CN103724336B - A kind of synthetic method of novel anticoagulation medicine - Google Patents
A kind of synthetic method of novel anticoagulation medicine Download PDFInfo
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Abstract
The present invention relates to a kind of synthetic method of novel anticoagulation medicine, comprise the step that 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai or its salt and 5-chlorothiophene-2-carboxylic acid carry out reacting under the effect of condensing agent N'N-carbonyl dimidazoles (CDI) or N, N'-dicyclohexylcarbodiimide (DCC).
Description
Technical field:
The present invention relates to a kind of preparation method of medical compounds, particularly a kind of preparation method of anticoagulation medicine razaxaban.
background technology:
Razaxaban (Rivaroxaban) structural formula is as follows:
For Bayer Bitterfeld GmbH medicine and Johnson Co.'s cooperative research and development success.Within 2008, to get the Green Light listing in Canada and European Union, commodity are called Xarelto.Razaxaban is the oral direct Xa factor inhibitor in first, the whole world, can highly selective, competitive inhibition dissociate and the Xa factor that combines and prothrombin activity, activated partial thromboplastin time plate (PT) and prothrombin time (aPTT) is extended with dose-dependent fashion, thus extend the clotting time, reduce zymoplasm and formed.It is high that it has bioavailability, and disease therapy spectrum is wide, and dose-effect relationship is stablized, convenient oral, the feature that bleeding risk is low.Razaxaban is also the venothrombotic medicine of control.Be mainly used in the formation preventing hip joint and knee prosthesis postoperative patient person deep venous thrombosis (DVT) and pulmonary infarction (PE) clinically.Also can be used for prevention non-valve artrial fibrillation patient's cerebral apoplexy and non-central nervous system embolism, reduce the risk etc. of coronary syndrome recurrence.
Chinese patent 200610081919.3 reports this compounds and synthetic method thereof, the method is with 4-(4-aminophenyl)-3-morpholone mai and (S)-(+)-N-(2, 3-ethoxycarbonyl propyl) phthalic imidine is starting raw material, through condensation reaction, ring closure reaction, deprotection reaction obtains 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai, 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai or its salt and 5-chlorothiophene-2-carboxylic acid obtain razaxaban under the effect of condensing agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI).Reaction scheme is as follows:
But the condensing agent used in the method is 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), N can also be used in addition, N ′ ?dicyclohexyl carbodiimide, 1 ?Qiang Ji ?1H ?the monohydrate etc. of benzotriazole, the shortcoming of the method is, condensing agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) price is higher, and reaction yield is lower.
This patent reports 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai simultaneously and 5-chlorothiophene-2-acyl chloride reaction obtains razaxaban, and reaction scheme is as follows:
But 5-chlorothiophene-2-acyl chlorides is prepared through thionyl chloride chlorination by 5-chlorothiophene-2-carboxylic acid, thionyl chloride has stronger corrodibility, and chlorination reaction produces a large amount of hydrogen chloride gas, etching apparatus, the post-processing difficulty being not easy to production operation, adding the waste gas and waste liquid produced in production, therefore, use 5-chlorothiophene-2-acyl chlorides can reduce the synthesis cost of razaxaban, but add the production cost of razaxaban.
Organic Process Research & Development2003; 7; 533-546 reports another synthetic method of razaxaban; with 4-(4-aminophenyl)-3-morpholone mai for starting raw material; obtain 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai trifluoroacetate through twice substitution reaction, ring closure reaction, deprotection, obtain razaxaban with the condensation of 5-chlorothiophene-2-acyl chlorides.
But the final step of this route is identical with the method for WO0147919, still etching apparatus during unresolved industrial production, be not easy to production operation, produce the problems such as acid waste gas waste water, yield is not high simultaneously.
Summary of the invention:
The present invention, through screening, have found a kind of condensing agent being applicable to preparing razaxaban, selects suitable raw material to feed intake simultaneously, solve the problem of prior art.
For this reason, the invention provides a kind of synthetic method of razaxaban: 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai or its salt, and 5-chlorothiophene-2-carboxylic acid is that raw material obtains through condensation, its reaction formula is as follows
The condensing agent that wherein condensation reaction is used is selected from: N'N-carbonyl dimidazoles (CDI) or N, N'-dicyclohexylcarbodiimide (DCC), and its structural formula is as follows:
N'N-carbonyl dimidazoles (CDI)
N, N'-dicyclohexylcarbodiimide (DCC)
Wherein the usage quantity of condensing agent N'N-carbonyl dimidazoles (CDI) or N, N'-dicyclohexylcarbodiimide (DCC) is 1-2 times of 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai or its salt molar weight.
