CN106543144A - A kind of industrialized process for preparing of dabigatran etcxilate - Google Patents
A kind of industrialized process for preparing of dabigatran etcxilate Download PDFInfo
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- CN106543144A CN106543144A CN201610858441.4A CN201610858441A CN106543144A CN 106543144 A CN106543144 A CN 106543144A CN 201610858441 A CN201610858441 A CN 201610858441A CN 106543144 A CN106543144 A CN 106543144A
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- 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
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Abstract
The invention discloses a kind of industrialized process for preparing of dabigatran etcxilate, belongs to medicinal chemistry art, its preparation method includes the steps such as condensation reaction, closure cyclization, Pinner reactions successively；The present invention prepares hydrogen chloride/alcohol/ester solution as raw material with acyl chlorides and alcohols, the equipment corrosion that must be brought using hydrogen chloride gas in solving prior art, potential safety hazard is big and the problems such as environmental pollution, the present invention has carried out the optimization for industrially scalable to each step reaction, reduce some unnecessary distillations, extraction, recrystallization process, simplify technique, the purification process of finished product dabigatran etcxilate is improved, in the case where process recovery ratio and product quality is ensured, improve purification efficiency, technique favorable reproducibility, preparation cost is low, it is a kind of Perfected process of preparation of industrialization dabigatran etcxilate.
Description
Technical field
The present invention relates to medicinal chemistry art, more particularly to a kind of industrialized process for preparing of dabigatran etcxilate.
Background technology
(Dabigatran Etexilate, 1), chemistry is entitled for dabigatran etcxilate：3- (2- (((4- (N '-((hexyloxy) carbonyl
Base) carbonamidine) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamides) propionic acid second
Ester, is a kind of new direct thrombin inhibitor.The medicine is dabigatran (Dabigatran, pro-drug 2), with good to eat
Clothes, safe, drug interaction is few, bleeding risk is low, be suitable for crowd it is wide the characteristics of, be clinically mainly used in prevent palsy
The field such as system thrombosis and the postoperative antithrombus formation of orthopaedics.
Dabigatran etcxilate was researched and developed by German Boehringer Ingelheim company (Boehringer-Ingelheim), in 2008 4
Take the lead in the moon in Germany and Britain's listing, trade name：Pradaxa.Since listing, dabigatran etcxilate sales volume is year by year into multiplication
Plus, occupation rate of market is improved rapidly, has become the global the third-largest anticoagulation for being only second to two big heparin at present.Therefore, to raw material
The research and development of medicine dabigatran etcxilate synthetic method, with Great significance.
The synthetic route of the dabigatran etcxilate of existing document report mainly has following several：
Route one：
Patent document WO9837075 first reported the synthetic method of dabigatran etcxilate, 4- methylamino -3- Methyl anthranilates
Acid amide condensation is carried out in CDI/DMF systems with (4- cyano-aniline bases) acetic acid first, Jing LiOH hydrolysis after closed loop, then with protochloride
The intermediate acid chloride that sulfone reaction is obtained, Jing Pinner reactions after acyl chlorides is condensed with 3- (pyridine -2- base amino) ethyl propionate are obtained
Amidine, finally, amidine generates target product dabigatran etcxilate, total recovery 9.6% with the just own ester reaction of chloro-carbonic acid.
The route acid amide condensation reaction, due to the impact of ortho position methylamino, reaction selectivity is relatively low, and intermediate product needs Jing posts
Chromatographic isolation.And Pinner reaction need carry out in the ethanol solution of hydrogen chloride of saturation, poor operability, security risk compared with
Greatly, cause whole piece route preparation cost higher, it is difficult to realize industrial applications.
Route two：
DocumentJ. Med. Chem. 2002, 45, 1757-1766、European patentEP2522662、Chinese Journal of Pharmaceuticals,
2010,41 (5), 321-325, report 4- methylaminos -3- nitros yl benzoic acid and thionyl chloride, 3- (pyridine -2- base amino)
Ethyl propionate first carries out being acylated condensation, then carries out acid amide and be condensed to yield benzimidazole intermediate with (4- cyano-aniline bases) acetic acid,
So as to avoid, the intermediate acylated accessory substance of benzimidazole is more, purification difficult problem, and route total recovery is brought up to
35%。
Acylated condensation product on this basis, is made hydrochloride, then uses Lian Erya by patent document WO2009111997
Sodium sulphate substitutes Pd/C reduction nitros, reduce further cost.And document：Chinese Journal of Pharmaceuticals, 2013,44 (7),
652-654, from zinc powder reduction nitro, has also reached same effect.Document：Fine chemistry industry, 2015,32 (3), 308-
311, Pinner reactions are improved, adds Lewis acid zinc chloride catalytic reactions, the yield that improve the step reaction (to reach
To 90%).
Relative to route one, route two has made certain improvement, but when amidine is prepared, it is still desirable in saturation hydrogen chloride second
Pinner reactions are carried out in alcoholic solution, larger to equipment corrosion, post processing has larger potential safety hazard；Nitro-reduction reaction
In, make reducing agent with sodium dithionite or zinc powder, the three wastes are larger, and environmental protection is relatively costly.Therefore, route two is not solved
The substantive issues such as equipment corrosion, safety and the environmental protection that technique amplification brings.
Route three：
Benzimidazole intermediate is first made hydrobromate by patent document WO2007071743 reports, then molten in ethanolic hydrogen chloride
Pinner reactions are carried out in liquid amidine is obtained.The purpose for making hydrobromate is to improve intermediate stablizing in Pinner reactions
Property, such asWorld patentBenzimidazole intermediate is first made oxalates or dihydrochloride by WO2010045900 reports, then is carried out
Pinner reacts.
More similar methods, are all that benzimidazole is made different salt, such as malate（Document：Chinese new drug is miscellaneous Will, 2012,21 (1), 88-91）, malonate（Document：Chinese Journal of Pharmaceuticals, 2012,43 (12), 961-964）, then
Carry out Pinner reactions.
