CN107382897B - Intermediate of betrixaban and preparation method and application thereof - Google Patents

Intermediate of betrixaban and preparation method and application thereof Download PDF

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CN107382897B
CN107382897B CN201710557504.7A CN201710557504A CN107382897B CN 107382897 B CN107382897 B CN 107382897B CN 201710557504 A CN201710557504 A CN 201710557504A CN 107382897 B CN107382897 B CN 107382897B
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CN107382897A (en
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汪海波
李霆
金辉
梅光耀
欧阳晓辉
冯尚军
郑海成
徐彩娥
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Zhejiang Hongyuan Pharmaceutical Co ltd
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    • C07D265/00Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/041,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/121,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/141,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/201,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 4
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    • 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
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Abstract

The invention discloses an intermediate of betrixaban and a preparation method and application thereof, wherein the intermediate has a structure shown in formula I, can be efficiently synthesized by cheap and easily-obtained raw materials, and meanwhile, when the raw materials are used for synthesizing betrixaban, the subsequent reaction yield is high, the post-treatment is simple, the purity of the obtained product is high, and the intermediate has a relatively high industrial application prospect.

Description

Intermediate of betrixaban and preparation method and application thereof
Technical Field
The invention belongs to the technical field of organic chemistry and pharmaceutical chemistry, and relates to an intermediate of betrixaban, and a preparation method and application thereof. More particularly, the present invention relates to a benzoxazinone compound and a preparation method thereof.
Background
Venous and arterial thromboembolic diseases have a significant impact on human morbidity and mortality, and therefore, new therapies for thromboembolism remain a major focus of drug development. In the coagulation cascade, vitamin K is an important cofactor for liver gamma-glutamyl carboxylase, which can add activated carboxylic acid esters to a series of proteases, such as factors II, VII, IX or X. Activated factor X dominates the coagulation cascade, and it communicates the intrinsic and extrinsic coagulation pathways, a rate-limiting step in thrombin generation. Thus, the effect of activated factor X on the coagulation cascade can be measured by its time to prolong prothrombin, thereby indicating its activation of the extrinsic pathway; it can also be measured by the time it activates a portion of thromboplastin, thereby indicating its activation of intrinsic pathways. The sand class of oral anticoagulants are coagulation factor Xa inhibitors, and are also the only oral anticoagulants except warfarin. Currently, the marketed sabainide anticoagulants mainly include rivaroxaban, apixaban and edoxaban.
Betrixaban, also known as betrixaban, is mainly used for the prevention and treatment of deep venous thrombosis and prevention of postoperative venous thrombosis and pulmonary embolism, and has the chemical name: n- (5-chloro-2-pyridyl) -2- [4- (N, N-dimethylcarbamimidoyl) benzoylamino ] -5-methoxybenzamide maleate with the structural formula shown in the specification.
Figure BDA0001346183930000011
Betriciban maleate
Betrixaban is a new family of coagulation factor Xa inhibitors developed by Millennium pharmaceuticals (Millennium) in the united states. In 2014, bordeaux Pharmaceuticals (Portola Pharmaceuticals) acquired exclusive rights to global development and commercialization of betrixaban from wutian (acquired millennium Pharmaceuticals). Currently, betrixaban has filed an NDA application in the united states, with FDA approval for marketing on 6/23 of 2017; betrixaban has also completed clinical studies in china and is expected to submit new drug applications for marketing in a short time. Betrixaban as a new member of the sandban class of drugs has its own unique advantages in clinical terms compared to marketed sandban drugs: its clinical research on thrombus prevention of acute patients reaches a main effective endpoint. Because clinical studies of rivaroxaban, apixaban and edoxaban in this respect have not been successful; moreover, there is currently no effective anticoagulant approved or recommended by guidelines for venous thrombosis prevention in acute medical patients; therefore, betrixaban is highly likely to form a monopoly in the prevention of venous thrombosis in acute patients.
Patent documents WO2008057972, WO2011084519, CN201610178032 and the like successively disclose preparation methods of betrixaban.
