CN104031036A - Method for preparing rivaroxaban - Google Patents
Method for preparing rivaroxaban Download PDFInfo
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- CN104031036A CN104031036A CN201410205693.8A CN201410205693A CN104031036A CN 104031036 A CN104031036 A CN 104031036A CN 201410205693 A CN201410205693 A CN 201410205693A CN 104031036 A CN104031036 A CN 104031036A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention discloses a method for preparing rivaroxaban, and is characterized in that the method comprises the following steps of synthesis of an intermediate I, synthesis of an intermediate II and synthesis of rivaroxaban, wherein the synthesis of the intermediate I comprises the synthetic steps of taking 4-(4-aminophenyl)-3-morpholinone and 2-[(2S)-2-oxiranyl-methyl)-1H-isoindole-1,3(2H)-diketone as raw materials, and in an alcohol solvent, carrying out a reaction with a condensating agent to obtain the intermediate I; the synthesis of the intermediate II comprises the synthetic steps of placing the intermediate I in a solvent, under the action of an amine reagent, carrying out a reaction to generate a primary amine compound, and forming an ammonium salt with an acid reagent to obtain the intermediate II; and the synthesis of rivaroxaban comprises the synthetic steps of placing 5-chlorothiophene carboxylic acid in a solvent, under the action of an acylation reagent, forming an acylated substance, then carrying out a reaction with the intermediate II under the action of an alkali reagent, and thus obtaining rivaroxaban. The method has the beneficial effects of cheap and easily obtained raw materials, simple and easily controlled operation, high reaction yield, high product purity, and low cost.
Description
Technical field
The present invention relates to a kind of preparation method of razaxaban.
Background technology
Razaxaban (Rivaroxaban) is that commodity are called Xarelto by a kind of small molecules oral anticoagulation of the common research and development of Beyer Co., Ltd and Johson & Johnson.On September 15th, 2008 and 10 months l days obtain listing approval in Canada and European Union respectively.On July 1st, 2011, FDA ratified this medicine for preventing knee or hip to replace the formation of patient with operation dvt.Its chemical name is: the chloro-N-of 5-(((5S)-2-oxo-3-(4-(3-oxo morpholine-4-yl) phenyl)-1,3-oxazoles quinoline-5-yl) methyl) thiophene-2-carboxamide derivatives.Structure is suc as formula 1:
Formula 1
The formation of thrombus is the important paathogenic factor of the cardiovascular disordeies such as myocardial infarction, palsy, deep venous thrombosis, pulmonary infarction.Antithrombotic therapy is the core of this class disease emergency measures and preventative strategies can always, and wherein anticoagulation is one of important method of antithrombotic therapy.Therefore find safer, efficient anticoagulation medicine has great importance on clinical treatment.Factor Xa can promote thrombosis, and Xa factor inhibitor becomes one of focus of anticoagulation medicine research in recent years.Some anticoagulation medicine goes on the market, as fondaparinux sodium of Organon company and Sanofi-Synthelabo company joint development (fondaparinuxs odium, trade(brand)name: square Da Palu) etc.
Factor Xa is a kind of serine protease, is positioned at the upstream of blood coagulation cascade, is in the central position that connects endogenous and exogenous activated pathway co-channel, and it can block the generation that intrinsic coagulation also can suppress extrinsic soagulation.Xa factor is the speed limit composition that zymoplasm generates, owing to also there being the amplification of bio signal in blood coagulation cascade reaction process, estimate that an Xa factor inhibitor molecules has the physiologic effect that can suppress 138 zymoplasm molecules, Xa factor inhibitor may be more more effective than thrombin inhibitors.Razaxaban is a new synthetic small molecules, can suppress the FXa of activation, and its concentration does not affect the serine protease being associated before reaching 20 μ mol L-1, is 1000 times of other serine proteases to the selectivity of FXa.In addition, do not need its anticoagulation process that has been used for of blood plasma cofactor, not with other serine protease effects, thereby its anticoagulating active does not rely on antithrombin (AT).
