CN105085387A

CN105085387A - Betrixaban salt, preparation method and application thereof

Info

Publication number: CN105085387A
Application number: CN201410214710.4A
Authority: CN
Inventors: 陈大峰; 惠帅; 程睿; 贾晓曼; 刘小凤; 闫树军; 罗杰; 向志祥
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2014-05-20
Filing date: 2014-05-20
Publication date: 2015-11-25
Also published as: WO2015176591A1; CN106458905B; CN106458905A

Abstract

The invention relates to betrixaban salt shown in a formula II, a preparation method of the betrixaban salt is simple, crystal form is easily controlled, stability and dissolvability are good, and the betrixaban salt is suitable for preparing a plurality of preparations. The invention also relates to the preparation method of the Betrixaban salt and a pharmaceutical composition containing the betrixaban salt, and also comprises an application of the betrixaban salt for preparing the medicines for preventing or treating mammals illness which takes bed thrombus formation as characteristic.

Description

Betrixaban salt and its production and use

Technical field

The present invention relates to organic chemistry filed and pharmaceutical field, salt being specifically related to betrixaban and preparation method thereof and these solid-state forms are in the purposes of the medicine for preventing or treat illness that Mammals is feature with bad thrombosis.

Background technology

Betrixaban (Betrixaban); chemistry is by name: N-(5-chloro-2-pyridyl)-2-[[4-[(dimethylamino) iminomethyl] benzoyl] is amino]-5-methoxy-b enzamide, and structure is such as formula shown in I:

Betrixaban, a kind of oral micromolecular compound, direct Xa factor inhibitor, is developed by Millennium the earliest, after transfer U.S. PortolaPharmaceuticals.This product is mainly used in the pulmonary embolisms that prevention and therapy dvt is formed and orthopedics is postoperative, can also be used for the apoplexy of preventing atrial fibrillation to cause simultaneously, can be used as the two wires prophylactic of myocardial infarction and apoplexy in addition.Be in III phase clinical stage at present.

Patent CN1391555A, CN102336702A, CN101595092A, CN102762538A etc. successively disclose the preparation method of betrixaban.Patent CN101304971A discloses the multiple salt shape of betrixaban: hydrochloric acid, lactic acid, maleic acid, phenoxy acetic acid, propionic acid, succinic acid, hexanodioic acid, xitix, dextrocamphoric acid, gluconic acid, phosphoric acid, tartrate, citric acid, methylsulfonic acid, FUMARIC ACID TECH GRADE, oxyacetic acid, naphthalene-1,5-disulfonic acid, gentisinic acid, Phenylsulfonic acid, camphorsulfonic acid, Alpha-hydroxy caproic acid, phenylformic acid, glucuronic acid, ketoglutaric acid, propanedioic acid, amygdalic acid, Pyrrolidonecarboxylic acid, sulfuric acid, trans-cinnamic acid.In above-mentioned salt shape, maleic acid salt (i.e. maleate) is chosen as preferably salt shape because having good crystallinity, stability and solvability; All the other salt shapes are all at one or more aspects Shortcomings such as crystallinity, solvability, stability.Although betrixaban maleate has good crystallinity, stability and solvability, it has heteromorphism, and polycrystalline is wayward.Such as, the crystal formation I of betrixaban maleate is disclosed in patent CN101304971A; Patent CN103261161A discloses betrixaban maleate crystal form II and crystal form II I, in this patent specification the 29th page, is specifically shown in the process preparing betrixaban maleate crystal formation I and has against expectation prepared crystal form II; In 21st page, clearly represent that crystal form II and crystal form II I can transform mutually, namely in drying and/or when crushing, crystal form II I can be converted into crystal form II, and when being exposed to the relative temperature being 25%, crystal form II can be converted into crystal form II I.Therefore, be necessary to continue to study the solid-state form of betrixaban, to obtaining the more excellent new salt of betrixaban of the physico-chemical properties such as polycrystallinity, stability, solvability.

Through the research to betrixaban solid-state form, what we were pleasantly surprised has found the new salt of multiple betrixaban, and these new salt production process are simple, crystal formation is easy to control, stability and favorable solubility, are suitable for preparing several formulations.

Summary of the invention

One object of the present invention is to provide betrixaban new salt, and these new salt production process are simple, crystal formation is easy to control, stability and favorable solubility.

Another object of the present invention is to the preparation method that above-mentioned betrixaban salt is provided.

Another object of the present invention is that providing package contains the pharmaceutical composition of the above-mentioned betrixaban salt for the treatment of significant quantity.

Another object of the present invention is the purposes of the medicine providing the illness of above-mentioned betrixaban salt being feature for the preparation of prevention or treatment Mammals with bad thrombosis.

Object of the present invention is realized by following proposal:

According to object of the present invention, the invention provides the betrixaban salt shown in formula II,

Wherein, when X is selected from L MALIC ACID, D-malic acid, DL-oxysuccinic acid, DL-tartrate, fourth disulfonic acid or ethionic acid, m value 0.5 or 1;

Or, when X is selected from isethionic acid or Hydrogen bromide, m value 1.

" salt " described in above-mentioned formula II not only comprises the salt in classical meaning that betrixaban and corresponding acid is combined by ionic linkage effect, but also comprise Qu Xiban and be combined by the effect of the non covalent bond such as hydrogen bond, ionic linkage with corresponding acid and the compound coexisted, namely comprise the salt in classical meaning well known in the art, eutectic or their mixed form etc." salt " described in above-mentioned formula II also comprises its form such as polycrystalline, solvate, solvate polycrystalline, hydrate, hydrate polycrystalline further.

In above-mentioned formula II, m value 0.5 or 1, refers to the approx. molar ratio of components of betrixaban and respective acids in said structure, can pass through ¹the modes such as H-NMR, ultimate analysis, HPLC, X-ray diffraction (such as Advances in crystal X-ray diffraction) characterize.Should the scope of " be similar to " be generally ± 0.15, preferred ± 0.1.

According to object of the present invention, the invention provides the preparation method of the betrixaban salt shown in a kind of formula II, the method comprises:

(1) betrixaban and L MALIC ACID, D-malic acid, DL-oxysuccinic acid, DL-tartrate, fourth disulfonic acid, ethionic acid, isethionic acid or Hydrogen bromide are dissolved in suitable solvent, wherein when in formula II during m value 0.5, the molar ratio of respective acids and betrixaban is not more than 0.7, when in formula II during m value 1, the molar ratio of respective acids and betrixaban is not less than 0.7;

(2) solid is separated out;

(3) solid of separating out is separated;

(4) alternatively, the solid of separation is carried out drying, or dry again after being further purified.

In the step (1) of above-mentioned preparation method, described betrixaban can obtain according to method disclosed in patent documentation CN1391555A, CN102336702A, CN101595092A, CN102762538A etc.These documents are incorporated in the application by way of reference.Described betrixaban can any form exist, as comprised crystal formation, amorphous or their mixed form.

In the step (1) of above-mentioned preparation method, when in formula II during m value 0.5, L MALIC ACID, D-malic acid, DL-oxysuccinic acid, DL-oxysuccinic acid, fourth disulfonic acid or ethionic acid and betrixaban molar ratio are not more than 0.7, are generally 0.3:1 ~ 0.7:1; When in formula II during m value 1, L MALIC ACID, D-malic acid, DL-oxysuccinic acid, DL-tartrate, fourth disulfonic acid, ethionic acid, isethionic acid or Hydrogen bromide and betrixaban molar ratio are not less than 1.0, are generally 1.0:1 ~ 2.0:1.

In the step (1) of above-mentioned preparation method, described " suitable solvent " refers to there is certain solubility to betrixaban and acid, and can form the solvent of betrixaban salt wherein, hereinafter the definition of " suitable solvent " is identical therewith simultaneously.These suitable solvent are selected from water, methyl alcohol, ethanol, Virahol, butanols, ethylene glycol, tetrahydrofuran (THF), acetonitrile, N,N-DIMETHYLACETAMIDE, dimethyl formamide, methyl-sulphoxide etc. or their mixture.The weight ratio of described suitable solvent and betrixaban is generally 5:1 ~ 15:1.

In the step (1) of above-mentioned preparation method, the temperature of described dissolving is generally 20 DEG C to solvent boiling point.

In the step (2) of above-mentioned preparation method, the method for described " precipitation solid " is method conventional in the art, as cooling, adds anti-solvent, concentrates out the alone of the methods such as partial solvent or coupling.Wherein said " anti-solvent " refers to bad to formed betrixaban salt solvability at normal temperatures and can be miscible with the suitable solvent of dissolving betrixaban and acid solvent.Anti-solvent is selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, sherwood oil, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, pimelinketone, toluene, dimethylbenzene etc. or their mixture.Described anti-solvent and the middle volume ratio of dissolving the suitable solvent of betrixaban and acid of step (1) are generally 0.5:1 ~ 5:1.To separate out solid process can be standing, may also be stirring.

In the step (3) of above-mentioned preparation method, described " separation " ordinary method of filtering and waiting in the art can be adopted.Alternatively, by the suitable solvent in step (1), collected solid can be washed.

In the step (4) of above-mentioned preparation method, the temperature of described " drying " is generally 20 ~ 100 DEG C; Can constant pressure and dry, also can drying under reduced pressure.The method " be further purified " comprises the forms such as recrystallization, pulp, washing.

In one embodiment, in formula II: m is 0.5, X is L MALIC ACID, be " half L MALIC ACID betrixaban "; Or m is 1, X is L MALIC ACID, be " L MALIC ACID betrixaban "; Or m is 0.5, X is D-malic acid, be " half D-malic acid betrixaban "; Or m is 1, X is D-malic acid, be " D-malic acid betrixaban "; Or m is 0.5, X is DL-oxysuccinic acid, be " half DL-oxysuccinic acid betrixaban "; Or m is 1, X is DL-oxysuccinic acid, be " DL-oxysuccinic acid betrixaban "; Or m is 1, X is DL-tartrate, be " DL-tartrate betrixaban "; Or m is 0.5, X is fourth disulfonic acid, be " half fourth disulfonic acid betrixaban "; Or m is 0.5, X is ethionic acid, be " half ethionic acid betrixaban "; Or m is 1, X is isethionic acid, be " isethionic acid betrixaban "; Or m is 1, X is Hydrogen bromide, i.e. " Hydrogen bromide betrixaban ".

half L MALIC ACID betrixaban

In one embodiment, in formula II, m elects 0.5, X as and elects L MALIC ACID as, namely provides the salt that betrixaban and L MALIC ACID are formed with 1:0.5 molar composition ratio, is called " half L MALIC ACID betrixaban ".

In one embodiment, the invention provides a kind of preparation method of half L MALIC ACID betrixaban, the method comprises:

(1) be dissolved in suitable solvent by betrixaban and L MALIC ACID, wherein the molar ratio of L MALIC ACID and betrixaban is not more than 0.7;

(2) solid is separated out;

(3) solid of separating out is separated;

In the step (1) of aforesaid method, described suitable solvent is selected from water, methyl alcohol, ethanol, Virahol, butanols, ethylene glycol, tetrahydrofuran (THF), acetonitrile, N, N-N,N-DIMETHYLACETAMIDE, N, dinethylformamide, methyl-sulphoxide etc. or their mixture, the wherein mixture of preferred tetrahydrofuran (THF) and water, the volume ratio of tetrahydrofuran (THF) and water is generally 5:1 ~ 10:1.The weight ratio of described suitable solvent and betrixaban is generally 5:1 ~ 15:1.

In the step (1) of above-mentioned preparation method, the temperature of described dissolving is generally 20 DEG C to solvent boiling point, preferred 50-60 DEG C.

In the step (1) of above-mentioned preparation method, the molar ratio of L MALIC ACID and betrixaban is generally 0.3:1 ~ 0.7:1.

In the step (2) of above-mentioned preparation method, the method for described " precipitation solid " is method conventional in the art, as cooling, adds anti-solvent, concentrates out the alone of the methods such as partial solvent or coupling.Wherein said anti-solvent is selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, sherwood oil, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, pimelinketone, toluene, dimethylbenzene etc. or their mixture, is wherein preferably acetone.Described anti-solvent and the middle volume ratio of dissolving the suitable solvent of betrixaban and L MALIC ACID of step (1) are generally 0.5:1 ~ 5:1.To separate out solid process can be standing, may also be stirring.

In the step (4) of above-mentioned preparation method, the temperature of described " drying " is generally 20 ~ 100 DEG C, is preferably 40 ~ 80 DEG C; Can constant pressure and dry, also can drying under reduced pressure.The method " be further purified " comprises the forms such as recrystallization, pulp, washing.

Half L MALIC ACID betrixaban prepared by this embodiment is a kind of crystal.

Therefore, the invention provides a kind of crystal formation (in order to express easily, being called by this crystal formation " half L MALIC ACID betrixaban crystal form A ") of half L MALIC ACID betrixaban.The feature of the X-ray powder diffraction of this crystal formation (using Cu-K α radiation) is: be that the position correspondence such as 8.6 ° ± 0.2 °, 12.3 ° ± 0.2 °, 13.3 ° ± 0.2 °, 14.2 ° ± 0.2 °, 15.7 ° ± 0.2 °, 19.2 ° ± 0.2 °, 19.6 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.3 ° ± 0.2 °, 21.7 ° ± 0.2 °, 22.8 ° ± 0.2 °, 24.1 ° ± 0.2 °, 26.9 ° ± 0.2 °, 29.3 ° ± 0.2 ° has characteristic diffraction peak in 2 θ values.