The route is actual without essential distinction with route one, route two, only increases by a step salt-forming reaction, does not solve
Pinner reactions are difficult to the root problem for amplifying, and also add chemical cost on the contrary.
Route four：
Patent document WO2006000353, patent document WO2007071743 report, with (4- (1,2,4- oxadiazole -5- ketone) -
Base anilino-) acetic acid substitute (4- cyano-aniline bases) acetic acid carry out acid amide condensation reaction, then Qingization Hai Yuan oxadiazoles be amidine, into
Dabigatran etcxilate is obtained with the just own ester reaction of chloro-carbonic acid again after salt.
Route Yin Ru oxadiazole rings are carried out so as to avoid in saturation ethanolic hydrogen chloride as the protection group of cyano group
Pinner prepares amidine, solves route one and route two equipment corrosion and potential safety hazard in technique amplification.But ， oxadiazoles
Compound producing step is tediously long, it is difficult to obtain, and involves great expense, and substantially increases the raw material and cost of labor of the route.
Route five：
Patent document WO2011061080 discloses one kind with 3- ((3- amino -4- methylamino benzoyls)-pyridine -2- base amino)
Ethyl propionate is raw material, carries out replacing with chloroacetic anhydride, cyclization obtains the benzimidazole intermediate of chlorine replacement, while with right
The just own ester of aminobenzene carbonamidine and monoxone carries out substitution reaction and obtains the just own ester of another intermediate, and then both condensation reactions are obtained
To the method for dabigatran etcxilate.
The parent of dabigatran etcxilate is split into two intermediate fragments by the route again, is then respectively synthesized the two again
Fragment, reduces reactions steps, but when the benzimidazole intermediate of chlorine replacement is prepared, needs uses expensive chlorine
Acetic anhydride, and easily there are two replacement side reactions in the reaction, and condition is difficult to control, and technology stability is bad, relatively costly, compares
Other routes do not have clear superiority.
Route six：
Patent document CN105669651 reports, the amino and chloro of two intermediate segments of route five exchanged, and by ammonia
Based compound carries out subsequent reactions into oxalates, it is to avoid the use of chloroacetic anhydride, meanwhile, inventor adopts improved, highly basic
Property under the conditions of Pinner reactions prepare another fragment to chlordimeform, it is to avoid the use of severe corrosive reagent.
The route has certain industrial applications potentiality, but remains a need for solving the benzimidazole intermediate that amino replaces
Stability problem, it is to avoid repeatedly into troublesome operations such as salt, dissociation；Meanwhile, the Pinner amidineizations reaction under strong basicity environment, by-product
Thing is more, and condition control is harsher.
Route seven：
DocumentChinese pharmaceutical chemistry magazine, 2012,22 (3), 204-208, to Pinner reaction improved, using hydrochloric acid
Cyano group is made intermediate oxime by azanol, then reduction amination obtains intermediate amidine under ammonium formate and Pd/C systems, so as to avoid
Using saturation ethanol solution of hydrogen chloride.But accessory substance is more when oxime is reduced, and the difficult reaction of raw material is complete, and product needs Jing post layers
Analysis is isolated and purified, and reduces yield only 67%, is not suitable for industrialization and is amplified.
In sum, although have the synthetic method of more document report dabigatran etcxilate, but these methods presence are obvious
Defect, it is difficult to realize prepared by dabigatran etcxilate and the industrially scalable of intermediate.Especially for the preparation of intermediate amidine, at present
Also there is no a kind of safe and environment-friendly, strong operability and reliable and stable method.On the other hand, in order to ensure the curative effect of clinical application
And security, the quality standard more and more higher that various countries are formulated to pharmaceutical intermediate and bulk drug, the Da Bijia of above-mentioned document report
The synthetic method of group's ester, lacks the research to technical process and control, is not set up perfect raw material and middle weight mark
It is accurate, it is impossible to ensure stablizing for finished product quality, it is difficult to directly apply to preparation of industrialization dabigatran etcxilate.
Therefore, develop method that is new, being adapted to preparation of industrialization dabigatran etcxilate, solve equipment corrosion, chemical toxicity, three
Safety and the environmental issues such as useless process, while carrying out technical process research, realize efficiently separating and quality control for intermediate, obtain
The product of pharmacopoeial quality standard must be met, with great society and economic implications.
The content of the invention
The present invention goal of the invention be：A kind of industrialized process for preparing of dabigatran etcxilate is provided, to solve above-mentioned asking
Topic.
The technical solution used in the present invention is such：A kind of industrialized process for preparing of dabigatran etcxilate, its feature exist
In concretely comprising the following steps：
(1) with compound 3 as raw material, carry out being condensed instead in condensing agent and organic solvent system with (4- cyano-aniline bases) acetic acid
Should, obtain compound 4；
(2) compound 4 obtained by step (1), under acid catalysis, in organic solvent, closure cyclisation, obtains compound 5；
(3) acyl chlorides is mixed with alcohol organic solvent, quantitative reaction is obtained the hydrogen chloride/alcohol/ester solution of prescribed concentration；
(4) compound 5 obtained by step (2), the hydrogen chloride/alcohol/ester solution obtained with step (3) carry out Pinner reactions
Imidate esters are obtained, and without isolation, directly compound 7 are obtained with ammoniacal liquor reaction；
(5) compound 7 obtained by step (4), with the just own ester of halogen formate under alkali and organic solvent effect, reaction is obtained
Dabigatran etcxilate crude product, it is purified, obtain target product；
The compound 3, compound 4, compound 5 and compound 7 and reaction equation are as follows：
。
As preferred technical scheme, in step (1), the condensing agent is CDI（N, N'- carbonyl dimidazoles）、DCC（Two
Carbodicyclo hexylimide）、EDCI（1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides）In one kind；It is described to have
Machine solvent is chloroform, dichloromethane, tetrahydrofuran, 1,4- dioxane, the one kind in isopropyl ether；Compound 3 and condensation
The mol ratio of agent is 1:1.2 ~1:3.0.
