CN104693114A - Improved method for preparing betrixaban - Google Patents

Improved method for preparing betrixaban Download PDF

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Publication number
CN104693114A
CN104693114A CN201310664433.2A CN201310664433A CN104693114A CN 104693114 A CN104693114 A CN 104693114A CN 201310664433 A CN201310664433 A CN 201310664433A CN 104693114 A CN104693114 A CN 104693114A
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preparation
acid
betrixaban
magnesium bromide
compound
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CN104693114B (en
Inventor
陈大峰
惠帅
胡志鹏
高炳坤
程睿
贾晓曼
刘晓凤
罗杰
向志祥
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72Nitrogen atoms
    • C07D213/75Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Abstract

The invention relates to the fields of organic chemistry and pharmacy, and particularly relates to an improved method for preparing betrixaban. Compared with the prior art, the method has the advantages that the defects of use of high-corrosion hydrogen chloride gas, heavy burden for 'three wastes' treatment, difficult refining and purification of products and the like can be overcome. The method is characterized in that a metal organic compound RMR' (M is selected from Mg and Zn, R is selected from Cl, Br, I, alkyl or aryl, and R' is selected from akly or aryl) is used for reacting with dimethylamine or salt thereof in an aprotic solvent; then the obtained reacting liquid reacts with the compound or salt thereof in a formula II to prepare betrixaban. The improved novel method has the advantages of use of easily available raw materials, mild reaction condition, convenience in operation, excellent product quality and low cost and is suitable for industrial large-scale production.

Description

A kind of preparation method of improvement of betrixaban
Technical field
The present invention relates to organic chemistry filed and pharmaceutical field, be specifically related to a kind of preparation method of improvement of betrixaban.
Background technology
Betrixaban (Betrixaban), chemistry is by name: N-(5-chloro-2-pyridyl)-2-[[4-[(dimethylamino) iminomethyl] benzoyl] is amino]-5-methoxy benzamide, 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. Portola Pharmaceuticals.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.Abroad be in III phase clinical study at present.
Patent documentation CN1391555A, CN101595092A, CN102762538A etc. successively disclose the preparation method of betrixaban.
Patent documentation CN1391555A discloses following preparation method (square case 1) the earliest:
As shown in scheme 1, this technique is for raw material obtains compound V through amidate action under phosphorus oxychloride and pyridine condition with 2-amino-5-chloropyridine (VII) and 5-methoxyl group-2-nitrobenzoic acid (VI); Compound V obtains compound IV through tindichloride reduction; Compound IV with amidate action occurred to cyano-benzoyl chloride (III) obtain Compound II per; Thereafter, Compound II per first reacts in the hydrogen chloride methanol solution of high density, then sloughs the hydrogenchloride in reaction system, then reacts with dimethylamine, obtain betrixaban I finally by column chromatographic isolation and purification.This preparation technology's final step need use and process the hydrogen chloride gas of a large amount of highly corrosives, require high, and " three wastes " processing load is heavier to equipment anticorrosion; In addition, last column chromatographic isolation and purification is also unfavorable for industrialized enforcement.
For the deficiency of scheme 1 technique, patent documentation CN101595092A improves technique, wherein that the acid-reaction condition of final step has been replaced to basic reaction conditions the most significantly, namely first in tetrahydrofuran (THF) with base lithium and dimethylamine make dimethylin lithium just, then dimethylin lithium and Compound II per react, and be separated through aftertreatment and obtain betrixaban I, yield can reach 77%, HPLC purity about 98%, but wherein containing the dechlorination impurity about 1% shown in formula VIII.(square case 2).
As shown in scheme 2, the method not only avoid the use of strong caustic gas hydrogenchloride, reduces the burden that equipment anticorrosion processes with " three wastes "; And simplify post-processing operation, be conducive to industrial applications.But, the reagent that the method uses just base lithium expensive and transport storage requirement comparatively harsh, cause the production cost of product higher.In addition, the product that the method obtains contains the impurity of some more difficult removings, as dechlorination foreign matter content reaches 1%; Further, patent documentation CN102762538A also points out, two kinds of by products are easily generated when preparing betrixaban I by the method, i.e. dechlorination impurity VIII and demethyl impurity IX, even if through salify purifying, their content also may respectively up to 0.25%, and the generation of these and betrixaban I similar impurity is unfavorable for the raising of being further purified of betrixaban and refining yield.
Patent documentation CN102762538A discloses another syntheti c route (square case 3) of betrixaban.
As shown in Scheme 3, this technique is that condensation under coupling reagent exists obtains highly purified betrixaban I through compounds X and compound IV.Wherein compounds X adopts two kinds of methods to obtain: method one is, under the alkaline condition in similar such scheme 2, paracyanobenzoic acid ethyl ester (XII-I) is converted into compounds X I-I, and then compounds X I-I hydrolysis under lithium hydroxide exists obtains compounds X; Method two is, under the acidic conditions of similar such scheme 1 final step, paracyanobenzoic acid methyl esters (XII-II) is converted into compounds X I-II, and then compounds X I-II hydrolysis under lithium hydroxide exists obtains compounds X.The method adopts the route of convergence type to prepare betrixaban, is conducive to the shortening of preparation cycle.But its key intermediate compound X adopts the method for similar such scheme one or scheme two to prepare, and has the deficiency of aforesaid method.In addition, when compounds X is prepared in compounds X I-I or compounds X I-II hydrolysis, the amidino groups facile hydrolysis in its molecular structure is acid amides, causes the generation of more by product XIII, is unfavorable for the raising of reaction yield; In addition, because the polarity of compounds X is large, good water solubility, after it be hydrolyzed by compounds X I-I or compounds X I-II and obtains in lithium hydroxide aqueous solution, is not easily separated it, causes separation yield lower from reacting solution; Experiment shows that this one-step hydrolysis reaction gained compounds X crude product is about 50% to compounds X I-I or compounds X I-II separation yield.
