CN104177337B

CN104177337B - A kind of intermediate of dabigatran etcxilate and preparation method thereof

Info

Publication number: CN104177337B
Application number: CN201410202121.4A
Authority: CN
Inventors: 陈洪; 杜全胜; 赵永龙; 李芳群; 徐同利; 曾琴; 向志祥
Original assignee: Haisike Pharmaceutical Group Ltd By Share Ltd
Current assignee: Haisike Pharmaceutical Group Ltd By Share Ltd
Priority date: 2013-05-28
Filing date: 2014-05-14
Publication date: 2019-04-23
Anticipated expiration: 2034-05-14
Also published as: CN104177337A

Abstract

The invention discloses the new intermediate forms of one kind of dabigatran etcxilate, that is the salt of 3- shown in Formula V-A [[[2- [[[4- [[ethyoxyl] formimino group] phenyl] amino] methyl] -1- methyl-1 H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] ethyl propionate, it such purity salt and has good stability, it can store and be used as process intermediates or starting material for a long time, and when preparing subsequent intermediates and dabigatran etcxilate, operation is easy, product purity is high, is conducive to industrial applications.

Description

A kind of intermediate of dabigatran etcxilate and preparation method thereof

Technical field

The present invention relates to pharmacy and organic chemistry filed, and in particular to a kind of new centre of anticoagulant dabigatran etcxilate Body, the preparation method of this new intermediate and its application for being used to prepare dabigatran etcxilate.

Background technique

In recent years, cerebrovascular disease incidence of disease is in rising trend, has seriously endangered human health, wherein thrombus or bolt Related disease caused by filling in is currently to lead to disabled and dead primary factor.The prevention and treatment of thrombus and its complication has become the world The important topic that medical field faces.Anticoagulation medicine can be effectively improved with cardiovascular and cerebrovascular disease caused by pre- preventing thrombosis, reduce dead Rate is died, thus the research and development of related drugs have become the hot spot for the treatment of cardiovascular disease.

For more than half a century, anticoagulation medicine is mainly made of vitamin K antagon and heparin substance.Wherein warfarin It (Warfarin) is that clinically the orally active vitamin K antagon of only one and only one are approved the anticoagulant of prolonged application Blood drug.Warfarin is although effectively, also bring along the bleeding risk of serious even lethal；Meanwhile because of the individual of pharmacokinetics Otherness is big, and drug interaction is complicated, and the influence vulnerable to diet, is clinically difficult to correct, easily determining to medicament Amount, palpus frequent progress coagulation function monitoring, compliance are poor；In addition, it works compared with slow, therapeutic window is relatively narrow.And heparin substance because Drug administration by injection is needed, therefore is often limited the use of in inpatient or prevented in short term venous thromboembolism；It is equally needed when the clinical application of heparin Coagulation function detection is carried out, side effect includes inducing decrease of platelet and osteoporosis etc..Therefore, urgent clinical needs it is new, The oral anticoagulant drug safer, medication is easier.

Dabigatran etcxilate (Dabigatran etexilate, formula I), the entitled 3- [[[2- [[[4- [[[(hexyloxy) of chemistry Carbonyl] amino] formimino group] phenyl] amino] methyl] -1- methyl-1 H- benzimidazole -5- base] carbonyl] (pyridine -2- base) Amino] ethyl propionate, it is the novel anticoagulation medicine developed by German Boehringer Ingelheim company, passes through on March 18th, 2008 The listing of EMEA is ratified, and April is first in Germany and Britain's listing；On October 19th, 2010 is ratified by the listing of U.S. FDA.It reaches Than adding group ester to be that the anticoagulation of the first listing over 50 years after warfarin takes orally new drug, it is known as anticoagulant therapy field and dives Another milestone in lethal thrombus prevention field.Dabigatran etcxilate is bi precursor drug, is converted into vivo active Dabigatran (Dabigatran, formula II), the latter by directly inhibit fibrin ferment and play anticoagulation effect.Dabigatran etcxilate System's oral administration, have the characteristics that it is potent, lack without special Medication monitor, drug interaction, to prevention of deep vein thrombosis and Prevent stroke etc. from having obvious action, successfully listing indicates the important breakthrough of anticoagulation medicine research field.

Patent CN1248251A makes public for the first time dabigatran etcxilate and dabigatran and preparation method thereof, the preparation method Are as follows:

Above-mentioned preparation method reacts compound IV in the ethanol solution of hydrogen chloride of saturation, then steams hydrogen chloride second Alcohol；Residue is dissolved in ethyl alcohol to react overnight with ammonium carbonate, chromatographs to obtain the hydrochloride of amidification object III, amidification object through precipitation, column The hydrochloride of III in the presence of potassium carbonate, is reacted with the just own ester of chloro-carbonic acid, and Da Bijia is made in post-treated and column chromatographic purifying Group's ester I.

Patent CN1861596A reacts compound IV in the ethanol solution of hydrogen chloride of saturation, is then concentrated；Residue It is reacted in the ammonia ethyl alcohol of saturation, concentrated, column chromatographs to obtain the hydrochloride of amidification object III, and the hydrochloride of amidification object III exists In the presence of potassium hydroxide, reacted with the just own ester of chloro-carbonic acid, post-treated and column chromatographic purifying obtains dabigatran etcxilate I.

Patent CN101600709A is anti-in ethanol solution of hydrogen chloride by the hydrobromate of intermediate compound IV and p-methyl benzenesulfonic acid It answers, then ethyl alcohol dilutes, and ammonium hydroxide reaction is added, steams part ethyl alcohol, is diluted with water, crystallization, pair of dry amidification object III Toluene fulfonate.The purity of the tosilate of the resulting amidification object III of this method is not high.

Patent WO2010045900 reacts the oxalates of compound IV in ethanol solution of hydrogen chloride, is then concentrated；It is residual Excess is dissolved in ethyl alcohol, and ammonium carbonate reaction is added, and is filtered to remove insoluble matter, and concentrating filter liquor, is done ethyl acetate/alcohol crystal The dry ethanolates for obtaining amidification object III hydrochloride, purity 89%；By the ethanolates of amidification object III hydrochloride be dissolved in ethyl alcohol and In the mixed solution of ethyl acetate, it is added equimolar ethanolic hydrogen chloride liquid, crystallization, filtering, the disalt of dry amidification object III Hydrochlorate, purity 96%；The dihydrochloride of amidification object III reacts to obtain dabigatran in the presence of triethylamine, with the just own ester of chloro-carbonic acid Ester I.

Due to the above method there are column chromatographic runs, steam that corrosive gas hydrogen chloride, intermediate purity is not high, it is big to generate Amount by-product ammonium chloride etc. is unfavorable for the factor of industrialized production.Patent CN102985416A improves the above method, During preparing amidification object III by the hydrochloride of compound IV, Intermediates chemical combination has been isolated under nitrogen protection Object V-1 (HCl in this structural formula represents 1 or 1 or more HCl), i.e. 3- [[[2- [[[4- [[ethyoxyl] formimino group] benzene Base] amino] methyl] -1- methyl-1 H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] propionate hydrochloride, with Lower abbreviation " imidic acid carbethoxy hydrochloride ", the purity of the intermediate state imidic acid carbethoxy hydrochloride of the separation is up to 94%；Then again The intermediate state imidic acid carbethoxy hydrochloride V-1 of the separation is reacted overnight under argon gas protection and anhydrous condition with ammonium carbonate or ammonia The hydrochloride of time amidification object III derived above, purity is up to 93%；The hydrochloride of amidification object III again with the just own ester of chloro-carbonic acid Reaction obtains dabigatran etcxilate I, and purity is up to 97%.This method avoid column chromatography for separation, and also improve amidification object III The purity of hydrochloride is conducive to the purifying of subsequent reactions and the raising of yield.But imidic acid carbethoxy hydrochloride V-1 in this method Purity is not high (< 95%), and then affects the purity (< 94%) of prepared amidification object III hydrochloride；And imidic acid second Ester hydrochloride V-1 stability is poor, needs to protect in noble gas and next step reaction is separated and carried out under anhydrous condition, be more not suitable for growing Phase storage.

