CN103864771A - Rivaroxaban preparation method - Google Patents

Abstract

The present invention discloses a new rivaroxaban preparation method, which comprises: adopting 4-(4-aminophenyl)-morpholin-3-one represented by a formula (1) as a raw material, carrying out an acylation reaction to obtain morpholone phenyl formate represented by a formula (3), and carrying out a reaction of 5-chlorothiophene-2-carboxylic acid ((S)-3-halo-2-hydroxy propyl)amide represented by a formula (8) and the morpholone phenyl formate represented by the formula (3) under alkali catalysis to prepare the rivaroxaban represented by a formula (9). The rivaroxaban preparation method has advantages of mild reaction conditions, easy operation, avoidance of use of toxic and hazardous reagents during the synthesis process, environmental pollution reduction and the like, and is suitable for industrial production.

Description

A kind of preparation method of razaxaban

Technical field

The invention belongs to technical field of medicine synthesis, be specifically related to the preparation method of a kind of anticoagulation medicine razaxaban and intermediate thereof.

Background technology

The formation of thrombus is the important paathogenic factor of the cardiovascular disordeies such as myocardial infarction, apoplexy, degree of depth phlebothrombosis, pulmonary infarction, and antithrombotic therapy is the core of this class disease emergency measures and preventative strategies can always.Antithrombotic therapy is mainly for thrombocyte and two links of zymoplasm, and antithrombotic reagent is mainly divided into antiplatelet drug and anticoagulation two classes.General surgical intervention patient, if not prevention, the incidence of deep venous thrombosis is up to 10%～40%, therefore searching is safely, antithrombotic reagent has great importance on clinical treatment efficiently.

Razaxaban (Rivaroxaban), chemistry is by name: and the chloro-N-of 5-((5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl }-methyl)-2-thenoyl amine, be the whole world first can be directly oral Xa factor inhibitor, be used for preventing and treating venothrombotic medicine, be particularly useful for treating myocardial infarction stenocardia etc.

Razaxaban obtains listing approval in Canada and European Union respectively on September 15th, 2008 and October 1, and commodity are called Xarelto.Razaxaban is got permission listing in 29 countries including China at present.Novel anti-coagulant razaxaban, razaxaban may become the most great-hearted anti-coagulant in future.

The synthetic method of bibliographical information razaxaban has following several at present:

Patent WO2005/068456 has openly reported take the chloro-thiophene-5-of 2-formic acid as raw material and phosphorus oxychloride generation acylation reaction makes the chloro-thiophene-5-of 2-formyl chloride; obtain with compound generation condensation reaction; make with hydrogen bromide generation substitution reaction; be substituted with 4-(4-aminophenyl)-3-morpholone mai; ring-closure reaction generates razaxaban, as follows.

This route need to use acetic anhydride and hydrogen bromide, and pungency and corrodibility are all very serious, and need to use toxic reagent toluene as solvent.

In the patent CN1262551 that Bayer A.G obtains the authorization in China, announce route as follows:

In this route, need to can synthesize the compound of cyclization through two-step reaction by 4-(4-aminophenyl)-3-morpholone mai, but due to the bad extraction and application of reaction product, cause yield low, and in building-up process, need to use expensive carbonyl dimidazoles and Dimethylamino pyridine, cause production cost high.

WO 2009/023233 discloses morpholine and p-fluoronitrobenzene condensation obtains 4-morpholine oil of mirbane, uses KMnO₄oxidation makes 4-morpholine ketone group oil of mirbane, shortening makes 4-(4-aminophenyl)-3-morpholone mai, then with (S)-epichlorohydrin reaction, with CDI (N, N '-carbonyl dimidazoles) cyclization, after Geberiel reacts, make chiral amino compound with methylamine ammonia solution in ethanolic soln with potassium phthalimide, under pyridine catalysis, make razaxaban with the chloro-thiophene-5-of 2-formyl chloride, reaction scheme is as follows.

Substrate 4-in this route (4-aminophenyl)-3-morpholone mai under reflux conditions reacts production d compound with 2-(chloromethyl) oxyethane under m-phthalic acid effect, in this step reaction, reagent m-phthalic acid easily and substrate 4-(4-aminophenyl)-easy salify of 3-morpholone mai, make the reaction of substrate 4-(4-aminophenyl)-3-morpholone mai not exclusively, need reflux to 150 ℃ by formula e compound production f compound take dimethyl formamide as solvent, temperature of reaction is high.Also need to use carbonyl dimidazoles by formula d compounds accepted way of doing sth e compound, therefore this route also can run into many problems in the time of industrialization.

