CN114716411A - Method for recovering and preparing dabigatran etexilate mesylate from production mother liquor - Google Patents
Method for recovering and preparing dabigatran etexilate mesylate from production mother liquor Download PDFInfo
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- CN114716411A CN114716411A CN202210466299.4A CN202210466299A CN114716411A CN 114716411 A CN114716411 A CN 114716411A CN 202210466299 A CN202210466299 A CN 202210466299A CN 114716411 A CN114716411 A CN 114716411A
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- dabigatran etexilate
- etexilate mesylate
- mother liquor
- mesylate
- acetone
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- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical compound C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 title claims abstract description 141
- 229960004951 dabigatran etexilate mesylate Drugs 0.000 title claims abstract description 91
- 239000012452 mother liquor Substances 0.000 title claims abstract description 48
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims abstract description 34
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 78
- 229960000288 dabigatran etexilate Drugs 0.000 claims abstract description 50
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000001816 cooling Methods 0.000 claims abstract description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000002425 crystallisation Methods 0.000 claims abstract description 24
- 230000008025 crystallization Effects 0.000 claims abstract description 24
- 239000003513 alkali Substances 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 229940098779 methanesulfonic acid Drugs 0.000 claims abstract description 20
- 239000008247 solid mixture Substances 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 230000009467 reduction Effects 0.000 claims abstract description 16
- 239000012458 free base Substances 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000008213 purified water Substances 0.000 claims abstract description 10
- 238000007670 refining Methods 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims description 41
- 238000001914 filtration Methods 0.000 claims description 32
- 239000013078 crystal Substances 0.000 claims description 26
- 238000010438 heat treatment Methods 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 238000001035 drying Methods 0.000 claims description 23
- 239000012065 filter cake Substances 0.000 claims description 22
- 239000012043 crude product Substances 0.000 claims description 18
- 239000000047 product Substances 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000012535 impurity Substances 0.000 claims description 11
- 238000004321 preservation Methods 0.000 claims description 11
- 238000004537 pulping Methods 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 238000005119 centrifugation Methods 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 230000008901 benefit Effects 0.000 abstract description 8
- 238000000746 purification Methods 0.000 abstract description 7
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- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000001556 precipitation Methods 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 208000005189 Embolism Diseases 0.000 description 3
- 208000001435 Thromboembolism Diseases 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 206010003658 Atrial Fibrillation Diseases 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229960003850 dabigatran Drugs 0.000 description 2
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
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- 210000003462 vein Anatomy 0.000 description 2
- 108090000371 Esterases Proteins 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 210000004394 hip joint Anatomy 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229940127066 new oral anticoagluant drug Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
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- 239000000651 prodrug Substances 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
Abstract
The invention provides a method for recovering and preparing dabigatran etexilate mesylate from production mother liquor, and relates to the technical field of preparation of dabigatran etexilate mesylate. The method specifically comprises the following steps: distilling the mother liquor of dabigatran etexilate mesylate production under reduced pressure to constant weight, sequentially adding acetonitrile, a pH regulator and purified water into the obtained solid mixture, and cooling and crystallizing to obtain dabigatran etexilate free alkali; then adding ethyl acetate, purifying and crystallizing to obtain refined dabigatran etexilate free alkali; dissolving the refined dabigatran etexilate free base in acetone, salifying with methanesulfonic acid to prepare dabigatran etexilate mesylate, crystallizing, and finally further refining the dabigatran etexilate mesylate through an alcohol-acetone system to obtain a high-quality refined dabigatran etexilate mesylate product. The method has the advantages of simple process, mild reaction, less solvent types, temperature reduction and crystallization only in the purification step, no need of column chromatography purification, effective recycling of the production mother liquor of dabigatran etexilate mesylate, reduction in production cost and reduction in waste discharge.
Description
Technical Field
The invention belongs to the technical field of preparation of dabigatran etexilate mesylate, and particularly relates to a method for recovering and preparing dabigatran etexilate mesylate from production mother liquor.