The patent document WO2008057972 of the original research company originally discloses a preparation method of betrixaban, and a synthetic route is shown as a route one. Route one using 5-methoxy-2-nitrobenzoic acid as raw material in POCl3Carrying out amidation reaction on acyl chloride prepared in situ by Vilsmeier reaction and 2-amino-5-chloropyridine under the action to obtain a compound 1; hydrogenating and reducing the compound 1 to obtain a compound 2; an intermediate 3 of the compound 2 and p-cyanobenzoyl chloride through acylation reaction; then, the intermediate 3 is subjected to a Pinner reaction in a high-concentration hydrogen chloride methanol solution, and then the betrixaban free alkali 4 is prepared through a dimethylaminolysis reaction; the free alkali and maleic acid form salt to obtain the betrixaban maleate.
Figure BDA0001346183930000031
Route one
In the first route, a virulent reagent POCl is used3The process is not friendly, and the three wastes treatment burden is heavy, which is not beneficial to the industrialized production. In the first route, a pressure hydrogenation reduction reaction is also used, so that the risk of EHS is increased, chlorine atoms on pyridine rings are easy to be hydrogenated and removed in the hydrogenation process, the content of each component in the reaction process needs to be monitored in real time, and the industrialization difficulty is increased.
In another patent document WO2011084519, the original company has adjusted the process described in route one, as shown in route two. Ethyl p-cyanobenzoate is used as a starting material, an amidino compound 5 is prepared by aminolysis with a dimethylamine lithium reagent, the compound 5 is hydrolyzed under an alkaline condition to prepare corresponding acid 6, the corresponding acid 6 and an intermediate 2 in the first route are subjected to condensation reaction to prepare free alkali 4, and finally salification is carried out to obtain the betrixaban maleate.
Figure BDA0001346183930000041
Route two
Route two also uses the same intermediate 2, so hydrogenation reduction process is still not avoided; further, the condensation reaction of the compound 2 with the compound 6 requires the reaction system to be anhydrous. In order to ensure the complete condensation reaction, a large amount of condensation agent 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC & HCl) is required to be used in the reaction process, and the by-product urea of EDC has good water solubility, but is difficult to degrade, so that the difficulty in wastewater treatment is increased.
Another process route for synthesizing betrixaban is disclosed in patent document CN201610178032, by the university of chongqing medicine, as shown in route three. Although the hydrogenation reduction process is avoided in the third route, the process does not effectively shorten the synthesis route of betrixaban, the overall yield is not ideal, the stability of the adopted starting materials is poor, and the commercial sources are not easily obtained.
Figure BDA0001346183930000051
Route three
Based on the defects of the preparation method of the betrixaban, the inventor researches the preparation method of the betrixaban and the key intermediate thereof, and develops a new method for preparing the betrixaban key intermediate. And the synthetic route for preparing the betrixaban is effectively shortened, and the synthetic cost of the betrixaban is reduced.
Disclosure of Invention
The invention provides a new betrixaban intermediate and a preparation method thereof, and also provides a new process route for synthesizing betrixaban, wherein the process has the advantages of mild reaction, simple and convenient operation, environmental friendliness and high yield, and is suitable for industrial production.
An intermediate of betrixaban has a structure shown in formula I:
Figure BDA0001346183930000052
the invention also provides a synthesis method of the compound shown in the formula I, which is characterized in that 5-methoxy-2-aminobenzoic acid or ester thereof and 4-cyanobenzene derivative are used as raw materials, and the compound shown in the formula I is prepared through amidation and cyclization reactions.
Figure BDA0001346183930000061
Wherein R is1Independently of each other is H atom, C1-C2Alkyl radical, C2-C3Alkenyl, substituted or unsubstituted phenyl, the substituents on the phenyl being selected from nitro, alkyl, alkoxy or halogen; r2Independently a carboxyl, haloacyl, isocyanato or chloroformyloxy group.
Further, the preparation method of the compound of formula I is preferably as follows:
5-methoxy-2-aminobenzoic acid or ester thereof and 4-cyanobenzoic acid or acyl halide thereof are subjected to amidation reaction under the action of an acid-binding agent to obtain a compound shown as a formula II, the compound shown as the formula II is subjected to cyclization under a heating condition without separation and purification, and is cooled and crystallized to obtain the compound shown as the formula I.