Due to the deficiency of above-mentioned dabigatran etcxilate preparation process, it is therefore necessary to continually look for more conducively industrializing implementation Preparation process.Through studying, we surprisingly have found that the acid weaker acid such as imines acetoacetic ester V and oxalic acid, phosphoric acid, citric acid is formed Imines acetoacetic ester salt, not only purity and stability improve, can store and be used as process intermediates or starting material for a long time, And when further reacting preparation intermediate III or its salt with ammonia reagent, operation is easier, resulting intermediate III Or its purity salt is higher, is more advantageous to industrial applications.

Summary of the invention

One of the objects of the present invention is to provide a kind of 3- [[[2- [[[4- [[ethyoxyl] formimino group] phenyl] amino] Methyl] -1- methyl-1 H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] ethyl propionate (Formula V) new solid-state shape Formula, the new solid-state form purity is higher, it is more stable, be more advantageous to preparation of industrialization dabigatran etcxilate.

Another object of the present invention is to provide above-mentioned 3- [[[2- [[[4- [[ethyoxyl] formimino group] phenyl] amino] Methyl] -1- methyl-1 H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] the new solid-state form of ethyl propionate (Formula V) Preparation method.

Another object of the present invention is to provide above-mentioned 3- [[[2- [[[4- [[ethyoxyl] formimino group] phenyl] amino] Methyl] -1- methyl-1 H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] the new solid-state form use of ethyl propionate (Formula V) In the application for preparing dabigatran etcxilate.

The purpose of the present invention is realized by following proposal:

On the one hand, the present invention provides a kind of salt of Formula V compound, i.e. Formula V-A compound represented,

Wherein, the value of n is 1 to 3；Acid of the A selected from pKa greater than -2, including phosphoric acid, oxalic acid, citric acid, formic acid, acetic acid, Glycolic, L- mandelic acid, D- mandelic acid, DL- mandelic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, DL-LACTIC ACID, pyruvic acid, malonic acid, amber Acid, fumaric acid, L MALIC ACID, D-malic acid, DL-malic acid, L-TARTARIC ACID, D- tartaric acid, DL- tartaric acid, meso winestone Acid, maleic acid, benzoic acid, 4-HBA, phenylacetic acid, niacin, cinnamic acid, salicylic acid, 2- phenoxy benzoic acid or acetyl Salicylic acid etc..

In formula V above-A, n refers to the molar composition ratio of contained acid in molecular structure, can pass through¹H-NMR, elemental analysis, The modes such as HPLC measure.N preferably 1,2 or 3.

In formula V above-A, pKa is the negative logarithm for being acid ionization constant Ka, if selected acid is polyacid, pKa is the acid PKa1.The preferred pKa of A is greater than -1 acid, and more preferable pKa is greater than 0 acid, and most preferably pKa is greater than 1 acid.The pKa of common acid exists Various kinds of document, handbook or reference book are on the books, " the Handbook of Pharmaceutical as published by WILEY-VCH The pKa value of a variety of acid is described in Salts Properties, Selection, and Use ".

In formula V above-A, imines acetoacetic ester (Formula V) is combined by way of the non-covalent bonds such as ionic bond, hydrogen bond with acid.It can be with Understand, although Formula V-A compound be referred to as salt in the present invention, it should include classics define salt, eutectic or they The forms such as mixed form and their polycrystalline, hydrate, solvate.

In one embodiment, the present invention provides imidic acid ethoxal salt shown in a kind of Formula V -2,

In one embodiment, the present invention provides imines acetoacetic ester dioxalic acid salt shown in a kind of Formula V -3,

In one embodiment, the present invention provides three oxalates of imines acetoacetic ester shown in a kind of Formula V -4,

In one embodiment, the present invention provides imines acetoacetic ester benzoate shown in a kind of Formula V -5,

In one embodiment, the present invention provides imines acetoacetic ester fumarate shown in a kind of Formula V -6,

In one embodiment, the present invention provides imidic acid ethyl ester phosphate shown in a kind of Formula V -7,

In one embodiment, the present invention provides imines acetoacetic ester citrate shown in a kind of Formula V -8,

On the other hand, the present invention provides the preparation methods of imines acetoacetic ester salt V-A, this method comprises:

(1), compound IV or its salt are mixed with ethyl alcohol, imidic acid carbethoxy hydrochloride is converted under the action of hydrogen chloride V-1；

(2), imines acetoacetic ester V is converted by imidic acid carbethoxy hydrochloride V-1 with alkali；

(3), imines acetoacetic ester V and corresponding acid A are dissolved in suitable solvent, solid is precipitated, point isolated solid；

(4), optional, isolated solid is dried, or rear re-dry is further purified.

In above-mentioned steps (1), compound IV or its salt can be by CN1248251A, CN1861596A, CN102985416A etc. Disclosed in method preparation.

In above-mentioned steps (1), the salt of compound IV includes hydrochloride, hydrobromate, hydriodate, sulfate, methanesulfonic acid Salt, benzene sulfonate, tosilate, phosphate, formates, acetate, maleate etc..

In above-mentioned steps (1), the dosage of hydrogen chloride should generally be such that ethanol solution is saturated；Reaction temperature is generally -30~60 DEG C, preferably 0~40 DEG C；The conventional method of this field can be used in the determination in reaction time, such as monitors reaction process with TLC or HPLC To determine the reaction time.

In above-mentioned steps (2), the alkali includes inorganic base, such as sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus, hydrogen-oxygen Change the aqueous solution of sodium, potassium hydroxide etc.；It also include organic base, such as the aqueous solution of triethylamine.

It include: step (1) direct alkaline cleaning after completion of the reaction with the method that alkali converts in above-mentioned steps (2)；If or step Suddenly the imidic acid carbethoxy hydrochloride V-1 that (1) is formed is precipitated in the reaction system, can be isolated, then use alkali process again；On or State the combination of one or more methods.The system pH of the V of acetoacetic ester containing imines is generally adjusted to alkali with alkali with the process of alkali process Property, preferably pH is 9-11；It is extracted again with the immiscible organic solvent of water, includes dichloromethane with the immiscible organic solvent of water Alkane, chloroform, butyl acetate, ethyl acetate, methyl acetate, methyl tertiary butyl ether(MTBE), toluene etc., wherein it is preferred that methylene chloride, Butyl acetate, ethyl acetate；Then concentration organic phase obtains imines acetoacetic ester V；Optionally, organic phase before concentration can be first through nothing The desiccant dryness such as aqueous sodium persulfate, anhydrous magnesium sulfate, molecular sieve.

In above-mentioned steps (3), A is selected from the acid that pKa is greater than -2, including phosphoric acid, oxalic acid, citric acid, formic acid, acetic acid, ethyl alcohol Acid, L- mandelic acid, D- mandelic acid, DL- mandelic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, DL-LACTIC ACID, pyruvic acid, malonic acid, succinic acid are rich Horse acid, L MALIC ACID, D-malic acid, DL-malic acid, L-TARTARIC ACID, D- tartaric acid, DL- tartaric acid, mesotartaric acid, horse Come sour, benzoic acid, 4-HBA, phenylacetic acid, niacin, cinnamic acid, salicylic acid, 2- phenoxy benzoic acid or acetylsalicylic acid Deng.

In above-mentioned steps (3), the molar ratio of sour A and imines acetoacetic ester V are generally in 0.5:1 to 4:1.