Background
Dabigatran etexilate is a new oral anticoagulant drug developed by Boehringer ingenhain, germany, which was first marketed in germany and the uk in 2008; FDA approval was obtained in the united states in 2010 for the reduction of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation; the Chinese market is shown in 2013. The dabigatran etexilate mesylate is a prodrug of dabigatran, has no activity per se, and is rapidly hydrolyzed by esterase in the liver and further converted into active dabigatran after being orally taken and absorbed by the stomach and intestine. Dabigatran etexilate exerts an anticoagulant effect by binding to fibrin-specific sites of thrombin, preventing cleavage of fibrinogen to fibrin. The dabigatran etexilate mesylate can be used for deep vein thromboembolism prevention after knee joint and hip joint replacement, deep vein thromboembolism treatment, atrial fibrillation, secondary prevention of coronary events, and has multiple advantages of fixed dose administration, no need of laboratory monitoring and the like.
According to the report of related documents (CN106543144), existing multiple process routes of dabigatran etexilate are applied to industrial mass production, but the crude product prepared by each process route needs to be further crystallized and purified by a solvent, so that the quality standard required by an API product can be achieved. The purification solvent used in the crystallization and purification process not only reduces the overall yield and improves the expected production cost, but also causes inconvenience for the later waste liquid treatment because a small part of the dabigatran etexilate mesylate product is dissolved in the crystallization mother liquid. Therefore, the recovery of dabigatran etexilate in the crude preparation and the refined mother liquor is necessary. In addition, the preparation of the crude dabigatran etexilate mesylate and the refined crystallization mother liquor are also enriched with more impurities, and the further purification of the dissolved dabigatran etexilate product from the mother liquor is difficult.
Therefore, the method for further preparing the dabigatran etexilate mesylate by recovering the dabigatran etexilate from the preparation of the crude dabigatran etexilate mesylate product and the refined mother liquor is developed, is favorable for improving the overall yield of the product, meets the requirements of energy conservation and environmental protection, and has important significance for increasing economic and social benefits.
Disclosure of Invention
The invention aims to provide a method for recovering and preparing dabigatran etexilate mesylate from production mother liquor, which is characterized in that a solvent and a large amount of impurities in the dabigatran etexilate mesylate production mother liquor are removed to obtain refined dabigatran etexilate free base, the free base and methanesulfonic acid are salified to obtain a crude product of the dabigatran etexilate mesylate, and the crude product is refined to obtain the high-quality dabigatran etexilate mesylate. The preparation method provided by the invention has the advantages of mild reaction, simple process, recoverable solvent, capability of greatly reducing waste discharge and reducing production cost, and high quality of the synthesized product, wherein the purity is more than or equal to 99.74%.
In order to achieve the aim, the invention provides a method for recovering and preparing dabigatran etexilate mesylate from production mother liquor, which comprises the following steps:
(1) carrying out reduced pressure distillation on the production mother liquor of dabigatran etexilate mesylate to constant weight to obtain a solid mixture;
(2) adding acetonitrile into the solid mixture obtained in the step (1), stirring and heating, sequentially adding a pH regulator and purified water, cooling and crystallizing, filtering, and drying a filter cake to obtain dabigatran etexilate free alkali;
(3) adding ethyl acetate into the dabigatran etexilate free alkali obtained in the step (2), heating to dissolve and clear, cooling to crystallize, filtering, and drying a filter cake to obtain refined dabigatran etexilate free alkali;
(4) dissolving the refined dabigatran etexilate free base obtained in the step (3) in acetone, dropwise adding methanesulfonic acid to generate dabigatran etexilate mesylate, crystallizing, filtering, and drying a filter cake to obtain a crude product of dabigatran etexilate mesylate;
(5) dissolving the dabigatran etexilate mesylate crude product obtained in the step (4) in an alcohol solvent, filtering, adding acetone into the filtrate, cooling, crystallizing, growing crystals, filtering, and collecting a filter cake;
(6) and (5) adding acetone into the filter cake obtained in the step (5), pulping, filtering and drying to constant weight to obtain the recovered refined dabigatran etexilate mesylate product.