Based on the deficiency of above betrixaban preparation method, the present inventor is studied its preparation method, have developed a kind of improvement novel method preparing betrixaban, these improvement novel method starting material are easy to get, reaction conditions is gentle, easy and simple to handle, good quality of product, cost is lower, is more suitable for industrialized production.
Summary of the invention
The novel method of the preparation that the object of the present invention is to provide a kind of betrixaban to improve.These improvement novel method starting material are easy to get, reaction conditions is gentle, easy and simple to handle, good quality of product, cost is lower, is more suitable for industrialized production.
In order to realize foregoing invention object, present invention employs following technical scheme:
The invention provides a kind of preparation method of formula I, the method comprises: by RMN (CH 3) 2react with formula II compound or its salt;
Wherein:
M is selected from Mg, Zn; R is selected from Cl, Br, I, alkyl or aryl; Wherein when R is alkyl, preferred C1-C7 straight or branched alkyl; When R is aryl, preferred phenyl or substituted-phenyl.In one embodiment, RMN (CH 3) 2for RMgN (CH 3) 2, be selected from ClMgN (CH 3) 2(dimethylin magnesium chloride), BrMgN (CH 3) 2(dimethylin magnesium bromide), IMgN (CH 3) 2(dimethylin magnesium iodide) etc.; In another embodiment, RMN (CH 3) 2for RZnN (CH 3) 2, be selected from CH 3znN (CH 3) 2(dimethylamino methyl zinc), CH 3cH 2znN (CH 3) 2(dimethylamino ethyl zinc), C 6h 5znN (CH 3) 2(dimethylaminophenyl zinc) etc.
In aforesaid method, RMN (CH 3) 2obtained by organometallics RMR ' and dimethylamine or its reactant salt; Wherein the definition of M and R is the same, and R ' is selected from alkyl or aryl; Wherein when R ' is for alkyl, preferred C1-C7 straight or branched alkyl; When R ' is for aryl, preferred phenyl or substituted-phenyl.In one embodiment, organometallics RMR ' is RMgR ', be selected from n-propyl magnesium chloride, isopropylmagnesium chloride, cyclohexyl magnesium chloride, phenyl-magnesium-chloride, benzylmagnesium chloride, methyl-magnesium-bromide, ethylmagnesium bromide, isopropyl magnesium bromide, selenium alkynide, n-pentyl magnesium bromide, cyclopentyl magnesium bromide, cyclohexyl magnesium bromide, n-heptyl magnesium bromide, o-tolyl magnesium bromide, 4-phenylbenzene magnesium bromide, 4-Phenoxyphenyl magnesium bromide, 4-flourophenyl magnesium bromide, 4-chlorophenylmagnesium bromide, methylpyridinium iodide magnesium etc., wherein preferred isopropylmagnesium chloride, isopropyl magnesium bromide or n-pentyl magnesium bromide, in one embodiment, organometallics RMR ' is RZnR ', is selected from zinc methide, zinc ethyl, phenylbenzene zinc etc., wherein preferred zinc ethyl.
The salt of dimethylamine refers to the salt that dimethylamine is formed with suitable mineral acid or organic acid; Wherein suitable mineral acid is selected from hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, phosphoric acid or sulfuric acid etc.; Suitable organic acid is selected from oxalic acid, acetic acid, trifluoroacetic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid etc.
Organometallics RMR ' is generally aprotic solvent with the solvent of dimethylamine or its reactant salt, be selected from tetrahydrofuran (THF), methyltetrahydrofuran, ether, methyl-phenoxide, methyl tertiary butyl ether, glycol dimethyl ether, Methylal(dimethoxymethane), diox, toluene, dimethylbenzene, hexane, heptane, hexanaphthene etc. or their mixed solvent, be wherein preferably tetrahydrofuran (THF), methyltetrahydrofuran, toluene.
Organometallics RMR ' is generally-10 DEG C to 40 DEG C with the temperature of reaction of dimethylamine or its salt, is preferably 0 DEG C to 30 DEG C.
Organometallics RMR ' is generally 1:1 to 1:3 with the molar ratio of dimethylamine, is preferably 1:1.1 to 1:1.5; If dimethylamine feeds intake in a salt form, so RMR ' generally needs Excess quantities to eliminate the impact of the reactive hydrogen of dimethylamine salt introducing, and the mole number of excessive portion is generally not less than the mole number of reactive hydrogen in dimethylamine salt.
After the reaction of organometallics RMR ' and dimethylamine or its salt completes, treatedly directly can not carry out subsequent reactions.
In aforesaid method, formula II compound or its salt can obtain according to method open in patent documentation CN1391555A, CN101595092A etc.