In one embodiment, the feature of the X-ray powder diffraction of half L MALIC ACID betrixaban crystal form A of the present invention (using Cu-K α radiation) is: be 4.2 ° ± 0.2 ° in 2 θ values, 8.6 ° ± 0.2 °, 11.7 ° ± 0.2 °, 12.3 ° ± 0.2 °, 12.6 ° ± 0.2 °, 12.9 ° ± 0.2 °, 13.3 ° ± 0.2 °, 14.2 ° ± 0.2 °, 15.7 ° ± 0.2 °, 15.9 ° ± 0.2 °, 18.9 ° ± 0.2 °, 19.2 ° ± 0.2 °, 19.6 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.3 ° ± 0.2 °, 21.7 ° ± 0.2 °, 22.0 ° ± 0.2 °, 22.8 ° ± 0.2 °, 23.8 ° ± 0.2 °, 24.1 ° ± 0.2 °, 24.7 ° ± 0.2 °, 25.4 ° ± 0.2 °, 25.7 ° ± 0.2 °, 26.3 ° ± 0.2 °, 26.9 ° ± 0.2 °, 29.3 ° ± 0.2 °, the position correspondence such as 31.5 ° ± 0.2 ° has characteristic diffraction peak.

In one embodiment, half L MALIC ACID betrixaban crystal form A provided by the invention has the feature representated by X-ray powder diffraction as shown in Figure 1.

In one embodiment, the crystal form purity of half L MALIC ACID betrixaban crystal form A provided by the invention is generally greater than 70% at (namely containing the mass percentage of crystal form A in half L MALIC ACID betrixaban), be preferably greater than 80%, be most preferably greater than 90%.This content can pass through x-ray powder diffraction, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc. record.

l MALIC ACID betrixaban

In one embodiment, in formula II, m elects 1, X as and elects L MALIC ACID as, namely provides the salt that betrixaban and L MALIC ACID are formed with 1:1 molar composition ratio, is called " L MALIC ACID betrixaban ".

In one embodiment, the invention provides a kind of preparation method of L MALIC ACID betrixaban, the method comprises:

(1) be dissolved in suitable solvent by betrixaban and L MALIC ACID, wherein the molar ratio of L MALIC ACID and betrixaban is not less than 1.0;

(2) solid is separated out;

(3) solid of separating out is separated;

In the step (1) of above-mentioned preparation method, the molar ratio of L MALIC ACID and betrixaban is generally 1.0:1 ~ 2.0:1, preferred 1.0:1 ~ 1.5:1.

In the step (2) of above-mentioned preparation method, the method for described " precipitation solid " is method conventional in the art, as cooling, adds anti-solvent, concentrates out the alone of the methods such as partial solvent or coupling.Wherein said anti-solvent is selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, sherwood oil, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, pimelinketone, toluene, dimethylbenzene etc. or their mixture, is preferably acetone.Described anti-solvent and the middle volume ratio of dissolving the suitable solvent of betrixaban and L MALIC ACID of step (1) are generally 0.5:1 ~ 5:1.To separate out solid process can be standing, may also be stirring.

L MALIC ACID betrixaban prepared by this embodiment is a kind of crystal.

Therefore, the invention provides a kind of crystal formation (in order to express easily, being called by this crystal formation " L MALIC ACID betrixaban crystal form A ") of L MALIC ACID betrixaban.The feature of the X-ray powder diffraction of this crystal formation (using Cu-K α radiation) is: be that the position correspondence such as 8.8 ° ± 0.2 °, 10.7 ° ± 0.2 °, 13.8 ° ± 0.2 °, 14.4 ° ± 0.2 °, 15.3 ° ± 0.2 °, 17.9 ° ± 0.2 °, 20.1 ° ± 0.2 °, 20.7 ° ± 0.2 °, 21.0 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.8 ° ± 0.2 °, 24.3 ° ± 0.2 °, 25.6 ° ± 0.2 ° has characteristic diffraction peak in 2 θ values.

In one embodiment, the feature of the X-ray powder diffraction of L MALIC ACID betrixaban crystal form A of the present invention (using Cu-K α radiation) is: be 4.3 ° ± 0.2 ° in 2 θ values, 8.8 ° ± 0.2 °, 10.7 ° ± 0.2 °, 12.0 ° ± 0.2 °, 13.8 ° ± 0.2 °, 14.4 ° ± 0.2 °, 15.3 ° ± 0.2 °, 16.5 ° ± 0.2 °, 17.9 ° ± 0.2 °, 20.1 ° ± 0.2 °, 20.7 ° ± 0.2 °, 21.0 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.8 ° ± 0.2 °, the position correspondences such as 24.3 ° ± 0.2 ° and 25.6 ° ± 0.2 ° have characteristic diffraction peak.

In one embodiment, L MALIC ACID betrixaban crystal form A provided by the invention has the feature representated by X-ray powder diffraction as shown in Figure 2.

In one embodiment, the crystal form purity of L MALIC ACID betrixaban crystal form A provided by the invention is generally greater than 70% at (namely containing the mass percentage of crystal form A in L MALIC ACID betrixaban), is preferably greater than 80%, is most preferably greater than 90%.This content can pass through x-ray powder diffraction, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc. record.

half D-malic acid betrixaban

In one embodiment, in formula II, m elects 0.5, X as and elects D-malic acid as, namely provides the salt that betrixaban and D-malic acid are formed with 1:0.5 molar composition ratio, is called " half D-malic acid betrixaban ".

In one embodiment, the invention provides a kind of preparation method of half D-malic acid betrixaban, the method comprises:

(1) be dissolved in suitable solvent by betrixaban and D-malic acid, wherein the molar ratio of D-malic acid and betrixaban is not more than 0.7;

(2) solid is separated out;

(3) solid of separating out is separated;

In the step (1) of above-mentioned preparation method, the temperature of described dissolving is generally 20 DEG C to solvent boiling point, preferred 50-60 DEG C.In the step (1) of above-mentioned preparation method, the molar ratio of D-malic acid and betrixaban is generally 0.3:1 ~ 0.7:1.

In the step (2) of above-mentioned preparation method, the method for described " precipitation solid " is method conventional in the art, as cooling, adds anti-solvent, concentrates out the alone or coupling of the methods such as partial solvent body.Wherein said anti-solvent is selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, sherwood oil, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, pimelinketone, toluene, dimethylbenzene etc. or their mixture, is preferably acetone.Described anti-solvent and the middle volume ratio of dissolving the suitable solvent of betrixaban and D-malic acid of step (1) are generally 0.5:1 ~ 5:1.To separate out solid process can be standing, may also be stirring.

Half D-malic acid betrixaban prepared by this embodiment is a kind of crystal.

Therefore, the invention provides a kind of crystal formation (in order to express easily, being called by this crystal formation " half D-malic acid betrixaban crystal form A ") of half D-malic acid betrixaban.The feature of the X-ray powder diffraction of this crystal formation (using Cu-K α radiation) is: be 8.6 ° ± 0.2 °, 12.3 ° ± 0.2 °, 13.3 ° ± 0.2 °, 14.2 ° ± 0.2 °, 15.7 ° ± 0.2 °, 19.2 ° ± 0.2 °, 19.6 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.7 ° ± 0.2 °, 22.8 ° ± 0.2 °, 24.1 ° ± 0.2 °, 26.8 ° ± 0.2 °, 29.4 ° ± 0.2 ° in 2 θ values; Characteristic diffraction peak is had Deng position correspondence.

In one embodiment, the feature of the X-ray powder diffraction of half D-malic acid betrixaban crystal form A of the present invention (using Cu-K α radiation) is: be 4.2 ° ± 0.2 ° in 2 θ values, 8.6 ° ± 0.2 °, 11.7 ° ± 0.2 °, 11.9 ° ± 0.2 °, 12.3 ° ± 0.2 °, 12.5 ° ± 0.2 °, 12.9 ° ± 0.2 °, 13.3 ° ± 0.2 °, 14.2 ° ± 0.2 °, 15.7 ° ± 0.2 °, 15.9 ° ± 0.2 °, 18.9 ° ± 0.2 °, 19.2 ° ± 0.2 °, 19.6 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.7 ° ± 0.2 °, 21.9 ° ± 0.2 °, 22.8 ° ± 0.2 °, 23.8 ° ± 0.2 °, 24.1 ° ± 0.2 °, 24.7 ° ± 0.2 °, 25.4 ° ± 0.2 °, 25.7 ° ± 0.2 °, 26.3 ° ± 0.2 °, 26.8 ° ± 0.2 °, 29.4 ° ± 0.2 °, the position correspondence such as 31.5 ° ± 0.2 ° has characteristic diffraction peak.

In one embodiment, half D-malic acid betrixaban crystal form A provided by the invention has the feature representated by X-ray powder diffraction as shown in Figure 3.

In one embodiment, the crystal form purity of half D-malic acid betrixaban crystal form A provided by the invention is generally greater than 70% at (namely containing the mass percentage of crystal form A in half D-malic acid betrixaban), be preferably greater than 80%, be most preferably greater than 90%.This content can pass through x-ray powder diffraction, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc. record.

d-malic acid betrixaban

In one embodiment, in formula II, m elects 1, X as and elects D-malic acid as, namely provides the salt that betrixaban and D-malic acid are formed with 1:1 molar composition ratio, is called " D-malic acid betrixaban ".

In one embodiment, the invention provides a kind of preparation method of D-malic acid betrixaban, the method comprises:

(1) be dissolved in suitable solvent by betrixaban and D-malic acid, wherein the molar ratio of D-malic acid and betrixaban is not less than 1.0;

(2) solid is separated out;

(3) solid of separating out is separated;

In the step (1) of above-mentioned preparation method, the molar ratio of D-malic acid and betrixaban is generally 1.0:1 ~ 2.0:1, preferred 1.0:1 ~ 1.5:1.

D-malic acid betrixaban prepared by this embodiment is a kind of crystal.

Therefore, the invention provides a kind of crystal formation (in order to express easily, being called by this crystal formation " D-malic acid betrixaban crystal form A ") of D-malic acid betrixaban.The feature of the X-ray powder diffraction of this crystal formation (using Cu-K α radiation) is: be that the position correspondence such as 8.8 ° ± 0.2 °, 10.7 ° ± 0.2 °, 13.8 ° ± 0.2 °, 14.4 ° ± 0.2 °, 15.2 ° ± 0.2 °, 17.9 ° ± 0.2 °, 20.0 ° ± 0.2 °, 20.7 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.8 ° ± 0.2 °, 24.4 ° ± 0.2 °, 25.6 ° ± 0.2 ° has characteristic diffraction peak in 2 θ values.

In one embodiment, the feature of the X-ray powder diffraction of D-malic acid betrixaban crystal form A of the present invention (using Cu-K α radiation) is: be 4.3 ° ± 0.2 ° in 2 θ values, 8.8 ° ± 0.2 °, 10.7 ° ± 0.2 °, 12.0 ° ± 0.2 °, 13.8 ° ± 0.2 °, 14.4 ° ± 0.2 °, 15.2 ° ± 0.2 °, 16.5 ° ± 0.2 °, 17.9 ° ± 0.2 °, 20.0 ° ± 0.2 °, 20.7 ° ± 0.2 °, 21.0 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.8 ° ± 0.2 °, 24.4 ° ± 0.2 °, the position correspondence such as 25.6 ° ± 0.2 ° has characteristic diffraction peak.

In one embodiment, D-malic acid betrixaban crystal form A provided by the invention has the feature representated by X-ray powder diffraction as shown in Figure 4.

In one embodiment, the crystal form purity of D-malic acid betrixaban crystal form A provided by the invention is generally greater than 70% at (namely containing the mass percentage of crystal form A in L MALIC ACID betrixaban), is preferably greater than 80%, is most preferably greater than 90%.This content can pass through x-ray powder diffraction, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc. record.

half DL-oxysuccinic acid betrixaban

In one embodiment, in formula II, m elects 0.5, X as and elects DL-oxysuccinic acid as, namely provides the salt that betrixaban and DL-oxysuccinic acid are formed with 1:0.5 molar composition ratio, is called " half DL-oxysuccinic acid betrixaban ".

In one embodiment, the invention provides a kind of preparation method of half DL-oxysuccinic acid betrixaban, the method comprises:

(1) be dissolved in suitable solvent by betrixaban and DL-oxysuccinic acid, wherein the molar ratio of DL-oxysuccinic acid and betrixaban is not more than 0.7;

(2) solid is separated out;

(3) solid of separating out is separated;

Half DL-oxysuccinic acid betrixaban prepared by this embodiment is a kind of crystal.

Therefore, the invention provides a kind of crystal formation (in order to express easily, being called by this crystal formation " half DL-oxysuccinic acid betrixaban crystal form A ") of half DL-oxysuccinic acid betrixaban.The feature of the X-ray powder diffraction of this crystal formation (using Cu-K α radiation) is: be that the position correspondence such as 8.6 ° ± 0.2 °, 12.3 ° ± 0.2 °, 13.2 ° ± 0.2 °, 14.2 ° ± 0.2 °, 15.7 ° ± 0.2 °, 19.2 ° ± 0.2 °, 19.6 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.2 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.8 ° ± 0.2 °, 24.1 ° ± 0.2 °, 26.8 ° ± 0.2 °, 29.4 ° ± 0.2 ° has characteristic diffraction peak in 2 θ values.