In a preferred embodiment, the production mother liquor of dabigatran etexilate mesylate described in step (1) specifically refers to:
during the preparation and refining of the dabigatran etexilate crude product, after the dabigatran etexilate crude product and methanesulfonic acid salifying reaction, filtrate obtained in the step of crystallization, centrifugation and filtration is carried out; the production mother liquor of dabigatran etexilate mesylate mainly comprises the following components: a crystallization solvent, dabigatran etexilate mesylate and impurities.
In a preferred embodiment, the mass ratio of the solid mixture to acetonitrile in step (2) is 1: (4-8), stirring and heating to 40-70 ℃.
In a preferred embodiment, the pH regulator in step (2) comprises one or more of sodium hydroxide, potassium hydroxide, ammonia, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate; adjusting the pH value of the system to 8-12; the mass ratio of the solid mixture to the purified water is 1: (2-4).
In a preferred embodiment, the mass ratio of ethyl acetate to solid mixture to solid in step (3) is (4-8): 1; after heating and dissolving, stirring for 0.5-1h under heat preservation.
In a preferred embodiment, the mass ratio of the refined dabigatran etexilate free base to acetone in step (4) is 1: (6-10), the mass ratio of the methanesulfonic acid to the refined dabigatran etexilate free alkali is (0.156-0.160):1, and after the acetone is added, the mixture can be heated to be dissolved and clear, and is stirred for 0.5-1h under the condition of heat preservation; the crystallization temperature is 0-5 ℃, and the crystallization time is 1-2 h.
In a preferred embodiment, the alcohol solvent in step (5) is selected from one or more of methanol, ethanol, isopropanol and n-butanol, and the alcohol solvent is added in an amount to fully dissolve the crude dabigatran etexilate mesylate and make the solution clear; the mass ratio of the acetone to the alcohol solvent is (4-6): 1, the acetone has been preheated to 40-50 ℃.
In a preferred embodiment, the temperature reduction mode in the step (5) is a gradient temperature reduction mode, and the temperature reduction rate is 5-10 ℃/h; the temperature of growing crystal is 0-10 ℃, and the time of growing crystal is 2-4 h.
In a preferred embodiment, the mass ratio of the acetone to the crude dabigatran etexilate mesylate in the step (6) is (1-3):1, and the mixture is pulped at the temperature of 5-10 ℃ for 0.5-1h after the acetone is added.
In a preferred embodiment, the drying in step (6) is vacuum drying at a temperature of 40-50 ℃.
Compared with the prior art, the technical scheme of the invention has the following advantages:
1. according to the method, the mother liquor discarded in the preparation and refining processes of the dabigatran etexilate mesylate can be utilized to the greatest extent, the purity of the dabigatran etexilate is improved by removing a plurality of impurities, and the dabigatran etexilate is subjected to salt forming reaction with methanesulfonic acid to obtain the high-quality dabigatran etexilate mesylate simply and efficiently.
2. According to the method, salt and water-soluble organic impurities in the dabigatran etexilate mesylate mother liquor are removed through acetonitrile-water system treatment, most impurities in a crude dabigatran etexilate product are removed through ethyl acetate refining, the crude dabigatran etexilate mesylate product is prepared through salification with methanesulfonic acid, and the crude dabigatran etexilate mesylate product is further refined through an alcohol-acetone system, so that a high-quality refined dabigatran etexilate mesylate product can be obtained.
3. The method has the advantages of simple process, mild reaction, safe and environment-friendly integral scheme, environmental protection, no pollution, processing and utilization of the recovered mother liquor, reduction of production cost and waste discharge, and cost reduction and efficiency improvement.
4. In the scheme of the invention, the solvent is few in category and easy to operate, the purification step is only crystallization by cooling, column chromatography purification is not needed, and the method is particularly suitable for large-scale industrial production and preparation.