In aforesaid method, the salt of formula II compound refers to the salt that formula II compound is formed with suitable mineral acid or organic acid; Wherein suitable mineral acid is selected from hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, phosphoric acid or sulfuric acid etc.; Suitable organic acid is selected from oxalic acid, trifluoroacetic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid etc.
In aforesaid method, formula II compound and RMN (CH 3) 2molar ratio be generally 1:1 to 1:7, wherein preferred 1:2 to 1:6, if formula II compound feeds intake in a salt form, so RMN (CH 3) 2generally need Excess quantities to carry out the impact of the reactive hydrogen that cancelling II compound salt is introduced, the mole number of excessive portion is generally not less than the mole number of reactive hydrogen in formula II compound salt.
In aforesaid method, formula II compound or its salt and RMN (CH 3) 2reaction solvent be generally aprotic solvent, be selected from tetrahydrofuran (THF), methyltetrahydrofuran, ether, methyl-phenoxide, methyl tertiary butyl ether, glycol dimethyl ether, Methylal(dimethoxymethane), diox, toluene, dimethylbenzene, hexane, heptane, hexanaphthene etc. or their mixed solvent, be wherein preferably tetrahydrofuran (THF), methyltetrahydrofuran, toluene.
In aforesaid method, formula II compound or its salt and RMN (CH 3) 2temperature of reaction be generally-10 DEG C to 40 DEG C, be preferably 0 DEG C to 30 DEG C.
In aforesaid method, the determination in reaction times can adopt the method for this area routine to carry out, as adopted TLC, HPLC monitoring etc.
In aforesaid method, after the completion of reaction, can comprise further with the method for this area routine product is separated, the aftertreatment such as purifying; Such as, after reaction terminates, with acid (example hydrochloric acid, toxilic acid etc.) cancellation reaction, then operate separation through conventional concentrated, filtrations, washing etc. and obtain betrixaban or its salt.In one embodiment, after reaction terminates, with acid (example hydrochloric acid etc.) cancellation reaction, then obtain betrixaban I through the operation such as concentrated, filtration, washing separation, being greater than 80%, HPLC purity to the yield of Compound II per is greater than 98%; Further by conventional purification method such as recrystallizations, purifying is carried out to betrixaban, such as, the mixed solvent of available N,N-dimethylacetamide/toluene carries out further recrystallization purifying to betrixaban, and its HPLC purity can be increased to more than 99.0% or 99.5% or 99.7%.In another embodiment, after reaction terminates, with common medicine acid (as toxilic acid, hydrochloric acid etc.) cancellation reaction, then be separated through operations such as conventional concentrated, filtrations the salt obtaining betrixaban, 80%, HPLC purity be greater than to the yield of Compound II per and be greater than 98%; Further carry out purifying by conventional purification method such as recrystallizations to the salt of betrixaban, such as, the further recrystallization of the salt of mixed solvent to betrixaban of available alcohol/water, its HPLC purity can be increased to more than 99.0% or 99.5% or 99.7%.
In aforesaid method, optionally, by further for the betrixaban of gained salify.Formed salt generally refers to the salt that betrixaban is formed with suitable mineral acid or organic acid; Wherein suitable mineral acid is selected from hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, phosphoric acid or sulfuric acid etc.; Suitable organic acid is selected from toxilic acid, lactic acid, phenoxy acetic acid, propionic acid, succinic acid, hexanodioic acid, xitix, dextrocamphoric acid, gluconic acid, citric acid, methylsulfonic acid, fumaric acid, 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, styracin etc.The mode of salify generally comprises two kinds: one is after the completion of reaction, directly with suitable sour cancellation reaction salify simultaneously; Another kind is after reaction being terminated, and is first separated the betrixaban free alkali obtained, and then with suitable sour salify.The separation of salify or institute's salify can adopt the method for this area routine to carry out.
In one embodiment, the invention provides a kind of preparation method of formula I, the method comprises:
(1), by organometallics RMR ' and dimethylamine or its reactant salt; Wherein M is selected from Mg, Zn, and R is selected from Cl, Br, I, alkyl or aryl, and R ' is selected from alkyl or aryl;
(2), the dimethylamine reaction solution of step (1) gained and formula II compound or its salt are reacted.
In aforesaid method step (1), for convenience of description, by the reaction solution of organometallics RMR ' and dimethylamine or its reactant salt gained referred to as " dimethylamine reaction solution ".
In aforesaid method step (1), when R or R ' is for alkyl, preferred C1-C7 straight or branched alkyl; When R is aryl, preferred phenyl or substituted-phenyl.
In aforesaid method step (1), when organometallics RMR ' is for RMgR ', be selected from n-propyl magnesium chloride, isopropylmagnesium chloride, cyclohexyl magnesium chloride, phenyl-magnesium-chloride, benzylmagnesium chloride, methyl-magnesium-bromide, ethylmagnesium bromide, isopropyl magnesium bromide, selenium alkynide, n-pentyl magnesium bromide, cyclopentyl magnesium bromide, cyclohexyl magnesium bromide, n-heptyl magnesium bromide, o-tolyl magnesium bromide, 4-phenylbenzene magnesium bromide, 4-Phenoxyphenyl magnesium bromide, 4-flourophenyl magnesium bromide, 4-chlorophenylmagnesium bromide, methylpyridinium iodide magnesium etc., wherein preferred isopropylmagnesium chloride, isopropyl magnesium bromide or n-pentyl magnesium bromide, when organometallics RMR ' is RZnR ', be selected from zinc methide, zinc ethyl, phenylbenzene zinc etc., wherein preferred zinc ethyl.