In one embodiment, the feature of the X-ray powder diffraction of half DL-oxysuccinic acid betrixaban crystal form A of the present invention (using Cu-K α radiation) is: be 4.3 ° ± 0.2 ° in 2 θ values, 8.6 ° ± 0.2 °, 11.6 ° ± 0.2 °, 12.3 ° ± 0.2 °, 12.5 ± 0.2 °, 13.2 ° ± 0.2 °, 14.2 ° ± 0.2 °, 15.7 ° ± 0.2 °, 15.9 ° ± 0.2 °, 18.9 ° ± 0.2 °, 19.2 ° ± 0.2 °, 19.6 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.2 ° ± 0.2 °, 21.6 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.8 ° ± 0.2 °, 23.9 ° ± 0.2 °, 24.1 ° ± 0.2 °, 24.7 ° ± 0.2 °, 25.4 ° ± 0.2 °, 25.6 ° ± 0.2 °, 26.4 ° ± 0.2 °, 26.8 ° ± 0.2 °, 29.4 ° ± 0.2 °, the position correspondence such as 31.5 ° ± 0.2 ° has characteristic diffraction peak.

In one embodiment, half DL-oxysuccinic acid betrixaban crystal form A provided by the invention has the feature representated by X-ray powder diffraction as shown in Figure 5.

In one embodiment, the crystal form purity of half DL-oxysuccinic acid betrixaban crystal form A provided by the invention is generally greater than 70% at (namely containing the mass percentage of crystal form A in half D-malic acid betrixaban), be preferably greater than 80%, be most preferably greater than 90%.This content can pass through x-ray powder diffraction, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc. record.

dL-oxysuccinic acid betrixaban

In one embodiment, in formula II, m elects 1, X as and elects DL-oxysuccinic acid as, namely provides the salt that betrixaban and DL-oxysuccinic acid are formed with 1:1 molar composition ratio, is called " DL-oxysuccinic acid betrixaban ".

In one embodiment, the invention provides a kind of preparation method of DL-oxysuccinic acid betrixaban, the method comprises:

(1) be dissolved in suitable solvent by betrixaban and DL-oxysuccinic acid, wherein the molar ratio of DL-oxysuccinic acid and betrixaban is not less than 1.0;

(2) solid is separated out;

(3) solid of separating out is separated;

In the step (1) of above-mentioned preparation method, the molar ratio of DL-oxysuccinic acid and betrixaban is generally 1.0:1 ~ 2.0:1, preferred 1.0:1 ~ 1.5:1.

In the step (2) of above-mentioned preparation method, the method for described " precipitation solid " is method conventional in the art, as cooling, adds anti-solvent, concentrates out the alone or coupling of the methods such as partial solvent body.Described anti-solvent is selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, sherwood oil, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, pimelinketone, toluene, dimethylbenzene etc. or their mixture, is preferably acetone.Described anti-solvent and the middle volume ratio of dissolving the suitable solvent of betrixaban and DL-oxysuccinic acid of step (1) are generally 0.5:1 ~ 5:1.To separate out solid process can be standing, may also be stirring.

DL-oxysuccinic acid betrixaban prepared by this embodiment is a kind of crystal.

Therefore, the invention provides a kind of crystal formation (in order to express easily, being called by this crystal formation " DL-oxysuccinic acid betrixaban crystal form A ") of DL-oxysuccinic acid betrixaban.The feature of the X-ray powder diffraction of this crystal formation (using Cu-K α radiation) is: be that the position correspondence such as 8.6 ° ± 0.2 °, 10.7 ° ± 0.2 °, 13.8 ° ± 0.2 °, 14.6 ° ± 0.2 °, 15.5 ° ± 0.2 °, 18.0 ° ± 0.2 °, 20.2 ° ± 0.2 °, 20.9 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.0 ° ± 0.2 °, 24.6 ° ± 0.2 °, 25.6 ° ± 0.2 ° has characteristic diffraction peak in 2 θ values.

In one embodiment, the feature of the X-ray powder diffraction of DL-oxysuccinic acid betrixaban crystal form A of the present invention (using Cu-K α radiation) is: be 4.4 ° ± 0.2 ° in 2 θ values, 8.6 ° ± 0.2 °, 10.4 ° ± 0.2 °, 10.7 ° ± 0.2 °, 12.2 ° ± 0.2 °, 13.8 ° ± 0.2 °, 14.6 ° ± 0.2 °, 15.5 ° ± 0.2 °, 16.5 ° ± 0.2 °, 18.0 ° ± 0.2 °, 20.2 ° ± 0.2 °, 20.9 ° ± 0.2 °, 21.2 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.0 ° ± 0.2 °, 24.6 ° ± 0.2 °, the position correspondence such as 25.6 ° ± 0.2 ° has characteristic diffraction peak.

In one embodiment, DL-oxysuccinic acid betrixaban crystal form A provided by the invention has the feature representated by X-ray powder diffraction as shown in Figure 6.

In one embodiment, the crystal form purity of DL-oxysuccinic acid betrixaban crystal form A provided by the invention is generally greater than 70% at (namely containing the mass percentage of crystal form A in DL-oxysuccinic acid betrixaban), is preferably greater than 80%, is most preferably greater than 90%.This content can pass through x-ray powder diffraction, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc. record.

dL-tartrate betrixaban

In one embodiment, in formula II, m elects 1, X as and elects DL-tartrate as, namely provides the salt that betrixaban and DL-tartrate are formed with 1:1 molar composition ratio, is called " DL-tartrate betrixaban ".

In one embodiment, the invention provides a kind of preparation method of DL-tartrate betrixaban, the method comprises:

(1) be dissolved in suitable solvent by betrixaban and DL-tartrate, wherein the molar ratio of DL-tartrate and betrixaban is not less than 1.0;

(2) solid is separated out;

(3) solid of separating out is separated;

In the step (1) of above-mentioned preparation method, described suitable solvent is selected from water, methyl alcohol, ethanol, Virahol, butanols, ethylene glycol, tetrahydrofuran (THF), acetonitrile, N, N-N,N-DIMETHYLACETAMIDE, N, dinethylformamide, methyl-sulphoxide etc. or their mixture, wherein preferred N, the mixture of N-N,N-DIMETHYLACETAMIDE and water, the volume ratio of N,N-dimethylacetamide and water is generally 5:1 ~ 10:1.The weight ratio of described suitable solvent and betrixaban is generally 5:1 ~ 15:1.

In the step (1) of above-mentioned preparation method, the molar ratio of DL-tartrate and betrixaban is generally 1.0:1 ~ 2.0:1, preferred 1.0:1 ~ 1.5:1.

In the step (2) of above-mentioned preparation method, the method for described " precipitation solid " is method conventional in the art, as cooling, adds anti-solvent, concentrates out the alone or coupling of the methods such as partial solvent body.Described anti-solvent is selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, sherwood oil, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, pimelinketone, toluene, dimethylbenzene etc. or their mixture, is preferably tetrahydrofuran (THF).Described anti-solvent and the middle volume ratio of dissolving betrixaban and the tartaric suitable solvent of DL-of step (1) are generally 0.5:1 ~ 5:1.To separate out solid process can be standing, may also be stirring.

DL-tartrate betrixaban prepared by this embodiment is a kind of crystal.

Therefore, the invention provides a kind of crystal formation (in order to express easily, being called by this crystal formation " DL-tartrate betrixaban crystal form A ") of DL-tartrate betrixaban.The feature of the X-ray powder diffraction of this crystal formation (using Cu-K α radiation) is: be that the position correspondences such as 4.5 ° ± 0.2 °, 13.8 ± 0.2 °, 15.4 ° ± 0.2 °, 16.0 ° ± 0.2 °, 18.4 ° ± 0.2 °, 20.1 ° ± 0.2 °, 23.0 ° ± 0.2 ° and 26.2 ° ± 0.2 ° have characteristic diffraction peak in 2 θ values.

In one embodiment, the feature of the X-ray powder diffraction of DL-tartrate betrixaban crystal form A of the present invention (using Cu-K α radiation) is: be 4.5 ° ± 0.2 ° in 2 θ values, 10.5 ° ± 0.2 °, 12.3 ° ± 0.2 °, 13.8 ° ± 0.2 °, 15.4 ° ± 0.2 °, 15.6 ° ± 0.2 °, 16.0 ° ± 0.2 °, 18.4 ° ± 0.2 °, 18.8 ° ± 0.2 °, 19.1 ° ± 0.2 °, 20.1 ° ± 0.2 °, 22.3 ° ± 0.2 °, 23.0 ° ± 0.2 °, 23.8 ° ± 0.2 °, 24.9 ° ± 0.2 °, the position correspondences such as 26.2 ° ± 0.2 ° and 27.8 ° ± 0.2 ° have characteristic diffraction peak.

In one embodiment, DL-tartrate betrixaban crystal form A provided by the invention has the feature representated by X-ray powder diffraction as shown in Figure 7.

In one embodiment, the crystal form purity of DL-tartrate betrixaban crystal form A provided by the invention is generally greater than 70% at (namely containing the mass percentage of crystal form A in DL-tartrate betrixaban), is preferably greater than 80%, is most preferably greater than 90%.This content can pass through x-ray powder diffraction, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc. record.

half fourth disulfonic acid betrixaban

In one embodiment, in formula II, m elects 0.5, X as and elects fourth disulfonic acid as, namely provides the salt that betrixaban and fourth disulfonic acid are formed with 1:0.5 molar composition ratio, is called " half fourth disulfonic acid betrixaban ".

In one embodiment, the invention provides one halfthe preparation method of fourth disulfonic acid betrixaban, the method comprises:

(1) be dissolved in suitable solvent by betrixaban and fourth disulfonic acid, wherein the molar ratio of fourth disulfonic acid and betrixaban is not more than 0.7;

(2) solid is separated out;

(3) solid of separating out is separated;

In the step (1) of above-mentioned preparation method, described suitable solvent is selected from water, methyl alcohol, ethanol, Virahol, butanols, ethylene glycol, tetrahydrofuran (THF), acetonitrile, N, N-N,N-DIMETHYLACETAMIDE, N, dinethylformamide, methyl-sulphoxide etc. or their mixture, the wherein mixture of preferred alcohol and water, the volume ratio of ethanol and water is generally 0.5:1 ~ 10:1.The weight ratio of described suitable solvent and betrixaban is generally 5:1 ~ 15:1.

In the step (1) of above-mentioned preparation method, the molar ratio of fourth disulfonic acid and betrixaban is generally 0.3:1 ~ 0.7:1.

In the step (2) of above-mentioned preparation method, the method for described " precipitation solid " is method conventional in the art, as cooling, adds anti-solvent, concentrates out the alone or coupling of the methods such as partial solvent body.Describedly be selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, sherwood oil, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, pimelinketone, toluene, dimethylbenzene etc. or their mixture, be preferably acetone.Described anti-solvent and the middle volume ratio of dissolving the suitable solvent of betrixaban and fourth disulfonic acid of step (1) are generally 0.5:1 ~ 5:1.To separate out solid process can be standing, may also be stirring.

Prepared by this embodiment halffourth disulfonic acid betrixaban is a kind of crystal.

Therefore, the invention provides a kind of crystal formation (in order to express easily, being called by this crystal formation " half fourth disulfonic acid betrixaban crystal form A ") of half fourth disulfonic acid betrixaban.The feature of the X-ray powder diffraction of this crystal formation (using Cu-K α radiation) is: be 6.6 ° ± 0.2 ° in 2 θ values, 9.3 ° ± 0.2 °, 11.1 ° ± 0.2 °, 11.7 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.4 ° ± 0.2 °, 15.8 ° ± 0.2 °, 17.2 ° ± 0.2 °, 18.0 ° ± 0.2 °, 18.5 ° ± 0.2 °, 19.6 ° ± 0.2 °, 20.5 ° ± 0.2 °, 22.1 ° ± 0.2 °, 25.0 ° ± 0.2 °, the position correspondence such as 25.6 ° ± 0.2 ° has characteristic diffraction peak.

In one embodiment, the feature of the X-ray powder diffraction of half fourth disulfonic acid betrixaban crystal form A of the present invention (using Cu-K α radiation) is: be 6.6 ° ± 0.2 ° in 2 θ values, 9.3 ° ± 0.2 °, 11.1 ° ± 0.2 °, 11.2 ° ± 0.2 °, 11.7 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.4 ° ± 0.2 °, 14.9 ° ± 0.2 °, 15.8 ° ± 0.2 °, 16.0 ° ± 0.2 °, 17.2 ° ± 0.2 °, 17.6 ° ± 0.2 °, 18.0 ° ± 0.2 °, 18.5 ° ± 0.2 °, 18.7 ° ± 0.2 °, 19.6 ° ± 0.2 °, 19.8 ° ± 0.2 °, 20.5 ° ± 0.2 °, 21.1 ° ± 0.2 °, 22.1 ° ± 0.2 °, 22.7 ° ± 0.2 °, 25.0 ° ± 0.2 °, 25.6 ° ± 0.2 °, 26.0 ° ± 0.2 °, 26.3 ° ± 0.2 °, 26.9 ° ± 0.2 °, the position correspondence such as 28.7 ° ± 0.2 ° has characteristic diffraction peak.

In one embodiment, half fourth disulfonic acid betrixaban crystal form A provided by the invention has the feature representated by X-ray powder diffraction as shown in Figure 8.