Figure BDA0001346183930000062
Scheme one
Wherein R is1Independently of each other is H atom, C1-C4Alkyl radical, C2-C4Alkenyl, substituted or unsubstituted phenyl, the substituents on the phenyl being selected from nitro, alkyl, alkoxy or halogen; r3independently-OH, a chlorine atom or a bromine atom;
the acid-binding agent in the first scheme is an organic base reagent selected from tertiary amine organic bases, preferably pyridine, triethylamine, diisopropylethylamine and N-methylmorpholine;
in the first scheme, the heating reaction temperature is 80-120 ℃, and preferably 110-120 ℃; the reaction time is 1 to 8 hours, preferably 2 hours;
the cooling crystallization in the first scheme has the cooling end point temperature of 0-30 ℃, and preferably 0-10 ℃.
In the first embodiment, the reaction solvent is preferably toluene.
Further, the preparation of said compounds of formula i, preferably the following scheme two:
5-methoxy-2-aminobenzoic acid or ester thereof and 4-cyanobenzoic acid or acyl halide thereof are subjected to amidation reaction under the action of chloroformate and acid-binding agent to obtain the compound shown as the formula II, and the compound shown as the formula II is subjected to dehydration cyclization in the presence of a condensing agent without separation and purification to obtain the compound shown as the formula I.
Figure BDA0001346183930000071
Scheme two
Wherein R is1Independently of each other is H atom, C1-C4Alkyl radical, C2-C4Alkenyl, substituted or unsubstituted phenyl, the substituents on the phenyl being selected from nitro, alkyl, alkoxy or halogen; r3independently-OH, a chlorine atom or a bromine atom; r4Independently is C1-C4Alkyl of (C)2-C4Alkenyl, substituted or unsubstituted phenyl, the substituents on the phenyl being selected from nitro, alkyl, alkoxy or halogen;
the acid-binding agent in the second scheme is an organic base reagent selected from tertiary amine organic bases, preferably pyridine, triethylamine, diisopropylethylamine and N-methylmorpholine;
the condensing agent in the second scheme is selected from a triphenylphosphine/carbon tetrachloride composition, a carbodiimide reagent or a carbodiimide reagent/1-hydroxybenzotriazole composition;
the carbodiimide reagent described in scheme two is preferably 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride or dicyclohexylcarbodiimide;
in scheme two, the reaction solvent is preferably dichloromethane.
Further, the preparation of said compounds of formula i, is preferably as follows scheme three:
5-methoxy-2-aminobenzoic acid or ester thereof and 4-cyanobenzene isocyanate or 4-cyanobenzene chloroformate are subjected to amidation and cyclization reaction under the action of an acid-binding agent to prepare the compound shown in the formula I.
Figure BDA0001346183930000072
Scheme three
Wherein R is1Independently of each other is H atom, C1-C4Alkyl radical, C2-C4Alkenyl, substituted or unsubstituted phenyl, the substituents on the phenyl being selected from nitro, alkyl, alkoxy or halogen; r5Independently is-NCO or-OCOCl;
the acid-binding agent in the third scheme is an organic base reagent, preferably pyridine, triethylamine, diisopropylethylamine and N-methylmorpholine; the reaction temperature in the third scheme is 20-80 ℃; the reaction time in the third scheme is 5-24 hours;
in the third embodiment, the reaction solvent is preferably DMF or pyridine, and when pyridine is used as the solvent, pyridine is also used as the acid-binding agent.
The betrixaban intermediate compound shown in the formula I can be used for synthesizing a compound shown in the formula 3.
Figure BDA0001346183930000081
The compound of the intermediate formula I of the betrixaban can also be used for synthesizing the betrixaban and is carried out according to the following steps:
step A: reacting the compound shown in the formula I with 5-chloro-2-aminopyridine under the action of a catalyst, and carrying out ring opening to obtain a compound 3;
and B: preparing a compound 4 under the action of the compound 3 and a dimethylamine metal reagent;
and C: salifying the compound 4 and maleic acid to prepare Betrixaban maleate;
the reaction equation is as follows:
Figure BDA0001346183930000082
in the application, the catalyst in the step A is an alkali reagent, preferably triethylene diamine, 1, 8-diazabicycloundec-7-ene and 1, 5-diazabicyclonon-5-ene; in the application, the dimethylamine metal reagent in the step B is preferably dimethylamine sodium solution.