Though above-mentioned all technical schemes are respectively had its own advantage, exist reaction scheme longer, environmental pollution is serious, and cost is higher, and yield is low, is unfavorable for the defect of suitability for industrialized production.In view of the good medicine prospect of razaxaban, therefore need to develop a kind of raw material cheap and easy to get, reaction safety is high, and cost is low, is easy to industrialized operational path.

Summary of the invention

The object of the invention is to overcome in above-mentioned prior art starting raw material expensive, agents useful for same is poisoned large, serious to equipment corrosion, separation and purification difficulty, be difficult for the shortcomings such as industrialization, provide that a kind of reactions steps is brief, reaction conditions is gentle, the synthetic method of easy and simple to handle, environment amenable razaxaban.

Reaction equation is as follows:

To achieve these goals, the technical solution used in the present invention is: provide one to have the compound of following formula (3) structure.

Formula (3)

Wherein R is C_1-8alkyl;

Wherein said R is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, isopentyl, hexyl, isohexyl, heptyl, different heptyl, octyl group or iso-octyl.

The purposes of described compound, is characterized in that, described formula (3) compound prepares razaxaban with following formula (8) compound effects under alkali exists;

Formula (3)

Wherein R is alkyl

Formula (8)

Wherein X is halogen;

Described halogen is preferably chlorine or bromine.

Described alkali is preferably organo-metallic alkali or alkaline earth metal alkali, and described organo-metallic alkali is specifically as follows sodium methylate, trimethyl carbinol lithium, sodium tert-butoxide, potassium tert.-butoxide, sodium ethylate or aluminum isopropylate; Described alkaline earth metal alkali is specifically as follows tert-butyl alcohol magnesium, hydrolith.

Described formula (3) compound with the mole dosage of described alkali than 1: (1.0～5.0), are preferably 1: (2.0～4.0).

The mole dosage ratio of described formula (3) compound and described formula (8) compound is 1: (1.0～2.0).

Described reaction solvent for use is preferably ethers or halo alkanes, and described ethers is preferably tetrahydrofuran (THF), methyltetrahydrofuran.

Described halo alkanes is preferably methylene dichloride, chloroform, 1,2-ethylene dichloride or 1,1-ethylene dichloride.

The temperature of reaction of described reaction is 20～80 ℃, and the reaction times is 5～24 hours.

Described formula (3) compound can prepare formula (3) compound with following formula (2) compound effects by following formula (1) compound under alkali exists;

Formula (1)

Formula (2)

Wherein the definition of R is identical with above-mentioned definition.

Described alkali is preferably mineral alkali or organic bases, and described mineral alkali is specifically as follows lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, salt of wormwood, cesium carbonate, sodium bicarbonate or saleratus; Described organic bases is specifically as follows diethylamine, triethylamine, tri-n-butylamine, diisopropyl ethyl amine, pyridine, 2,6-lutidine or piperidines.

Described formula (1) compound is 1 with the mole dosage ratio of described alkali: (2.0～5.0), are preferably 1: (1.0～1.5).

The mole dosage ratio of described formula (1) compound and described formula (2) compound is 1: (1.0～1.7).

Described reaction solvent for use is preferably ketone, ethers or its any mixture, and wherein ketone is preferably acetone; Described ethers is preferably tetrahydrofuran (THF), methyltetrahydrofuran, dioxane.

The temperature of reaction of described reaction is 0～50 ℃, and the reaction times is 1～10 hour.

Described formula (8) compound, can obtain Acibenzolar by following formula (2) compound and the effect of formula (7) compound 5-chlorothiophene-2-formic acid, then react and prepare with formula (6) compound:

Formula (6)

Wherein X definition is identical with above-mentioned definition.

Described alkali is preferably organic bases, and described organic bases is specifically as follows triethylamine, tri-n-butylamine, diisopropyl ethyl amine.

Described formula (7) compound is preferably 1 with the mole dosage ratio of described alkali: (2.0～3.0).