In one embodiment, provided by the invention halfthe crystal form purity of fourth disulfonic acid betrixaban crystal form A is generally greater than 70% at (namely containing the mass percentage of crystal form A in half fourth disulfonic acid betrixaban), is preferably greater than 80%, is most preferably greater than 90%.This content can pass through x-ray powder diffraction, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc. record.

half ethionic acid betrixaban

In one embodiment, in formula II, m elects 0.5, X as and elects ethionic acid as, namely provides the salt that betrixaban and ethionic acid are formed with 1:0.5 molar composition ratio, is called " half ethionic acid betrixaban ".

In one embodiment, the invention provides a kind of preparation method of half ethionic acid betrixaban, the method comprises:

(1) be dissolved in suitable solvent by betrixaban and ethionic acid, wherein the molar ratio of ethionic acid and betrixaban is not more than 0.7;

(2) solid is separated out;

(3) solid of separating out is separated;

In the step (1) of above-mentioned preparation method, described suitable solvent is selected from water, methyl alcohol, ethanol, Virahol, butanols, ethylene glycol, tetrahydrofuran (THF), acetonitrile, N, N-N,N-DIMETHYLACETAMIDE, N, dinethylformamide, methyl-sulphoxide etc. or their mixture, the wherein mixture of preferred alcohol and water, the volume ratio of ethanol and water is generally 5:1 ~ 10:1.The weight ratio of described suitable solvent and betrixaban is generally 5:1 ~ 15:1.

In the step (1) of above-mentioned preparation method, the molar ratio of ethionic acid and betrixaban is generally 0.3:1 ~ 0.7:1.

In the step (2) of above-mentioned preparation method, the method for described " precipitation solid " is method conventional in the art, as cooling, adds anti-solvent, concentrates out the alone or coupling of the methods such as partial solvent body.Described anti-solvent is selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, sherwood oil, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, pimelinketone, toluene, dimethylbenzene etc. or their mixture, is preferably acetone.Described anti-solvent and the middle volume ratio of dissolving the suitable solvent of betrixaban and ethionic acid of step (1) are generally 0.5:1 ~ 5:1.To separate out solid process can be standing, may also be stirring.

Half ethionic acid betrixaban prepared by this embodiment is a kind of crystal.

Therefore, the invention provides a kind of crystal formation (in order to express easily, being called by this crystal formation " half ethionic acid betrixaban crystal form A ") of half ethionic acid betrixaban.The feature of the X-ray powder diffraction of this crystal formation (using Cu-K α radiation) is: be that the position correspondences such as 4.9 ° ± 0.2 °, 5.6 ° ± 0.2 °, 14.7 ° ± 0.2 °, 15.2 ° ± 0.2 °, 16.8 ° ± 0.2 °, 17.4 ° ± 0.2 °, 17.9 ° ± 0.2 °, 19.0 ° ± 0.2 °, 19.1 ° ± 0.2 °, 21.0 ° ± 0.2 °, 24.0 ° ± 0.2 ° and 24.5 ° ± 0.2 ° have characteristic diffraction peak in 2 θ values.

In one embodiment, the feature of the X-ray powder diffraction (use Cu-K α radiation) of half ethionic acid betrixaban crystal form A of the present invention is: be 4.9 ° ± 0.2 °, 5.6 ° ± 0.2 °, 9.7 ° ± 0.2 °, 14.7 ° ± 0.2 °, 15.2 ° ± 0.2 °, 16.8 ° ± 0.2 °, 17.4 ° ± 0.2 °, 17.9 ° ± 0.2 °, 19.0 ° ± 0.2 °, 19.1 ± 0.2 °, 19.3 ° ± 0.2 °, 19.6 in 2 θ values ^°the position correspondences such as ± 0.2 °, 21.0 ° ± 0.2 °, 24.0 ° ± 0.2 °, 24.5 ° ± 0.2 °, 25.3 ° ± 0.2 °, 26.4 ° ± 0.2 ° and 27.6 ° ± 0.2 ° have characteristic diffraction peak.

In one embodiment, half ethionic acid betrixaban crystal form A provided by the invention has the feature representated by X-ray powder diffraction as shown in Figure 9.

In one embodiment, the crystal form purity of half ethionic acid betrixaban crystal form A provided by the invention is generally greater than 70% at (namely containing the mass percentage of crystal form A in half ethionic acid betrixaban), be preferably greater than 80%, be most preferably greater than 90%.This content can pass through x-ray powder diffraction, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc. record.

isethionic acid betrixaban

In one embodiment, in formula II, m elects 1, X as and elects isethionic acid as, namely provides the salt that betrixaban and isethionic acid are formed with 1:1 molar composition ratio, is called " isethionic acid betrixaban ".

In one embodiment, the invention provides a kind of preparation method of isethionic acid betrixaban, the method comprises:

(1) be dissolved in suitable solvent by betrixaban and isethionic acid, wherein the molar ratio of isethionic acid and betrixaban is not less than 1.0;

(2) solid is separated out;

(3) solid of separating out is separated;

In the step (1) of above-mentioned preparation method, the temperature of described dissolving is generally 20 DEG C to solvent boiling point, preferred 50-60 DEG C.In the step (1) of above-mentioned preparation method, the molar ratio of isethionic acid and betrixaban is generally 1.0:1 ~ 2.0:1, preferred 1.0:1 ~ 1.5:1.

In the step (2) of above-mentioned preparation method, the method for described " precipitation solid " is method conventional in the art, as cooling, adds anti-solvent, concentrates out the alone or coupling of the methods such as partial solvent body.Described anti-solvent is selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, sherwood oil, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, pimelinketone, toluene, dimethylbenzene etc. or their mixture, is preferably acetone.Described anti-solvent and the middle volume ratio of dissolving the suitable solvent of betrixaban and isethionic acid of step (1) are generally 0.5:1 ~ 5:1.To separate out solid process can be standing, may also be stirring.

Isethionic acid betrixaban prepared by this embodiment is a kind of crystal.

Therefore, the invention provides a kind of crystal formation (in order to express easily, being called by this crystal formation " isethionic acid betrixaban crystal form A ") of isethionic acid betrixaban.The feature of the X-ray powder diffraction of this crystal formation (using Cu-K α radiation) is: be that the position correspondences such as 12.5 ° ± 0.2 °, 12.9 ° ± 0.2 °, 15.9 ° ± 0.2 °, 16.5 ° ± 0.2 °, 17.1 ° ± 0.2 °, 17.4 ° ± 0.2 °, 18.8 ° ± 0.2 °, 22.7 ° ± 0.2 °, 28.5 ° ± 0.2 ° and 28.7 ° ± 0.2 ° have characteristic diffraction peak in 2 θ values.

In one embodiment, the feature of the X-ray powder diffraction of isethionic acid betrixaban crystal form A of the present invention (using Cu-K α radiation) is: be 12.5 ° ± 0.2 ° in 2 θ values, 12.9 ° ± 0.2 °, 15.9 ° ± 0.2 °, 16.5 ° ± 0.2 °, 17.1 ° ± 0.2 °, 17.4 ° ± 0.2 °, 18.8 ° ± 0.2 °, 19.4 ° ± 0.2 °, 22.7 ° ± 0.2 °, 23.1 ° ± 0.2 °, 23.7 ° ± 0.2 °, 24.2 ° ± 0.2 °, 25.4 ° ± 0.2 °, 27.9 ° ± 0.2 °, 28.6 ° ± 0.2 °, 28.7 ° ± 0.2 °, 30.2 ° ± 0.2 °, the position correspondences such as 34.7 ° ± 0.2 ° and 35.1 ° ± 0.2 ° have characteristic diffraction peak.

In one embodiment, isethionic acid betrixaban crystal form A provided by the invention has the feature representated by X-ray powder diffraction as shown in Figure 10.

In one embodiment, the crystal form purity of isethionic acid betrixaban crystal form A provided by the invention is generally greater than 70% at (namely containing the mass percentage of crystal form A in isethionic acid betrixaban), is preferably greater than 80%, is most preferably greater than 90%.This content can pass through x-ray powder diffraction, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc. record.

hydrogen bromide betrixaban

In one embodiment, in formula II, m elects 1, X as and elects Hydrogen bromide as, namely provides the salt that betrixaban and Hydrogen bromide are formed with 1:1 molar composition ratio, is called " Hydrogen bromide betrixaban ".

In one embodiment, the invention provides a kind of preparation method of Hydrogen bromide betrixaban, the method comprises:

(1) be dissolved in suitable solvent by betrixaban and Hydrogen bromide, wherein the molar ratio of Hydrogen bromide and betrixaban is not less than 1.0;

(2) solid is separated out;

(3) solid of separating out is separated;

In the step (1) of above-mentioned preparation method, described suitable solvent is selected from water, methyl alcohol, ethanol, Virahol, butanols, ethylene glycol, tetrahydrofuran (THF), acetonitrile, N, N-N,N-DIMETHYLACETAMIDE, N, dinethylformamide, methyl-sulphoxide etc. or their mixture, the wherein mixture of preferred tetrahydrofuran (THF) and water, the volume ratio of ethanol and water is generally 5:1 ~ 10:1.The weight ratio of described suitable solvent and betrixaban is generally 5:1 ~ 15:1.

In the step (1) of above-mentioned preparation method, the molar ratio of Hydrogen bromide and betrixaban is generally 1.0:1 ~ 2.0:1, preferred 1.0:1 ~ 1.5:1.

In the step (2) of above-mentioned preparation method, the method for described " precipitation solid " is method conventional in the art, as cooling, adds anti-solvent, concentrates out the alone or coupling of the methods such as partial solvent body.Described anti-solvent is selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, sherwood oil, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, pimelinketone, toluene, dimethylbenzene etc. or their mixture, is preferably acetone.Described anti-solvent and the middle volume ratio of dissolving betrixaban and hydrobromic suitable solvent of step (1) are generally 0.5:1 ~ 5:1.To separate out solid process can be standing, may also be stirring.

Hydrogen bromide betrixaban prepared by this embodiment is a kind of crystal.

Therefore, the invention provides a kind of crystal formation (in order to express easily, being called by this crystal formation " Hydrogen bromide betrixaban crystal form A ") of Hydrogen bromide betrixaban.The feature of the X-ray powder diffraction of this crystal formation (using Cu-K α radiation) is: be that the position correspondence such as 5.8 ° ± 0.2 °, 6.5 ° ± 0.2 °, 8.8 ° ± 0.2 °, 11.7 ° ± 0.2 °, 15.1 ° ± 0.2 °, 17.8 ° ± 0.2 °, 21.3 ° ± 0.2 °, 21.7 ° ± 0.2 °, 22.3 ° ± 0.2 °, 25.3 ° ± 0.2 °, 26.7 ° ± 0.2 ° has characteristic diffraction peak in 2 θ values.

In one embodiment, the feature of the X-ray powder diffraction of Hydrogen bromide betrixaban crystal form A of the present invention (using Cu-K α radiation) is: be 4.4 ° ± 0.2 ° in 2 θ values, 5.8 ° ± 0.2 °, 6.5 ° ± 0.2 °, 6.9 ° ± 0.2 °, 8.8 ° ± 0.2 °, 8.9 ° ± 0.2 °, 11.7 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.3 ° ± 0.2 °, 14.7 ° ± 0.2 °, 15.1 ° ± 0.2 °, 17.8 ° ± 0.2 °, 21.3 ° ± 0.2 °, 21.7 ° ± 0.2 °, 22.3 ° ± 0.2 °, 24.7 ° ± 0.2 °, 25.3 ° ± 0.2 °, 25.7 ° ± 0.2 °, 26.7 ° ± 0.2 °, 27.4 ° ± 0.2 °, the position correspondence such as 33.5 ° ± 0.2 ° has characteristic diffraction peak.

In one embodiment, Hydrogen bromide betrixaban crystal form A provided by the invention has the feature representated by X-ray powder diffraction as shown in figure 11.

In one embodiment, the crystal form purity of Hydrogen bromide betrixaban crystal form A provided by the invention is generally greater than 70% at (namely containing the mass percentage of crystal form A in Hydrogen bromide betrixaban), is preferably greater than 80%, is most preferably greater than 90%.This content can pass through x-ray powder diffraction, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc. record.

According to object of the present invention, the invention provides a kind of pharmaceutical composition or the preparation that comprise the betrixaban salt shown in formula II that the treatment betrixaban salt shown in formula II of significant quantity or above-mentioned preparation method obtain and pharmaceutical excipient.

In one embodiment, the invention provides and a kind ofly comprise the treatment betrixaban salt shown in formula II of significant quantity and the pharmaceutical composition of pharmaceutical excipient or preparation.

In one embodiment, the invention provides a kind of half L MALIC ACID betrixaban comprising treatment significant quantity, L MALIC ACID betrixaban, half D-malic acid betrixaban, D-malic acid betrixaban, half DL-oxysuccinic acid betrixaban, DL-oxysuccinic acid betrixaban, DL-tartrate betrixaban, half fourth disulfonic acid betrixaban, half ethionic acid betrixaban, isethionic acid betrixaban, Hydrogen bromide betrixaban, half L MALIC ACID betrixaban crystal form A, L MALIC ACID betrixaban crystal form A, half D-malic acid betrixaban crystal form A, D-malic acid betrixaban crystal form A, half DL-oxysuccinic acid betrixaban crystal form A, DL-oxysuccinic acid betrixaban crystal form A, DL-tartrate betrixaban crystal form A, half fourth disulfonic acid betrixaban crystal form A, half ethionic acid betrixaban crystal form A, the pharmaceutical composition of isethionic acid betrixaban crystal form A or Hydrogen bromide betrixaban crystal form A and pharmaceutical excipient or preparation.