In above-mentioned steps (3), " suitable solvent " includes ethyl alcohol, methylene chloride, acetone etc..Dissolution mechanism includes by imines Acetoacetic ester V and acid A is dissolved in suitable solvent simultaneously；Or imines acetoacetic ester V and acid A are dissolved in suitable solvent respectively, it remixes.It is molten Solution temperature is generally 0 DEG C to solvent boiling point, preferably 10~30 DEG C.

In above-mentioned steps (3), the method for " precipitation solid " is method conventional in the art, including reaction is precipitated admittedly Body, it is cooling that solid is precipitated, poor solvent is added, solid is precipitated, be concentrated out after partial solvent and solid etc. is precipitated, these methods can be with Exclusive use can also be applied in combination, and can carry out, can also be carried out under static conditions under agitation." the reaction Precipitation solid " refers in suitable solvent at a certain temperature that imines acetoacetic ester V and acid are because being bound to each other to form solubility more Small imines acetoacetic ester salt V-A and solid is precipitated." poor solvent " refers at normal temperature to being formed by imines acetoacetic ester Salt V-A dissolubility it is bad and can with the miscible solvent of suitable solvent of dissolution imines acetoacetic ester V and acid A, such as ether, isopropyl Ether, methyl tertiary butyl ether(MTBE), normal hexane, normal heptane etc..

In above-mentioned steps (3), " separation " can be using the conventional method in the art such as filtering.It optionally, can be with Collected solid is washed with suitable solvent.

In above-mentioned steps (4), " drying " mode includes constant pressure and dry, is dried under reduced pressure or their combination application." further The method of purifying " includes the forms such as recrystallization, pulp, washing.

Illustratively, in one embodiment, the present invention provides imidic acid ethoxals shown in a kind of Formula V -2 The preparation method of salt.This method comprises:

(3), imines acetoacetic ester V and oxalic acid are dissolved in suitable solvent with the molar ratio of 1:0.8 to 1:1.5, are analysed Solid out, point isolated solid；

(4), optional, isolated solid is dried, or rear re-dry is further purified.

In above-mentioned steps (2), the alkali includes inorganic base, such as sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus, hydrogen-oxygen Change the aqueous solution of sodium, potassium hydroxide etc.；It also include organic base, such as the aqueous solution of triethylamine, preferably aqueous sodium carbonate, carbonic acid The aqueous solution of aqueous solutions of potassium or triethylamine.

In above-mentioned steps (2), add alkali tune system pH to alkalinity after completion of the reaction to step (1), preferably pH is 9-11；It uses again With the immiscible organic solvent of water, such as methylene chloride, chloroform, butyl acetate, ethyl acetate, methyl acetate, methyl- tert fourth The extraction such as base ether, toluene, wherein it is preferred that methylene chloride, butyl acetate, ethyl acetate；Then concentration organic phase obtains imidic acid second Ester V；Optionally, organic phase before concentration can be first through desiccant dryness such as anhydrous sodium sulfate, anhydrous magnesium sulfate, molecular sieves.

In above-mentioned steps (3), the preferred acetone of suitable solvent.Dissolution mechanism include by imines acetoacetic ester V and oxalic acid simultaneously It is dissolved in suitable solvent；Or imines acetoacetic ester V and oxalic acid are dissolved in suitable solvent respectively, it remixes.Solution temperature is generally 0 DEG C To solvent boiling point, preferably 10~30 DEG C.

In above-mentioned steps (3), the method for " precipitation solid " is method conventional in the art, including reaction is precipitated admittedly Body, it is cooling that solid is precipitated, poor solvent is added, solid is precipitated, be concentrated out after partial solvent and solid etc. is precipitated, these methods can be with Exclusive use can also be applied in combination, and can carry out, can also be carried out under static conditions under agitation.Poor solvent packet Include ether, isopropyl ether, methyl tertiary butyl ether(MTBE), normal hexane, normal heptane etc..

Imidic acid ethoxal salt shown in Formula V -2 prepared by the embodiment is a kind of crystal.

Therefore, the present invention provides the crystal of imidic acid ethoxal salt V-2 a kind of.The powder x-ray diffraction of the crystal The feature of map (use the source CuK α) are as follows: 2 θ values be 7.0 ° ± 0.2 °, 15.7 ° ± 0.2 °, 16.3 ° ± 0.2 °, 19.2 ° ± 0.2 °, 22.5 ° ± 0.2 °, 23.8 ° of ± 0.2 ° of equipotentials be equipped with corresponding characteristic diffraction peak.In order to express easily, which is claimed For " imidic acid ethoxal salt crystal form A ".

In one embodiment, the powder x-ray diffraction of imidic acid ethoxal salt crystal form A provided by the invention In map (use the source CuK α), 2 θ values be 7.0 ° ± 0.2 °, 14.1 ° ± 0.2 °, 14.5 ° ± 0.2 °, 15.7 ° ± 0.2 °, 16.3°±0.2°、16.8°±0.2°、19.2°±0.2°、22.0±0.2°、22.5°±0.2°、23.8°±0.2°、28.8° ± 0.2 ° of equipotential is equipped with corresponding characteristic diffraction peak.

In one embodiment, imidic acid ethoxal salt crystal form A provided by the invention has powder as shown in Figure 1 Feature representated by last X-ray diffracting spectrum.

In one embodiment, crystal form purity (the i.e. imines of imidic acid ethoxal salt crystal form A provided by the invention The mass percentage of the A containing crystal form in acetoacetic ester oxalates) it is generally higher than 10%, preferably greater than 40%, most preferably greater than 70%.

The above method is not required to the protection of the inert gases such as nitrogen, and operation is easy；Imidic acid ethoxal salt obtained V-2 without the purity that is further purified generally 96% or more, and it is with good stability, be suitable for long-term storage.

Illustratively, in another embodiment, the present invention provides imines acetoacetic esters two shown in a kind of Formula V -3 The preparation method of oxalates.This method comprises:

(3), imines acetoacetic ester V and oxalic acid are dissolved in suitable solvent with the molar ratio of 1:1.8 to 1:2.5, are analysed Solid out, point isolated solid；

(4), optional, isolated solid is dried, or rear re-dry is further purified.

Imines acetoacetic ester dioxalic acid salt shown in Formula V -3 prepared by the embodiment is a kind of crystal.

Therefore, the present invention provides the crystal of imines acetoacetic ester dioxalic acid salt V-3 a kind of.The powder X-ray of the crystal spreads out Penetrate the feature of map (using the source CuK α) are as follows: 2 θ values be 4.7 ° ± 0.2 °, 5.0 ° ± 0.2 °, 5.8 ° ± 0.2 °, 9.3 ° ± 0.2 °, 19.5 ° ± 0.2 °, 25.3 ° of ± 0.2 ° of equipotentials be equipped with corresponding characteristic diffraction peak.In order to express easily, which is claimed For " imines acetoacetic ester dioxalic acid salt crystal form A ".

In one embodiment, the powder X-ray of imines acetoacetic ester dioxalic acid salt crystal form A provided by the invention spreads out Penetrate in map (using the source CuK α), 2 θ values be 4.7 ° ± 0.2 °, 5.0 ° ± 0.2 °, 5.8 ° ± 0.2 °, 9.3 ° ± 0.2 °, 11.6°±0.2°、 13.5°±0.2°、14.8°±0.2°、19.5°±0.2°、20.5°±0.2°、21.4°±0.2°、 22.9 ° ± 0.2 °, 25.3 ° ± 0.2 °, 27.0 ° of ± 0.2 ° of equipotentials be equipped with corresponding characteristic diffraction peak.

In one embodiment, imines acetoacetic ester dioxalic acid salt crystal form A provided by the invention has as shown in Figure 2 Feature representated by powder x-ray diffraction map.