Drawings
These and/or other aspects and advantages of the present invention will become more apparent and more readily appreciated from the following detailed description of the embodiments of the invention, taken in conjunction with the accompanying drawings of which:
FIG. 1 is an HPLC purity chart of a solid mixture obtained by distilling a mother liquor under reduced pressure to constant weight in example 1 of the present invention;
FIG. 2 is an HPLC purity chart of dabigatran etexilate mesylate prepared in example 1 of the present invention;
FIG. 3 is an HPLC purity chart of dabigatran etexilate mesylate prepared in example 2 of the present invention.
Detailed Description
In order that those skilled in the art will better understand the present invention, the following detailed description is given with reference to the accompanying drawings and the specific embodiments, but it should be understood that the scope of the present invention is not limited by the specific embodiments.
The embodiment of the invention provides a method for recovering and preparing dabigatran etexilate mesylate from production mother liquor, and solves the problems of more impurities and high recovery difficulty of the production mother liquor of dabigatran etexilate mesylate in the prior art.
In order to solve the above problems, the technical solution in the embodiments of the present invention has the following general idea:
the invention provides a method for recovering and preparing dabigatran etexilate mesylate from production mother liquor, which comprises the following steps:
(1) carrying out reduced pressure distillation on the production mother liquor of dabigatran etexilate mesylate to constant weight to obtain a solid mixture;
(2) adding acetonitrile into the solid mixture obtained in the step (1), stirring and heating, sequentially adding a pH regulator and purified water, cooling and crystallizing, filtering, and drying a filter cake to obtain dabigatran etexilate free alkali;
(3) adding ethyl acetate into the dabigatran etexilate free alkali obtained in the step (2), heating to dissolve and clear, cooling to crystallize, filtering, and drying a filter cake to obtain refined dabigatran etexilate free alkali;
(4) dissolving the refined dabigatran etexilate free base obtained in the step (3) in acetone, dropwise adding methanesulfonic acid to generate dabigatran etexilate mesylate, crystallizing, filtering, and drying a filter cake to obtain a crude product of dabigatran etexilate mesylate;
(5) dissolving the dabigatran etexilate mesylate crude product obtained in the step (4) in an alcohol solvent, filtering, adding acetone into the filtrate, cooling, crystallizing, growing crystals, filtering, and collecting a filter cake;
(6) and (5) adding acetone into the filter cake obtained in the step (5), pulping, filtering and drying to constant weight to obtain the recovered refined dabigatran etexilate mesylate product.
In a preferred embodiment, the production mother liquor of dabigatran etexilate mesylate described in step (1) specifically refers to: during the preparation and refining of the dabigatran etexilate crude product, after the dabigatran etexilate crude product and methanesulfonic acid salifying reaction, filtrate obtained in the step of crystallization, centrifugation and filtration is carried out; the production mother liquor of dabigatran etexilate mesylate mainly comprises the following components: a crystallization solvent, dabigatran etexilate mesylate and impurities; it should be noted that: the source of the mother liquor for producing the dabigatran etexilate mesylate is not limited to a certain preparation process, and the technical scheme of the invention can be realized by only preparing and refining a crude dabigatran etexilate product and carrying out a salt forming reaction of the dabigatran etexilate and methanesulfonic acid and filtering the obtained filtrate.
In a preferred embodiment, the mass ratio of the solid mixture to acetonitrile in step (2) is 1: (4-8), stirring and heating to 40-70 ℃; more preferably, the mass ratio of the solid mixture to acetonitrile is 1: (6-7), stirring and heating to 55-60 ℃.
In a preferred embodiment, the pH regulator in step (2) comprises one or more of sodium hydroxide, potassium hydroxide, ammonia, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate; adjusting the pH value of the system to 8-12, and preferably, adjusting the pH value of the system to 8-9; in order to improve the mixing effect of the pH regulator and the reactant, the mixture can be stirred for 0.5 to 1 hour under the condition of heat preservation after the pH regulator is added. In the invention, a pH regulator is added to make the reaction system alkaline, so as to generate the dabigatran etexilate free alkali. And salifying the free alkali and methanesulfonic acid in the subsequent reaction process to obtain the dabigatran etexilate mesylate.