Aforementioned pharmaceutical compositions or preparation can per os or not oral administrations.Preferred oral formulation, comprises tablet, capsule, pill, granule, solution, syrup, dry suspensoid, suspensoid, powder, sustained release preparation or controlled release preparation etc.Wherein preferred tablet, capsule, granule, dry suspensoid and the solid orally ingestible such as sustained release preparation or controlled release preparation, wherein more preferably Tablet and Capsula agent.

The various formulations of aforementioned pharmaceutical compositions can be prepared according to the ordinary method of pharmaceutical field.Such as the betrixaban salt shown in the formula II for the treatment of significant quantity (is comprised half L MALIC ACID betrixaban, L MALIC ACID betrixaban, half D-malic acid betrixaban, D-malic acid betrixaban, half DL-oxysuccinic acid betrixaban, DL-oxysuccinic acid betrixaban, DL-tartrate betrixaban, half fourth disulfonic acid betrixaban, half ethionic acid betrixaban, isethionic acid betrixaban, Hydrogen bromide betrixaban, half L MALIC ACID betrixaban crystal form A, L MALIC ACID betrixaban crystal form A, half D-malic acid betrixaban crystal form A, D-malic acid betrixaban crystal form A, half DL-oxysuccinic acid betrixaban crystal form A, DL-oxysuccinic acid betrixaban crystal form A, DL-tartrate betrixaban crystal form A, half fourth disulfonic acid betrixaban crystal form A, half ethionic acid betrixaban crystal form A, isethionic acid betrixaban crystal form A, Hydrogen bromide betrixaban crystal form A), alternatively with activeconstituents that is another kind of or multiple treatment significant quantity, mix with one or more pharmaceutical excipients or contact, being then made into required formulation.

In one embodiment, the betrixaban salt shown in formula II provided by the invention (comprises half L MALIC ACID betrixaban, L MALIC ACID betrixaban, half D-malic acid betrixaban, D-malic acid betrixaban, half DL-oxysuccinic acid betrixaban, DL-oxysuccinic acid betrixaban, DL-tartrate betrixaban, half fourth disulfonic acid betrixaban, half ethionic acid betrixaban, isethionic acid betrixaban, Hydrogen bromide betrixaban, half L MALIC ACID betrixaban crystal form A, L MALIC ACID betrixaban crystal form A, half D-malic acid betrixaban crystal form A, D-malic acid betrixaban crystal form A, half DL-oxysuccinic acid betrixaban crystal form A, DL-oxysuccinic acid betrixaban crystal form A, DL-tartrate betrixaban crystal form A, half fourth disulfonic acid betrixaban crystal form A, half ethionic acid betrixaban crystal form A, isethionic acid betrixaban crystal form A, Hydrogen bromide betrixaban crystal form A) to mix with one or more pharmaceutical excipients or to contact, be then made into oral dosage form, preferred tablet and capsule.In this oral dosage form, pharmaceutical excipient is selected from the pharmaceutical excipient of this area routine, comprises weighting agent, disintegrating agent, tackiness agent, dispersion agent, lubricant or retention aid and all types of coating materials etc.

Described weighting agent generally comprises pregelatinized Starch, starch, lactose, dextrin, secondary calcium phosphate, calcium carbonate, N.F,USP MANNITOL, Microcrystalline Cellulose, sorbyl alcohol, glucose etc., they can be used alone also can be used in combination, wherein preferred pregelatinized Starch, lactose, Microcrystalline Cellulose, N.F,USP MANNITOL.

Described disintegrating agent generally comprises cross-linked carboxymethyl cellulose sodium, Xylo-Mucine, sodium starch glycolate, cross-linked polyvinylpyrrolidone, starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose etc., they can be used alone also can be used in combination, is wherein preferably cross-linked carboxymethyl cellulose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose.

Described tackiness agent generally comprises the ethanolic soln of Microcrystalline Cellulose, pre-paying starch, Vltra tears, hydroxypropylcellulose, polyvidone, starch slurry, gum arabic, Macrogol 4000, polyvinyl alcohol, alginate, water, various concentration, they can be used alone also can be used in combination, wherein preferred Vltra tears, hydroxypropylcellulose, polyvidone, starch slurry.

Described lubricant generally comprises Magnesium Stearate, stearic acid, calcium stearate, sodium stearyl fumarate, stearic acid Potassium fumarate, palmitinic acid, differential silica gel, stearylamide, talcum powder, solid polyethylene glycol, vanay etc.They can be used alone also can be used in combination, wherein preferred Magnesium Stearate, stearic acid, talcum powder, differential silica gel, vanay.

If needed, other auxiliary materials can also be added in above-mentioned composition or preparation, as sweeting agent (as aspartame, Steviosin etc.), tinting material (medicinal or food dye as various in lemon yellow, ferric oxide etc.), stablizer (as calcium carbonate, Calcium hydrogen carbonate, sodium bicarbonate, sodium carbonate, calcium phosphate, secondary calcium phosphate, glycine etc.), tensio-active agent (as tween 80, sodium lauryl sulphate etc.) coating material (as Opadry, Vltra tears, hydroxypropylcellulose, acrylic resin multipolymer etc.

In one embodiment, in aforementioned pharmaceutical compositions or preparation, the betrixaban salt shown in formula II (comprises half L MALIC ACID betrixaban, L MALIC ACID betrixaban, half D-malic acid betrixaban, D-malic acid betrixaban, half DL-oxysuccinic acid betrixaban, DL-oxysuccinic acid betrixaban, DL-tartrate betrixaban, half fourth disulfonic acid betrixaban, half ethionic acid betrixaban, isethionic acid betrixaban, Hydrogen bromide betrixaban, half L MALIC ACID betrixaban crystal form A, L MALIC ACID betrixaban crystal form A, half D-malic acid betrixaban crystal form A, D-malic acid betrixaban crystal form A, half DL-oxysuccinic acid betrixaban crystal form A, DL-oxysuccinic acid betrixaban crystal form A, DL-tartrate betrixaban crystal form A, half fourth disulfonic acid betrixaban crystal form A, half ethionic acid betrixaban crystal form A, isethionic acid betrixaban crystal form A, Hydrogen bromide betrixaban crystal form A) size distribution control to be less than 100 μm 90%, be preferably less than 50 μm, be more preferably less than 10 μm.

In one embodiment, in above-mentioned unitary pharmaceutical composition or preparation, the betrixaban salt shown in formula II (comprises half L MALIC ACID betrixaban, L MALIC ACID betrixaban, half D-malic acid betrixaban, D-malic acid betrixaban, half DL-oxysuccinic acid betrixaban, DL-oxysuccinic acid betrixaban, DL-tartrate betrixaban, half fourth disulfonic acid betrixaban, half ethionic acid betrixaban, isethionic acid betrixaban, Hydrogen bromide betrixaban, half L MALIC ACID betrixaban crystal form A, L MALIC ACID betrixaban crystal form A, half D-malic acid betrixaban crystal form A, D-malic acid betrixaban crystal form A, half DL-oxysuccinic acid betrixaban crystal form A, DL-oxysuccinic acid betrixaban crystal form A, DL-tartrate betrixaban crystal form A, half fourth disulfonic acid betrixaban crystal form A, half ethionic acid betrixaban crystal form A, isethionic acid betrixaban crystal form A, Hydrogen bromide betrixaban crystal form A) weight content be generally 1mg to 2g, preferred 5mg to 200mg, more preferably between 10mg to 100mg.

According to object of the present invention, the invention provides the betrixaban salt shown in formula II that the betrixaban salt shown in formula II or above-mentioned preparation method the obtain purposes at the medicine of the illness being feature with bad thrombosis for the preparation of prevention or treatment Mammals.

In one embodiment, the invention provides half L MALIC ACID betrixaban, L MALIC ACID betrixaban, half D-malic acid betrixaban, D-malic acid betrixaban, half DL-oxysuccinic acid betrixaban, DL-oxysuccinic acid betrixaban, DL-tartrate betrixaban, half fourth disulfonic acid betrixaban, half ethionic acid betrixaban, isethionic acid betrixaban, Hydrogen bromide betrixaban, half L MALIC ACID betrixaban crystal form A, L MALIC ACID betrixaban crystal form A, half D-malic acid betrixaban crystal form A, D-malic acid betrixaban crystal form A, half DL-oxysuccinic acid betrixaban crystal form A, DL-oxysuccinic acid betrixaban crystal form A, DL-tartrate betrixaban crystal form A, half fourth disulfonic acid betrixaban crystal form A, half ethionic acid betrixaban crystal form A, isethionic acid betrixaban crystal form A or Hydrogen bromide betrixaban crystal form A are in the purposes of the medicine of the illness being feature with bad thrombosis for the preparation of prevention or treatment Mammals.

The experiment proved that, betrixaban salt provided by the invention has following advantage:

(1), preparation method is easy, and crystal formation is easy to control; Can obtain high purity, such as HPLC area normalization method purity can reach the product of more than 98%, 99% or 99.5%.

(2), there is good solubility.Quite or more excellent, such as wherein half L MALIC ACID salt, L MALIC ACID salt, half D-malic acid salt, D-malic acid salt, half D-malic acid salt, DL-malate, DL-tartrate, hydrobromate are better than maleate in the solubleness of some pH condition for the solvability of betrixaban salt provided by the invention and maleate.

(3), there is physical behavior that is good or that improve, chemical stability or preparation adaptability.Such as, the stability of betrixaban salt provided by the invention and maleate are quite or more excellent; And for example, the crystal formation of betrixaban salt provided by the invention is single, and crystal formation controllability is stronger.

The X-ray powder diffraction analysis of above-mentioned crystal of the present invention is under envrionment temperature and ambient moisture, and the Cu-K α radiation detection through Dutch PANalytical X`PertPRO type X-ray powder diffractometer completes." envrionment temperature " is generally 0 ~ 40 DEG C; " ambient moisture " is generally the relative humidity of 30% ~ 80%.Be understandable that in test process, due to be subject to many factors (as test sample granularity, test time sample treatment process, instrument, test parameter, test operation etc.) impact, characteristic diffraction peak position or the intensity of the X-ray powder diffraction measured by same crystal formation have certain difference.Generally, in X-ray powder diffraction the experimental error of characteristic diffraction peak 2 θ value can be ± 0.2 °.

Accompanying drawing explanation

Fig. 1 is the X-ray powder diffraction of half L MALIC ACID betrixaban crystal form A.

Fig. 2 is the X-ray powder diffraction of L MALIC ACID betrixaban crystal form A.

Fig. 3 is the X-ray powder diffraction of half D-malic acid betrixaban crystal form A.

Fig. 4 is the X-ray powder diffraction of D-malic acid betrixaban crystal form A

Fig. 5 is the X-ray powder diffraction of half DL-oxysuccinic acid betrixaban crystal form A.

Fig. 6 is the X-ray powder diffraction of DL-oxysuccinic acid betrixaban crystal form A.

Fig. 7 is the X-ray powder diffraction of DL-tartrate betrixaban crystal form A.

Fig. 8 is the X-ray powder diffraction of half fourth disulfonic acid betrixaban crystal form A.

Fig. 9 is the X-ray powder diffraction of half ethionic acid betrixaban crystal form A.

Figure 10 is the X-ray powder diffraction of isethionic acid betrixaban crystal form A.

Figure 11 is the X-ray powder diffraction of Hydrogen bromide betrixaban crystal form A.

Embodiment

The embodiment of form by the following examples, foregoing invention content of the present invention is described in further details, but should not be construed as summary of the invention of the present invention and be only limitted to following examples, all inventions made based on foregoing of the present invention all belong to scope of the present invention.

In following examples ¹hNMR test is using deuterated methanol or deuterated dimethyl sulfoxide as test solvent, mark in doing with tetramethylsilane, at room temperature measures by BrukeAV-III400MHz nuclear magnetic resonance analyser.

In following examples, X-ray powder diffraction is measured by Dutch PANalytical X`PertPRO type X-ray powder diffractometer, and test condition is for being 4 °-40 ° with θ-θ configuration, sweep limit, and step-length is 0.0130 °, continuous sweep.Testing light source is copper target K α radiation, PIXcel detector; Voltage and current is respectively 40kV and 40mA.Method for making sample is: get with spoon the groove that appropriate sample is placed in glass load sample sheet at ambient conditions, suitably roll with slide glass, sample is evenly distributed in load sample sheet groove, then is struck off by sample surfaces with slide glass.Test period sample is non rotating in himself plane.

The preparation of embodiment 1: half L MALIC ACID betrixaban and the preparation of crystal form A thereof

At 55 ~ 60 DEG C, betrixaban 6.0g (13.3mmol), L MALIC ACID 1.1g (8.0mmol) are dissolved in tetrahydrofuran (THF) 70mL/ water 7mL mixed solvent, add acetone 60mL under stirring, be cooled to room temperature, crystallization.Separate out solid, filter, by gained solid drying under reduced pressure at 40 ~ 45 DEG C, obtain half L MALIC ACID betrixaban.

¹HNMR(400MHz,MeOD)δ:2.355-2.419(dd,0.5H),2.735-2.781(dd,0.5H),3.226(s,6H),3.907(s,3H),4.302-4.326(dd,0.5H),7.195-7.224(dd,1H),7.448-7.455(d,1H),7.744-7.764(d,2H),7.821-7.849(dd,1H),8.145-8.165(d,2H),8.196-8.219(d,1H),8.238-8.261(d,1H),8.323-8.329(d,1H).