Used as further preferred technical scheme, the condensing agent is CDI；The Compound Compound 3 and condensing agent
Mol ratio is 1:1.2.
The consumption of less condensing agent, makes post processing be easier to remove excessive condensing agent, is more favorable to the control of impurity
System, mitigates environmental protection pressure, and so, 4 need of compound are blunged to wash and fully decentralized solid product is obtained.
As preferred technical scheme, in step (2), described acid is inorganic acid or organic acid, and wherein inorganic acid is phosphorus
Acid, organic acid are acetic acid；Described organic solvent is acetonitrile, chloroform, dichloromethane, 1,2- dichloroethanes, tert-butyl group first
One kind in ether；Post-process for neutralizing superacid alkali for the one kind in ammoniacal liquor, sodium carbonate, sodium acid carbonate, NaOH；Weight
Recrystallisation solvent be methyl alcohol, ethanol, isopropanol, N ', the one kind in dinethylformamide, ethyl acetate.
Used as further preferred technical scheme, described organic solvent is 1,2- dichloroethanes, is post-processed for neutralizing
Superacid alkali is sodium acid carbonate.
From lower boiling solvent, be conducive to Distillation recovery；Excessive acid is neutralized from inorganic base, it is easier to extraction point
Layer, operation are easier, more environment friendly.
As preferred technical scheme, in step (3), the acyl chlorides is chloroacetic chloride, the one kind in propionyl chloride；The alcohols
Organic solvent is methyl alcohol, ethanol, the one kind in isopropanol；Described hydrogen chloride/alcohol/ester solution includes hydrogen chloride/methyl alcohol/acetic acid
Methyl ester solution, hydrogen chloride/methyl alcohol/methyl propionate solution, hydrogen chloride/ethanol/ethyl acetate solution, hydrogen chloride/ethanol/propionic acid second
Ester solution, hydrogen chloride/isopropanol/isopropyl acetate solution, hydrogen chloride/isopropanol/isopropyl propionate solution；The chlorine of the preparation
The concentration for changing hydrogen/alcohol/ester solution is 4.0 ~ 12.0mol/L；Acyl chlorides is 1 with the mol ratio of alcohol organic solvent:1.1~1:
4.0。
Used as further preferred technical scheme, the concentration of the hydrogen chloride/alcohol/ester solution of the preparation is 6.0mol/L；
Acyl chlorides is 1 with the mol ratio of alcohol organic solvent:1.6.
As preferred technical scheme, in step (4), compound 5 is 1 with the mol ratio of hydrogen chloride/alcohol/ester solution:
20~1:100。
As preferred technical scheme, in step (5), the just own ester of described halogen formate is the just own ester of chloro-carbonic acid, bromine first
One kind in the just own ester of acid；Described alkali be sodium carbonate, potassium carbonate, saleratus, triethylamine, diisopropylethylamine, in pyridine
One kind；The organic solvent that reacts is in methyl alcohol, ethanol, acetone, isopropanol, dichloromethane, chloroform, isopropyl ether
Kind；Described recrystallization solvent is ethanol, isopropanol, ethyl acetate, the one kind in isopropyl acetate.
Used as further preferred technical scheme, the just own ester of described halogen formate is the just own ester of chloro-carbonic acid, more economical, more
Suitable industrialized production.
Using in dabigatran etcxilate crude product prepared by the technical program, major impurity is the water bigger compared to product polarity
Dissolubility and fat-soluble impurity, therefore, the technical program utilizes the dissolving sex differernce of impurity and product, from solvent cyclohexanone,
Most of oil-soluble impurities is removed by dissolving, the method for filtering, recrystallization number of times is reduced, is improve purification efficiency.
In sum, as a result of above-mentioned technical proposal, the invention has the beneficial effects as follows：
(1) present invention prepares hydrogen chloride/alcohol/ester solution as raw material with acyl chlorides and alcohols, solves necessary in prior art
The problems such as equipment corrosion, big potential safety hazard and environmental pollution for being brought using hydrogen chloride gas；
(2) compared with prior art, the present invention has carried out the optimization for industrially scalable to each step reaction, reduces one
A little unnecessary distillations, extraction, recrystallization process, simplify technique；
(3) compared with prior art, the present invention is improved to the purification process of finished product dabigatran etcxilate, is ensureing work
In the case of skill yield and product quality, purification efficiency is improve；
(4) compared with prior art, the present invention prepares the technique of dabigatran etcxilate, have passed through actual industrial metaplasia and produces checking, matter
Amount is stable, mild condition, safe operation, " three wastes ", pollutes little, and technique favorable reproducibility, preparation cost are low, is a kind of industrialization system
The Perfected process of standby dabigatran etcxilate.
Specific embodiment
The present invention is described in detail below.
In order that the objects, technical solutions and advantages of the present invention become more apparent, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that specific embodiment described herein is not used to only to explain the present invention
Limit the present invention.