Patent US7576111 reported first razaxaban compound and synthesis route thereof, as shown in Scheme1.This synthetic route reactions steps is longer, and intermediate need be through column chromatography separating purification, and the low deficiency that waits of route yield, is unfavorable for that heavy industrialization generates.
Scheme1
Therefore,, for addressing the above problem, spy provides a kind of new technical scheme to satisfy the demands.
Summary of the invention
The invention provides a kind of preparation method of razaxaban.
The technical solution used in the present invention is:
A preparation method for razaxaban, comprises the following steps successively: the synthetic and razaxaban of synthetic, the intermediate II of intermediate I synthetic,
The synthesis step of described intermediate I is: with 4-(4-aminophenyl)-3-morpholone mai and 2-[(2S)-2-Oxyranyle-methyl]-1H-isoindole-1,3(2H)-diketone is raw material, in alcoholic solvent, react with condensing agent, obtain intermediate I;
The synthesis step of described intermediate II is: intermediate I is placed in solvent under amine reagent effect, and reaction generates primary amine, and obtains intermediate II with sour reagent formation ammonium salt;
The synthesis step of described razaxaban is: 5-chlorothiophene formic acid is placed in solvent and forms acylate under acylating reagent effect, then reacts under alkali reagent effect with intermediate II, obtains razaxaban.
In intermediate I synthetic, alcoholic solvent is tetrahydrofuran (THF), ethanol, Virahol or propyl carbinol, condensing agent is CDI or DCC, temperature of reaction is 50-60 DEG C, 4-(4-aminophenyl)-3-morpholone mai, 2-[(2S)-2-Oxyranyle-methyl]-1H-isoindole-1,3(2H) the quality proportioning of-diketone and condensing agent is 1:1～1.5:1.2～1.6.
In intermediate II synthetic, amine reagent is methylamine or dimethylamine, and sour reagent is methylsulfonic acid or Hydrogen bromide, and solvent is tetrahydrofuran (THF), acetonitrile or ethanol, and the quality proportioning of intermediate I and amine reagent is 1.1～3:1.
In razaxaban synthetic, acylating reagent is sulfur oxychloride, phosphorus oxychloride or oxalyl chloride, and alkali reagent is triethylamine, and solvent is tetrahydrofuran (THF), acetonitrile or ethanol, and the quality proportioning of intermediate II and acylate is 1:1.5～2.5.
The invention has the beneficial effects as follows: this processing method raw material is cheaply easy to get, easy control simple to operate, reaction yield is high, and product purity is high, and cost is low, is suitable for large-scale industrial production.
Embodiment
In order to deepen the understanding of the present invention, below in conjunction with embodiment, the invention will be further described, and this embodiment only, for explaining the present invention, does not form limiting the scope of the present invention.