Above-mentioned ¹in H-NMR result, δ: 3.907 (s, 3H) are attributed to methyl CH in betrixaban molecule ₃, 4.302-4.326 (dd, 0.5H) is attributed to methyne CH in L MALIC ACID molecule, can judge that the molar composition ratio of betrixaban and L MALIC ACID in this title product is 2:1.

Fig. 1 is shown in by the powder x-ray diffraction collection of illustrative plates surveyed, its observed value is following (gets observed value corresponding to diffraction peak that relative intensity within the scope of 4 °-40 °, 2 θ angle is greater than 2%, three decimals are got in the observed value round off of 2 θ and d, and a decimal is got in the round off of relative intensity measure value):

The above-mentioned crystal formation called after of gained " half L MALIC ACID betrixaban crystal form A "

The preparation of embodiment 2:L-oxysuccinic acid betrixaban and the preparation of crystal form A thereof

At 55 ~ 60 DEG C, betrixaban 6.0g (13.3mmol), L MALIC ACID 2.1g (16.0mmol) are dissolved in tetrahydrofuran (THF) 48mL/ water 12mL mixed solvent, stir lower dropping acetone 80mL, be cooled to room temperature, leave standstill, crystallization.Separate out solid, filter, by gained solid drying under reduced pressure at 45 ~ 50 DEG C, obtain L MALIC ACID betrixaban.

¹HNMR(400MHz,MeOD)δ:2.491-2.549(dd,1H),2.779-2.832(dd,1H),3.122(s,3H),3.350(s,3H),3.925(s,3H),4.267-4.300(dd,1H),7.220-7.250(dd,1H),7.474-7.481(d,1H),7.755-7.776(d,2H),7.841-7.869(dd,1H),8.164-8.185(d,2H),8.207-8.230(d,1H),8.275-8.298(d,1H),8349-8.357(d,1H).

Above-mentioned ¹in H-NMR result, δ: 3.925 (s, 3H) are attributed to methyl CH in betrixaban molecule ₃, δ: 4.267-4.300 (dd, 1H) is attributed to methyne CH in L MALIC ACID molecule, can judge that the molar composition ratio of betrixaban and L MALIC ACID in this title product is 1:1.

Fig. 2 is shown in by the powder x-ray diffraction collection of illustrative plates surveyed, its observed value is following (gets observed value corresponding to diffraction peak that relative intensity within the scope of 4 °-40 °, 2 θ angle is greater than 2%, three decimals are got in the observed value round off of 2 θ and d, and a decimal is got in the round off of relative intensity measure value):

The above-mentioned crystal formation called after of gained " L MALIC ACID betrixaban crystal form A "

The preparation of embodiment 3: half D-malic acid betrixaban and the preparation of crystal form A thereof

At 55 ~ 60 DEG C, betrixaban 6.0g (13.3mmol), D-malic acid 1.1g (8.0mmol) are dissolved in tetrahydrofuran (THF) 70mL/ water 7mL mixed solvent, stir lower dropping acetone 60mL, be cooled to room temperature, leave standstill, crystallization 12h.Separate out solid, filter, by gained solid drying under reduced pressure at 50 ~ 55 DEG C, obtain half D-malic acid betrixaban.

¹HNMR(400MHz,MeOD)δ:2.492-2.540(dd,0.5H),2.763-2.771(dd,0.5H),3.321(s,3H),3.148(s,3H),3.927(s,3H),4.277-4.301(dd,0.5H),7.223-7.253(dd,1H),7.474-7.481(d,1H),7.755-7.775(d,2H),7.843-7.871(dd,1H),8.163-8.183(d,2H),8.207-8.2229(d,1H),8.268-8.290(d,1H),8.352-8.358(d,1H).

Above-mentioned ¹in H-NMR result, δ: 3.927 (s, 3H) are attributed to methyl CH in betrixaban molecule ₃, δ: 4.277-4.301 (dd, 0.5H) is attributed to methyne CH in D-malic acid molecule, can judge that the molar composition ratio of betrixaban and D-malic acid in this title product is 2:1.

Fig. 3 is shown in by the powder x-ray diffraction collection of illustrative plates surveyed, its observed value is following (gets observed value corresponding to diffraction peak that relative intensity within the scope of 4 °-40 °, 2 θ angle is greater than 2%, three decimals are got in the observed value round off of 2 θ and d, and a decimal is got in the round off of relative intensity measure value):

The above-mentioned crystal formation called after of gained " half D-malic acid betrixaban crystal form A "

The preparation of embodiment 4:D-oxysuccinic acid betrixaban and the preparation of crystal form A thereof

At 55 ~ 60 DEG C, betrixaban 6.0g (13.3mmol), D-malic acid 2.1g (16.0mmol) are dissolved in tetrahydrofuran (THF) 48mL/ water 12mL mixed solvent, stir lower dropping acetone 80mL, be cooled to room temperature, leave standstill, crystallization.Separate out solid, filter, by gained solid drying under reduced pressure at 45 ~ 50 DEG C, obtain L MALIC ACID betrixaban.

¹HNMR(400MHz,MeOD)δ:2.499-2.556(dd,1H),2.779-2.833(dd,1H),3.122(s,6H),3.924(s,3H),4.272-4.304(dd,1H),7.218-7.248(dd,1H),7.472-7.479(d,1H),7.754-7.775(d,2H),7.839-7.868(dd,1H),8.163-8.184(d,2H),8.206-8.228(d,1H),8.275-8.297(d,1H),8348-8.354(d,1H).

Above-mentioned ¹in H-NMR result, δ: 3.924 (s, 3H) are attributed to methyl CH in betrixaban molecule ₃, 4.272-4.304 (dd, 1H) is attributed to methyne CH in D-malic acid molecule, can judge that the molar composition ratio of betrixaban and D-malic acid in this title product is 1:1.

Fig. 4 is shown in by the powder x-ray diffraction collection of illustrative plates surveyed, its observed value is following (gets observed value corresponding to diffraction peak that relative intensity within the scope of 4 °-40 °, 2 θ angle is greater than 2%, three decimals are got in the observed value round off of 2 θ and d, and a decimal is got in the round off of relative intensity measure value):

The above-mentioned crystal formation called after of gained " D-malic acid betrixaban crystal form A "

The preparation of embodiment 5: half DL-oxysuccinic acid betrixaban and the preparation of crystal form A thereof

At 55 ~ 60 DEG C, betrixaban 6.0g (13.3mmol), DL-oxysuccinic acid 1.1g (8.0mmol) are dissolved in tetrahydrofuran (THF) 70mL/ water 7mL mixed solvent, stir lower dropping acetone 60mL, be cooled to room temperature, leave standstill, crystallization 12h.Separate out solid, filter, by gained solid drying under reduced pressure at 50 ~ 55 DEG C, obtain half DL-oxysuccinic acid betrixaban.

¹HNMR(400MHz,MeOD)δ:2.341-2.405(dd,0.5H),2.733-2.779(dd,0.5H),3.225(s,6H)3.905(s,3H),4.300-4.333(dd,0.5H),7.211-7.240(dd,1H),7.464-7.471(d,1H),7.746-7.765(d,2H),7.833-7.862(dd,1H),8.153-8.173(d,2H),8.205-8.227(d,1H),8.254-8.276(d,1H),8.339-8.346(d,1H).

Above-mentioned ¹in H-NMR result, δ: 3.905 (s, 3H) are attributed to methyl CH in betrixaban molecule ₃, δ: 4.300-4.333 (dd, 0.5H) is attributed to methyne CH in half DL-oxysuccinic acid molecule, can judge that the molar composition ratio of betrixaban and DL-oxysuccinic acid in this title product is 2:1.

Fig. 5 is shown in by the powder x-ray diffraction collection of illustrative plates surveyed, its observed value is following (gets observed value corresponding to diffraction peak that relative intensity within the scope of 4 °-40 °, 2 θ angle is greater than 2%, three decimals are got in the observed value round off of 2 θ and d, and a decimal is got in the round off of relative intensity measure value):

The above-mentioned crystal formation called after of gained " half DL-oxysuccinic acid betrixaban crystal form A "

The preparation of embodiment 6:DL-oxysuccinic acid betrixaban and the preparation of crystal form A thereof

At 55 ~ 60 DEG C, betrixaban 6g (13.3mmol), DL-oxysuccinic acid 1.8g (13.3mmol) are dissolved in tetrahydrofuran (THF) 48mL/ water 12mL mixed solvent, stir lower dropping acetone 80mL, be cooled to room temperature, leave standstill, crystallization.Separate out solid, filter, by gained solid drying under reduced pressure at 55 ~ 60 DEG C, obtain DL-oxysuccinic acid betrixaban.

¹HNMR(400MHz,MeOD)δ:2.494-2.552(dd,1H),2.781-2.835(dd,1H),3.123(s,3H),3.349(s,3H),3.928(s,3H),4.268-4.301(dd,3H),7.225-7.255(dd,1H),7.478-7.485(d,1H),7.755-7.776(d,2H),7.843-7.872(dd,1H),8.166-8.188(d,2H),8.208-8.231(d,1H),8.282-8.304(d,1H),8.355-8.361(d,1H).

Above-mentioned ¹in H-NMR result, δ: 3.928 (s, 3H) are attributed to methyl CH in betrixaban molecule ₃, δ: 4.268-4.301 (dd, 3H), is attributed to methyne CH in DL-oxysuccinic acid molecule, can judge that the molar composition ratio of betrixaban and DL-oxysuccinic acid in this title product is 1:1.

Fig. 6 is shown in by the powder x-ray diffraction collection of illustrative plates surveyed, its observed value is following (gets observed value corresponding to diffraction peak that relative intensity within the scope of 4 °-40 °, 2 θ angle is greater than 2%, three decimals are got in the observed value round off of 2 θ and d, and a decimal is got in the round off of relative intensity measure value):

The above-mentioned crystal formation called after of gained " DL-oxysuccinic acid betrixaban crystal form A "

The preparation of embodiment 7:DL-tartrate betrixaban and the preparation of crystal form A thereof

At 55 ~ 60 DEG C, betrixaban 6g (13.3mmol), DL-tartrate 2.0g (6.7mmol) are dissolved in N,N-dimethylacetamide 12mL/ water 18mL mixed solvent, stir lower dropping tetrahydrofuran (THF) 60mL, be cooled to room temperature, leave standstill, crystallization.Separate out solid, filter, by gained solid drying under reduced pressure at 60 ~ 65 DEG C, obtain DL-tartrate betrixaban.

¹HNMR(300MHz,DMSO-d ₆)δ:3.116(s,6H),3.765(s,2H),3.869(s,3H),7.186-7.215(dd,1H),7.445-7.452(d,1H),7.746-7.767(d,2H),7.949-7.977(dd,1H),8.024-8.046(d,1H),8.083-8.132(m,3H),8.444-8.449(d,1H).

Above-mentioned ¹in H-NMR result, δ: 3.869 (s, 3H) are attributed to methyl CH in betrixaban molecule ₃, δ: 3.765 (s, 2H), are attributed to methyne CH in DL-tartaric acid molecules, can judge that in this title product, betrixaban and the tartaric molar composition ratio of DL-are 1:1.

Fig. 7 is shown in by the powder x-ray diffraction collection of illustrative plates surveyed, its observed value is following (gets observed value corresponding to diffraction peak that relative intensity within the scope of 4 °-40 °, 2 θ angle is greater than 2%, three decimals are got in the observed value round off of 2 θ and d, and a decimal is got in the round off of relative intensity measure value):

The above-mentioned crystal formation called after of gained " DL-tartrate betrixaban crystal form A "

The preparation of embodiment 8: half fourth disulfonic acid betrixaban and the preparation of crystal form A thereof

At 55 ~ 60 DEG C, betrixaban 6g (13.3mmol), fourth disulfonic acid 2.4g (6.7mmol) are dissolved in ethanol 120mL/ water 60mL mixed solvent, add acetone 120mL under stirring, be cooled to room temperature, stirring and crystallizing.Separate out solid, filter, by gained solid drying under reduced pressure at 65 ~ 70 DEG C, obtain half fourth disulfonic acid betrixaban.

¹HNMR(400MHz,DMSO-d ₆)δ:1.548-1.586(m,2H),2.329-2.367(t,2H),2.993(s,3H),3.250(s,3H),3.871(s,3H),7.189-7.218(dd,1H),7.437-7.445(d,1H),7.754-7.775(d,2H),7.954-7.983(dd,1H),8.009-8.032(d,1H),8.077-8.131(m,3H),8.442-8.448(d,1H),9.019(s,1H),9.375(s,1H),11.030(s,1H),11.121(s,1H).

Above-mentioned ¹in H-NMR result, δ: 3.871 (s, 3H) are attributed to methyl CH in betrixaban molecule ₃, δ: 1.548-1.586 (m, 2H), 2.329-2.367 (t, 2H) are attributed to fourth disulfonic acid molecule methylene CH ₂, can judge that the molar composition ratio of betrixaban and fourth disulfonic acid in this title product is 2:1.