In one embodiment, the crystal form purity of imines acetoacetic ester dioxalic acid salt crystal form A provided by the invention is (i.e. sub- The mass percentage of the A containing crystal form in amino acid ethyl ester dioxalic acid salt) it is generally higher than 10%, preferably greater than 40%, most preferably greater than 70%.

The above method is not required to the protection of the inert gases such as nitrogen, and operation is easy；Imines acetoacetic ester dioxalic acid obtained Salt V-3 without the purity that is further purified generally 96% or more, and it is with good stability, be suitable for long-term storage.

In another embodiment, present invention benzoic acid is instead of in above-mentioned specific embodiment step (3) Oxalic acid, and the molar ratio of imines acetoacetic ester V and benzoic acid is 1:1 to 1:3.5, obtains imines acetoacetic ester shown in Formula V -5 Benzoate.

In another embodiment, present invention fumaric acid is instead of in above-mentioned specific embodiment step (3) Oxalic acid, and the molar ratio of imines acetoacetic ester V and fumaric acid is 1:1 to 1:3.5, obtains imines acetoacetic ester shown in Formula V -6 Fumarate.

In another embodiment, present invention phosphoric acid is instead of the grass in above-mentioned specific embodiment step (3) Acid, and the molar ratio of imines acetoacetic ester V and phosphoric acid is 1:1 to 1:3.5, obtains imidic acid ethyl ester phosphoric acid shown in Formula V -7 Salt.

In another embodiment, present invention citric acid is instead of in above-mentioned specific embodiment step (3) Oxalic acid, and the molar ratio of imines acetoacetic ester V and citric acid is 1:1 to 1:3.5, obtains imines acetoacetic ester shown in Formula V -8 Citrate.

In another aspect, the present invention provides prepare amidification object III or the method for its salt, the party with imines acetoacetic ester salt V-A Method includes: to react imines acetoacetic ester salt V-A with ammonia reagent.

In the above method, " ammonia reagent ", which refers to, to be included or can release ammonia (NH₃) reagent, including ammonium hydroxide, ammonia Ethanol, ammonium carbonate, ammonium chloride, ammonium acetate etc..

In the above method, directly imino acid ester ethyl ester salt V-A can be reacted with ammonia reagent；It can also be first by imino acid ester second Ester salt V-A alkali dissociates into imines acetoacetic ester V, and then imines acetoacetic ester V is reacted with ammonia reagent again, wherein " free with alkali " is available The art routine techniques carries out, and such as imino acid ester ethyl ester salt V-A is added to by sodium carbonate, potassium carbonate, sodium bicarbonate, carbon Aqueous solution and methylene chloride, chloroform, ethyl acetate, methyl acetate, the methyl of potassium hydrogen phthalate, sodium hydroxide, potassium hydroxide etc. In the two-phase system of the immiscible organic solvent composition of the water such as tertbutyl ether, toluene, organic phase is then demultiplex out, is concentrated；It is optional , organic phase before concentration can be first through desiccant dryness such as anhydrous sodium sulfate, anhydrous magnesium sulfate, molecular sieves.

In the above method, when imino acid ester ethyl ester salt V-A is directly reacted with ammonia reagent, available amidification object III with The salt that sour A is formed；Another acid, such as sulfuric acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, methanesulfonic acid, second sulphur can also be added in reaction system body Acid etc..

In the above method, reaction dissolvent includes the mixed of ethyl alcohol or ethyl alcohol and other solvents (such as water, methylene chloride, acetone) Close solution.

In the above method, the molar ratio of imines acetoacetic ester salt V-A and ammonia reagent is generally 1:1 to 1:20, preferably 1:3 To 1:10.

In the above method, reaction temperature is generally 0 DEG C to solvent boiling point, preferably 10~30 DEG C；The determination in reaction time can Using the conventional method of this field, the reaction time such as is determined with TLC or HPLC monitoring reaction process.

In the above method, after completion of the reaction, filtering etc. can be used, and the method for routine is separating obtained in the art Amidification object III or its salt.Optionally, isolated solid can be further purified, the method for purifying includes recrystallization, slurry The forms such as change, washing；Optionally, isolated solid can be dried；Drying mode includes constant pressure and dry, be dried under reduced pressure or Their combination application.

It can further comprise reacting to obtain with the just own ester of chloro-carbonic acid by resulting amidification object III or its salt in the above method Dabigatran etcxilate I.The operation can be public in CN1861596A, WO2010045900, CN102985416A etc. by CN1248251A The method opened carries out.

In the above method, can further comprise resulting amidification object III or its salt hydrolysis are obtained dabigatran II or its Salt.Since dabigatran II is amphoteric compound, it both can be with alkali at salt, can also be with acid at salt.Such as dabigatran II can with sodium hydroxide, potassium hydroxide etc. at opposite sodium salt or sylvite, can also with hydrochloric acid, hydrobromic acid, methanesulfonic acid, to first Benzene sulfonic acid, sulfuric acid, phosphoric acid etc. are at salt.

Illustratively, the present invention in one embodiment, provides a kind of by imidic acid ethoxal salt V-2 preparation The method of amidification object III or its salt, this method comprises: imidic acid ethoxal salt V-2 is reacted with ammonia reagent.

In the above method, ammonia reagent includes ammonium hydroxide, the ethanol of ammonia, ammonium carbonate, ammonium chloride, ammonium acetate etc., preferably ammonium hydroxide.

In the above method, directly imidic acid ethoxal salt V-2 can be reacted with ammonia reagent；It can also be first by imino acid ester Ethoxal salt V-2 alkali dissociates into imines acetoacetic ester V, and then imines acetoacetic ester V is reacted with ammonia reagent again, wherein " being swum with alkali From " process can for imino acid ester ethoxal salt V-2 be added to by sodium carbonate, potassium carbonate etc. aqueous solution and methylene chloride, In the two-phase system of the immiscible organic solvent composition of the water such as ethyl acetate, organic phase is then demultiplex out, is concentrated；Optionally, have Machine mutually before concentration can be first through desiccant dryness such as anhydrous sodium sulfate, anhydrous magnesium sulfate, molecular sieves.

In the above method, another acid, such as p-methyl benzenesulfonic acid, benzene sulfonic acid, methanesulfonic acid, second sulphur can be added in reaction system body Acid etc..

In the above method, reaction dissolvent includes ethyl alcohol or ethyl alcohol and other solvents, such as water, methylene chloride, acetone is mixed Close solution.

In the above method, the molar ratio of imidic acid ethoxal salt V-2 and ammonia reagent is generally 1:1 to 1:20, excellent Select 1:3 to 1:10.

In the above method, after completion of the reaction, filtering etc. can be used, and the method for routine is separating obtained in the art Amidification object intermediate III or its salt.Optionally, isolated solid can be further purified, the method for purifying includes tying again The forms such as crystalline substance, pulp, washing；Optionally, isolated solid can be dried；Drying mode includes constant pressure and dry, decompression Dry or their combination application.

Illustratively, the present invention in another embodiment, provides one kind by imines acetoacetic ester dioxalic acid salt V-3 Amidification object III or the method for its salt are prepared, this method comprises: imines acetoacetic ester dioxalic acid salt V-3 is reacted with ammonia reagent.

In the above method, directly imines acetoacetic ester dioxalic acid salt V-3 can be reacted with ammonia reagent；It can also be first by imines ester Acetoacetic ester dioxalic acid salt V-3 alkali dissociates into imines acetoacetic ester V, and then imines acetoacetic ester V is reacted with ammonia reagent again, wherein " using Alkali is free " process can be added to aqueous solution and dichloro by sodium carbonate, potassium carbonate etc. for imino acid ester ethyl ester dioxalic acid salt V-3 In the two-phase system of the immiscible organic solvent composition of the water such as methane, ethyl acetate, organic phase is then demultiplex out, is concentrated；It is optional , organic phase before concentration can be first through desiccant dryness such as anhydrous sodium sulfate, anhydrous magnesium sulfate, molecular sieves.