In a preferred embodiment, the mass ratio of the solid mixture to the purified water in step (2) is 1: (2-4); in order to improve the reaction effect, purified water is added, and then the mixture can be stirred for 0.5 to 1 hour under the condition of heat preservation.
In a preferred embodiment, in the cooling crystallization in step (2), after crystal precipitation is observed by cooling, the temperature for crystal precipitation can be maintained and stirring is carried out for 0.5-1h to increase the crystallization effect. Specifically, after the crystals are separated out, the crystallization temperature is kept to be fully and slowly crystallized, so that the crystal wrapping impurities caused by too fast temperature reduction can be avoided; after stirring, continuously cooling to 0-10 ℃, stirring and crystallizing for 2-4h, preferably cooling to 0-5 ℃, and stirring and crystallizing for 2 h.
In a preferred embodiment, the mass ratio of ethyl acetate to the solid mixture in step (3) is (4-8): 1; more preferably, the mass ratio of the ethyl acetate to the solid mixture is (6-7): 1; in the invention, the heating and the solution clearing are both heating to clarify the solution, preferably, the solution clearing temperature is 55-60 ℃ after ethyl acetate is added; in order to improve the reaction effect, the mixture can be stirred for 0.5 to 1 hour under the condition of heat preservation after being heated and dissolved.
In a preferred embodiment, during the cooling crystallization in the step (3), after crystal precipitation is observed by cooling, the crystal precipitation temperature can be kept and stirred for 0.5-1h to increase the crystallization effect; after stirring, continuously cooling to 0-10 ℃, stirring and crystallizing for 2-4h, preferably cooling to 0-5 ℃, and stirring and crystallizing for 2 h.
In a preferred embodiment, the mass ratio of the refined dabigatran etexilate free base to acetone in step (4) is 1: (6-10), more preferably, the mass ratio of the refined dabigatran etexilate free base to the acetone is 1: 8; in order to improve the mixing effect of the reaction system, after adding the acetone, the temperature can be raised to 55-60 ℃, and the mixture is stirred for 0.5-1h under the condition of heat preservation.
In a preferred embodiment, the mass ratio of methanesulfonic acid to purified dabigatran etexilate free base in step (4) is (0.156-0.160) to 1, more preferably the mass ratio of methanesulfonic acid to purified dabigatran etexilate free base is 0.158: 1; in order to improve the mixing effect of the reaction system, after methanesulfonic acid is added, the stirring can be continued for 0.5 to 1 hour under heat preservation.
In a preferred embodiment, the crystallization temperature in step (4) is 0-5 ℃ and the stirring crystallization time is 1-2 h.
In a preferred embodiment, the alcohol solvent in step (5) is selected from one or more of methanol, ethanol, isopropanol and n-butanol, and the alcohol solvent is added in an amount to fully dissolve the crude dabigatran etexilate mesylate and make the solution clear; the mass ratio of the acetone to the alcohol solvent is (4-6): 1, more preferably, the mass ratio of the acetone to the alcohol solvent is 5: 1; the acetone has been preheated to 40-50 ℃.
In a preferred embodiment, the temperature reduction mode in the step (5) is a gradient temperature reduction mode, and the temperature reduction rate is 5-10 ℃/h; the crystal growth temperature is 0-10 ℃, the crystal growth time is 2-4h, and more preferably, the crystal growth temperature is 0-5 ℃, and the crystal growth time is 6 h.
In a preferred embodiment, the mass ratio of the acetone to the crude dabigatran etexilate mesylate in the step (6) is (1-3):1, and preferably, the mass ratio of the acetone to the crude dabigatran etexilate mesylate is 2: 1; in order to improve the dissolving effect of the reaction system, adding acetone and pulping for 0.5-1h at the temperature of 5-10 ℃. The method has the advantages that the acetone is used for pulping, so that excessive methanesulfonic acid and a small amount of impurities in wet products are sufficiently carried out, the product purity is further improved, and the pulping temperature and the pulping time are optimal pulping conditions which are optimized and confirmed through a large number of experiments.