Embodiment 1
Synthesizing of intermediate I: by 19g 4-(4-aminophenyl)-3-morpholone mai and 20g 2-[(2S)-2-Oxyranyle-methyl]-1H-isoindole-1,3(2H)-diketone is placed in 180ml Virahol and 100ml water, stir, be heated to 50 DEG C, 19.4g CDI is dissolved in 50mL tetrahydrofuran (THF), slowly drop in above-mentioned reaction solution, be then warming up to back flow reaction, TLC monitors reaction; React complete, room temperature when cooling, removes tetrahydrofuran (THF) and Virahol under reduced pressure, then be heated to 60 degrees Celsius, slowly drip 100mL ethanol, stir, be cooled to 20 DEG C, suction filtration, dries, obtain 41g solid crude product, this solid crude product is placed in to 240mL Virahol, add thermosol clear, be cooled to 15 DEG C of crystallizatioies, suction filtration, dries, obtain 35.4g white solid product, yield: 85%;
Synthesizing of intermediate II: 35g intermediate I is placed in to 280ml acetonitrile, stirs, be warming up to 50 DEG C, drip 20g 25% methylamine; Drip and finish, be warming up to back flow reaction, TLC monitors reaction; React complete, be naturally cooled to 35 DEG C; 16.3g methylsulfonic acid is dissolved in 60mL acetonitrile, drips in above-mentioned reaction; Drip and finish, stirring reaction 3 hours, is then cooled to 10 DEG C of crystallizatioies and spends the night, and suction filtration is dried, and obtains 27g white solid crude product, and this solid crude product, as for the making beating of 150ml methylene dichloride, is filtered, and dries, and obtains 22.9g white solid product, yield: 84%;
Synthesizing of razaxaban: 11 g 5-chlorothiophene formic acid are placed in to 50mL tetrahydrofuran (THF), stir, be cooled to 5 DEG C, drip at a slow speed 13.6g oxalyl chloride, drip and finish, be warming up to 25 DEG C of reactions, 20g intermediate II is dissolved in 60mL tetrahydrofuran (THF), carry out after 4 hours in above-mentioned reaction, drip in the above-mentioned reaction solution of this solution, and then dropping 12.3g triethylamine, drip and finish, reaction at 30 DEG C, TLC monitors reaction, react complete, remove most of solvent under reduced pressure, in residue, add 200mL water, stir, suction filtration, use a small amount of washing with alcohol, dry, obtain 27g white solid crude product, by this crude product as in 135g acetic acid, heating for dissolving, then be cooled to 5 DEG C of crystallizatioies, suction filtration, dry, the 21.8g purity white solid product that is 98.8%, yield: 82 %.
Embodiment 2
Synthesizing of intermediate I: by 23g 4-(4-aminophenyl)-3-morpholone mai and 29g 2-[(2S)-2-Oxyranyle-methyl]-1H-isoindole-1,3(2H)-diketone is placed in 240ml Virahol and 120ml water, stir, be heated to 50 DEG C, 24.7g DCC is dissolved in 80mL tetrahydrofuran (THF), slowly drop in above-mentioned reaction solution, be then warming up to back flow reaction, TLC monitors reaction; React complete, room temperature when cooling, removes tetrahydrofuran (THF) and Virahol under reduced pressure, then be heated to 60 degrees Celsius, slowly drip 150mL ethanol, stir, be cooled to 20 DEG C, suction filtration, dries, obtain 48g solid crude product, this solid crude product is placed in to 280mL Virahol, add thermosol clear, be cooled to 15 DEG C of crystallizatioies, suction filtration, dries, obtain 43.5g white solid product, yield: 87%;
Synthesizing of intermediate II: 40g intermediate I is placed in to 350ml tetrahydrofuran (THF), stirs, be warming up to 45 DEG C, drip 36g 25% methylamine, drip and finish, be warming up to back flow reaction, TLC monitors reaction, react complete, naturally be cooled to 35 DEG C, 15.4g Hydrogen bromide is dripped in above-mentioned reaction, drip and finish, stirring reaction 3 hours, then be cooled to 10 DEG C of crystallizatioies and spend the night, suction filtration, dries, obtain 31g white solid crude product, this solid crude product, as for the making beating of 200ml methylene dichloride, is filtered, dry, obtain 27.1g white solid product, yield: 87%;
Synthesizing of razaxaban: 14.9g 5-chlorothiophene formic acid is placed in to 80mL tetrahydrofuran (THF), stir, be cooled to 5 DEG C, drip at a slow speed 28.5g sulfur oxychloride, drip and finish, be warming up to 25 DEG C of reactions, 27g intermediate II is dissolved in 80mL tetrahydrofuran (THF), carry out after 4 hours in above-mentioned reaction, drip in the above-mentioned reaction solution of this solution, and then dropping 16.6g triethylamine, drip and finish, reaction at 30 DEG C, TLC monitors reaction, react complete, remove most of solvent under reduced pressure, in residue, add 300mL water, stir, suction filtration, use a small amount of washing with alcohol, dry, obtain 36g white solid crude product, by this crude product as in 180g acetic acid, heating for dissolving, then be cooled to 5 DEG C of crystallizatioies, suction filtration, dry, the 30.1g purity white solid product that is 99.0%, yield: 84 %.