Fig. 8 is shown in by the powder x-ray diffraction collection of illustrative plates surveyed, its observed value is following (gets observed value corresponding to diffraction peak that relative intensity within the scope of 4 °-40 °, 2 θ angle is greater than 2%, three decimals are got in the observed value round off of 2 θ and d, and a decimal is got in the round off of relative intensity measure value):

The above-mentioned crystal formation called after of gained " half fourth disulfonic acid betrixaban crystal form A "

The preparation of embodiment 9: half ethionic acid betrixaban and the preparation of crystal form A thereof

At 55 ~ 60 DEG C, betrixaban 6g (13.3mmol), ethionic acid 1.3g (6.7mmol) are dissolved in ethanol 24mL/ water 6mL mixed solvent, stir lower dropping acetone 24mL, be cooled to room temperature, stirring and crystallizing.Separate out solid, filter, by gained solid drying under reduced pressure at 70 ~ 75 DEG C, obtain half ethionic acid betrixaban.

¹HNMR(400MHz,DMSO-d ₆)δ:2.621(s,2H),2.993(s,3H),3.246(s,3H),3.870(s,3H),7.188-7.218(dd,1H),7.436-7.444(d,1H),7.750(d,2H),7.952-7.981(dd,1H),8.007-8.029(d,1H),8.073-8.130(m,3H),8.441-8.449(d,1H),9.001(s,1H),9.373(s,1H),11.028(s,1H),11.117(s,1H).

Above-mentioned ¹in H-NMR result, δ: 3.870 (s, 3H) are attributed to methyl CH in betrixaban molecule ₃, δ: 2.621 (s, 2H), are attributed to ethionic acid molecule methylene CH ₂, can judge that the molar composition ratio of betrixaban and ethionic acid in this title product is 2:1.

Fig. 9 is shown in by the powder x-ray diffraction collection of illustrative plates surveyed, its observed value is following (gets observed value corresponding to diffraction peak that relative intensity within the scope of 4 °-40 °, 2 θ angle is greater than 2%, three decimals are got in the observed value round off of 2 θ and d, and a decimal is got in the round off of relative intensity measure value):

The above-mentioned crystal formation called after of gained " half ethionic acid betrixaban crystal form A "

Embodiment 10: the preparation of isethionic acid betrixaban and the preparation of crystal form A thereof

At 55 ~ 60 DEG C, betrixaban 6g (13.3mmol), isethionic acid 1.8g (14.6mmol) are dissolved in ethanol 12mL/ water 18mL mixed solvent, stir lower dropping acetone 54mL, be cooled to room temperature, stirring and crystallizing.Separate out solid, filter, by gained solid drying under reduced pressure at 75 ~ 80 DEG C, obtain isethionic acid betrixaban.

¹HNMR(400MHz,DMSO-d ₆)δ:2.588-2.622(t,2H),2.994(s,3H),3.244(s,3H),3.614-3.647(t,3H),3.871(s,3H),4.445(s,1H),7.190-7.220(dd,1H),7.443-7.450(d,1H),7.752-7.773(d,2H),7.953-7.982(dd,1H),8.019-8.042(d,1H),8.078-8.129(m,3H),8.446-8.451(d,1H),8.991(s,1H),9.364(s,1H),11.033(s,1H),11.129(s,1H).

Above-mentioned ¹in H-NMR result, δ: 3.871 (s, 3H) are attributed to methyl CH in betrixaban molecule ₃, δ: 2.588-2.622 (t, 2H) is attributed to isethionic acid molecule methylene CH ₂, can judge that the molar composition ratio of betrixaban and isethionic acid in this title product is 1:1.

Figure 10 is shown in by the powder x-ray diffraction collection of illustrative plates surveyed, its observed value is following (gets observed value corresponding to diffraction peak that relative intensity within the scope of 4 °-40 °, 2 θ angle is greater than 2%, three decimals are got in the observed value round off of 2 θ and d, and a decimal is got in the round off of relative intensity measure value):

The above-mentioned crystal formation called after of gained " isethionic acid betrixaban crystal form A "

Embodiment 11: the preparation of Hydrogen bromide betrixaban and the preparation of crystal form A thereof

At 55 ~ 60 DEG C, betrixaban 6g (13.3mmol), Hydrogen bromide (47%) 2.5g (14.6mmol) are dissolved in tetrahydrofuran (THF) 25mL/ water 6mL mixed solvent, stir lower dropping acetone 40mL, be cooled to room temperature, leave standstill, crystallization.Separate out solid, filter, by gained solid drying under reduced pressure at 70 ~ 75 DEG C, obtain Hydrogen bromide betrixaban.

¹HNMR(400MHz,DMSO-d ₆)δ:2.993(s,3H),3.254(s,3H),3.868(s,3H),7.188-7.217(dd,1H),7.437-7.444(d,1H),7.757-7.777(d,2H),7.956-7.985(dd,1H),8.011-8.034(d,1H),8.076-8.126(m,3H),8.442-8.447(d,1H),9.020(s,1H),9.378(s,1H),11.029(s,1H),11.123(s,1H).

Above-mentioned ¹in H-NMR result, δ: 3.868 (s, 3H) are attributed to methyl CH in betrixaban molecule ₃, δ: 11.123 (s, 1H), are attributed to H in Hydrogen bromide molecule, can judge that in this title product, betrixaban and hydrobromic molar composition ratio are 1:1.

Figure 11 is shown in by the powder x-ray diffraction collection of illustrative plates surveyed, its observed value is following (gets observed value corresponding to diffraction peak that relative intensity within the scope of 4 °-40 °, 2 θ angle is greater than 2%, three decimals are got in the observed value round off of 2 θ and d, and a decimal is got in the round off of relative intensity measure value):

The above-mentioned crystal formation called after of gained " Hydrogen bromide betrixaban crystal form A "

Embodiment 12: stability study

Get toxilic acid betrixaban (by the preparation of method disclosed in patent documentation CN101304971A), half L MALIC ACID betrixaban (preparing by the method for embodiment 1), L MALIC ACID betrixaban (preparing by the method for embodiment 2), half D-malic acid betrixaban (preparing by the method for embodiment 3), D-malic acid betrixaban (preparing by the method for embodiment 4), half DL-oxysuccinic acid betrixaban (preparing by the method for embodiment 5), DL-oxysuccinic acid betrixaban (preparing by the method for embodiment 6), DL-tartrate betrixaban (preparing by the method for embodiment 7), half fourth disulfonic acid betrixaban (preparing by the method for embodiment 8), half ethionic acid betrixaban (preparing by the method for embodiment 9), isethionic acid betrixaban (preparing by the method for embodiment 10) and Hydrogen bromide betrixaban (preparing by the method for embodiment 11) are respectively at high temperature (60 DEG C), high humidity (RH90%), test under high light (4500lx) condition, 0 day, the HPLC purity detecting result of 10 days is as follows:

Above-mentioned HPLC purity detecting condition is:

Chromatographic column: octadecylsilane chemically bonded silica post (250mm × 4.6mm, 5m);

Column temperature: 35 DEG C;

Determined wavelength: 235nm;

Moving phase: according to the form below carries out gradient elution

Flow velocity 1.0ml/min;

Detection method: sample thief is appropriate, accurately weighed, add dissolve with methanol and dilution make every 1ml about containing 1mg solution as need testing solution, precision measures 10 μ l, injection liquid chromatography, and record color atlas, calculates its related substances according to area normalization method.

Above-mentioned research shows, the stability of betrixaban salt provided by the invention and toxilic acid betrixaban are quite or more excellent.

Embodiment 13: solubility studies

Get toxilic acid betrixaban (by the preparation of method disclosed in patent documentation CN101304971A), half L MALIC ACID betrixaban (preparing by the method for embodiment 1), L MALIC ACID betrixaban (preparing by the method for embodiment 2), half D-malic acid betrixaban (preparing by the method for embodiment 3), D-malic acid betrixaban (preparing by the method for embodiment 4), half DL-oxysuccinic acid betrixaban (preparing by the method for embodiment 5), DL-oxysuccinic acid betrixaban (preparing by the method for embodiment 6), DL-tartrate betrixaban (preparing by the method for embodiment 7), half fourth disulfonic acid betrixaban (preparing by the method for embodiment 8), half ethionic acid betrixaban (preparing by the method for embodiment 9), isethionic acid betrixaban (preparing by the method for embodiment 10) and Hydrogen bromide betrixaban (preparing by the method for embodiment 11), at 25 DEG C, measure their solvabilities in different pH medium respectively, result is as follows:

Above-mentioned research shows, the solvability of betrixaban salt provided by the invention and toxilic acid betrixaban are quite or more excellent.

Embodiment 14: polymorphic is studied

Study with the polymorphic of the conditions such as different recrystallisation solvents, charge ratio, crystallization mode to L MALIC ACID betrixaban, DL-oxysuccinic acid betrixaban, half fourth disulfonic acid betrixaban, Hydrogen bromide betrixaban etc., main research is as follows:

Above-mentioned research shows, L MALIC ACID betrixaban, DL-oxysuccinic acid betrixaban, half fourth disulfonic acid betrixaban and Hydrogen bromide betrixaban do not occur heteromorphism at multiple crystallization condition, and namely their crystal formation is single, easy to control.

Embodiment 15: containing tablet and the preparation thereof of 20mg betrixaban

Prescription:

Component	Content (mg/ sheet)
		L MALIC ACID betrixaban (preparing by the method for embodiment 2)	25.9
Microcrystalline Cellulose	30.2
		Zeparox	14.0
Polyvidone	4.0
		Croscarmellose sodium	3.5
Magnesium Stearate	0.4

Preparation: after L MALIC ACID betrixaban, Microcrystalline Cellulose, Zeparox, polyvidone and the croscarmellose sodium mixing in upper table component, use water wet granulation, dry, whole grain, mixes with Magnesium Stearate, compressing tablet, to obtain final product.

Embodiment 16: containing tablet and the preparation thereof of 30mg betrixaban

Prescription:

Component	Content (mg/ sheet)
		DL-oxysuccinic acid betrixaban (preparing by the method for embodiment 6)	38.9
Microcrystalline Cellulose	44.3
		Zeparox	21.0
Polyvidone	6.0
		Croscarmellose sodium	5.3
Magnesium Stearate	0.6

Preparation: after DL-oxysuccinic acid betrixaban, Microcrystalline Cellulose, Zeparox, polyvidone and the croscarmellose sodium mixing in upper table component, use water wet granulation, dry, whole grain, mixes with Magnesium Stearate, compressing tablet, to obtain final product.

Embodiment 17: containing tablet and the preparation thereof of 40mg betrixaban

Prescription:

Component	Content (mg/ sheet)
		Half fourth disulfonic acid betrixaban (preparing by the method for embodiment 8)	49.6
Microcrystalline Cellulose	51.0
		Zeparox	24.0
Polyvidone	8.0
		Croscarmellose sodium	7.6
Magnesium Stearate	0.8

Preparation: after half fourth disulfonic acid betrixaban, Microcrystalline Cellulose, Zeparox, polyvidone and the croscarmellose sodium mixing in upper table component, use water wet granulation, dry, whole grain, mixes with Magnesium Stearate, compressing tablet, to obtain final product.

Embodiment 18: containing tablet and the preparation thereof of 80mg betrixaban

Prescription:

Component	Content (mg/ sheet)
		Hydrogen bromide betrixaban (preparing by the method for embodiment 11)	94.3
Microcrystalline Cellulose	118.0
		Zeparox	56.0
Polyvidone	16.0
		Croscarmellose sodium	14.0
Magnesium Stearate	1.7

Preparation: after Hydrogen bromide betrixaban, Microcrystalline Cellulose, Zeparox, polyvidone and the croscarmellose sodium mixing in upper table component, use water wet granulation, dry, whole grain, mixes with Magnesium Stearate, compressing tablet, to obtain final product.

The above; be only the specific embodiment of the present invention; but protection scope of the present invention is not limited thereto; any those of ordinary skill in the art are in the technical scope disclosed by the present invention; the change can expected without creative work or replacement, all should be encompassed within protection scope of the present invention.Therefore, the protection domain that protection scope of the present invention should limit with claims is as the criterion.

Claims

1. the betrixaban salt shown in formula II,

II

Or, when X is selected from isethionic acid or Hydrogen bromide, m value 1.

2. betrixaban salt according to claim 1, wherein,

M is 0.5, X is L MALIC ACID, is half L MALIC ACID betrixaban; Or,

M is 1, X is L MALIC ACID, is L MALIC ACID betrixaban; Or,

M is 0.5, X is D-malic acid, is half D-malic acid betrixaban; Or,

M is 1, X is D-malic acid, is D oxysuccinic acid betrixaban; Or,

M is 0.5, X is DL-oxysuccinic acid, is half DL-oxysuccinic acid betrixaban; Or,

M is 1, X is DL-oxysuccinic acid, is DL-oxysuccinic acid betrixaban; Or,

M is 1, X is DL-tartrate, is DL-tartrate betrixaban; Or,

M is 0.5, X is fourth disulfonic acid, is half fourth disulfonic acid betrixaban; Or,

M is 0.5, X is ethionic acid, is half ethionic acid betrixaban; Or,

M is 1, X is isethionic acid, i.e. isethionic acid betrixaban; Or,

M is 1, X is Hydrogen bromide, i.e. Hydrogen bromide betrixaban.