The mole dosage ratio of described formula (7) compound and described formula (2) compound is preferably 1: (1.0～1.5).

The mole dosage ratio of described formula (7) compound and described formula (6) compound is preferably 1: (1.0～1.5).

Described reaction solvent for use is organic solvent, and described organic solvent is preferably aprotic polar solvent class, and described aprotic polar solvent class is preferably tetrahydrofuran (THF), dioxane, DMF, acetone; The volume ratio of described water and organic solvent is 1: (1.0～2.0).

The temperature of reaction of described reaction is 0～40 ℃, is preferably 5～20 ℃; Reaction times is 1～10 hour.

The method that the preparation method of wherein said formula (6) compound announces in can referenced patent CN101619061 embodiment is as follows:

The novel process of the synthetic razaxaban that the present invention provides, beneficial effect is: the operated process of the present invention, without severe condition such as low temperature and anhydrous, anaerobics, effectively raises reaction yield.In addition, in the present invention, in each step reaction, the reagent that uses is small molecules alkali, is easy to purifying.Therefore, the preparation method of razaxaban of the present invention has the advantages such as reaction conditions gentleness, easy and simple to handle, environmentally friendly, production cost is low, is suitable for suitability for industrialized production.

Embodiment

Set forth more specifically the present invention by following embodiment.But described embodiment not meaning that limits the scope of the invention.

Synthesizing of embodiment 1N-ethoxycarbonyl-4-morpholine ketone group aniline [formula (3)]

In reaction flask, add 4-(4-aminophenyl)-3-morpholone mai (150g, 0.78mol), then add acetone (600ml) and water (300ml), stir the lower sodium bicarbonate (128.4g, 1.53mol) that adds.Drip dissolved Vinyl chloroformate (118.3g, 1.09mol), stir and within 1 hour, react complete, add water (1500ml) to continue to stir 1 hour thereafter.Solid filtering, hexanaphthene washing leaching cake, is dried to obtain the fluoro-4-morpholine of N-ethoxycarbonyl-3-ketone group aniline 184.6g, yield 89.6%.

Synthesizing of embodiment 2N-ethoxycarbonyl-4-morpholine ketone group aniline [formula (3)]

In reaction flask, add 4-(4-aminophenyl)-3-morpholone mai (90g, 0.47mol), then add dioxane (420ml) and triethylamine (65.8g,, 0.65mol), stirring and dissolving.Drip dissolved Vinyl chloroformate (71.0g, 0.65mol), stir and within 1 hour, react complete, add water (900ml) to continue to stir 1 hour thereafter.Solid filtering, hexanaphthene washing leaching cake, is dried to obtain the fluoro-4-morpholine of N-ethoxycarbonyl-3-ketone group aniline 157.9g, yield 76.6%.

Synthesizing of the pungent oxygen carbonyl-4-of embodiment 3N-morpholine ketone group aniline [formula (3)]

In reaction flask, add 4-(4-aminophenyl)-3-morpholone mai (180g, 0.94mol), then add acetone (720ml) and water (360ml), stir the lower sodium bicarbonate (154.1g, 1.84mol) that adds.Drip dissolved chloroformic acid monooctyl ester (252.0g, 1.31mol), stir and within 1 hour, react complete, add water (1800ml) to continue to stir 1 hour thereafter.Solid filtering, hexanaphthene washing leaching cake, is dried to obtain the fluoro-4-morpholine of the pungent oxygen carbonyl-3-of N-ketone group aniline 245.9g, yield 71.3%.

The chloro-3-[(phenyl of embodiment 4 (S)-1-methyne)-amino]-propyl-2-alcohol [formula (5)] synthetic

In reaction flask, add phenyl aldehyde (139.0g, 1.31mol), ethanol (350ml), 25% ammoniacal liquor (136.0g, 2.01mol), more slowly splash into (S)-epoxy chloropropane (118.0g, 1.28mol), stirring at room temperature 20 hours, concentrated, dry, obtain white solid 212.7g, yield 82.1%.