In the step A, the reaction solvent is dichloromethane, and after the reaction is finished, the solid product can be separated out by directly cooling to obtain the ring-opening intermediate.
The "alkyl group" in the present invention means a group formed by a straight-chain or branched saturated aliphatic hydrocarbon having one hydrogen atom removed; alkyl groups of 1 to 4 carbon atoms are preferred, including but not limited to methyl, ethyl, t-butyl, and the like.
In the present invention, alkoxy means a group formed by a straight-chain or branched saturated aliphatic alcohol having one hydrogen atom of a hydroxyl group removed; preferably 1-4, including but not limited to methoxy, ethoxy, propoxy, and the like
In the present invention, halogen means F, Cl, Br or I, preferably F, Cl or Br.
The "alkenyl group" in the present invention means a group formed by losing one hydrogen atom from a straight-chain or branched unsaturated aliphatic hydrocarbon having a carbon-carbon double bond; alkenyl of 2 to 4 carbon atoms is preferred, including but not limited to vinyl, allyl, and the like.
The "substituted phenyl group" in the present invention refers to a phenyl group formed by substituting a hydrogen atom on a benzene ring with one or more groups, including but not limited to 4-nitrophenyl group, 2-chloro-4-nitrophenyl group, and the like.
Compared with the prior art, the invention has the beneficial effects that:
(1) the method is used for synthesizing the intermediate of the betrixaban, is convenient to synthesize, has cheap and easily obtained raw materials, and has high ring closing yield;
(2) when the intermediate is used for synthesizing a subsequent intermediate, the reaction condition is mild, strong alkali potassium tert-butoxide and the like are not needed, the yield and the purity are high, and the cost of the whole route is effectively reduced.
(3) When the intermediate is used for synthesizing the betrixaban, compared with the prior art, the intermediate obviously reduces the synthesis steps, shortens the synthesis route and reduces the cost for synthesizing the betrixaban.
Detailed Description
The following specific examples are presented to enable those skilled in the art to make a complete understanding of the invention and are not intended to limit the invention in any way.
In the following examples, all temperatures are in degrees celsius unless otherwise indicated; the room temperature is 20-30 ℃ unless otherwise indicated; unless otherwise indicated, various starting materials and reagents were obtained commercially and were used without further purification; unless otherwise indicated, each solvent is a technical grade solvent and is used without further treatment; unless otherwise indicated, commercial manufacturers include, but are not limited to, Hangzhou chemical reagents, national drug reagents, and the like.
Example 1: preparation of 2- (4-cyanophenyl) -6-methoxybenzo [ d ] -1, 3-oxazin-4-one (I)
Figure BDA0001346183930000101
To a 150mL reaction flask were added 5.0g of 5-methoxy-2-aminobenzoic acid (29.9mmol) and 25mL of dichloromethane, and after stirring to dissolve the clear, 5.0mL of Triethylamine (TEA) (36.1mmol) was added. The mixed solution is cooled to 0-10 ℃, and 5.9g of 4-cyanobenzoyl chloride is dripped into the mixed solution(35.6mmol) in toluene (25mL), and the reaction mixture was warmed to room temperature and stirred for 8 hours. After TLC detection of 5-methoxy-2-aminobenzoic acid reaction, 35mL of purified water was added to wash the reaction solution. The organic layer was separated, heated to toluene reflux temperature and stirred for 2 hours. After TLC detection reaction is completed, the reaction liquid is slowly cooled to 0-10 ℃, and precipitated solid is filtered, washed and dried to obtain 7.36g of the compound I, wherein the yield is 88.6%, and the purity is 99.8%.1H-NMR(500MHz,CDCl3):δ8.12(d,2H,J=7.8Hz),7.83(d,2H,J=7.8Hz),7.74(s,1H),7.40(d,1H,J=8.1Hz),7.31(d,1H,J=8.1Hz),3.86(s,3H)。13C-NMR(125MHz,CDCl3):δ159.1,157.8,149.6,146.6,136.5,133.6,129.5,128.5,126.6,125.3,118.4,114.8,114.7,114.5,110.1,55.6。ESI-MS:m/z279.32[M+H]+
Example 2: preparation of 2- (4-cyanophenyl) -6-methoxybenzo [ d ] -1, 3-oxazin-4-one (I)
Figure BDA0001346183930000102
A100 mL reaction flask was charged with 2.0g of 5-methoxy-2-aminobenzoic acid (12.0mmol), 10mL of dichloromethane, and 1mL of methyl morpholine (NMM), stirred to dissolve, cooled to 0-10 deg.C, and to the mixture was added 1.76g of 4-cyanobenzoic acid (12.0mmol) and 1.8g of isobutyl chloroformate. The reaction solution was warmed to room temperature and stirred for 5 hours. Detecting 5-methoxy-2-aminobenzoic acid by TLC, concentrating the reaction solution at 35-45 deg.C under reduced pressure to dry, adding 10mL carbon tetrachloride (CCl) into the slurry4) And 3.46g of triphenylphosphine (13.2mmol), reacting at 30-35 ℃ for 5 hours, after TLC detection reaction, adding 50mL of n-hexane into the reaction solution, precipitating suspended matters, stirring for 30 minutes, filtering, and drying the solid to obtain 2.84g of a compound I, wherein the yield is 85.2%, and the purity is 99.6%.