In a preferred embodiment, the drying in step (6) is vacuum drying at a temperature of 40-50 ℃.
In the above operation steps, if no special description is given: the cooling crystallization mode or equipment can be any mode or equipment known by the technical personnel in the field, and the preferable cooling crystallization mode is natural cooling; the filter cake can be dried by any method or equipment known to those skilled in the art, and the preferred drying method is drying under reduced pressure at 40-50 ℃ for 3-5 h; the stirring can be carried out in any mode or equipment known by the technical personnel in the field, the stirring mainly has the effect of fully mixing the reaction substances to improve the reaction effect, and preferably, the stirring speed is 30-45 rpm; the filtration is performed by using a filter membrane known to those skilled in the art, preferably, a 0.45 micron filter membrane or a 0.22 micron filter membrane is used for ensuring the microbial qualification, and more preferably, the filter membrane used in the embodiment of the invention is 0.45 micron; the heating and clearing refers to fully dissolving the solute in the solution, and heating to clear the solution.
Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art, and the raw materials used are commercially available.
Unless otherwise specifically indicated, various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or can be prepared by existing methods.
The dabigatran etexilate mesylate production mother liquor used in the examples of the present invention is the mother liquor obtained by filtering in steps 3 and 4 of claim 1 of CN 108864048A. In addition, the inventor also experiments 7 reaction routes described in the background art of the specification of CN106543144, and the technical effects of the invention can be achieved by using the filtrate obtained in the preparation and refining of the crude product as mother liquor, which shows that the recovery scheme of the mother liquor for producing dabigatran etexilate mesylate disclosed by the invention has universality.
Example 1
Collecting dabigatran etexilate mesylate production mother liquor, concentrating under reduced pressure at 50 deg.C to dryness, collecting 50g of the evaporated dry matter (HPLC chromatogram is shown in figure 1), putting into 1000ml three-neck flask, adding 300g acetonitrile, stirring and heating to 55-60 deg.C. Adjusting the pH value of the system to 8 by using ammonia water, keeping the temperature and stirring for 1 hour, slowly adding 150g of purified water, continuing to keep the temperature and stirring for 30min after water is added, cooling, observing the crystal precipitation, keeping the temperature and stirring for 1 hour when the crystal is precipitated, continuing to cool to 5 ℃, crystallizing for 4 hours, filtering and drying to obtain 35g of dabigatran etexilate free base.
Putting 35g of dabigatran etexilate free alkali into a 500ml three-necked bottle, adding 210g of ethyl acetate, stirring, heating and dissolving until the solution is clear, wherein the temperature of the solution is 55-60 ℃, keeping the temperature and stirring for 30min, stopping heating, naturally cooling, observing crystal precipitation, keeping the temperature and stirring for 1 hour when the crystal is precipitated, continuously cooling to 5 ℃, crystallizing for 2 hours, filtering, and drying to obtain 24.5g of refined dabigatran etexilate free alkali.
Adding 180g of acetone into a 500ml three-necked bottle, slowly adding 24.5g of refined dabigatran etexilate free alkali, heating, dissolving until the solution is clear, stirring for 1 hour, slowly dropwise adding 3.87g of methanesulfonic acid, keeping the temperature, stirring for 1 hour after the dropwise adding is finished, slowly cooling to 0-5 ℃, keeping the temperature, stirring for 2 hours, filtering and drying to obtain 25.6g of crude dabigatran etexilate mesylate.