In the above method, the molar ratio of imines acetoacetic ester dioxalic acid salt V-3 and ammonia reagent is generally 1:1 to 1:20, It is preferred that 1:3 to 1:10.

It according to the above method, can also be by imines acetoacetic ester benzoate V-5, imines acetoacetic ester fumarate V-6, imidic acid second Obtained amidification object III or its salt such as ester phosphate V-7, imines acetoacetic ester citrate V-8.

It can further comprise reacting to obtain with the just own ester of chloro-carbonic acid by resulting amidification object III or its salt in the above method Dabigatran etcxilate I.

In the above method, can further comprise resulting amidification object III or its salt hydrolysis are obtained dabigatran II or its Salt.

In one embodiment, by amidification object or its salt in the mixed solution of ethyl alcohol and water, through sodium hydroxide, hydroxide Solid is precipitated in the basic hydrolysis such as potassium, and resulting solid is optionally dried, obtains dabigatran by a point isolated solid (II).It is a kind of dabigatran hydrate that dabigatran, which is made, in the program；It is further dabigatran monohydrate；More into one Step, which is a kind of crystal, the spy of the powder x-ray diffraction map (using the source CuK α) of the crystal Sign are as follows: 2 θ values be 10.7 ° ± 0.2 °, 12.9 ° ± 0.2 °, 15.8 ° ± 0.2 °, 18.9 ° ± 0.2 °, 22.5 ° ± 0.2 °, 25.9 ° of ± 0.2 ° of equipotentials are equipped with corresponding characteristic diffraction peak.In order to express easily, which is known as " dabigatran crystal form A ". In one embodiment, the powder x-ray diffraction map (using the source CuK α) of dabigatran crystal form A provided by the invention In, 2 θ values be 9.6 ° ± 0.2 °, 10.7 ° ± 0.2 °, 12.1 ° ± 0.2 °, 12.9 ° ± 0.2 °, 15.8 ° ± 0.2 °, 18.9 ° ± 0.2 °, 20.4 ° ± 0.2 °, 22.5 ° ± 0.2 °, 25.9 ° ± 0.2 °, 26.7 ° of ± 0.2 ° of equipotentials be equipped with corresponding feature diffraction Peak.In one embodiment, dabigatran crystal form A provided by the invention has powder x-ray diffraction as shown in Figure 3 Feature representated by map.In one embodiment, the differential scanning calorimetry of dabigatran crystal form A provided by the invention (DSC) feature of map (heating rate: 10 DEG C/minute) are as follows: have endothermic peak within the scope of about 75 DEG C to 190 DEG C.It is specific real one It applies in scheme, dabigatran crystal form A provided by the invention has spy representated by Differential Scanning Calorimetry as shown in Figure 4 Sign.In one embodiment, dabigatran crystal form A provided by the invention thermogravimetric analysis (TGA) map (heating rate: 10 DEG C/minute) feature are as follows: have 3~4% weightlessness within the scope of about 75 DEG C to 125 DEG C.In one embodiment, this hair The dabigatran crystal form A of bright offer has feature representated by thermogravimetric analysis map as shown in Figure 5.In a specific embodiment In, the crystal form purity (mass percentage of the A containing crystal form i.e. in dabigatran) one of dabigatran crystal form A provided by the invention As be greater than 10%, preferably greater than 40%, most preferably greater than 70%.

In one embodiment, dabigatran is dispersed in the mixed solution of alcohol and water, be then added the acid such as hydrochloric acid into Row adjusts acid, makes system dissolved clarification, then carry out alkali tune with alkali such as sodium bicarbonate, saleratus, solid is precipitated, point isolated solid, Optionally, resulting solid can be dried, obtains another crystal form of dabigatran (II), the powder X-ray of the crystal The feature of diffracting spectrum (use the source CuK α) are as follows: 2 θ values be 11.8 ° ± 0.2 °, 15.3 ° ± 0.2 °, 16.9 ° ± 0.2 °, 17.5 ° ± 0.2 °, 22.0 ° ± 0.2 °, 24.3 ° of ± 0.2 ° of equipotentials be equipped with corresponding characteristic diffraction peak.In order to express easily, by this Crystal form is known as " dabigatran crystal form B ".In one embodiment, the powder X-ray-of dabigatran crystal form B provided by the invention It is 8.4 ° ± 0.2 °, 11.8 ° ± 0.2 °, 15.3 ° ± 0.2 °, 16.4 ° in 2 θ values in x ray diffraction map (using the source CuK α) ±0.2°、16.9°±0.2°、17.5°±0.2°、19.3°±0.2°、21.3°±0.2°、22.0°±0.2°、22.8°± 0.2 °, 23.6 ± 0.2 °, 24.3 ° ± 0.2 °, 25.4 ± 0.2 °, 27.1 ± 0.2 °, 28.1 ± 0.2 ° of equipotentials be equipped with corresponding spy Levy diffraction maximum.In one embodiment, there is dabigatran crystal form B provided by the invention powder X-ray-as shown in FIG. 6 to penetrate The representative feature of ray diffraction diagram spectrum.In one embodiment, the crystal form purity of dabigatran crystal form B provided by the invention (mass percentage of the B containing crystal form i.e. in dabigatran) is generally higher than 10%, preferably greater than 40%, most preferably greater than 70%.

Above-mentioned dabigatran crystal form A and crystal form B stability are good, easily prepared, are suitble to storage.

The preparation method of above-mentioned amidification object III or its salt is not necessarily to carry out under noble gas protection, anhydrous condition, operation letter Just；By imidic acid ethoxal salt V-2, the amidification object intermediate III of the preparations such as imines acetoacetic ester dioxalic acid salt V-3 or its salt are not Purity through being further purified generally 98.5% or more, is more advantageous to industrial applications.

Powder x-ray diffraction analysis of the present invention is spread out through Dutch Panaco X`Pert PRO type powder X-ray Penetrate the source CuK α of instrumentWhat measurement was completed.It can be understood that during the test, due to by many factors (such as Processing method, instrument, test parameter, the test operation etc. of sample when the granularity of test sample, test) influence, same crystalline substance Peak position or the peak intensity out of X-ray powder diffraction collection measured by type have certain difference.Under normal circumstances, X- is penetrated The experimental error of 2 θ value of diffraction maximum can be ± 0.2 ° in line powder diffraction spectrum.Differential scanning calorimetric analysis of the present invention It is to measure to complete through U.S.'s TA DSC Q200 type differential scanning calorimeter.Thermogravimetric analysis of the present invention is through U.S. TA The measurement of TGA Q500 type thermogravimetric analyzer is completed.

In conclusion the present invention has following improvement and effect:

(1), imines acetoacetic ester salt V-A (such as imidic acid ethoxal salt V-2, two grass of imines acetoacetic ester provided by the invention Hydrochlorate V-3 etc.) compared with prior art, purity is more preferable, and stability is more preferable, is suitable for carrying out as process intermediates or starting material Storage and use.

(2), imines acetoacetic ester salt V-A (such as imidic acid ethoxal salt V-2, two grass of imines acetoacetic ester provided by the invention Hydrochlorate V-3 etc.) when preparing subsequent product amidification object III or its salt compared with prior art, operation is easier, gained Amidification object III or its purity salt it is higher, be conducive to it in the process for further preparing dabigatran etcxilate I or dabigatran II Middle simplified purification process, raising prepare yield, reduce production cost, are more suitable for industrial applications.