Embodiment 1：
A kind of industrialized process for preparing of dabigatran etcxilate, concretely comprises the following steps：
（1）, 3- (3- ((2- (4- cyano-phenyls) amino) acetylamino) -4- (methylamino)-N- (pyridine -2- bases) benzamide)
The preparation of ethyl propionate (4)
The suction chloroform 200kg in 500L reactors, open dog-house, successively put into (4- cyano-aniline bases) acetic acid 11.3kg,
CDI 12.2kg；Feed intake and finish, open stirring, chuck enters coolant, and temperature in the kettle is down to 0～5oC, and insulation reaction 3 is little
When；Dog-house is opened, 3 20kg of compound under tiny structure, is slowly put into；Finish, in discharge chuck after freezing liquid, squeeze into running water
HPLC detections are sampled after being gradually heating to reaction be stirred at room temperature 24 hours, compound 3≤1%, compound 4 >=95.0% stop
Reaction；Suction 50kg water, stirring squeeze into hot water circuit in chuck, chloroform is reclaimed in vacuum distillation（Can apply mechanically）To doing, raffinate is quick
Stirring disperses solid；Rejection filter, is dried, censorship, packaging, warehouse-in；Off-white powder 28.2kg, HPLC purity 99.3%, mole
Yield 97.2%；mp: 112.4~112.9oC；
（2）, 3- (2- (((4- cyano-phenyls) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5-
Acylamino-) ethyl propionate (5) preparation
Dog-house is opened in the suction 1 in 500L reactors, 2- dichloroethanes 141kg, phosphatase 11 6.9kg, puts into compound 4
28.2kg, is steam heated to 80 ~ 85oC back flow reactions 10 hours；Steam off, chuck enter running water, are cooled to room temperature, by height
Position groove is slowly added to ammoniacal liquor, adjusts pH=9；Stand, layering, organic phase washed with water once, is dried, and suction filtration, filtrate draw back reaction
In kettle, hot water circuit is squeezed in stirring in chuck, 1,2- dichloroethanes is reclaimed in vacuum distillation（Can apply mechanically）It is extremely dry；Suction 35kg first
Alcohol, stirring are steam heated to residue dissolving clarification after backflow, are then shut off steam, and chuck enters running water, slowly cools to room
Temperature, rejection filter, a small amount of methyl alcohol drip washing are dried, censorship, packaging, warehouse-in；Off-white powder 22.5kg is obtained, HPLC purity 98.9% is rubbed
That yield 82.7%；mp: 152.1~152.9oC；
（3）, 3- (2- (((4- first carbamimido-phenyls) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- first
Amide groups) propionate hydrochloride (7) preparation
Suction absolute methanol 89.5kg in dry, clean reactor, stirring, chuck enter coolant and are cooled to 10oBelow C；By height
Position groove is slowly added dropwise chloroacetic chloride 146.5kg, and drop finishes, insulation 10oC is stirred below 3 hours, obtains final product hydrogen chloride/methyl alcohol/acetic acid first
Ester solution, titration detect that its molar concentration is 9.7mol/L；Under tiny structure, 5 22.5kg of compound is put into, open steam heating
To 40oC stirring reactions 10 hours；Concentrated ammonia liquor is slowly added dropwise by head tank, pH=9 is adjusted, is opened and be steam heated to 50oC stirring reactions
10 hours；Vacuum distillation, reclaims methyl alcohol and methyl acetate, and then suction water 67.5kg, ethyl acetate 180kg in reactor, stir
Mix, open and be steam heated to 80 ~ 90oC flows back 30 minutes, now residue dissolving clarification；Steam off, chuck enter running water, delay
Slowly it is cooled to room temperature；Rejection filter, filter cake are stirred with water successively and are washed twice, and ethyl acetate is stirred to be washed twice, is dried, censorship, packaging, warehouse-in；
Obtain off-white powder 18.7kg, HPLC purity 97.6%, molar yield 74.8%；mp: 120.6~121.3oC；
（4）, 3- (2- (((4- (N '-((hexyloxy) carbonyl) carbonamidine) phenyl) amino) methyl) -1- methyl-N- (pyridine -2-
Base) -1H- benzos [d] imidazoles -5- formamides) ethyl propionate (1) preparation
Suction isopropyl ether 93.5kg in dry, clean reactor, opens dog-house, puts into 7 18.7kg of compound, and room temperature is stirred
Mix to dissolving clarification；The just own ester 8.6kg of suction triethylamine 5.3kg, bromine formic acid successively, stirring reaction 6 hours under room temperature；Chuck enters
Coolant, is cooled to interior temperature 5oBelow C, is slowly dropped into water 93.5kg by head tank；Drop finishes, and continues insulation 0 ~ 5oC stirring analysis
It is brilliant 5 hours；Rejection filter, filter cake suitable quantity of water are fully washed twice, and obtain light yellow solid；Suction cyclohexanone 150kg in crystallization kettle,
Dog-house is opened, light yellow solid wet product obtained above is put into, is stirred 30 minutes under room temperature, is made most of solid dissolving；Take out
Filter, filter cake are discarded, and filtrate proceeds to distillation still, open steam heating, and cyclohexanone is reclaimed in vacuum distillation（Can apply mechanically）It is extremely dry；Then react
Suction isopropanol 84kg in kettle, opens dog-house, puts into activated carbon 1kg, and stirring is opened after being steam heated to backflow 30 minutes, taken advantage of
Hot suction filtration, filtrate are proceeded in crystallization kettle, and chuck enters coolant, are cooled to interior temperature 10oBelow C, and stirring and crystallizing 3 hours；Get rid of
Filter, washing are dried, censorship, packaging, warehouse-in；Off-white powder 11.5kg is obtained, HPLC purity 99.6%, maximum list miscellaneous 0.06% are rubbed
That yield 52.5%；mp: 132.3~132.7oC。
Embodiment 2
A kind of industrialized process for preparing of dabigatran etcxilate, concretely comprises the following steps：
（1）, 3- (3- ((2- (4- cyano-phenyls) amino) acetylamino) -4- (methylamino)-N- (pyridine -2- bases) benzamide)
The preparation of ethyl propionate (4)
Suction Isosorbide-5-Nitrae-dioxane 200kg in 500L reactors, opens dog-house, puts into (4- cyano-aniline bases) acetic acid successively