Synthesizing of the chloro-2-propylate of embodiment 5 (S)-1-amino-3-hydrochlorate [formula (6)]

In reaction flask, add the chloro-3-[(phenyl of (S)-1-methyne)-amino]-propyl-2-alcohol (205.0g, 1.04mol), hydrochloric acid (153.3g, 1.56mol) and purified water (400ml), stir, react 3 hours.Reaction solution is chilled to room temperature, ethyl acetate (100ml) extraction 2 times, removes solvent under reduced pressure, adds Virahol (500ml), there are a large amount of white solids to separate out, be cooled to room temperature, spend the night in 0～5 ℃ of placement, by reaction product suction filtration, the a small amount of washed with isopropyl alcohol of filter cake, dry, obtain off-white color solid 109.5g, yield 72.1%.

Synthesizing of embodiment 65-chlorothiophene-2-carboxylic acid ((S)-3-halogen-2-hydroxypropyl) acid amides [formula (8)]

In reaction flask, add 5-chlorothiophene-2-formic acid (100.0g, 0.62mol), then add N, dinethylformamide (300ml) and tri-n-butylamine (137.2g, 0.74),, after stirring and dissolving, slowly drip wherein Vinyl chloroformate (80.3g, 0.74mol), finish, slowly drip wherein the N of (S)-1-amino-3-chloro-2-propylate hydrochlorate (108.0g, 0.74mol), dinethylformamide (200ml) and tri-n-butylamine (137.2g, 0.74) solution, finishes, and reacts 2 hours.Reaction solution decompression is steamed to solvent, add ethyl acetate (500ml) to dissolve, organic phase saturated sodium bicarbonate solution, the each washing of purified water 3 times, anhydrous magnesium sulfate drying, steams solvent, ethyl acetate-sherwood oil recrystallization, obtains faint yellow solid 82.7g, and yield is 52.5%.

Synthesizing of embodiment 75-chlorothiophene-2-carboxylic acid ((S)-3-halogen-2-hydroxypropyl) acid amides [formula (8)]

In reaction flask, add 5-chlorothiophene-2-formic acid (120.0g, 0.74mol), then add N, dinethylformamide (360ml) and tri-n-butylamine (164.6g, 0.89mol), after stirring and dissolving, slowly drip wherein Vinyl chloroformate (309.4g, 0.89mol), finish, slowly drip wherein the N of (S)-1-amino-3-chloro-2-propylate hydrochlorate (129.6g, 0.89mol), dinethylformamide (240ml) and tri-n-butylamine ((164.6g, 0.89mol) solution, finishes, and reacts 2 hours.Reaction solution decompression is steamed to solvent, add ethyl acetate (500ml) to dissolve, organic phase saturated sodium bicarbonate solution, the each washing of purified water 3 times, anhydrous magnesium sulfate drying, steams solvent, ethyl acetate-sherwood oil recrystallization, obtains faint yellow solid 77.1g, and yield is 48.9%.

Synthesizing of embodiment 8 razaxabans

In reaction flask, add the pungent oxygen carbonyl-4-of N-morpholine ketone group aniline (27.0g, 77.6mmol), N, dinethylformamide (51ml), under room temperature, drip trimethyl carbinol lithium (18.6g, tetrahydrofuran (THF) (236ml) solution 232.7mmol), then add 5-chlorothiophene-2-carboxylic acid ((S)-3-halogen-2-hydroxypropyl) acid amides (31.6g, 124.2mmol) add wherein, be warming up to backflow, stirring reaction 8 hours.Reaction is finished, and decompression steams solvent, adds methylene dichloride (300ml), with purified water (50ml) washing 3 times, anhydrous MgSO₄dry, concentrated rear column chromatography purification, obtains off-white color solid 10.8g, yield 31.9%, and 229.8～231.7 ℃ of fusing points, consistent with document through Structural Identification.

Synthesizing of embodiment 9 razaxabans

In reaction flask, add N-ethoxycarbonyl-4-morpholine ketone group aniline (10.3g, 38.8mmol), N, dinethylformamide (25ml), under room temperature, drip tetrahydrofuran (THF) (118ml) solution of tert-butyl alcohol magnesium (9.9g, 58.2mmol), then add 5-chlorothiophene-2-carboxylic acid ((S)-3-halogen-2-hydroxypropyl) acid amides (15.8g, 62.1mmol) add wherein, be warming up to backflow, stirring reaction 10 hours.Reaction is finished, and decompression steams solvent, adds methylene dichloride (150ml), with purified water (30ml) washing 3 times, anhydrous MgSO₄dry, concentrated rear column chromatography purification, obtains off-white color solid 3.1g, yield 18.3%, and 231.3～232.6 ℃ of fusing points, consistent with document through Structural Identification.