Detailed description of the invention

Fig. 1 is imidic acid ethoxal salt crystal form A powder x-ray diffraction map

Fig. 2 is imines acetoacetic ester dioxalic acid salt crystal form A powder x-ray diffraction map

Fig. 3 is dabigatran crystal form A powder x-ray diffraction map

Fig. 4 is dabigatran crystal form A Differential Scanning Calorimetry

Fig. 5 is dabigatran crystal form A thermogravimetric analysis map

Fig. 6 is dabigatran crystal form B powder x-ray diffraction map

Fig. 7 is amidification object Mesylate Form A powder x-ray diffraction map

Specific embodiment

Further detailed description is done to the present invention below with reference to embodiment, professional and technical personnel in the field can be made more complete The understanding present invention in face, embodiments of the present invention are not limited thereto.

Embodiment 1

The preparation of imines acetoacetic ester (V)

At 10~15 DEG C, compound IV48.2g (100mmol) is stirred in saturation ethanol solution of hydrogen chloride 600mL Reaction 18 hours, it is about 10 that wet chemical, which is added, and adjusts pH, is then extracted, is associated in three times with methylene chloride 2000mL Machine phase successively uses water, and saturated sodium-chloride water solution washing, anhydrous sodium sulfate is dry, and concentration obtains imines acetoacetic ester V.

(+) ESI-MS:(M+1)⁺=529.2

Embodiment 2

The preparation of imidic acid ethoxal salt (V-2)

It is stirred at room temperature down, oxalic acid dihydrate 5.0g (40mmol) and acetone the 100mL solution being made into is added dropwise to imines In the solution that acetoacetic ester V26.4g (50mmol) and acetone 200mL are made into, after being added dropwise, continue stirring 2 hours, is precipitated solid Body, filtering, filter cake acetone washing are dried under reduced pressure at 40-50 DEG C, obtain imidic acid ethoxal salt V-2, white solid.

HPLC purity: 98.1%；Oxalic acid content: 14.3% (passing through HPLC external standard method).

¹H-NMR(400MHz,d₆- DMSO, δ/ppm): 8.38-8.39 (m, 1H), 7.83-7.80 (d, 2H), 7.56- 7.51 (m, 2H), 7.48 (s, 1H), 7.41-7.38 (d, 1H), 7.17-7.09 (m, 2H), 6.90-6.84 (m, 3H), 4.67 (s, 2H), 4.47-4.40 (q, 2H), 4.25-4.21 (t, 2H), 4.00-3.93 (q, 2H), 3.76 (s, 3H), 2.71-2.66 (t, 2H), 1.41-1.36 (t, 3H), 1.13-1.09 (t, 3H).

It is measured through powder x-ray diffraction, powder x-ray diffraction map is shown in Fig. 1, and measured value such as following table (takes opposite Intensity is greater than the 3% corresponding measured value of diffraction maximum, and measured value round off takes two-decimal):

Above-mentioned crystal form is named as " imidic acid ethoxal salt crystal form A ".

Embodiment 3

The preparation of imidic acid ethoxal salt (V-2)

It is stirred at room temperature down, oxalic acid dihydrate 9.5g (75mmol) and acetone the 100mL solution being made into is added dropwise to imines In the solution that acetoacetic ester V26.4g (50mmol) and acetone 200mL are made into, after being added dropwise, continue stirring 2 hours, is precipitated solid Body, filtering, filter cake acetone washing are dried under reduced pressure at 40-50 DEG C, obtain imidic acid ethoxal salt V-2, white solid.

HPLC purity: 98.4%；Oxalic acid content: 14.7% (passing through HPLC external standard method).

Embodiment 4

The preparation of imines acetoacetic ester dioxalic acid salt (V-3)

It is stirred at room temperature down, oxalic acid dihydrate 12.6g (100mmol) and acetone the 200mL solution being made into is added dropwise to Asia In the solution that amino acid ethyl ester V26.4g (50mmol) and acetone 400mL are made into, after being added dropwise, continues stirring 2 hours, be precipitated Solid, filtering, filter cake acetone washing are dried under reduced pressure at 40-50 DEG C, obtain imines acetoacetic ester dioxalic acid salt V-3, and white is solid Body.

HPLC purity: 97.3%；Oxalic acid content: 26.8% (passing through HPLC external standard method).

¹H-NMR(400MHz,d₆- DMSO, δ/ppm): 8.39-8.37 (m, 1H), 7.81-7.79 (d, 2H), 7.59- 7.46 (m, 3H), 7.42-7.40 (d, 1H), 7.17-7.11 (m, 2H), 6.88-6.85 (m, 3H), 4.67-4.66 (d, 2H), 4.49-4.44 (m, 2H), 4.24-4.20 (m, 2H), 4.00-3.95 (m, 2H), 3.76 (s, 3H), 2.70-2.66 (m, 2H), 1.44-1.41 (t, 3H), 1.14-1.10 (t, 3H).

It is measured through powder x-ray diffraction, powder x-ray diffraction map is shown in Fig. 2, and measured value such as following table (takes opposite Intensity is greater than the 3% corresponding measured value of diffraction maximum, and measured value round off takes two-decimal):

Above-mentioned crystal form is named as " imines acetoacetic ester dioxalic acid salt crystal form A ".

Embodiment 5

The preparation of imines acetoacetic ester benzoate (V-5)

It is stirred at room temperature down, benzoic acid 3.66g (30mmol) and acetone the 20mL solution being made into is added dropwise to imines acetoacetic ester The solution that V5.28g (10mmol) and acetone 40mL are made into after being added dropwise, continues stirring 6 hours, filtering, and filter cake is washed with acetone It washs, imines acetoacetic ester benzoate V-5, white solid is dried in vacuo to obtain at 40~50 DEG C.

HPLC purity: 96.2%.

¹H-NMR(400MHz,d₆- DMSO, δ/ppm): 8.39 (s, 1H), 7.95-7.93 (m, 2H), 7.64-7.46 (m, 7H), 7.40-7.38(d,1H),7.16-7.10(m,2H),6.89-6.87(d,1H),6.74-6.72(m,3H),4.55- 4.54(d,2H), 4.24-4.20(m,2H),4.18-4.12(m,2H),4.00-3.94(m,2H),3.76(s,3H),2.70- 2.66(m,2H), 1.29-1.26(t,3H),1.14-1.10(t,3H)。

It is above-mentioned¹In H-NMR result, δ 8.39-6.72 (m, 17H) is attributed to phenyl ring, H and active hydrogen on heterocycle, It may determine that the molar composition ratio of imidic acid ethyl ester and benzoic acid is 1:1 in the title product from its H number.

Embodiment 6

The preparation of imines acetoacetic ester fumarate (V-6)

It is stirred at room temperature down, fumaric acid 3.48g (30mmol) and ethyl alcohol the 20mL solution being made into is added dropwise to imines acetoacetic ester V5.28g (10mmol) and acetone 40mL solution in, after being added dropwise, continue stirring 6 hours, filtering, filter cake washed with acetone It washs, imines acetoacetic ester fumarate V-6, white solid is dried in vacuo to obtain at 40~50 DEG C.

HPLC purity: 96.5%.

¹H-NMR(400MHz,d₆- DMSO, δ/ppm): 8.39 (s, 1H), 7.60-7.38 (m, 5H), 7.16-7.10 (m, 2H), 6.89-6.87 (d, 1H), 6.78-6.82 (m, 1H), 6.75-6.73 (d, 2H), 6.61 (s, 2H), 4.55-4.54 (d, 2H), 4.24-4.20 (m, 2H), 4.19-4.15 (m, 2H), 4.00-3.94 (m, 2H), 3.76 (s, 3H), 2.70-2.66 (m, 2H), 1.32-1.27 (t, 3H), 1.14-1.10 (t, 3H).