11.3kg、EDCI-HCl 13.5kg、DMAP 14.3kg；Feed intake and finish, open stirring, chuck enters coolant, temperature in the kettle drop
To 0～5oC, and insulation reaction 3 hours；Dog-house is opened, 3 20kg of compound under tiny structure, is slowly put into；Finish, discharge folder
In set after freezing liquid, squeeze into and after running water is gradually heating to reaction be stirred at room temperature 24 hours, sample HPLC detections, compound 3≤
1%, compound 4 >=95.0% stops reaction；Suction 50kg water, stirring squeeze into hot water circuit in chuck, vacuum distillation reclaims 1,
4- dioxane（Can apply mechanically）To doing, quickly stirring disperses solid to raffinate；Rejection filter, is dried, censorship, packaging, warehouse-in；Obtain class white
Color solid 27.6kg, HPLC purity 99.8%, molar yield 94.3%；mp: 113.0~113.5oC；
（2）, 3- (2- (((4- cyano-phenyls) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5-
Acylamino-) ethyl propionate (5) preparation
Suction t-butyl methyl ether 138kg in 500L reactors, acetic acid 13.2kg open dog-house, put into compound 4
27.6kg, is steam heated to 80 ~ 85oC back flow reactions 10 hours；Steam off, chuck enter running water, are cooled to room temperature, by height
Position groove is slowly added to saturated sodium carbonate solution, adjusts pH=9；Stand, layering, organic phase washed with water once, is dried, suction filtration, filter
Liquid is drawn back in reactor, stirring, and hot water circuit is squeezed in chuck, and t-butyl methyl ether is reclaimed in vacuum distillation（Can apply mechanically）It is extremely dry；Take out
Enter 45kg isopropanols, stir, be steam heated to residue dissolving clarification after backflow, be then shut off steam, chuck enters running water, delays
Slow cool down is dried, censorship to room temperature, rejection filter, a small amount of methyl alcohol drip washing, packaging, warehouse-in；Off-white powder 22.1kg is obtained, HPLC is pure
Degree 98.4%, molar yield 83.1%；mp: 151.7~152.3oC；
（3）, 3- (2- (((4- first carbamimido-phenyls) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- first
Amide groups) propionate hydrochloride (7) preparation
Suction absolute ethyl alcohol 164kg in dry, clean reactor, stirring, chuck enter coolant and are cooled to 10oBelow C；By height
Position groove is slowly added dropwise propionyl chloride 254kg, and drop finishes, insulation 10oC is stirred below 3 hours, obtains final product hydrogen chloride/ethanol/ethyl propionate
Solution, titration detect that its molar concentration is 7.1mol/L；Under tiny structure, 5 22.1kg of compound is put into, is opened and is steam heated to
40 oC stirring reactions 10 hours；Concentrated ammonia liquor is slowly added dropwise by head tank, pH=9 is adjusted, is opened and be steam heated to 50oC stirring reactions 10
Hour；Vacuum distillation, reclaims ethanol and ethyl propionate, then suction water 66.5kg, ethyl acetate 177kg in reactor, stirring,
Open and be steam heated to 80 ~ 90oC flows back 30 minutes, now residue dissolving clarification；Steam off, chuck enter running water, slowly
It is cooled to room temperature；Rejection filter, filter cake are stirred with water successively and are washed twice, and ethyl acetate is stirred to be washed twice, is dried, censorship, packaging, warehouse-in；
Off-white powder 18.5kg, HPLC purity 98.2%, molar yield 75.4%；mp: 120.8~121.4oC；
（4）, 3- (2- (((4- (N '-((hexyloxy) carbonyl) carbonamidine) phenyl) amino) methyl) -1- methyl-N- (pyridine -2-
Base) -1H- benzos [d] imidazoles -5- formamides) ethyl propionate (1) preparation
Suction ethanol 92.5kg in dry, clean reactor, opens dog-house, puts into 7 18.5kg of compound, is stirred at room temperature
To dissolving clarification；The just own ester 7.8kg of suction triethylamine 5.2kg, chloro-carbonic acid successively, stirring reaction 6 hours under room temperature；Chuck enters cold
But liquid, is cooled to interior temperature 5oBelow C, is slowly dropped into water 92.5kg by head tank；Drop finishes, and continues insulation 0 ~ 5oC stirring and crystallizings 5
Hour；Rejection filter, filter cake suitable quantity of water are fully washed twice, and obtain light yellow solid；In crystallization kettle, suction cyclohexanone 148kg, beats
Dog-house is opened, light yellow solid wet product obtained above is put into, is stirred 30 minutes under room temperature, is made most of solid dissolving；Suction filtration,
Filter cake is discarded, and filtrate proceeds to distillation still, opens steam heating, and cyclohexanone is reclaimed in vacuum distillation（Can apply mechanically）It is extremely dry；Then reactor
Middle suction ethanol 83kg, opens dog-house, puts into activated carbon 1kg, and stirring is opened after being steam heated to backflow 30 minutes, taken out while hot
Filter, filtrate are proceeded in crystallization kettle, and chuck enters coolant, is cooled to interior temperature 10oBelow C, and stirring and crystallizing 3 hours；Rejection filter, washes
Wash, be dried, censorship, packaging, warehouse-in；Obtain off-white powder 11.7kg, HPLC purity 99.8%, maximum list miscellaneous 0.03%, mole receipts
Rate 54.0%；mp: 132.5~132.9oC。
Embodiment 3
A kind of industrialized process for preparing of dabigatran etcxilate, concretely comprises the following steps：
（1）3- (3- ((2- (4- cyano-phenyls) amino) acetylamino) -4- (methylamino)-N- (pyridine -2- bases) benzamide)
The preparation of ethyl propionate (4)
The suction dichloromethane 1000kg in 3000L reactors, opens dog-house, puts into (4- cyano-aniline bases) acetic acid successively
62kg、CDI 62kg；Feed intake and finish, open stirring, chuck enters coolant, and temperature in the kettle is down to 0～5oC, and insulation reaction 6
Hour；Dog-house is opened, 3 100kg of compound under tiny structure, is slowly put into；Finish, in discharge chuck after freezing liquid, squeeze into certainly
