain compound 3: Compound 2 is added to the reaction solvent, and lutidine and a base are added. After stirring evenly, BOC-acetic anhydride is added, and the mixture is stirred at 15-35°C until the reaction is complete. The mixture is washed with water until neutral, concentrated to a small volume, and cooled to crystallize to obtain compound 3. The reaction solvent is dichloromethane; the base is sodium hydroxide and triethylamine, and the amount of the base added is 0-2% of the amount of compound 2 added.

[0018] Step 3, compound 3 and methyl acrylate are subjected to addition reaction to obtain compound 4: compound 3 is added to the reaction solvent, and after cooling, chiral cytisine and lithium diisopropylamide are added, and after stirring for 2-4 hours, methyl acrylate is added and the temperature is slowly raised to room temperature. After the reaction is complete, water and ethyl acetate are added for extraction, and the mixture is concentrated to a small volume, crystallized, and dried to obtain compound 4; the reaction solvent is anhydrous tetrahydrofuran and dichloromethane;

[0019] Step 4, removing Boc protection from compound 4 to obtain compound 5: Compound 4 is added to the reaction solvent, and then hydrochloric acid is added, the temperature is lowered to 15-25°C and stirred until the reaction is complete, saturated sodium bicarbonate aqueous solution is added, the pH value is adjusted to neutral, and the mixture is concentrated to a small volume, crystallized, and dried to obtain compound 5. The reaction solvent is: acetone, methanol, and ethanol.

[0020] In the above technical solution, in step 1, the condensation agent includes concentrated sulfuric acid or concentrated sulfuric acid treatment followed by addition of one or more of HBTU, TBTU, and HOBT.

[0021] In the above technical scheme, in step 2, the reaction solvent is methanol or ethanol, that is, compound 2 is added to the reaction solvent, diluted hydrochloric acid is added to adjust to neutrality, concentrated to dryness, ethyl acetate is added to redissolve, concentrated to a small volume, and cooled to crystallize to obtain compound 3;

[0022] In the above technical solution, in the step three, according to the weight ratio, 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.

[0023] In the above technical solution, in the step 4, according to the weight ratio, the compound 4: hydrochloric acid = 0.05-0.3.

[0024] The invention uses 2-(2-amino-5-bromo-benzoyl)pyridine as a raw material to first synthesize bromazepam, then protects the amide of bromazepam, and then performs an asymmetric Michael addition reaction with methyl acrylate to obtain a protected remimazolam intermediate, and finally removes the protecting group to obtain a key intermediate. The invention is a preparation method of remimazolam which has the advantages of simple and stable operation, easy separation of products in each step, high yield, environmental friendliness, and is suitable for industrial-scale production. DETAILED DESCRIPTION

[0025] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0026] The synthetic route of the present invention is as follows:

[0027]

[0028] The technical solution of the present invention uses 2-(2-amino-5-bromo-benzoyl)pyridine (compound 1) and glycine to condense to obtain compound 2. Then the N group is Boc protected to obtain compound 3, and compound 4 is obtained by addition reaction with methyl acrylate, and then the Boc protection is removed to obtain compound 5.

[0029] The specific steps are as follows:

[0030] Step 1, compound 1: 2-(2-amino-5-bromo-benzoyl)pyridine and glycine are condensed to obtain compound 2, that is, compound 1 and glycine are added to a reaction solvent, a condensing agent is added for condensation, the reaction solvent is distilled under reduced pressure, the reaction solvent is added again for redissolution, saturated brine is extracted, and compound 2 is obtained by drying. The reaction solvent includes one of anhydrous tetrahydrofuran, dichloromethane or ethyl acetate; the condensing agent includes concentrated sulfuric acid or one or more of HBTU, TBTU, and HOBT after concentrated sulfuric acid treatment. This reaction avoids the use of glycine condensation under Boc protection in the prior art, reduces the reaction steps, improves the reaction yield, and reduces the generation of impurities.

[0031] Step 2, protecting Boc on the N group to obtain compound 3: when the reaction solvent is dichloromethane, add compound 2, lutidine and base to the reaction solvent, stir evenly, add BOC-acetic anhydride, stir at 15-35°C until the reaction is complete, wash with water until neutral, concentrate to a small volume, cool and crystallize to obtain compound 3; the base is sodium hydroxide, triethylamine, and the amount of the base added is 0-2% of the amount of compound 2 added;

[0032] When the reaction solvent in step 2 is changed to methanol or ethanol, this step is to add compound 2 to the reaction solvent, add dilute hydrochloric acid to adjust to neutrality, concentrate to dryness, add ethyl acetate to redissolve, concentrate to a small volume, cool and crystallize to obtain compound 3;

[0033] Step 3, compound 3 and methyl acrylate are subjected to addition reaction to obtain compound 4: compound 3 is added to the reaction solvent, and after cooling, chiral cytisine and lithium diisopropylamide are added, and after stirring for 2-4 hours, methyl acrylate is added and the temperature is slowly raised to room temperature. After the reaction is complete, water and ethyl acetate are added for extraction, and the compound 4 is obtained by crystallization and drying. The reaction solvent is anhydrous tetrahydrofuran and dichloromethane. According to the weight ratio, 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.