In aforesaid method step (1), the salt of dimethylamine refers to the salt that dimethylamine is formed with suitable mineral acid or organic acid; Wherein suitable mineral acid is selected from hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, phosphoric acid or sulfuric acid etc.; Suitable organic acid is selected from oxalic acid, acetic acid, trifluoroacetic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid etc.
In aforesaid method step (1), reaction solvent is generally aprotic solvent, be selected from tetrahydrofuran (THF), methyltetrahydrofuran, ether, methyl-phenoxide, methyl tertiary butyl ether, glycol dimethyl ether, Methylal(dimethoxymethane), diox, toluene, dimethylbenzene, hexane, heptane, hexanaphthene etc. or their mixed solvent, be wherein preferably tetrahydrofuran (THF), methyltetrahydrofuran, toluene.
In aforesaid method step (1), temperature of reaction is generally-10 DEG C to 40 DEG C, is preferably 0 DEG C to 30 DEG C.
In aforesaid method step (1), organometallics RMR ' is generally 1:1 to 1:3 with the molar ratio of dimethylamine, is preferably 1:1.1 to 1:1.5; If dimethylamine feeds intake in a salt form, so RMR ' generally needs Excess quantities to eliminate the impact of the reactive hydrogen of dimethylamine salt introducing, and the mole number of excessive portion is generally not less than the mole number of reactive hydrogen in dimethylamine salt.
In aforesaid method step (1), after the reaction of organometallics RMR ' and dimethylamine or its salt completes, treatedly can not be directly used in the reaction of step (2).
In aforesaid method step (2), the salt of formula II compound refers to the salt that formula II compound is formed with suitable mineral acid or organic acid; Wherein suitable mineral acid is selected from hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, phosphoric acid or sulfuric acid etc.; Suitable organic acid is selected from oxalic acid, trifluoroacetic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid etc.
In aforesaid method step (2), the molar ratio of formula II compound and the middle organometallics RMR ' of step (1) is generally 1:1 to 1:7, wherein preferred 1:2 to 1:6; If formula II compound feeds intake in a salt form, so the organometallics RMR ' of organometallics RMR ' and corresponding dimethylamine or its salt and correspondence generally needs Excess quantities to carry out the impact of the reactive hydrogen that cancelling II compound salt is introduced, and the mole number of excessive portion is generally not less than the mole number of reactive hydrogen in formula II compound salt.
In aforesaid method step (2), reaction solvent is generally aprotic solvent, be selected from tetrahydrofuran (THF), methyltetrahydrofuran, ether, methyl-phenoxide, methyl tertiary butyl ether, glycol dimethyl ether, Methylal(dimethoxymethane), diox, toluene, dimethylbenzene, hexane, heptane, hexanaphthene etc. or their mixed solvent, be wherein preferably tetrahydrofuran (THF), methyltetrahydrofuran, toluene.
In aforesaid method step (2), temperature of reaction is generally-10 DEG C to 40 DEG C, is preferably 0 DEG C to 30 DEG C.
In aforesaid method step (2), the determination in reaction times can adopt the method for this area routine to carry out, as adopted TLC, HPLC monitoring etc.
In aforesaid method step (2), after the completion of reaction, can comprise further with the method for this area routine product is separated, the aftertreatment such as purifying; Such as, after reaction terminates, with acid (example hydrochloric acid, toxilic acid etc.) cancellation reaction, then operate separation through conventional concentrated, filtrations, washing etc. and obtain betrixaban or its salt.In one embodiment, after reaction terminates, with acid (example hydrochloric acid etc.) cancellation reaction, then obtain betrixaban I through the operation such as concentrated, filtration, washing separation, being greater than 80%, HPLC purity to the yield of Compound II per is greater than 98%; Further by conventional purification method such as recrystallizations, purifying is carried out to betrixaban, such as, the mixed solvent of available N,N-dimethylacetamide/toluene carries out further recrystallization purifying to betrixaban, and its HPLC purity can be increased to more than 99.0% or 99.5% or 99.7%.In another embodiment, after reaction terminates, with common medicine acid (example hydrochloric acid, toxilic acid etc.) cancellation reaction, then be separated through operations such as conventional concentrated, filtrations the salt obtaining betrixaban, 80%, HPLC purity is greater than to the yield of Compound II per and is greater than 98%; Further carry out purifying by conventional purification method such as recrystallizations to the salt of betrixaban, such as, the further recrystallization of the salt of mixed solvent to betrixaban of available alcohol/water, its HPLC purity can be increased to more than 99.0% or 99.5% or 99.7%.