Example 3: preparation of 2- (4-cyanophenyl) -6-methoxybenzo [ d ] -1, 3-oxazin-4-one (I)
Figure BDA0001346183930000111
To a 100mL reaction flask were added 2.0g of 5-methoxy-2-aminobenzoic acid (12.0mmol), 10mL of dichloromethane, and 5.1g of 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDC) (26.4mmol), the mixture was cooled to 0-10 ℃ after stirring to dissolve the supernatant, and to the mixture was added 1.76g of 4-cyanobenzoic acid (12.0mmol) and 1.9g of 1-hydroxybenzotriazole (14.4mmol) (HOBT). The reaction mixture was warmed to room temperature and stirred for 12 hours. After TLC detection of 5-methoxy-2-aminobenzoic acid reaction, 50mL of n-hexane was added to the reaction solution, suspended matter was precipitated and stirred for 30 minutes, and then filtration was carried out, and the solid was dried to obtain 2.83g of compound I, with a yield of 84.8% and a purity of 99.3%.
Example 4: preparation of 2- (4-cyanophenyl) -6-methoxybenzo [ d ] -1, 3-oxazin-4-one (I)
Figure BDA0001346183930000112
2.0g of 5-methoxy-2-aminobenzoic acid (12.0mmol), 10mL of DMF and 1mL of pyridine were put in a 100mL reaction flask, and after stirring to dissolve, 1.73g of 4-cyanobenzeneisocyanate (12.0mmol) was added to the mixture. The reaction solution was heated to 80 ℃ and stirred for 5 hours. After TLC detection of 5-methoxy-2-aminobenzoic acid reaction, the reaction liquid was cooled to room temperature, 50mL of purified water was added dropwise to the reaction mixture, suspended matter was precipitated and stirred for 30 minutes, filtration was carried out, and the solid was dried to obtain 2.77g of compound I, with a yield of 83% and a purity of 99.5%.
Example 5: preparation of 2- (4-cyanophenyl) -6-methoxybenzo [ d ] -1, 3-oxazin-4-one (I)
Figure BDA0001346183930000113
2.0g of 5-methoxy-2-aminobenzoic acid (12.0mmol), 10mL of DMF and 1mL of pyridine were put in a 100mL reaction flask, stirred to dissolve, cooled to 0-10 ℃ and 2.61g of 4-cyanophenyl chloroformate (14.4mmol) was added to the mixture. The reaction mixture was warmed to room temperature and stirred for 8 hours. After TLC detection of 5-methoxy-2-aminobenzoic acid reaction, 50mL of purified water was added dropwise to the reaction mixture, suspended matter was precipitated and stirred for 30 minutes, and then filtration was carried out, and the solid was dried to obtain 2.72g of compound I, with a yield of 81.5% and a purity of 99.4%.