Embodiment 3
Synthesizing of intermediate I: by 28g 4-(4-aminophenyl)-3-morpholone mai and 37g 2-[(2S)-2-Oxyranyle-methyl]-1H-isoindole-1, 3(2H)-diketone is placed in 300ml isopropyl ether and 150ml water, stir, be heated to 50 DEG C, 39.1g CDI is dissolved in 100mL tetrahydrofuran (THF), slowly drop in above-mentioned reaction solution, then be warming up to back flow reaction, TLC monitors reaction, react complete, room temperature when cooling, remove tetrahydrofuran (THF) and isopropyl ether under reduced pressure, then be heated to 60 degrees Celsius, slowly drip 200mL ethanol, stir, be cooled to 20 DEG C, suction filtration, dry, obtain 56g solid crude product, this solid crude product is placed in to 350mL Virahol, add thermosol clear, be cooled to 15 DEG C of crystallizatioies, suction filtration, dry, obtain 51g white solid product, yield: 85%,
Synthesizing of intermediate II: 48g intermediate I is placed in to 400ml ethanol, stirs, be warming up to 45 DEG C, drip 17.6g dimethylamine solution, drip and finish, be warming up to back flow reaction, TLC monitors reaction, reacts complete, is naturally cooled to 35 DEG C; 18.5g Hydrogen bromide is dripped in above-mentioned reaction, drip and finish, stirring reaction 3 hours, is then cooled to 10 DEG C of crystallizatioies and spends the night, suction filtration, dries, and obtains 36g white solid crude product, and this solid crude product is pulled an oar as for 200ml methylene dichloride, filter, dry, obtain 31.8g white solid product, yield: 85%;
Synthesizing of razaxaban: 17.1g 5-chlorothiophene formic acid is placed in to 100mL tetrahydrofuran (THF), stir, be cooled to 5 DEG C, drip at a slow speed 15.6g phosphorus oxychloride, drip and finish, be warming up to 25 DEG C of reactions, 31g intermediate II is dissolved in 100mL tetrahydrofuran (THF), carry out after 4 hours in above-mentioned reaction, drip in the above-mentioned reaction solution of this solution, and then dropping 19.1g triethylamine, drip and finish, reaction at 30 DEG C, TLC monitors reaction, react complete, remove most of solvent under reduced pressure, in residue, add 400mL water, stir, suction filtration, use a small amount of washing with alcohol, dry, obtain 38g white solid crude product, by this crude product as in 190g acetic acid, heating for dissolving, then be cooled to 5 DEG C of crystallizatioies, suction filtration, dry, the 35.4g purity white solid product that is 99.2%, yield: 86 %.
The synthetic middle alcoholic solvent of intermediate I can also be propyl carbinol.
In razaxaban synthetic, solvent can also be acetonitrile or ethanol.
The invention has the beneficial effects as follows: this processing method raw material is cheaply easy to get, easy control simple to operate, reaction yield is high, and product purity is high, and cost is low, is suitable for large-scale industrial production.
The above, be only preferred embodiment of the present invention, is not the restriction of the present invention being made to any other form, and according to any amendment or equivalent variations that technical spirit of the present invention is done, still belong to the present invention's scope required for protection.
Claims (4)
1. a preparation method for razaxaban, is characterized in that: comprise the following steps successively: the synthetic and razaxaban of synthetic, the intermediate II of intermediate I synthetic,
The synthesis step of described intermediate I is: with 4-(4-aminophenyl)-3-morpholone mai and 2-[(2S)-2-Oxyranyle-methyl]-1H-isoindole-1,3(2H)-diketone is raw material, in alcoholic solvent, react with condensing agent, obtain intermediate I;
The synthesis step of described intermediate II is: intermediate I is placed in solvent under amine reagent effect, and reaction generates primary amine, and obtains intermediate II with sour reagent formation ammonium salt;
The synthesis step of described razaxaban is: 5-chlorothiophene formic acid is placed in solvent and forms acylate under acylating reagent effect, then reacts under alkali reagent effect with intermediate II, obtains razaxaban.