In aforesaid method step (2), optionally, can salify further by the betrixaban of gained.Formed salt generally refers to the salt that betrixaban is formed with suitable mineral acid or organic acid; Wherein suitable mineral acid is selected from hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, phosphoric acid or sulfuric acid etc.; Suitable organic acid is selected from toxilic acid, lactic acid, phenoxy acetic acid, propionic acid, succinic acid, hexanodioic acid, xitix, dextrocamphoric acid, gluconic acid, citric acid, methylsulfonic acid, fumaric acid, 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, styracin etc.The mode of salify generally comprises two kinds: one is after the completion of reaction, with directly reacting salify simultaneously with suitable sour cancellation; Another kind is after reaction being terminated, and is first separated the betrixaban free alkali obtained, and then with suitable sour salify.The separation of salify or institute's salify can adopt the method for this area routine to carry out.
Above-mentioned betrixaban provided by the invention improves preparation method, compared with immediate prior art, in reaction conditions, quality product, product cost etc., has improvement effect.Such as:
As can be seen from upper table contrast, the reagent safety that improvement preparation method provided by the invention uses is better, cheaper, is conducive to the reduction of products production cost; And the product purity that this improvement preparation method obtains improves, dechlorination impurity VIII and the demethyl impurity IX of wherein more difficult removing significantly reduce, and are conducive to the preparation of pharmaceutical grade high purity betrixaban or its salt.
Generally speaking, the improvement preparation method starting material of above-mentioned betrixaban provided by the invention are easy to get, reaction conditions is gentle, easy and simple to handle, and good quality of product, cost is lower, is more suitable for industrialized production.
Accompanying drawing explanation
Fig. 1 betrixaban structural formula
Fig. 2 formula II structural formula of compound
Embodiment
Below in conjunction with the embodiment of embodiment, foregoing of the present invention is described in further detail again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following example.Without departing from the idea case in the present invention described above, the various replacement made according to ordinary skill knowledge and customary means or change, all should comprise within the scope of the invention.
In following examples, mass spectroscopy is measured by the ESI ion source holotype of the mono-quadrupole mass spectrometer of Agilent 6120B; Nmr analysis is at room temperature, by BRUKER AVANCE III HD400 nuclear magnetic resonance analyser, and deuterated dimethyl sulfoxide (DMSO-d 6) make test solvent, in tetramethylsilane work, mapping completes surely.
The preparation of embodiment 1 betrixaban
Under stirring, temperature control 15 ~ 20 DEG C, drip isopropylmagnesium chloride tetrahydrofuran solution (can the commercialization buy) 308ml(0.615mol of 2mol/L, 5eq) to dimethylamine tetrahydrofuran solution (can the commercialization buy) 339ml(0.677mol of 2mol/L, 5.5eq), obtain dimethylamine reaction solution.
Under stirring, temperature control 15 ~ 20 DEG C, by formula II compound 50.0g(0.123mol, 1eq) mix with tetrahydrofuran (THF) 500ml, then drip above-mentioned dimethylamine reaction solution; Dropwise rear continuation stirring reaction at 25 ~ 30 DEG C, monitor reaction process with HPLC.After reaction terminates, at 15 ~ 20 DEG C, reaction solution is added in about 2mol/L aqueous hydrochloric acid 700ml, then use hydrochloric acid regulation system pH to 2 ~ 3; Concentrating under reduced pressure steams organic solvent, the solid of separating out in filtering and concentrating liquid, the appropriate water washing of filter cake; Filter cake and acetone 500ml are uniformly mixed, with triethylamine regulation system pH to 7 ~ 8; Filter; Filter cake is drying under reduced pressure at 40 ~ 45 DEG C, obtains betrixaban 45.5g.Yield: 82.0%; HPLC purity: 98.9%, wherein dechlorination impurity VIII is 0.05%, and demethyl impurity IX does not detect.
Get above-mentioned betrixaban 45.0g, stir at about 70 DEG C and be dissolved in N,N-dimethylacetamide 180ml, drip toluene 360ml; Cooling crystallization, filter, filter cake proper amount of acetone is washed, drying under reduced pressure at 40 ~ 45 DEG C; Gained betrixaban HPLC purity 99.7%.
(+)LC-MS:m/z=452([M+H] +)。 1H NMR(400MHz,DMSO-d 6)δ:2.96(s,6H),3.83(s,3H),7.06-7.09(dd,1H),7.55-7.59(m,3H),7.80-7.83(dd,1H),8.21-8.23(d,1H),8.27-8.30(d,2H),8.37-8.40(d,1H),8.41-8.43(d,1H),10.54(br.,2H)。
The preparation of embodiment 2 betrixaban maleate
Under stirring, temperature control 0 ~ 5 DEG C, drips isopropylmagnesium chloride tetrahydrofuran solution (can commercialization buy) 105ml(0.21mol, the 8.4eq of 2mol/L) to dimethylamine hydrochloride 8.91g(0.11mol, in the suspension of tetrahydrofuran (THF) 60ml 4.4eq), obtain dimethylamine reaction solution.
Under stirring, temperature control 0 ~ 5 DEG C, by formula II compound 10.0g(0.025mol, 1eq) mix with tetrahydrofuran (THF) 100ml, then drip above-mentioned dimethylamine reaction solution; Dropwise rear continuation stirring reaction at 10 ~ 15 DEG C, monitor reaction process with HPLC.After reaction terminates, at 10 ~ 15 DEG C, reaction solution is added in the solution that toxilic acid 45g and aqueous solution 100ml is made into; Concentrating under reduced pressure steams organic solvent, the solid of separating out in filtering and concentrating liquid, the appropriate water washing of filter cake.Filter cake is drying under reduced pressure at 40 ~ 45 DEG C, obtains betrixaban maleate 12.1g.Yield: 85.4%; HPLC purity: 98.6%, wherein dechlorination impurity VIII is 0.03%, and demethyl impurity IX does not detect.