It is above-mentioned¹In H-NMR result, δ 6.61 (s, 2H) is attributed to the H of the double bond of fumaric acid, may determine that the mark from its H number Inscribing the molar composition ratio of imidic acid ethyl ester and fumaric acid in product is 1:1.

Embodiment 7

The preparation of imidic acid ethyl ester phosphate (V-7)

It is stirred at room temperature down, phosphatase 11 .96g (20mmol) and ethyl alcohol the 20mL solution being made into is added dropwise to imines acetoacetic ester V5.28g (10mmol) and acetone 40mL solution in, after being added dropwise, continue stirring 6 hours, filtering, filter cake washed with acetone It washs, imidic acid ethyl ester phosphate V-7, white solid is dried in vacuo to obtain at 40~50 DEG C.

HPLC purity: 97.5%, P elements analysis: 4.80%.

¹H-NMR(400MHz,d₆- DMSO, δ/ppm): 8.39-8.38 (d, 1H), 7.71-7.68 (d, 2H), 7.56-7.52 (t, 1H), 7.46 (s, 1H), 7.41-7.39 (d, 1H), 7.21-7.09 (m, 3H), 6.89-6.87 (d, 1H), 6.84-6.78 (m, 2H), 4.61 (s, 2H), 4.34-4.19 (m, 4H), 4.00-3.94 (m, 2H), 3.76 (s, 3H), 2.70-2.65 (m, 2H), 1.37-1.32 (t, 3H), 1.14-1.03 (m, 3H).

From elemental analysis, it is possible to determine that the molar composition ratio of imidic acid ethyl ester and phosphoric acid is 1:1 (its phosphorus in the title product 4.94%) content theoretical value is.

Embodiment 8

The preparation of imines acetoacetic ester citrate (V-8)

It is stirred at room temperature down, citric acid 3.84g (20mmol) and ethyl alcohol the 20mL mixed solution being made into is added dropwise to imidic acid Ethyl ester V5.28g (10mmol) and acetone 40mL solution in, after being added dropwise, continue stirring 6 hours, filtering, filter cake acetone Washing, is dried in vacuo to obtain imines acetoacetic ester citrate V-8, white solid at 40~50 DEG C.

HPLC purity: 97.0%.

¹H-NMR(400MHz,d₆- DMSO, δ/ppm): 8.39-8.38 (d, 1H), 7.69-7.66 (d, 2H), 7.56-7.52 (t, 1H), 7.46 (s, 1H), 7.42-7.39 (d, 1H), 7.18-7.09 (m, 3H), 6.90-6.87 (d, 1H), 6.81-6.78 (m, 2H), 4.62-4.60 (d, 2H), 4.33-4.19 (m, 4H), 4.00-3.86 (m, 2H), 3.76 (s, 3H), 2.70-2.55 (m, 6H), 1.37-1.32 (t, 3H), 1.14-1.03 (m, 3H).

It is above-mentioned¹In H-NMR result, four hydrogen in δ 2.70-2.55 (m, 6H) are attributed to the H of citric acid methylene, from it H number may determine that the molar composition ratio of imidic acid ethyl ester and citric acid is 1:1 in the title product.

Embodiment 9

The preparation of amidification object oxalates (III-1)

At 15~20 DEG C, imines acetoacetic ester dioxalic acid salt V-37.08g (10mmol) is added into ethyl alcohol 100mL, then Concentrated ammonia liquor 6mL (about 80mmol) is added, is stirred to react, to filter after reaction, filter cake successively uses ethyl alcohol, water washing, Amidification object oxalates (III-1), white solid are dried in vacuo to obtain at 50~55 DEG C.

HPLC purity: 99.0%.

¹H-NMR (400MHz, d-DMSO, δ/ppm): 8.39-8.37 (d, 1H), 7.63-7.39 (m, 6H), 7.16-7.13 (d 2H), 6.91-6.84 (m, 3H), 4.63 (s, 2H), 4.24-4.20 (m, 2H), 4.00-3.96 (m, 2H), 3.76 (s, 3H), 2.70-2.66 (m, 2H), 1.14-1.09 (t, 3H).

Elemental analysis: C59.2%, H5.02%, N16.5%.

Embodiment 10

The preparation of amidification object oxalates (III-1)

At 15~20 DEG C, imidic acid ethoxal salt V-26.18g (10mmol) is added into ethyl alcohol 100mL, then again It is added concentrated ammonia liquor 7mL (about 100mmol), is stirred to react, to filter after reaction, filter cake successively uses ethyl alcohol, water washing, 50 Amidification object oxalates (III-1), white solid are dried in vacuo to obtain at~55 DEG C.

HPLC purity: 99.4%.

Embodiment 11

The preparation of amidification object mesylate (III-2)

At 20~25 DEG C, wet chemical is added to imines acetoacetic ester dioxalic acid salt V-37.08g under stirring In (10mmol), adjusting pH value is about 10, is extracted in three times with methylene chloride 150mL, merges organic phase, uses saturated sodium-chloride Aqueous solution washing, anhydrous sodium sulfate is dry, concentration；It will be dissolved in concentrate in ethyl alcohol 60mL, add 1.92 g of methanesulfonic acid (20mmol) is then added dropwise concentrated ammonia liquor 3.0mL (about 40mmol), is stirred to react 8 hours；It filters, filter cake successively uses ethyl alcohol, washing It washs, amidification object mesylate (III-2), white solid is dried in vacuo to obtain at 40~45 DEG C.

HPLC purity: 99.2%.

¹H-NMR(400MHz,d₆- DMSO, δ/ppm): 8.39-8.38 (d, 1H), 7.63-7.16 (m, 6H), 7.13-7.10 (m, 2H), 6.90-6.85 (m, 3H), 4.65-4.64 (d, 2H), 4.23-4.20 (m, 2H), 3.99-3.94 (m, 2H), 3.76 (s, 3H), 2.69-2.66 (m, 2H), 2.31 (s, 3H), 1.14-1.10 (t, 3H).

It is above-mentioned¹In H-NMR result, δ 2.31 (s, 3H) is attributed to the H of the methyl of methanesulfonic acid, may determine that the mark from its H number Inscribing the molar composition ratio of amidification object and methanesulfonic acid in product is 1:1.

It is measured through powder x-ray diffraction, powder x-ray diffraction figure is shown in Fig. 7, and measured value such as following table (takes relatively strong Degree is greater than the 5% corresponding measured value of diffraction maximum, and measured value round off takes two-decimal):

Above-mentioned crystal form is named as " amidification object Mesylate Form A ".

Embodiment 12

The preparation of dabigatran etcxilate (I)

Amidification object oxalates (III-1) 5.0g (8.5mmol), acetone 40mL and water 40mL are mixed, triethylamine is added 4.24g (42mmol) controls temperature at 20~25 DEG C, stirs the lower dropwise addition just own ester 2.10g (12.8mmol) of chloro-carbonic acid, drips Continue to be stirred to react after finishing, solid is precipitated in reaction process, filters after reaction, Da Bijia is dried in vacuo to obtain at 45~55 DEG C Group's ester (I).

HPLC purity: 98.6%.

Embodiment 13

The preparation of dabigatran etcxilate (I)

Amidification object mesylate (III-2) 5.0g (8.4mmol) and acetone 100mL is mixed, triethylamine 4.24g is added (42mmol) controls temperature at 20~25 DEG C, the lower dropwise addition just own ester 2.10g (12.8mmol) of chloro-carbonic acid is stirred, after being added dropwise Continue to stir, filter after reaction, concentrate filtrate to about 15mL, is cooled to 0~10 DEG C of stirring, filters consolidating for precipitation Body is dried in vacuo to obtain dabigatran etcxilate (I) at 45~55 DEG C.