Water samples HPLC after being gradually heating to reaction be stirred at room temperature 24 hours and detects, compound 3≤1%, compound 4 >=95.0%,
Stop reaction；Suction 250kg water, stirring squeeze into hot water circuit in chuck, dichloromethane is reclaimed in vacuum distillation（Can apply mechanically）Extremely
Dry, quickly stirring disperses solid to raffinate；Rejection filter, is dried, censorship, packaging, warehouse-in；Obtain off-white powder 145kg, HPLC purity
98.8%, molar yield 99.3%；mp: 111.8~112.3oC；
（2）, 3- (2- (((4- cyano-phenyls) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5-
Acylamino-) ethyl propionate (5) preparation
The suction dichloromethane 500kg in 2000L reactors, acetic acid 48kg, open dog-house, put into 4 100kg of compound, steam
Vapour is heated to 80 ~ 85oC back flow reactions 10 hours；Steam off, chuck enter running water, are cooled to room temperature, slow by head tank
Ammoniacal liquor is added, pH=9 is adjusted；Stand, layering, organic phase washed with water once, is dried, and suction filtration, filtrate are drawn back in reactor, stirred
Mix, in chuck, squeeze into hot water circuit, dichloromethane is reclaimed in vacuum distillation（Can apply mechanically）It is extremely dry；Suction 125kg absolute ethyl alcohols, stir
Mix, be steam heated to residue dissolving clarification after backflow, be then shut off steam, chuck enters running water, is slowly cooled to room temperature, and gets rid of
Filter, a small amount of absolute ethyl alcohol drip washing are dried, censorship, packaging, warehouse-in；Obtain off-white powder 80kg, HPLC purity 99.1%, mole receipts
Rate 83.3%；mp: 151.8~152.6oC；
（3）, 3- (2- (((4- first carbamimido-phenyls) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- first
Amide groups) propionate hydrochloride (7) preparation
Suction absolute methanol 371kg in dry, clean reactor, stirring, chuck enter coolant and are cooled to 10oBelow C；By height
Position groove is slowly added dropwise propionyl chloride 670kg, and drop finishes, insulation 10oC is stirred below 5 hours, obtains final product hydrogen chloride/methyl alcohol/methyl propionate
Solution, titration detect that its molar concentration is 7.9mol/L；Under tiny structure, 5 100kg of compound is put into, is opened and is steam heated to 40oC stirring reactions 15 hours；Concentrated ammonia liquor is slowly added dropwise by head tank, pH=9 is adjusted, is opened and be steam heated to 50oC stirring reactions 15 are little
When；Vacuum distillation, reclaims methyl alcohol and methyl propionate, then suction water 300kg, ethyl acetate 800kg in reactor, and stirring is opened
It is steam heated to 80 ~ 90oC flows back 1 hour, now residue dissolving clarification；Steam off, chuck enter running water, slow cooling
To room temperature；Rejection filter, filter cake are stirred with water successively and are washed twice, and ethyl acetate is stirred to be washed twice, is dried, censorship, packaging, warehouse-in；Obtain class white
Color solid 79kg, HPLC purity 98.2%, molar yield 71.1%；mp: 120.9~121.7oC；
（4）, 3- (2- (((4- (N '-((hexyloxy) carbonyl) carbonamidine) phenyl) amino) methyl) -1- methyl-N- (pyridine -2-
Base) -1H- benzos [d] imidazoles -5- formamides) ethyl propionate (1) preparation
Be dried, suction acetone 500kg in clean reactor, open dog-house, put into 7 100kg of compound, be stirred at room temperature to
Dissolving clarification；The just own ester 42kg of suction pyridine 22kg, chloro-carbonic acid successively, stirring reaction 10 hours under room temperature；Chuck enters coolant,
It is cooled to interior temperature 5oBelow C, is slowly dropped into water 500kg by head tank；Drop finishes, and continues insulation 0 ~ 5oC stirring and crystallizings 15 hours；
Rejection filter, filter cake suitable quantity of water are fully washed twice, and obtain light yellow solid；Suction cyclohexanone 800kg in crystallization kettle, opening feed intake
Mouthful, light yellow solid wet product obtained above is put into, is stirred 30 minutes under room temperature, is made most of solid dissolving；Suction filtration, filter cake are abandoned
Go, filtrate proceeds to distillation still, open steam heating, cyclohexanone is reclaimed in vacuum distillation（Can apply mechanically）It is extremely dry；Then suction in reactor
Ethyl acetate 450kg, opens dog-house, puts into activated carbon 5kg, and stirring is opened after being steam heated to backflow 30 minutes, taken out while hot
Filter, filtrate are proceeded in crystallization kettle, and chuck enters coolant, is cooled to interior temperature 10oBelow C, and stirring and crystallizing 10 hours；Rejection filter, washes
Wash, be dried, censorship, packaging, warehouse-in；Obtain off-white powder 64kg, HPLC purity 99.5%, maximum list miscellaneous 0.07%, molar yield
54.7%；mp: 132.8~133.5oC。
Embodiment 4
A kind of industrialized process for preparing of dabigatran etcxilate, concretely comprises the following steps：
（1）, 3- (3- ((2- (4- cyano-phenyls) amino) acetylamino) -4- (methylamino)-N- (pyridine -2- bases) benzamide)
The preparation of ethyl propionate (4)
The suction isopropyl ether 1000kg in 3000L reactors, opens dog-house, puts into (4- cyano-aniline bases) acetic acid successively
62kg、CDI 66kg；Feed intake and finish, open stirring, chuck enters coolant, and temperature in the kettle is down to 0～5oC, and insulation reaction 6
Hour；Dog-house is opened, 3 100kg of compound under tiny structure, is slowly put into；Finish, in discharge chuck after freezing liquid, squeeze into certainly
Water samples HPLC after being gradually heating to reaction be stirred at room temperature 24 hours and detects, compound 3≤1%, compound 4 >=95.0%,
Stop reaction；Suction 250kg water, stirring squeeze into hot water circuit in chuck, isopropyl ether is reclaimed in vacuum distillation（Can apply mechanically）It is extremely dry,
Quickly stirring disperses solid to raffinate；Rejection filter, is dried, censorship, packaging, warehouse-in；Obtain off-white powder 139kg, HPLC purity