Get above-mentioned betrixaban maleate 10.0g, stir at about 70 DEG C and be dissolved in the mixed solvent of ethanol 50ml and water 25ml, drip water 150ml; Cooling crystallization, filter, filter cake is drying under reduced pressure at 40 ~ 45 DEG C; Gained betrixaban maleate HPLC purity 99.9%.
1H NMR(400MHz,DMSO-d 6)δ:3.25(s,3H),3.32(s,3H),3.87(s,3H),6.02(s,2H),7.19-7.21(dd,1H),7.44-7.45(1H),7.75-7.77(d,2H),7.97-9.98(d,2H),8.08-8.13(m,3H),8.44-8.45(d,1H),9.01(br.,1H),9.37(br.,1H),11.04(s,1H),11.13(s,1H).
The preparation of embodiment 3 betrixaban
Under stirring, temperature control 25 ~ 30 DEG C, drip isopropylmagnesium chloride tetrahydrofuran solution (can the commercialization buy) 81ml(0.161mol of 2mol/L, 7eq) to dimethylamine tetrahydrofuran solution (can the commercialization buy) 121ml(0.242mol of 2mol/L, 10.5eq), obtain dimethylamine reaction solution.
Under stirring, temperature control 25 ~ 30 DEG C, by formula II compound hydrochloride 10.0g(0.023mol, 1eq) mix with tetrahydrofuran (THF) 100ml, then drip above-mentioned dimethylamine reaction solution; Dropwise rear continuation stirring reaction at 25 ~ 30 DEG C, monitor reaction process with HPLC.After reaction terminates, at 15 ~ 20 DEG C, reaction solution is added in about 2mol/L aqueous hydrochloric acid 210ml, then use hydrochloric acid regulation system pH to 2 ~ 3; Concentrating under reduced pressure steams organic solvent, the solid of separating out in filtering and concentrating liquid, the appropriate water washing of filter cake; Filter cake and acetone 90ml are uniformly mixed, with triethylamine regulation system pH to 7 ~ 8; Filter; Filter cake is drying under reduced pressure at 45 ~ 50 DEG C, obtains betrixaban 8.35g.Yield: 80.5%.HPLC purity: 98.7%, wherein dechlorination impurity VIII is 0.03%, and demethyl impurity IX does not detect.
The preparation of embodiment 4 betrixaban hydrochloride
Under stirring, temperature control 15 ~ 20 DEG C, drip n-pentyl magnesium bromide tetrahydrofuran solution (can the commercialization buy) 75ml(0.075mol of 1mol/L, 3eq) to dimethylamine tetrahydrofuran solution (can the commercialization buy) 56ml(0.113mol of 2mol/L, 4.5eq), obtain dimethylamine reaction solution.
Under stirring, temperature control 15 ~ 20 DEG C, by formula II compound 10.0g(0.025mol, 1eq) mix with tetrahydrofuran (THF) 100ml, then drip above-mentioned dimethylamine reaction solution; Dropwise rear continuation stirring reaction at 25 ~ 30 DEG C, monitor reaction process with HPLC.After reaction terminates, at 15 ~ 20 DEG C, reaction solution is added in about 2mol/L aqueous hydrochloric acid 100ml, then use hydrochloric acid regulation system pH to 2 ~ 3; Concentrating under reduced pressure steams organic solvent, the solid of separating out in filtering and concentrating liquid, the appropriate water washing of filter cake.Filter cake is drying under reduced pressure at 40 ~ 45 DEG C, obtains betrixaban hydrochloride 10.1g, yield: 82.9%; HPLC purity: 99.0%, wherein dechlorination impurity VIII is 0.02%, and demethyl impurity IX does not detect.
Get above-mentioned betrixaban hydrochloride 10.0g, stir at about 70 DEG C and be dissolved in N,N-dimethylacetamide 40ml, drip toluene 80ml; Cooling crystallization, filter, filter cake is drying under reduced pressure at 40 ~ 45 DEG C; Gained betrixaban hydrochloride HPLC purity 99.8%.
The preparation of embodiment 5 betrixaban
Under stirring, temperature control 0 ~ 5 DEG C, drip toluene solution (can the commercialization buy) 50ml(0.050mol of the zinc ethyl of 1mol/L, 2eq) to dimethylamine tetrahydrofuran solution (can the commercialization buy) 28ml(0.055mol of 2mol/L, 2.2eq), obtain dimethylamine reaction solution.