Example 6: preparation of 2- (4-cyanophenyl) -6-methoxybenzo [ d ] -1, 3-oxazin-4-one (I)
Figure BDA0001346183930000121
To a 150mL reaction flask were added 5.0g of 5-methoxy-2-aminobenzoic acid (29.9mmol) and 30mL of pyridine, stirred to dissolve and clear, cooled to 0-10 deg.C, and 5.9g of 4-cyanobenzoyl chloride (35.6mmol) was added to the mixture. The reaction solution was warmed to room temperature and stirred for 24 hours. After TLC detection of 5-methoxy-2-aminobenzoic acid reaction, pyridine was concentrated to dryness under reduced pressure at 60 deg.C, and the obtained slurry was separated and purified by silica gel column chromatography to obtain 6.47g of compound I, with a yield of 77.9% and a purity of 99.3%.
Example 7: preparation of 2- (4-cyanophenyl) -6-methoxybenzo [ d ] -1, 3-oxazin-4-one (I)
Figure BDA0001346183930000122
A100 mL reaction flask was charged with 2.0g of 5-methoxy-2-aminobenzoic acid (12.0mmol), 10mL of DCM and 1mL of Diisopropylethylamine (DIPEA), stirred to dissolve and clear, cooled to 0-10 ℃ and 2.61g of 4-cyanophenyl chloroformate (14.4mmol) was added to the mixture. The reaction solution is heated to 40-45 ℃ and stirred and refluxed for 6 hours. After TLC detection of 5-methoxy-2-aminobenzoic acid reaction, the reaction liquid is cooled to 0-10 ℃, 50mL of n-hexane is dripped into the reaction mixed liquid, suspended matters are separated out and stirred for 30 minutes, filtration is carried out, and the solid is dried to obtain 2.75g of the compound I, wherein the yield is 82.4% and the purity is 99.6%.
Example 8: preparation of N- (5-chloro-2-pyridyl) -2- [ (4-cyanobenzoyl) amino ] -5-methoxybenzamide (3)
Figure BDA0001346183930000131
A150 mL reaction flask was charged with 5g of Compound I (18.0mmol) and 2.76g of 5-chloro-2-aminopyridine, and 30mL of dichloromethane was added and the solution was stirred. The mixture was cooled to 0-10 ℃ and 2.0g of triethylenediamine (18mmol) was added to the cooled solution. Heating the reaction solution to 35-40 ℃, refluxing and stirring for 4 hours, detecting by TLC that the compound I is reacted, cooling the reaction solution to 0-10 ℃, separating out solids, performing suction filtration and drying to obtain 6.42g of the compound 3, wherein the yield is 87.7 percent, and the purity is 99.7 percent.1H-NMR(500MHz,DMSO-d6):δ11.1(s,1H),10.9(s,1H),8.42(d,1H,J=2.0Hz),8.11(d,1H,J=9.0Hz),8.04~8.01(m,4H),7.95(d,2H,J=8.5Hz),7.42(d,1H,J=2.5Hz),7.18~7.15(m,1H),3.84(s,3H)。
Example 9: preparation of N- (5-chloro-2-pyridyl) -2- [ (4-cyanobenzoyl) amino ] -5-methoxybenzamide (3)
Figure BDA0001346183930000132
A150 mL reaction flask was charged with 5g of Compound I (18.0mmol) and 2.76g of 5-chloro-2-aminopyridine, and 30mL of dichloromethane was added and the solution was stirred. The mixture was cooled to 0-10 ℃ and 2.74g1, 8-diazabicycloundecen-7-ene (18mmol) were added to the cooled solution. Heating the reaction solution to 35-40 ℃, refluxing and stirring for 5 hours, detecting by TLC that the compound I is reacted, cooling the reaction solution to 0-10 ℃, separating out solids, performing suction filtration and drying to obtain 6.44g of compound 3, wherein the yield is 88%, and the purity is 99.5%.
Example 10: preparation of N- (5-chloro-2-pyridinyl) -2- [ [4- [ methoxyamidino ] benzoyl ] amino ] -5-methoxybenzamide (4)
Figure BDA0001346183930000141
30mL of 2mol/L dimethylamine tetrahydrofuran solution (60mmol) is cooled to 0-10 ℃, 1.2g (50mmol) of sodium hydride is added in batches under stirring, and the temperature is controlled at 0-10 ℃ to obtain the dimethylamine sodium tetrahydrofuran solution for later use.