98.3%, molar yield 95.2%；mp: 111.6~112.2oC；
（2）, 3- (2- (((4- cyano-phenyls) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5-
Acylamino-) ethyl propionate (5) preparation
The suction acetonitrile 500kg in 2000L reactors, acetic acid 48kg, open dog-house, put into 4 100kg of compound, and steam adds
Heat is to 80 ~ 85oC back flow reactions 10 hours；Steam off, chuck enter running water, are cooled to room temperature, are slowly added to by head tank
Saturated sodium bicarbonate solution, adjusts pH=9；Stand, layering, organic phase washed with water once, is dried, and suction filtration, filtrate draw back reaction
In kettle, hot water circuit is squeezed in stirring in chuck, acetonitrile is reclaimed in vacuum distillation（Can apply mechanically）It is extremely dry；Suction N ' N- dimethyl formyls
Amine 125kg, stirring, is steam heated to 80 ~ 90oAfter C, residue dissolving clarification, is then shut off steam, and chuck enters running water, delays
Slow cool down is dried, censorship to room temperature, rejection filter, a small amount of N ' dinethylformamides 125kg drip washing, packaging, warehouse-in；Obtain off-white color
Solid 77kg, HPLC purity 99.5%, molar yield 80.2%；mp: 152.0~152.9oC；
（3）, 3- (2- (((4- first carbamimido-phenyls) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- first
Amide groups) propionate hydrochloride (7) preparation
Suction isopropanol 671kg in dry, clean reactor, stirring, chuck enter coolant and are cooled to 10oBelow C；By a high position
Groove is slowly added dropwise propionyl chloride 325kg, and drop finishes, insulation 10oC is stirred below 5 hours, obtains final product hydrogen chloride/isopropanol/propionic acid isopropyl
Ester solution, titration detect that its molar concentration is 4.1mol/L；Under tiny structure, 5 100kg of compound is put into, is opened and is steam heated to
40 oC stirring reactions 15 hours；Concentrated ammonia liquor is slowly added dropwise by head tank, pH=9 is adjusted, is opened and be steam heated to 50oC stirring reactions 15
Hour；Vacuum distillation, reclaims isopropanol and isopropyl propionate, and then suction water 300kg, ethyl acetate 800kg in reactor, stir
Mix, open and be steam heated to 80 ~ 90oC flows back 1 hour, now residue dissolving clarification；Steam off, chuck enter running water, delay
Slowly it is cooled to room temperature；Rejection filter, filter cake are stirred with water successively and are washed twice, and ethyl acetate is stirred to be washed twice, is dried, censorship, packaging, warehouse-in；
Obtain off-white powder 83kg, HPLC purity 97.6%, molar yield 74.7%；mp: 120.0~120.7oC；
（4）, 3- (2- (((4- (N '-((hexyloxy) carbonyl) carbonamidine) phenyl) amino) methyl) -1- methyl-N- (pyridine -2-
Base) -1H- benzos [d] imidazoles -5- formamides) ethyl propionate (1) preparation
Suction dichloromethane 500kg in dry, clean reactor, opens dog-house, input 7 100kg of compound, bicarbonate
Potassium 28kg, is stirred at room temperature 30 minutes；The just own ester 54kg of suction bromine formic acid, stirring reaction 8 hours under room temperature；Chuck enters coolant,
It is cooled to interior temperature 5oBelow C, is slowly dropped into water 500kg by head tank；Drop finishes, and continues insulation 0 ~ 5oC stirring and crystallizings 15 hours；
Rejection filter, filter cake suitable quantity of water are fully washed twice, and obtain light yellow solid；Suction cyclohexanone 800kg in crystallization kettle, opening feed intake
Mouthful, light yellow solid wet product obtained above is put into, is stirred 30 minutes under room temperature, is made most of solid dissolving；Suction filtration, filter cake are abandoned
Go, filtrate proceeds to distillation still, open steam heating, cyclohexanone is reclaimed in vacuum distillation（Can apply mechanically）It is extremely dry；Then suction in reactor
Isopropyl acetate 450kg, opens dog-house, puts into activated carbon 5kg, and stirring is opened after being steam heated to backflow 30 minutes, taken out while hot
Filter, filtrate are proceeded in crystallization kettle, and chuck enters coolant, is cooled to interior temperature 10oBelow C, and stirring and crystallizing 10 hours；Rejection filter, washes
Wash, be dried, censorship, packaging, warehouse-in；Obtain off-white powder 67kg, HPLC purity 99.8%, maximum list miscellaneous 0.05%, molar yield
57.3%, mp: 133.4~133.9oC。
Claims (10)
1. a kind of industrialized process for preparing of dabigatran etcxilate, it is characterised in that concretely comprise the following steps：
(1) with compound 3 as raw material, carry out being condensed instead in condensing agent and organic solvent system with (4- cyano-aniline bases) acetic acid
Should, obtain compound 4；
(2) compound 4 obtained by step (1), under acid catalysis, in organic solvent, closure cyclisation, obtains compound 5；
(3) acyl chlorides is mixed with alcohol organic solvent, quantitative reaction is obtained the hydrogen chloride/alcohol/ester solution of prescribed concentration；
(4) compound 5 obtained by step (2), the hydrogen chloride/alcohol/ester solution obtained with step (3) carry out Pinner reactions
Imidate esters are obtained, and without isolation, directly compound 7 are obtained with ammoniacal liquor reaction；
(5) compound 7 obtained by step (4), with the just own ester of halogen formate under alkali and organic solvent effect, reaction is obtained
Dabigatran etcxilate crude product, it is purified, obtain target product；
The compound 3, compound 4, compound 5 and compound 7 and reaction equation are as follows：
。
2. the industrialized process for preparing of dabigatran etcxilate according to claim 1, it is characterised in that in step (1), described
Condensing agent is the one kind in CDI, DCC, EDCI；The organic solvent is chloroform, dichloromethane, tetrahydrofuran, 1,4- bis-
One kind in six ring of oxygen, isopropyl ether；Compound 3 is 1 with the mol ratio of condensing agent:1.2 ~1:3.0, preferably 1:1.2.