[0034] Step 4, removing Boc protection from compound 4 to obtain compound 5: Compound 4 is added to the reaction solvent, and then hydrochloric acid is added, the temperature is lowered to 15-25°C and stirred until the reaction is complete, saturated sodium bicarbonate aqueous solution is added, the pH value is adjusted to neutral, and the mixture is concentrated to a small volume, crystallized, and dried to obtain compound 5. The reaction solvent is: acetone, methanol, and ethanol.

[0035] Specific implementation cases:

[0036] Embodiment 1:

[0037] Into the reaction kettle, 500 ml of anhydrous tetrahydrofuran, 46.7 g of compound 1, and 37.1 g of glycine were added. 3.6 g of concentrated sulfuric acid was added, the temperature was lowered to 0 °C and stirred for 30 min, the temperature was raised to 20 °C, 4 g of TBTU was added, stirring was continued for 5 h, and the mixture was heated to reflux for 30 min. The mixture was concentrated under reduced pressure to a small volume, dichloromethane was added to dissolve, the mixture was washed three times with 300 ml of saturated brine, and dried overnight with 300 g of anhydrous magnesium sulfate. The mixture was concentrated to a small volume and crystallized to obtain 31.6 g of compound 2.

[0038] Add 31.6g of compound 2 and 12.2g of lutidine to the reaction kettle, dissolve with 500g of dichloromethane, add triethylamine to adjust the pH to 8.5, slowly add 21.8g of Boc-anhydride in 100ml of dichloromethane solution at 20-25°C, stir until HPLC detects that compound 2 reacts completely, add purified water for washing, dry and concentrate to obtain 40.5g of compound 3.

[0039] Add 40.5g of compound 3 to the reactor, add 500g of anhydrous tetrahydrofuran, cool to -78°C, drop 19g of chiral cytisine and 70g of lithium diisopropylamide, stir at this temperature for 2-4 hours, then slowly drop 8.6g of methyl acrylate, and slowly warm to room temperature within 6-8 hours. HPLC detection of the reaction is complete, add purified water, extract with ethyl acetate, concentrate to a small volume, crystallize and dry to obtain 42.1g of Boc-protected compound 4.

[0040] 42.1 g of compound 4 and 500 g of acetone were added to the reaction kettle, 50 ml of 6N hydrochloric acid was added dropwise, and the mixture was stirred at 20-25 °C until HPLC showed that the raw material disappeared. Saturated sodium bicarbonate aqueous solution was slowly added to adjust the pH to neutral. The mixture was concentrated to precipitate a large amount of solid, which was filtered, washed with purified water, and dried to obtain 32.2 g of compound 5.

[0041] Embodiment 2:

[0042] Add 500 g of dichloromethane, 46.7 g of compound 1, and 37.1 g of glycine to the reactor, add 4.3 g of concentrated sulfuric acid, cool to 5 ° C and stir for 30 min, heat to 20 ° C and keep stirring for 5 h, heat to reflux for 30 min, concentrate under reduced pressure to a small volume, add dichloromethane to dissolve, wash three times with 300 ml of saturated brine, dry overnight with 300 g of anhydrous magnesium sulfate, concentrate to a small volume, and crystallize 29.7 g of compound 2.

[0043] 29.7 g of compound 2g and 11.6 g of lutidine were added to the reaction kettle, dissolved with 500 g of methanol, triethylamine was added to adjust the pH value to 8.5, and 20.6 g of Boc-anhydride in 100 ml of methanol solution was slowly added dropwise at 20-25°C. After the addition was completed, the mixture was stirred until the reaction of compound 2 was complete as detected by HPLC. Dilute hydrochloric acid was added to adjust the pH value to neutral, the mixture was concentrated to a small volume, 300 g of ethyl acetate was added to redissolve, the mixture was concentrated to a small volume, stirred for crystallization, and dried to obtain 36.8 g of compound 3.

[0044] Add 36.8g of compound 3 to the reactor, add 500g of dichloromethane, cool to -78°C, drop 21.3g of chiral cytisine and 71.4g of lithium diisopropylamide, stir at this temperature for 2-4 hours, then slowly drop 8.9g of methyl acrylate, after addition, slowly warm to room temperature within 6-8 hours. HPLC detection of the reaction is complete, add purified water, extract with ethyl acetate, concentrate to a small volume, crystallize and dry to obtain 36.7g of Boc-protected compound 4.

[0045] 36.7 g of compound 4 and 500 g of methanol were added to the reaction kettle, 50 ml of 6N hydrochloric acid was added dropwise, and the mixture was stirred at 20-25°C until HPLC showed that the raw material disappeared. Saturated sodium bicarbonate aqueous solution was slowly added, and the pH was adjusted to neutral. The mixture was concentrated to precipitate a large amount of solid, which was filtered, washed with purified water, and dried to obtain 31.1 g of compound 5.