In a 150mL reaction flask4.0g of Compound 3(9.8mmol) and 20mL of tetrahydrofuran were added, stirred and dissolved, the temperature was controlled at 0-10 ℃ and the above dimethylamine sodium tetrahydrofuran solution was added dropwise. After the dropwise addition, the temperature is raised to room temperature and the reaction is stirred. After TLC monitoring reaction, 2mol/L dilute hydrochloric acid solution is added into the reaction solution dropwise, pH value is adjusted to 2-3, tetrahydrofuran is removed by decompression and concentration at 45 ℃, and the obtained suspended substance is filtered. Transferring the wet cake to a 150mL reaction bottle, adding 30mL acetone, uniformly stirring, adding triethylamine to adjust the pH value to 7-8, filtering, and drying to obtain 3.61g of betrixaban free base, wherein the yield is 81.7%, and the purity is 99.8%.1H-NMR(500MHz,DMSO-d6):δ11.1(s,1H),11.0(s,1H),9.38(s,1H),9.17(s,1H),8.41(d,1H,J=2.5Hz),8.10~8.07(m,3H),7.98(d,1H,J=9.0Hz),7.96~7.94(m,1H),7.72(d,2H,J=8.5Hz),7.42(d,1H,J=2.5Hz),7.19~7.16(m,1H),3.86(s,3H),3.22(s,3H),2.98(s,3H)。
Example 11: preparation of N- (5-chloro-2-pyridinyl) -2- [ [4- [ methoxyamidino ] benzoyl ] amino ] -5-methoxybenzamide (4)
Figure BDA0001346183930000142
Cooling 15mL of 2mol/L dimethylamine tetrahydrofuran solution to 0-10 ℃, slowly dripping 12.5mL of 2mol/L bis (trimethylsilyl) amino sodium (NaHMDS) while stirring, and controlling the temperature at 0-10 ℃ to obtain the dimethylamine sodium tetrahydrofuran solution for later use.
A150 mL reaction flask was charged with 2.0g of Compound 3(4.9mmol) and 10mL of tetrahydrofuran, stirred to dissolve, the temperature was controlled at 0-10 deg.C, and the above dimethylamine sodium tetrahydrofuran solution was added dropwise. After the dropwise addition, the temperature is raised to room temperature and the reaction is stirred. After TLC monitoring reaction, 2mol/L dilute hydrochloric acid solution is added into the reaction solution dropwise, pH value is adjusted to 2-3, tetrahydrofuran is removed by decompression and concentration at 45 ℃, and the obtained suspended substance is filtered. Transferring the wet cake to a 100mL reaction bottle, adding 15mL acetone, uniformly stirring, adding triethylamine to adjust the pH value to 7-8, filtering, and drying to obtain 1.56g of betrixaban free base, wherein the yield is 70.6%, and the purity is 99.6%.
Example 12: preparation of N- (5-chloro-2-pyridinyl) -2- [ [4- [ methoxyamidino ] benzoyl ] amino ] -5-methoxybenzamide maleate (Betrixaban)
Figure BDA0001346183930000151
A100 mL reaction flask was charged with 3.0g (6.64mmol) of free base, 40mL of 80% aqueous ethanol (volume fraction), stirred at room temperature for 15 minutes, and 1.6g (13.8mmol) of maleic acid in 80% aqueous ethanol (10mL) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2.5 hours, 50mL of purified water was added to the reaction mixture, and the reaction mixture was concentrated under reduced pressure at 45 ℃ to about 50mL to precipitate a pale yellow solid. The suspension was cooled from a temperature of 45 ℃ to 10 ℃ at a cooling rate of 1 ℃/5 min. After cooling to the end point temperature, stirring for 15 minutes at 15 ℃, filtering, and drying to obtain 3.54g of light yellow solid compound, namely the betrixaban maleate, with the yield of 78.6% and the purity of 99.9%.1H-NMR(500MHz,DMSO-d6):δ11.1(s,1H),11.0(s,1H),9.35(s,1H),8.98(s,1H),8.42(d,1H,J=2.5Hz),8.10~8.06(m,3H),7.99(d,1H,J=9.0Hz),7.96~7.93(m,1H),7.73(d,2H,J=8.5Hz),7.42(d,1H,J=3.0Hz),7.19~7.17(m,1H),3.85(s,3H),3.21(s,3H),2.98(s,3H)。13C-NMR(125MHz,DMSO-d6):δ167.7,167.6,164.6,164.3,156.1,151.0,146.9,138.3,138.1,136.6,132.7,130.9,129.1,128.3,127.1,126.4,125.3,118.7,116.7,114.4,56.1,42.3。
While the method of the present invention has been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the relevant art that the techniques of the present invention may be practiced and applied with little or no adaptation, modification, or combination of the methods and applications described herein as appropriate within the spirit and scope of the present invention. The skilled person can also use the present disclosure to realize the above by appropriately modifying the process parameters. It is expressly intended that all such modifications and adaptations which are apparent to those skilled in the art are intended to be included within the present invention.