3. the industrialized process for preparing of dabigatran etcxilate according to claim 1, it is characterised in that in step (2), described
Acid be inorganic acid or organic acid, the inorganic acid is preferably phosphoric acid, and the organic acid is preferably acetic acid；Described organic solvent
For the one kind in acetonitrile, chloroform, dichloromethane, 1,2- dichloroethanes, t-butyl methyl ether, preferably 1,2- dichloroethanes.
4. the industrialized process for preparing of dabigatran etcxilate according to claim 1, it is characterised in that in step (2), cyclisation
After post-processed, including the excessive acid of neutralization, then recrystallize.
5. the industrialized process for preparing of dabigatran etcxilate according to claim 4, it is characterised in that for neutralizing excess acid
Alkali be ammoniacal liquor, sodium carbonate, sodium acid carbonate, the one kind in NaOH, preferred sodium acid carbonate；Recrystallization solvent is methyl alcohol, second
Alcohol, isopropanol, N ', the one kind in dinethylformamide, ethyl acetate.
6. the industrialized process for preparing of dabigatran etcxilate according to claim 1, it is characterised in that in step (3), described
Acyl chlorides is chloroacetic chloride, the one kind in propionyl chloride；The alcohol organic solvent is methyl alcohol, ethanol, the one kind in isopropanol；Described
Hydrogen chloride/alcohol/ester solution include hydrogen chloride/methanol/methyl acetate solution, hydrogen chloride/methyl alcohol/methyl propionate solution, hydrogen chloride/
Ethanol/ethyl acetate solution, hydrogen chloride/ethanol/ethyl propionate solution, hydrogen chloride/isopropanol/isopropyl acetate solution, chlorination
One kind in hydrogen/isopropanol/isopropyl propionate solution；The concentration of the hydrogen chloride/alcohol/ester solution of the preparation be 4.0 ~
12.0mol/L, preferred 6.0mol/L；Acyl chlorides is 1 with the mol ratio of alcohol organic solvent:1.1~1:4.0, preferably 1:1.6.
7. the industrialized process for preparing of dabigatran etcxilate according to claim 1, it is characterised in that in step (4), chemical combination
Thing 5 is 1 with the mol ratio of hydrogen chloride/alcohol/ester solution:20~1:100.
8. the industrialized process for preparing of dabigatran etcxilate according to claim 1, it is characterised in that step（5）In, it is described
Way of purification is：After the dabigatran etcxilate crude product filters major impurity in being dissolved in cyclohexanone, tied with organic solvent again
Crystalline substance is twice.
9. the industrialized process for preparing of dabigatran etcxilate according to claim 8, it is characterised in that described recrystallization is molten
Agent is ethanol, isopropanol, ethyl acetate, the one kind in isopropyl acetate.
10. the industrialized process for preparing of dabigatran etcxilate according to claim 1, it is characterised in that step（5）In, it is described
The just own ester of halogen formate be the just own ester of chloro-carbonic acid, the one kind in the just own ester of bromine formic acid, the just own ester of preferred chloro-carbonic acid；Described alkali
For the one kind in sodium carbonate, potassium carbonate, saleratus, triethylamine, diisopropylethylamine, pyridine；It is described reaction organic solvent be
One kind in methyl alcohol, ethanol, acetone, isopropanol, dichloromethane, chloroform, isopropyl ether.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114716411A (en) * | 2022-04-29 | 2022-07-08 | 天方药业有限公司 | Method for recovering and preparing dabigatran etexilate mesylate from production mother liquor |
| WO2022198361A1 (en) * | 2021-03-22 | 2022-09-29 | 天津睿创康泰生物技术有限公司 | Novel crystal form of dabigatran etexilate ethyl ester hydrochloride, preparation method therefor and use thereof |
| CN115417854A (en) * | 2022-09-21 | 2022-12-02 | 安徽美诺华药物化学有限公司 | Preparation method of key intermediate of anticoagulant drug |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2522662A1 (en) * | 2011-05-11 | 2012-11-14 | Medichem, S.A. | Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers |
| CN105566297A (en) * | 2015-12-31 | 2016-05-11 | 哈药集团技术中心 | Preparation method of dabigatran etexilate mesylate |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2522662A1 (en) * | 2011-05-11 | 2012-11-14 | Medichem, S.A. | Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers |
| CN105566297A (en) * | 2015-12-31 | 2016-05-11 | 哈药集团技术中心 | Preparation method of dabigatran etexilate mesylate |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022198361A1 (en) * | 2021-03-22 | 2022-09-29 | 天津睿创康泰生物技术有限公司 | Novel crystal form of dabigatran etexilate ethyl ester hydrochloride, preparation method therefor and use thereof |
| CN114716411A (en) * | 2022-04-29 | 2022-07-08 | 天方药业有限公司 | Method for recovering and preparing dabigatran etexilate mesylate from production mother liquor |
| CN114716411B (en) * | 2022-04-29 | 2024-03-15 | 天方药业有限公司 | Method for recovering and preparing dabigatran etexilate mesylate from production mother liquor |
| CN115417854A (en) * | 2022-09-21 | 2022-12-02 | 安徽美诺华药物化学有限公司 | Preparation method of key intermediate of anticoagulant drug |
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