Synthesizing of embodiment 10 razaxabans

In reaction flask, add N-ethoxycarbonyl-4-morpholine ketone group aniline (24.6g, 93.1mmol), N, dinethylformamide (50.0ml), under room temperature, drip trimethyl carbinol lithium (22.3g, methylene dichloride (283.0ml) solution 279.2mmol), then add 5-chlorothiophene-2-carboxylic acid ((S)-3-halogen-2-hydroxypropyl) acid amides (37.9g, 149.0mmol) add wherein, be warming up to backflow, stirring reaction 10 hours.Reaction is finished, and decompression steams solvent, adds methylene dichloride (360ml), with purified water (50ml) washing 3 times, anhydrous MgSO₄dry, concentrated rear column chromatography purification, obtains off-white color solid 9.8g, yield 24.2%, and 231.3～233.7 ℃ of fusing points, consistent with document through Structural Identification.

Synthesizing of embodiment 11 razaxabans

In reaction flask, add N-ethoxycarbonyl-4-morpholine ketone group aniline (20.5g, 77.6mmol), N, dinethylformamide (51ml), under room temperature, drip trimethyl carbinol lithium (18.6g, tetrahydrofuran (THF) (236ml) solution 232.7mmol), then add 5-chlorothiophene-2-carboxylic acid ((S)-3-halogen-2-hydroxypropyl) acid amides (31.6g, 124.2mmol) add wherein, be warming up to backflow, stirring reaction 10 hours.Reaction is finished, and decompression steams solvent, adds methylene dichloride (300ml), with purified water (50ml) washing 3 times, anhydrous MgSO₄dry, concentrated rear column chromatography purification, obtains off-white color solid 9.2g, yield 27.2%, and 230.3～231.7 ℃ of fusing points, consistent with document through Structural Identification.

¹H?NMR(400MHz，DMSO)：δ8.95(t，J＝5.6Hz，1H)，7.68(d，J＝4.2Hz，1H)，7.56(t，J＝8.8Hz，2H)，7.40(t，J＝8.8Hz，2H)，7.12(t，J＝4.2Hz，1H)，4.84(m，1H)，4.19(t，J＝7.6Hz，3H)，3.96(t，J＝4.4Hz，2H)，3.85(m，1H)，3.71(t，J＝5.6Hz，2H)，3.61(t，J＝5.6Hz，2H)：MS：437.2(M+H⁺)。

Claims (8)

1. the preparation method of formula (9) compound razaxaban, the morpholine ketone group phenyl manthanoate of its use formula (3) reacts and prepares with formula (8) compound as intermediate under alkali exists:

Formula (9)

Formula (3)

Wherein R is alkyl;

Formula (8)

Wherein X is halogen.

2. the preparation method of formula (9) compound according to claim 1, is characterized in that, wherein said alkali is organo-metallic alkali or alkaline earth metal alkali.

3. the preparation method of formula (9) compound according to claim 1, is characterized in that, solvent for use is aprotic polar solvent, and aprotic polar solvent is ether solvents, chlorinated solvent or its mixed solvent.

4. formula (3) compound that the preparation method of (9) according to claim 1 compound relates to, wherein R is C1-8 alkyl.

5. formula according to claim 4 (3) compound, wherein said R is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, isopentyl, hexyl, isohexyl, heptyl, different heptyl, octyl group or iso-octyl.

6. formula claimed in claim 4 (3) compound, is characterized in that, is prepared under alkali exists by following formula (1) compound with following formula (2) compound effects:

Formula (1)

Formula (2)

Wherein R definition is identical with the definition of claim 1.

7. the preparation method of formula claimed in claim 6 (3) compound, it is characterized in that, alkali used is organic bases or mineral alkali, and organic bases is selected from diethylamine, triethylamine, tri-n-butylamine, diisopropyl ethyl amine, pyridine, 2,6-lutidine or piperidines; Mineral alkali is selected from sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide or calcium hydroxide.

8. formula (8) compound that the preparation method of (9) according to claim 1 compound relates to, is prepared by following formula (6) compound and the effect of 5-chlorothiophene-2-formic acid:

Formula (6)

Wherein X definition is identical with the definition of claim 1.