Claims (3)

1. The preparation method of the betrixaban maleate is characterized by comprising the following steps:
step A: reacting the compound shown in the formula I with 5-chloro-2-aminopyridine under the action of a catalyst, and carrying out ring opening to obtain a compound 3;
and B: preparing a compound 4 under the action of the compound 3 and a dimethylamine metal reagent;
and C: salifying the compound 4 and maleic acid to prepare Betrixaban maleate;
the reaction equation is as follows:
Figure 348426DEST_PATH_IMAGE001
wherein,
the catalyst in the step A is selected from triethylene diamine and 1, 8-diazabicycloundecen-7-ene;
in step B, the dimethylamine metal reagent is dimethylamine sodium solution.
2. The process for the preparation of betrixaban maleate, as claimed in claim 1, further comprising the preparation of a compound of formula i:
carrying out amidation reaction on 5-methoxy-2-aminobenzoic acid or ester thereof and 4-cyanobenzoic acid or acyl halide thereof under the action of an acid-binding agent to obtain a compound shown as a formula II, carrying out cyclization on the compound shown as the formula II under a heating condition without separation and purification, and cooling and crystallizing to obtain a compound shown as a formula I;
Figure 862584DEST_PATH_IMAGE002
wherein,
R1independently of each other is H atom, C1-C4Alkyl radical, C2-C4Alkenyl, substituted phenyl or unsubstituted phenyl, the substituents on the phenyl being selected from nitro, alkyl, alkoxy or halogen; r3independently-OH, a chlorine atom or a bromine atom;
the acid-binding agent is an organic base reagent selected from pyridine, triethylamine, diisopropylethylamine and N-methylmorpholine;
the heating reaction temperature is selected from 80-120 ℃; the reaction time is selected from 1-8 hours;
the cooling crystallization is carried out, wherein the cooling end point temperature is selected from 0-30 ℃.
3. The process for the preparation of betrixaban maleate, as claimed in claim 1, further comprising the preparation of a compound of formula i:
carrying out amidation reaction on 5-methoxy-2-aminobenzoic acid or ester thereof and 4-cyanobenzoic acid or acyl halide thereof under the action of chloroformate and acid-binding agent to obtain a compound shown as a formula II, and carrying out dehydration cyclization on the compound shown as the formula II in the presence of a condensing agent without separation and purification to obtain a compound shown as a formula I;
Figure 257794DEST_PATH_IMAGE003
wherein R is1Independently of each other is H atom, C1-C4Alkyl radical, C2-C4Alkenyl, substituted or unsubstituted phenyl, the substituents on the phenyl being selected from nitro, alkyl, alkoxy or halogen; r3independently-OH, a chlorine atom or a bromine atom; r4Independently is C1-C4Alkyl of (C)2-C4Alkenyl, substituted or unsubstituted phenyl, the substituents on the phenyl being selected from nitro, alkyl, alkoxy or halogen;
the acid-binding agent is an organic base reagent selected from pyridine, triethylamine, diisopropylethylamine and N-methylmorpholine;
the condensing agent is selected from a triphenylphosphine/carbon tetrachloride composition, a carbodiimide reagent or a carbodiimide reagent/1-hydroxybenzotriazole composition;
the carbodiimide reagent is selected from 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride or dicyclohexylcarbodiimide.
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