2. the preparation method of a kind of razaxaban according to claim 1, it is characterized in that: in intermediate I synthetic, alcoholic solvent is tetrahydrofuran (THF), ethanol, Virahol or propyl carbinol, condensing agent is CDI or DCC, temperature of reaction is 50-60 DEG C, 4-(4-aminophenyl)-3-morpholone mai, 2-[(2S)-2-Oxyranyle-methyl]-1H-isoindole-1,3(2H) the quality proportioning of-diketone and condensing agent is 1:1～1.5:1.2～1.6.
3. the preparation method of a kind of razaxaban according to claim 1, it is characterized in that: in intermediate II synthetic, amine reagent is methylamine or dimethylamine, acid reagent is methylsulfonic acid or Hydrogen bromide, solvent is tetrahydrofuran (THF), acetonitrile or ethanol, and the quality proportioning of intermediate I and amine reagent is 1.1～3:1.
4. the preparation method of a kind of razaxaban according to claim 1; it is characterized in that: in razaxaban synthetic, acylating reagent is sulfur oxychloride, phosphorus oxychloride or oxalyl chloride; alkali reagent is triethylamine; solvent is tetrahydrofuran (THF), acetonitrile or ethanol, and the quality proportioning of intermediate II and acylate is 1:1.5～2.5.
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| CN201410205693.8A CN104031036A (en) | 2014-05-16 | 2014-05-16 | Method for preparing rivaroxaban |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646470A (en) * | 2014-11-21 | 2016-06-08 | 北大方正集团有限公司 | Refining method for rivaroxaban |
| CN105669662A (en) * | 2014-11-21 | 2016-06-15 | 北大方正集团有限公司 | Synthetic method for rivaroxaban |
| CN105777738A (en) * | 2014-12-16 | 2016-07-20 | 南京生命能科技开发有限公司 | Rivaroxaban bulk drug and preparation method thereof |
| WO2019163731A1 (en) * | 2018-02-26 | 2019-08-29 | 住友化学株式会社 | Production method for oxazolidinone compound |
| CN111039937A (en) * | 2019-12-16 | 2020-04-21 | 浙江海翔药业股份有限公司 | Preparation method of rivaroxaban intermediate |
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| WO2013120465A1 (en) * | 2012-02-16 | 2013-08-22 | Zentiva, K.S. | A process for the preparation of rivaroxaban based on the use of (s)-epichlorohydrin |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646470A (en) * | 2014-11-21 | 2016-06-08 | 北大方正集团有限公司 | Refining method for rivaroxaban |
| CN105669662A (en) * | 2014-11-21 | 2016-06-15 | 北大方正集团有限公司 | Synthetic method for rivaroxaban |
| CN105777738A (en) * | 2014-12-16 | 2016-07-20 | 南京生命能科技开发有限公司 | Rivaroxaban bulk drug and preparation method thereof |
| WO2019163731A1 (en) * | 2018-02-26 | 2019-08-29 | 住友化学株式会社 | Production method for oxazolidinone compound |
| JPWO2019163731A1 (en) * | 2018-02-26 | 2021-02-04 | 住友化学株式会社 | Method for producing oxazolidinone compound |
| JP7205529B2 (en) | 2018-02-26 | 2023-01-17 | 住友化学株式会社 | Method for producing oxazolidinone compound |
| CN111039937A (en) * | 2019-12-16 | 2020-04-21 | 浙江海翔药业股份有限公司 | Preparation method of rivaroxaban intermediate |
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Application publication date: 20140910 |