Under stirring, temperature control 0 ~ 5 DEG C, by formula II compound 10.0g(0.025mol, 1eq) mix with tetrahydrofuran (THF) 100ml, then drip above-mentioned dimethylamine reaction solution; Dropwise rear continuation stirring reaction at 5 ~ 10 DEG C, monitor reaction process with HPLC.After reaction terminates, at 5 ~ 10 DEG C, reaction solution is added in about 2mol/L diluted hydrochloric acid aqueous solution 70ml, then use hydrochloric acid regulation system pH to 2 ~ 3; Concentrating under reduced pressure steams organic solvent, the solid of separating out in filtering and concentrating liquid, and appropriate water washing used successively by filter cake; Filter cake and acetone 100ml are uniformly mixed, with triethylamine regulation system pH to 7 ~ 8; Filter; Filter cake is drying under reduced pressure at 40 ~ 45 DEG C, obtains betrixaban 9.03g.Yield: 80.1%; HPLC purity: 99.0%, wherein dechlorination impurity VIII is 0.02%, and demethyl impurity IX does not detect.
The preparation of preparation example 1 formula II compound
(1) preparation of N-(the chloro-pyridine of 5--2-base)-5-methoxyl group-2-nitro-benzamide (compound V)
Under stirring at room temperature, by 5-methoxyl group-2-nitrobenzoic acid (compound VI, can commercialization buy) 250g(1.27mol, 1eq) with 2-amino-5-chloropyridine (compound VI I) 163g(1.27mol, 1eq) be suspended in acetonitrile 1700ml, add pyridine 301g(3.81mol, 3eq), then phosphorus oxychloride 231g(1.52mol, 1.2eq is dripped); Stirring reaction adds water 3500ml cancellation crystallization after 1 hour; Filter, filter cake use water 1700ml × 2 are washed; Drying under reduced pressure obtains compound V349g.
(2) preparation of 2-amino-N-(the chloro-pyridine of 5--2-base)-5-methoxy-b enzamide (compound IV)
Under stirring at room temperature, by N-(the chloro-pyridine of 5--2-base)-5-methoxyl group-2-nitro-benzamide (compound V) 300g(0.977mol, 1.0eq) be dissolved in acetic acid 3000ml, add iron powder 546g(9.77mol, 10eq) in batches; Continue stirring reaction after adding iron powder 3 hours, then add ethyl acetate 6000ml and water 3000ml, separatory; Aqueous phase ethyl acetate 3000ml × 2 extraction separated; Merge organic phase, successively with water, saturated aqueous solution of sodium bicarbonate, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains compound IV 244g.
(3) preparation of N-(the chloro-pyridine of 5--2-base)-2-(4-cyano-benzoyl-amino)-5-methoxy-b enzamide (Compound II per)
At 10 ~ 20 DEG C, by formula IV compound 200g(0.72mol, 1.0eq) with triethylamine 109g(1.08mol, 1.5eq) be dissolved in tetrahydrofuran (THF) 2000ml, drip cyano-benzoyl chloride (compound III wherein, can commercialization buy) 130g(0.79mol, 1.1eq) and the solution that is made into of tetrahydrofuran (THF) 1000ml, HPLC monitors reaction process; Reaction terminates rear filtration, and filter cake washs through ethanol in proper amount, and drying under reduced pressure obtains Compound II per 263g.HPLC purity: 98.7%.
(+)LC-MS:m/z=407([M+H] +)。 1H NMR(400MHz,DMSO-d6)δ:3.85(s,3H),7.16-7.19(dd,1H),7.39-7.41(d,1H),7.93-7.96(d,2H),8.02-8.04(m,4H),8.13-8.14(d,2H),8.42-8.43(d,1H),11.06(br.2H)。
The preparation of preparation example 2 formula II compound hydrochloride
At 10 ~ 20 DEG C, by formula IV compound 40.0g(0.14mol, 1.0eq) be dissolved in tetrahydrofuran (THF) 400ml, drip cyano-benzoyl chloride (compound III wherein, can commercialization buy) 24.8g(0.15mol, solution 1.1eq) be made into tetrahydrofuran (THF) 200ml, HPLC monitors reaction process; Reaction terminates rear filtration, and filter cake washs through ethanol in proper amount, and drying under reduced pressure obtains formula II compound hydrochloride.HPLC purity: 99.5%.

Claims (13)

1. a preparation method for the improvement of betrixaban, is characterized in that RMN (CH 3) 2with formula iIcompound or its salt reacts;
Wherein: M is selected from Mg, Zn; R is selected from Cl, Br, I, alkyl or aryl.
2. preparation method according to claim 1, is characterized in that described RMN (CH 3) 2be selected from ClMgN (CH 3) 2, BrMgN (CH 3) 2, IMgN (CH 3) 2, CH 3znN (CH 3) 2, CH 3cH 2znN (CH 3) 2or C 6h 5znN (CH 3) 2.
3. preparation method according to claim 1, is characterized in that described formula iIcompound and RMN (CH 3) 2molar ratio be generally 1:1 to 1:7, preferred 1:2 to 1:6.
4. preparation method according to claim 1, is characterized in that the temperature of described reaction is-10 DEG C to 40 DEG C, is preferably 0 DEG C to 30 DEG C.
5. preparation method according to claim 1, is characterized in that described RMN (CH 3) 2obtained by organometallics RMR ' and dimethylamine or its reactant salt; Wherein the definition of M and R is the same, and R ' is selected from alkyl or aryl.
6. a preparation method for the improvement of betrixaban, is characterized in that adopting following methods:
(1), by organometallics RMR ' and dimethylamine or its reactant salt; Wherein M is selected from Mg, Zn, and R is selected from Cl, Br, I, alkyl or aryl, and R ' is selected from alkyl or aryl;
(2), by the dimethylamine reaction solution of step (1) gained and formula iIcompound or its salt reacts.