[0046] Embodiment 3:

[0047] Add 500 g of ethyl acetate, 50 g of compound 1, and 39 g of glycine to the reactor, add 4.3 g of concentrated sulfuric acid, cool to 0 ° C and stir for 30 min, heat to 20 ° C, add 6 g of HOBT, continue stirring for 5 h, heat to reflux for 30 min, concentrate under reduced pressure to a small volume, add ethyl acetate to dissolve, wash three times with 300 ml of saturated brine, dry overnight with 300 g of anhydrous magnesium sulfate, concentrate to a small volume, and crystallize 39.4 g of compound 2.

[0048] 39.4 g of compound 2 and 13.2 g of lutidine were added to the reaction kettle, dissolved with 500 g of ethanol, sodium hydroxide was added to adjust the pH value to 8.5, and 21.8 g of Boc-anhydride in 100 ml of ethanol solution was slowly added dropwise at 20-25°C. After the addition was completed, the mixture was stirred until the reaction of compound 2 was complete as detected by HPLC. Dilute hydrochloric acid was added to adjust the pH value to neutral, the mixture was concentrated to a small volume, 300 g of ethyl acetate was added to redissolve, the mixture was concentrated to a small volume, stirred for crystallization, and dried to obtain 34.5 g of compound 3.

[0049] Add 34.5g of compound 3 to the reactor, add 500g of anhydrous tetrahydrofuran, cool to -78°C, drop 20.1g of chiral cytisine and 73.1g of lithium diisopropylamide, stir at this temperature for 2-4 hours, then slowly drop 9.1g of methyl acrylate, slowly warm to room temperature after addition (6-8 hours). HPLC detection of the reaction is complete, add purified water, extract with ethyl acetate, concentrate to a small volume, crystallize and dry to obtain 35.1g of Boc-protected compound 4.

[0050] 35.1 g of compound 4 and 500 g of methanol were added to the reaction kettle, 50 ml of 6N hydrochloric acid was added dropwise, and the mixture was stirred at 20-25°C until HPLC showed that the raw material disappeared. Saturated aqueous sodium bicarbonate solution was slowly added, and the pH was adjusted to neutral. The mixture was concentrated to precipitate a large amount of solid, which was filtered, washed with purified water, and dried to obtain 30.6 g of compound 5.

[0051] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A method for synthesizing a key intermediate of remazolam, characterized in that: The synthetic route is: Includes steps: Step 1, condensing compound 1: 2-(2-amino-5-bromo-benzoyl)pyridine and glycine to obtain compound 2, that is, adding compound 1 and glycine in a reaction solvent, adding a condensing agent for condensation, distilling the reaction solvent under reduced pressure, adding a reaction solvent for redissolution, extracting with saturated brine, and drying to obtain compound 2, wherein the reaction solvent is selected from anhydrous tetrahydrofuran, dichloromethane or ethyl acetate; Step 2, protecting Boc on the N group to obtain compound 3: Compound 2 is added to the reaction solvent, lutidine and a base are added, and after stirring evenly, BOC-acetic anhydride is added, and the mixture is stirred at 15-35°C until the reaction is complete, and water is added to wash until neutral, and the mixture is concentrated to a small volume, and the temperature is lowered to crystallize to obtain compound 3; the reaction solvent is dichloromethane; the base is selected from sodium hydroxide and triethylamine, and the amount of the base added is 0-2% of the amount of compound 2 added; Step 3, compound 3 and methyl acrylate are subjected to addition reaction to obtain compound 4: compound 3 is added to the reaction solvent, and after cooling, chiral cytisine and lithium diisopropylamide are added, and after stirring for 2-4 hours, methyl acrylate is added and the temperature is slowly raised to room temperature. After the reaction is complete, water and ethyl acetate are added for extraction, and the mixture is concentrated to a small volume, crystallized, and dried to obtain compound 4; the reaction solvent is selected from: anhydrous tetrahydrofuran, dichloromethane; Step 4, removing Boc protection from compound 4 to obtain compound 5: Compound 4 is added to the reaction solvent, and then hydrochloric acid is added, the temperature is lowered to 15-25° C. and stirred until the reaction is complete, saturated sodium bicarbonate aqueous solution is added, the pH value is adjusted to neutral, and the mixture is concentrated to a small volume, crystallized, and dried to obtain compound 5. The reaction solvent is selected from: acetone, methanol, and ethanol.

2. The method for synthesizing a key intermediate of remazolam according to claim 1, characterized in that: In step 2, the reaction solvent can be replaced by methanol or ethanol instead of dichloromethane.

3. A method for synthesizing a key intermediate of remazolam according to claim 1 or 2, characterized in that: In the step 1, the condensing agent is selected from concentrated sulfuric acid or concentrated sulfuric acid treatment followed by addition of one or more of HBTU, TBTU, and HOBT.

4. The method for synthesizing a key intermediate of remazolam according to claim 3, characterized in that: In the step 3, according to the weight ratio, 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 a key intermediate of remazolam according to claim 4, characterized in that: In the step 4, according to the weight ratio, the compound 4: hydrochloric acid = 0.05-0.3.

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