3. betrixaban salt according to claim 2, wherein,

Described half L MALIC ACID betrixaban is specially half L MALIC ACID betrixaban crystal form A, use Cu-K α radiation, its X-ray powder diffraction has characteristic diffraction peak in following 2 θ positions: 8.6 ° ± 0.2 °, 12.3 ° ± 0.2 °, 13.3 ° ± 0.2 °, 14.2 ° ± 0.2 °, 15.7 ° ± 0.2 °, 19.2 ° ± 0.2 °, 19.6 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.3 ° ± 0.2 °, 21.7 ° ± 0.2 °, 22.8 ° ± 0.2 °, 24.1 ° ± 0.2 °, 26.9 ° ± 0.2 ° and 29.3 ° ± 0.2 °;

Described L MALIC ACID betrixaban is specially L MALIC ACID betrixaban crystal form A, use Cu-K α radiation, its X-ray powder diffraction has characteristic diffraction peak in following 2 θ positions: 8.8 ° ± 0.2 °, 10.7 ° ± 0.2 °, 13.8 ° ± 0.2 °, 14.4 ° ± 0.2 °, 15.3 ° ± 0.2 °, 17.9 ° ± 0.2 °, 20.1 ° ± 0.2 °, 20.7 ° ± 0.2 °, 21.0 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.8 ° ± 0.2 °, 24.3 ° ± 0.2 ° and 25.6 ° ± 0.2 °;

Described half D-malic acid betrixaban is specially half D-malic acid betrixaban crystal form A, use Cu-K α radiation, its X-ray powder diffraction has characteristic diffraction peak in following 2 θ positions: 8.6 ° ± 0.2 °, 12.3 ° ± 0.2 °, 13.3 ° ± 0.2 °, 14.2 ° ± 0.2 °, 15.7 ° ± 0.2 °, 19.2 ° ± 0.2 °, 19.6 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.7 ° ± 0.2 °, 22.8 ° ± 0.2 °, 24.1 ° ± 0.2 °, 26.8 ° ± 0.2 ° and 29.4 ° ± 0.2 °;

Described D-malic acid betrixaban is specially D oxysuccinic acid betrixaban crystal form A, use Cu-K α radiation, its X-ray powder diffraction has characteristic diffraction peak in following 2 θ positions: 8.8 ° ± 0.2 °, 10.7 ° ± 0.2 °, 13.8 ° ± 0.2 °, 14.4 ° ± 0.2 °, 15.2 ° ± 0.2 °, 17.9 ° ± 0.2 °, 20.0 ° ± 0.2 °, 20.7 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.8 ° ± 0.2 °, 24.4 ° ± 0.2 °, 25.6 ° ± 0.2 °;

Described half DL-oxysuccinic acid betrixaban is specially half DL-oxysuccinic acid betrixaban crystal form A, use Cu-K α radiation, its X-ray powder diffraction has characteristic diffraction peak in following 2 θ positions: 8.6 ° ± 0.2 °, 12.3 ° ± 0.2 °, 13.2 ° ± 0.2 °, 14.2 ° ± 0.2 °, 15.7 ° ± 0.2 °, 19.2 ° ± 0.2 °, 19.6 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.2 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.8 ° ± 0.2 °, 24.1 ° ± 0.2 °, 26.8 ° ± 0.2 ° and 29.4 ° ± 0.2 °;

Described DL-oxysuccinic acid betrixaban is specially single DL-oxysuccinic acid betrixaban crystal form A, use Cu-K α radiation, its X-ray powder diffraction has characteristic diffraction peak in following 2 θ positions: 8.6 ° ± 0.2 °, 10.7 ° ± 0.2 °, 13.8 ° ± 0.2 °, 14.6 ° ± 0.2 °, 15.5 ° ± 0.2 °, 18.0 ° ± 0.2 °, 20.2 ° ± 0.2 °, 20.9 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.0 ± 0.2 °, 24.6 ° ± 0.2 °, 25.6 ° ± 0.2 °;

Described DL-tartrate betrixaban is specially single DL-tartrate betrixaban crystal form A, use Cu-K α radiation, its X-ray powder diffraction has characteristic diffraction peak in following 2 θ positions: 4.5 ° ± 0.2 °, 13.8 ° ± 0.2 °, 15.4 ° ± 0.2 °, 16.0 ° ± 0.2 °, 18.4 °± 0.2 °, 20.1 ° ± 0.2 °, 23.0 ° ± 0.2 ° and 26.2 ° ± 0.2 °;

Described half fourth disulfonic acid betrixaban is specially half fourth disulfonic acid betrixaban crystal form A, use Cu-K α radiation, its X-ray powder diffraction has characteristic diffraction peak in following 2 θ positions: 6.6 ° ± 0.2 °, 9.3 ° ± 0.2 °, 11.1 ° ± 0.2 °, 11.7 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.4 ° ± 0.2 °, 15.8 ° ± 0.2 °, 17.2 ° ± 0.2 °, 18.0 ° ± 0.2 °, 18.5 ° ± 0.2 °, 19.6 ° ± 0.2 °, 20.5 ° ± 0.2 °, 22.1 ° ± 0.2 °, 25.0 ° ± 0.2 ° and 25.6 ° ± 0.2 °;

Described half ethionic acid betrixaban is specially half ethionic acid betrixaban crystal form A, use Cu-K α radiation, its X-ray powder diffraction has characteristic diffraction peak in following 2 θ positions: 4.9 ° ± 0.2 °, 5.6 ° ± 0.2 °, 14.7 ° ± 0.2 °, 15.2 ° ± 0.2 °, 16.8 ° ± 0.2 °, 17.4 ° ± 0.2 °, 17.9 ° ± 0.2 °, 19.0 ° ± 0.2 °, 19.1 ° ± 0.2 °, 21.0 ° ± 0.2 °, 24.0 ± 0.2 ° and 24.5 ° ± 0.2 °;

Described isethionic acid betrixaban is specially single isethionic acid betrixaban crystal form A, use Cu-K α radiation, its X-ray powder diffraction has characteristic diffraction peak in following 2 θ positions: 12.5 ° ± 0.2 °, 12.9 ° ± 0.2 °, 15.9 ° ± 0.2 °, 16.5 ° ± 0.2 °, 17.1 ° ± 0.2 °, 17.4 ° ± 0.2 °, 18.8 ° ± 0.2 °, 22.7 ° ± 0.2 °, 28.5 ° ± 0.2 ° and 28.7 ° ± 0.2 °;

Described Hydrogen bromide betrixaban is specially single Hydrogen bromide betrixaban crystal form A, use Cu-K α radiation, its X-ray powder diffraction has characteristic diffraction peak in following 2 θ positions: 5.8 ° ± 0.2 °, 6.5 ° ± 0.2 °, 8.8 ° ± 0.2 °, 11.7 ° ± 0.2 °, 15.1 ° ± 0.2 °, 17.8 ° ± 0.2 °, 21.3 ° ± 0.2 °, 21.7 ° ± 0.2 °, 22.3 ° ± 0.2 °, 25.3 ° ± 0.2 ° and 26.7 ° ± 0.2 °.

4. betrixaban salt according to claim 3, wherein,

The X-ray powder diffraction of described half L MALIC ACID betrixaban crystal form A substantially as shown in Figure 1;

The X-ray powder diffraction of described L MALIC ACID betrixaban crystal form A substantially as shown in Figure 2;

The X-ray powder diffraction of described half D-malic acid betrixaban crystal form A substantially as shown in Figure 3;

The X-ray powder diffraction of described D-malic acid betrixaban crystal form A substantially as shown in Figure 4;

The X-ray powder diffraction of described half DL-oxysuccinic acid betrixaban crystal form A substantially as shown in Figure 5;

The X-ray powder diffraction of described DL-oxysuccinic acid betrixaban crystal form A substantially as shown in Figure 6;

The X-ray powder diffraction of described DL-tartrate betrixaban crystal form A substantially as shown in Figure 7;

The X-ray powder diffraction of described half fourth disulfonic acid betrixaban crystal form A substantially as shown in Figure 8;

The X-ray powder diffraction of described half ethionic acid betrixaban crystal form A substantially as shown in Figure 9;

The X-ray powder diffraction of described isethionic acid betrixaban crystal form A substantially as shown in Figure 10;

The X-ray powder diffraction of described Hydrogen bromide betrixaban crystal form A substantially as shown in figure 11.

5. the preparation method of the betrixaban salt according to any one of claim 1 ~ 4, the method comprises:

(1) betrixaban and L MALIC ACID, D-malic acid, DL-oxysuccinic acid, DL-tartrate, fourth disulfonic acid, ethionic acid, isethionic acid or Hydrogen bromide are dissolved in suitable solvent, wherein when in formula II during m value 0.5, the molar ratio of respective acids and betrixaban is not more than 0.7, when in formula II during m value 1, the molar ratio of respective acids and betrixaban is not less than 1.0;

(2) solid is separated out;

(3) solid of separating out is separated;

6. the preparation method of betrixaban salt according to claim 5, wherein,

When in formula II during m value 0.5 in step (1), L MALIC ACID, D-malic acid, DL-oxysuccinic acid, DL-tartrate, fourth disulfonic acid or ethionic acid and betrixaban molar ratio are 0.3:1 ~ 0.7:1; When in formula II during m value 1, L MALIC ACID, D-malic acid, DL-oxysuccinic acid, DL-tartrate, fourth disulfonic acid, ethionic acid, isethionic acid or Hydrogen bromide and betrixaban molar ratio are 1.0:1 ~ 2.0:1; Described suitable solvent is selected from water, methyl alcohol, ethanol, Virahol, butanols, ethylene glycol, tetrahydrofuran (THF), acetonitrile, N,N-dimethylacetamide, DMF, methyl-sulphoxide or their mixture;

The method separating out solid described in step (2) comprises cooling, add anti-solvent, concentrate out the alone of partial solvent or coupling, wherein anti-solvent is selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, sherwood oil, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, pimelinketone, toluene, dimethylbenzene or their mixture.

7. the preparation method of betrixaban salt according to claim 6, wherein,

When described betrixaban salt be half L MALIC ACID betrixaban or its crystal form A time, the molar ratio of L MALIC ACID and betrixaban is 0.3:1 ~ 0.7:1 in step (1), and described suitable solvent is the mixture of tetrahydrofuran (THF) and water; Described in step (2), anti-solvent is acetone;

When described betrixaban salt be L MALIC ACID betrixaban or its crystal form A time, L MALIC ACID and betrixaban molar ratio are 1.0:1 ~ 2.0:1 in step (1), and described suitable solvent is the mixture of tetrahydrofuran (THF) and water; Described in step (2), anti-solvent is acetone;

When described betrixaban salt be half D-malic acid betrixaban or its crystal form A time, D-malic acid and betrixaban molar ratio are 0.3:1 ~ 0.7:1 in step (1), and described suitable solvent is the mixture of tetrahydrofuran (THF) and water; Described in step (2), anti-solvent is acetone;

When described betrixaban salt be D-malic acid betrixaban or its crystal form A time, D-malic acid and betrixaban molar ratio are 1.0:1 ~ 2.0:1 in step (1), and described suitable solvent is the mixture of tetrahydrofuran (THF) and water; Described in step (2), anti-solvent is acetone;

When described betrixaban salt be half DL-oxysuccinic acid betrixaban or its crystal form A time, D-malic acid and betrixaban molar ratio are 0.3:1 ~ 0.7:1 in step (1), and described suitable solvent is the mixture of tetrahydrofuran (THF) and water; Described in step (2), anti-solvent is acetone;

When described betrixaban salt be DL-oxysuccinic acid betrixaban or its crystal form A time, DL-apple and betrixaban molar ratio are 1.0:1 ~ 2.0:1 in step (1), and described suitable solvent is the mixture of tetrahydrofuran (THF) and water; Described in step (2), anti-solvent is acetone;

When described betrixaban salt be DL-tartrate betrixaban or its crystal form A time, DL-tartrate and betrixaban molar ratio are 1.0:1 ~ 2.0:1 in step (1), and described suitable solvent is the mixture of N,N-dimethylacetamide and water; Described in step (2), anti-solvent is tetrahydrofuran (THF);

When described betrixaban salt be half fourth disulfonic acid betrixaban or its crystal form A time, fourth disulfonic acid and betrixaban molar ratio are 0.3:1 ~ 0.7:1 in step (1), and described suitable solvent is the mixture of ethanol and water; Described in step (2), anti-solvent is acetone;

When described betrixaban salt be half ethionic acid betrixaban or its crystal form A time, ethionic acid and betrixaban molar ratio are 0.3:1 ~ 0.7:1 in step (1), and described suitable solvent is the mixture of ethanol and water; Described in step (2), anti-solvent is acetone;

When described betrixaban salt be isethionic acid betrixaban or its crystal form A time, isethionic acid and betrixaban molar ratio are 1.0:1 ~ 2.0:1 in step (1), and described suitable solvent is the mixture of ethanol and water; Described in step (2), anti-solvent is acetone;

When described betrixaban salt be Hydrogen bromide betrixaban or its crystal form A time, Hydrogen bromide and betrixaban molar ratio are 1.0:1 ~ 2.0:1 in step (1), and described suitable solvent is the mixture of tetrahydrofuran (THF) and water; Described in step (2), anti-solvent is acetone.

8. a pharmaceutical composition, it comprises the betrixaban salt that any one of the treatment betrixaban salt according to any one of claim 1 ~ 4 of significant quantity or claim 5 ~ 7, preparation method obtains, and pharmaceutical excipient.

9. the betrixaban salt that the betrixaban salt according to any one of claim 1 ~ 4 or the preparation method described in any one of claim 5 ~ 7 obtain is in the purposes of the medicine of the illness being feature with bad thrombosis for the preparation of prevention or treatment Mammals.