7. according to the preparation method of claim 5 or 6, it is characterized in that described organometallics RMR ' is selected from n-propyl magnesium chloride, isopropylmagnesium chloride, cyclohexyl magnesium chloride, phenyl-magnesium-chloride, benzylmagnesium chloride, methyl-magnesium-bromide, ethylmagnesium bromide, isopropyl magnesium bromide, selenium alkynide, n-pentyl magnesium bromide, cyclopentyl magnesium bromide, cyclohexyl magnesium bromide, n-heptyl magnesium bromide, o-tolyl magnesium bromide, 4-phenylbenzene magnesium bromide, 4-Phenoxyphenyl magnesium bromide, 4-flourophenyl magnesium bromide, 4-chlorophenylmagnesium bromide, methylpyridinium iodide magnesium etc., wherein preferred isopropylmagnesium chloride, isopropyl magnesium bromide, n-pentyl magnesium bromide, zinc methide, zinc ethyl or phenylbenzene zinc, wherein preferred isopropylmagnesium chloride, isopropyl magnesium bromide, n-pentyl magnesium bromide or zinc ethyl.
8. according to the arbitrary described preparation method of claim 1,5 or 6, it is characterized in that the solvent of described reaction is selected from tetrahydrofuran (THF), methyltetrahydrofuran, ether, methyl-phenoxide, methyl tertiary butyl ether, glycol dimethyl ether, Methylal(dimethoxymethane), diox, toluene, dimethylbenzene, hexane, heptane, hexanaphthene or their mixed solvent, be wherein preferably tetrahydrofuran (THF), methyltetrahydrofuran, toluene.
9., according to the preparation method of claim 5 or 6, it is characterized in that described organometallics RMR ' is-10 DEG C to 40 DEG C with the temperature of reaction of dimethylamine or its salt, be preferably 0 DEG C to 30 DEG C.
10., according to the preparation method of claim 5 or 6, it is characterized in that described organometallics RMR ' is generally 1:1 to 1:3 with the molar ratio of dimethylamine, be preferably 1:1.1 to 1:1.5.
11. preparation methods according to claim 6, is characterized in that described step (2) Chinese style iIthe molar ratio of compound and the middle organometallics RMR ' of step (1) is generally 1:1 to 1:7, preferred 1:2 to 1:6.
12. preparation methods according to claim 6, is characterized in that described step (2) temperature of reaction is-10 DEG C to 40 DEG C, are preferably 0 DEG C to 30 DEG C.
13., according to the preparation method of claim 1 or 6, is characterized in that further for the betrixaban of gained salify.
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CN105732490A (en) * 2016-03-25 2016-07-06 重庆医科大学 Preparation method of betrixaban
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CN108530349A (en) * 2018-04-09 2018-09-14 重庆三圣实业股份有限公司 The preparation method and products thereof of betrixaban intermediate and betrixaban
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CN106518758A (en) * 2015-09-11 2017-03-22 扬子江药业集团江苏紫龙药业有限公司 Preparation method of Betrixaban intermediate N-(5-chloro-2-pyridyl)-2-(4-cyanobenzeneformamido)-5-metoxybenzamide
CN106831553A (en) * 2015-09-11 2017-06-13 天津科伦药物研究有限公司 The preparation method of betrixaban or its analog
CN105348187B (en) * 2015-12-02 2017-12-08 安徽省逸欣铭医药科技有限公司 A kind of betrixaban analogue and its production and use
CN105348187A (en) * 2015-12-02 2016-02-24 安徽省逸欣铭医药科技有限公司 Betrixaban structural analogue as well as preparation method and application thereof
WO2017117189A1 (en) * 2015-12-30 2017-07-06 Tetraphase Pharmaceuticals, Inc. Preparation of mixed amidomagnesium halides
CN107098853A (en) * 2016-02-20 2017-08-29 天津科伦药物研究有限公司 The preparation method of betrixaban maleate
CN105732490A (en) * 2016-03-25 2016-07-06 重庆医科大学 Preparation method of betrixaban
CN107778224A (en) * 2016-08-31 2018-03-09 鲁南制药集团股份有限公司 A kind of preparation method of betrixaban intermediate
CN107778224B (en) * 2016-08-31 2020-06-26 鲁南制药集团股份有限公司 Preparation method of betrixaban intermediate
CN108586325A (en) * 2017-03-16 2018-09-28 上海度德医药科技有限公司 A kind of preparation method of Betrixaban intermediates
WO2018229796A2 (en) 2017-06-14 2018-12-20 Mylan Laboratories Limited A process for betrixaban hydrochloride and betrixaban maleate salt
WO2018229796A3 (en) * 2017-06-14 2019-01-24 Mylan Laboratories Limited A process for the preparation of betrixaban hydrochloride
CN108530349A (en) * 2018-04-09 2018-09-14 重庆三圣实业股份有限公司 The preparation method and products thereof of betrixaban intermediate and betrixaban
CN113620869A (en) * 2020-05-06 2021-11-09 江西同和药业股份有限公司 Preparation method of betrixaban
CN113620869B (en) * 2020-05-06 2023-04-18 江西同和药业股份有限公司 Preparation method of betrixaban

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