Embodiment 14

The preparation of dabigatran (II) and crystal form A

Amidification object mesylate (III-2) 4.5g (7.5mmol) is added in ethyl alcohol 60mL, lower dropwise addition hydroxide is stirred The aqueous solution 150mL of sodium 1.2g (30mmol) continues stirring 6 hours, filtering after being added dropwise, filter cake is washed with water, and 40~50 Dabigatran (II) crystal form A is dried in vacuo to obtain at DEG C.

HPLC purity: 99.0%

(+) ESI-MS:(M+H)⁺=472.2

¹H-NMR(400MHz,d₆-DMSO+H₂SO₄, δ/ppm): 8.92 (s, 2H), 8.60 (s, 2H), 8.36-8.35 (d, 1H), 7.86-7.84 (d, 1H), 7.76-7.62 (m, 4H), 7.43-7.40 (d, 1H), 7.26-7.22 (m, 2H), 6.90-6.87 (d, 2H), 5.00 (d, 2H), 4.17-4.12 (t, 2H), 3.95 (s, 3H), 2.64-2.59 (t, 2H).

Elemental analysis (C₂₅H₂₅N₇O₃·H₂O): C61.28%, H5.65%, N19.83%.

It is measured through powder x-ray diffraction, powder x-ray diffraction figure is shown in Fig. 3, and measured value such as following table (takes relatively strong Degree is greater than the 5% corresponding measured value of diffraction maximum, and measured value round off takes two-decimal):

Above-mentioned crystal form is named as " dabigatran crystal form A ".

Through differential scanning calorimetric analysis, differential scanning calorimetry (DSC) figure is shown in Fig. 4.

Through thermogravimetric analysis, thermogravimetric analysis (TGA) figure is shown in Fig. 5.

Embodiment 15

The preparation of dabigatran crystal form B

Dabigatran (II) 2.0g is taken, is added to the in the mixed solvent of water 30mL and methanol 30mL, dilute hydrochloric acid is added dropwise to complete Full dissolved clarification is added dropwise saturated aqueous solution of sodium bicarbonate to there is white solid precipitation, continues stir about 1 hour, filtering, filter cake is washed with water It washs, is dried under reduced pressure, obtain dabigatran crystal form B.

It is measured through powder x-ray diffraction, powder x-ray diffraction figure is shown in Fig. 6, and measured value such as following table (takes relatively strong Degree is greater than the 10% corresponding measured value of diffraction maximum, and measured value round off takes two-decimal):

Above-mentioned crystal form is named as " dabigatran crystal form B ".

Embodiment 16

The stability study of imines ester salt

Take imidic acid carbethoxy hydrochloride V-1 (by method system disclosed in embodiment 2a in patent CN102985416A respectively It is standby), imidic acid ethoxal salt V-2 (is prepared) by 2 method of embodiment, and imines acetoacetic ester dioxalic acid salt V-3 (presses 4 side of embodiment Method preparation), imines acetoacetic ester fumarate V-6 (is prepared) by 6 method of embodiment, and imidic acid ethyl ester phosphate V-7 (presses embodiment The preparation of 7 methods), imines acetoacetic ester citrate V-8 (is prepared) by 8 method of embodiment, and it is placed at 60 DEG C and is tested, 10 days Related substance is detected with HPLC afterwards, as a result as follows:

* the oxalic acid listed in table, fumaric acid, phosphoric acid, the corresponding pKa of citric acid are the value of its pKa1.

The studies above shows: imidic acid ethoxal salt provided by the invention, imines acetoacetic ester dioxalic acid salt, imidic acid second Ester fumarate, imidic acid ethyl ester phosphate, imines acetoacetic ester citrate stability be substantially better than imines acid ethyl ester hydrochloride Salt.

Claims

1. the imines acetoacetic ester salt that a kind of acid of imines acetoacetic ester and pKa greater than -2 is formed, is selected from,

Imidic acid ethoxal salt shown in a kind of Formula V -2,

Imines acetoacetic ester dioxalic acid salt shown in a kind of Formula V -3,

Imines acetoacetic ester fumarate shown in a kind of Formula V -6,

Imidic acid ethyl ester phosphate shown in a kind of Formula V -7,

Imines acetoacetic ester citrate shown in a kind of Formula V -8,

2. salt described in claim 1, wherein

Imidic acid ethoxal salt shown in the Formula V -2 is specially imidic acid ethoxal salt crystal form A, using the source CuK α, Powder x-ray diffraction map the position following 2 θ have characteristic diffraction peak: 7.0 ° ± 0.2 °, 15.7 ° ± 0.2 °, 16.3 ° ± 0.2°,19.2°±0.2°,22.5°±0.2°,23.8°±0.2°；

Imines acetoacetic ester dioxalic acid salt shown in the Formula V -3 is specially imines acetoacetic ester dioxalic acid salt crystal form A, uses CuK α Source, powder x-ray diffraction map is in the position following 2 θ with characteristic diffraction peak: 4.7 ° ± 0.2 °, 5.0 ° ± 0.2 °, 5.8 ° ±0.2°、9.3°±0.2°、19.5°±0.2°、25.3°±0.2°。

3. the preparation method of imines acetoacetic ester salt as claimed in claim 1 or 2, this method comprises:

(1) compound IV or its salt are mixed with ethyl alcohol, imidic acid carbethoxy hydrochloride V-1 is converted under the action of hydrogen chloride；

(2) imines acetoacetic ester V is converted by imidic acid carbethoxy hydrochloride V-1 with alkali；

(3) imines acetoacetic ester V and corresponding acid are dissolved in suitable solvent, solid is precipitated, point isolated solid,

When the imines acetoacetic ester salt is imidic acid ethoxal salt V-2, the molar ratio of imines acetoacetic ester V and oxalic acid is 1:0.8 to 1:1.5,

When the imines acetoacetic ester salt is imines acetoacetic ester dioxalic acid salt V-3, the molar ratio of imines acetoacetic ester V and oxalic acid For 1:1.8 to 1:2.5,

When the imines acetoacetic ester salt is imines acetoacetic ester fumarate V-6, imines acetoacetic ester V and fumaric acid feed intake mole Than for 1:1 to 1:3.5,

When the imines acetoacetic ester salt is imidic acid ethyl ester phosphate V-7, the molar ratio of imines acetoacetic ester V and phosphoric acid is 1:1 to 1:3.5,

When the imines acetoacetic ester salt is imines acetoacetic ester citrate V-8, imines acetoacetic ester V and citric acid feed intake mole Than for 1:1 to 1:3.5；

(4) optionally, isolated solid is dried, or rear re-dry is further purified；

4. method as claimed in claim 3, wherein

In step (2), alkali is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, triethylamine Aqueous solution；

In step (3), suitable solvent is selected from ethyl alcohol, methylene chloride, acetone.

5. the method for a kind of imines acetoacetic ester salt preparation amidification object III as claimed in claim 1 or 2 or its salt, this method comprises: will Imines acetoacetic ester salt as claimed in claim 1 or 2 is reacted with ammonia reagent, and the ammonia reagent is selected from the ethanol of ammonium hydroxide, ammonia,

6. another acid is added in the reaction system, is selected from p-methyl benzenesulfonic acid, benzene sulfonic acid, methylsulphur for method described in claim 5 Acid, ethanesulfonic acid.

7. a kind of preparation method of dabigatran etcxilate I, this method comprises: by imines acetoacetic ester salt as claimed in claim 1 or 2 and ammonia Reagent reaction is prepared into amidification object III or its salt, and the amidification object III or its salt are further reacted with the just own ester of chloro-carbonic acid To dabigatran etcxilate I；The ammonia reagent is selected from the ethanol of ammonium hydroxide, ammonia,