25.5g of the dabigatran etexilate mesylate crude product is dissolved in 45g of methanol, filtered, slowly and dropwise added into 225g of acetone preheated to 50 ℃, and stirred for 1 hour under the condition of heat preservation. Cooling to 0-5 deg.C at a rate of 8 deg.C/h, keeping the temperature for 4 hr, and vacuum filtering to obtain filter cake. And putting the filter cake into 50g of acetone, pulping for 0.5-1h at the temperature of 5-10 ℃, performing suction filtration, and performing vacuum drying on the filter cake to constant weight at the temperature of 45 ℃ to obtain 23.6g of dabigatran etexilate mesylate dry weight and 47.2% of yield. The purity of the recovered dabigatran etexilate mesylate was checked by HPLC, and as a result, as shown in fig. 2, it was found from fig. 2 that the purity of the recovered dabigatran etexilate mesylate from the production mother liquor was 99.76%.
Example 2
Collecting dabigatran etexilate mesylate production mother liquor, concentrating under reduced pressure at 50 deg.C to dry, collecting 50g of evaporated dry matter (HPLC chromatogram is shown in figure 1), putting into 1000ml three-neck flask, adding 350g acetonitrile, stirring and heating to 55-60 deg.C. And (3) regulating the pH value of the system to 8 by using triethylamine, keeping the temperature and stirring for 1 hour, slowly adding 180g of purified water, continuing to keep the temperature and stirring for 30min after water is added, cooling, observing that crystals are separated out, keeping the temperature and stirring for 1 hour when the crystals are separated out, continuing cooling to 5 ℃, crystallizing for 5 hours, filtering, and drying to obtain 34.6g of dabigatran etexilate free base.
Putting 34.6g of dabigatran etexilate free alkali into a 500ml three-necked bottle, adding 230g of ethyl acetate, stirring, heating and dissolving until the solution is clear, keeping the temperature and stirring for 30min at the temperature of 55-60 ℃, stopping heating, naturally cooling, observing crystal precipitation, keeping the temperature and stirring for 1 hour when the crystal is precipitated, continuously cooling to 5 ℃, crystallizing for 2 hours, filtering, and drying to obtain 24.2g of refined dabigatran etexilate free alkali.
Adding 190g of acetone into a 500ml three-necked bottle, slowly adding 24.2g of refined dabigatran etexilate free alkali, heating, dissolving until the solution is clear, stirring for 1 hour, slowly dropwise adding 3.82g of methanesulfonic acid, keeping the temperature, stirring for 1 hour after the dropwise adding is finished, slowly cooling to 0-5 ℃, keeping the temperature, stirring for 2 hours, filtering and drying to obtain 25.1g of crude dabigatran etexilate mesylate.
25g of dabigatran etexilate mesylate crude product is dissolved in 75g of ethanol, filtered, slowly dropped into 450g of acetone preheated to 50 ℃, and stirred for 1 hour under the condition of heat preservation. Cooling to 0-5 ℃ at the cooling rate of 7 ℃/h, keeping the temperature for growing the crystals for 6 hours, and filtering to obtain a filter cake. And putting the filter cake into 50g of acetone, pulping for 0.5-1h at 5-10 ℃, performing suction filtration, and performing vacuum drying on the filter cake at 45 ℃ to constant weight to obtain 23.4g of dabigatran etexilate mesylate dry weight, wherein the yield is 46.8%. The purity of the recovered dabigatran etexilate mesylate was checked by HPLC, and as a result, as shown in fig. 3, it was found from fig. 3 that the purity of the recovered dabigatran etexilate mesylate from the production mother liquor was 99.74%.
The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.
Claims (10)
1. A method for recovering and preparing dabigatran etexilate mesylate from production mother liquor is characterized by comprising the following steps:
(1) carrying out reduced pressure distillation on dabigatran etexilate mesylate production mother liquor to constant weight to obtain a solid mixture;
(2) adding acetonitrile into the solid mixture obtained in the step (1), stirring and heating, sequentially adding a pH regulator and purified water, cooling and crystallizing, filtering, and drying a filter cake to obtain dabigatran etexilate free alkali;
(3) adding ethyl acetate into the dabigatran etexilate free alkali obtained in the step (2), heating to dissolve and clear, cooling to crystallize, filtering, and drying a filter cake to obtain refined dabigatran etexilate free alkali;
(4) dissolving the refined dabigatran etexilate free base obtained in the step (3) in acetone, dropwise adding methanesulfonic acid to generate dabigatran etexilate mesylate, crystallizing, filtering, and drying a filter cake to obtain a crude product of dabigatran etexilate mesylate;
(5) dissolving the dabigatran etexilate mesylate crude product obtained in the step (4) in an alcohol solvent, filtering, adding acetone into the filtrate, cooling, crystallizing, growing crystals, filtering, and collecting a filter cake;
(6) and (5) adding acetone into the filter cake obtained in the step (5), pulping, filtering and drying to constant weight to obtain the recovered refined dabigatran etexilate mesylate product.
2. The method for recovering and preparing dabigatran etexilate mesylate from production mother liquor according to claim 1, wherein the production mother liquor of dabigatran etexilate mesylate in the step (1) specifically refers to:
during the preparation and refining of the dabigatran etexilate crude product, after the dabigatran etexilate crude product and methanesulfonic acid salifying reaction, filtrate obtained in the step of crystallization, centrifugation and filtration is carried out; the production mother liquor of dabigatran etexilate mesylate mainly comprises the following components: a crystallization solvent, dabigatran etexilate mesylate and impurities.
3. The method for recovering and preparing dabigatran etexilate mesylate from production mother liquor according to claim 1, wherein the mass ratio of the solid mixture to acetonitrile in the step (2) is 1: (4-8), stirring and heating to 40-70 ℃.
4. The method for recovering and preparing dabigatran etexilate mesylate from production mother liquor according to claim 1, wherein the pH regulator in the step (2) comprises one or more of sodium hydroxide, potassium hydroxide, ammonia water, triethylamine, sodium carbonate, sodium bicarbonate and potassium carbonate; adjusting the pH value of the system to 8-12;
the mass ratio of the solid mixture to the purified water is 1: (2-4).
5. The method for recovering and preparing dabigatran etexilate mesylate from production mother liquor according to claim 1, wherein the mass ratio of the ethyl acetate to the solid mixture in the step (3) is (4-8): 1; after heating and dissolving, stirring for 0.5-1h under heat preservation.
6. The method for recovering and preparing dabigatran etexilate mesylate from production mother liquor according to claim 1, wherein the mass ratio of the refined dabigatran etexilate free base to acetone in step (4) is 1: (6-10), the mass ratio of the methanesulfonic acid to the refined dabigatran etexilate free alkali is (0.156-0.160):1, and after the acetone is added, the mixture can be heated to be dissolved and clear, and is stirred for 0.5-1h under the condition of heat preservation; the crystallization temperature is 0-5 ℃, and the crystallization time is 1-2 h.
7. The method for recovering and preparing dabigatran etexilate mesylate from production mother liquor according to claim 1, wherein the alcohol solvent in step (5) is selected from one or more of methanol, ethanol, isopropanol and n-butanol, and is added in an amount such that the crude dabigatran etexilate mesylate is fully dissolved and the solution is clear; the mass ratio of the acetone to the alcohol solvent is (4-6): 1, the acetone has been preheated to 40-50 ℃.
8. The method for recovering and preparing dabigatran etexilate mesylate from production mother liquor according to claim 1, wherein the temperature reduction mode in the step (5) is a gradient temperature reduction mode, and the temperature reduction rate is 5-10 ℃/h; the temperature of growing crystal is 0-10 ℃, and the time of growing crystal is 2-4 h.
9. The method for recovering and preparing dabigatran etexilate mesylate from production mother liquor as claimed in claim 1, wherein the mass ratio of the acetone to the crude dabigatran etexilate mesylate in the step (6) is (1-3):1, and the crude dabigatran etexilate mesylate is pulped for 0.5-1h at 5-10 ℃ after the acetone is added.
10. The method for recovering and preparing dabigatran etexilate mesylate from production mother liquor according to claim 1, wherein the drying in step (6) is vacuum drying at a temperature of 40-50 ℃.
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