The reaction solvent that condensation reaction uses is selected from the mixed solvent of several solvent of DMF (DMF), dimethyl sulfoxide (DMSO) (DMSO), methylene dichloride (DCM), trichloromethane (CHCl3), tetrahydrofuran (THF) (THF) or more.
The temperature of condensation reaction is 0-70 DEG C.
The time of condensation reaction is 2-48 hour.
The salt of wherein said 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai is selected from: hydrochloride, trifluoroacetate, fluoroform sulphonate, vitriol, formate, oxalate, succinate, mesylate, tosilate, L-TARTARIC ACID salt, L-mandelate, preferably L-mandelate.
Wherein, the synthesis of 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai, according to WO0147919 or Organic Process Research & Development2003, the preparation method of 7,533-546 obtains.
The salt of 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai or 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai, according to mention in WO2013098833 preparation method obtain.
5-chlorothiophene-2-carboxylic acid, N'N-carbonyl dimidazoles (CDI), N, N'-dicyclohexylcarbodiimide (DCC) are market and buy.Preferably, the synthetic method of razaxaban, step is as follows:
A:CDI condensation method.
By 5-chlorothiophene-2-carboxylic acid in reaction solvent, add N'N-carbonyl dimidazoles, stirring at room temperature 1 hour.Add 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai or its salt, continue to stir 12-48 hour.Be poured into water by reaction solution, after stirring, filtration drying obtains white solid, is razaxaban.
B:DCC condensation method.
By 5-chlorothiophene-2-carboxylic acid, 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai or its salt, be dissolved in solvent, add N, N'-dicyclohexylcarbodiimide, stirring at room temperature 12-48 hour.Be poured into water by reaction solution, after stirring, filtration, drying obtain white solid and are razaxaban.
The synthetic method of the particularly preferred razaxaban of the present invention, step is as follows:
5-chlorothiophene-2-carboxylic acid is dissolved in DMF, add N'N-carbonyl dimidazoles stirring reaction 1 hour, add 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai hydrochloride, trifluoroacetate or its L-mandelate, continue stirring reaction 24 hours, reaction solution is poured into water, stirring reaction 2 hours, filtration drying obtains razaxaban solid.
The invention reside in the improvement of the synthetic method to WO0147919 patent, main improvement is: select cheap, selectivity is high, simple to operate, the not N'N-carbonyl dimidazoles (CDI) of etching apparatus or N, N'-dicyclohexylcarbodiimide (DCC) is as the condensing agent of razaxaban building-up reactions, find to use 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai L-mandelate as reaction raw materials through screening in addition, yield improves greatly, and cost reduces greatly.
The most preferred synthetic method of the present invention is through screening acquisition, and screening process is as follows:
The screening of condensing agent:
Wherein with N, ' N-carbonyl dimidazoles (CDI) reaction process that is condensing agent adopts the method for example 5, the reaction process being condensing agent with N, N'-dicyclohexylcarbodiimide (DCC) adopts the method for example 13, and result is as follows:
Result shows: use N'N-carbonyl dimidazoles (CDI) better than the result of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), compared with thionyl chloride (SOCl2), easy handling, not etching apparatus, wherein, N'N-carbonyl dimidazoles (CDI) is optimum as condensing agent effect.
The screening of reaction solvent:
Reaction process adopts the method for example 5, and result is as follows:
Result shows: optimum using DMF as reaction solvent effect, DMSO takes second place.
The screening of reaction raw materials 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai (being called for short: morpholone mai) salt:
Reaction process adopts the method for example 5, and result is as follows:
| Molar yield (%) | Cost | The difficulty or ease of operating process | Whether etching apparatus | |
| Morpholone mai | 75 | Low | Easily | No |
| Morpholone mai hydrochloride | 85 | Low | Easily | No |
| Morpholone mai trifluoroacetate | 84 | Low | Easily | No |
| Morpholone mai vitriol | 79 | Low | Easily | No |
| Morpholone mai oxalate | 76 | Low | Easily | No |
| Morpholone mai succinate | 78 | Low | Easily | No |
| Morpholone mai tartrate | 79 | Low | Easily | No |
| Morpholone mai L-mandelate | 92 | Low | Easily | No |
Result shows: use morpholone mai L-mandelate effect optimum.
Through improving, the present invention achieves following unexpected beneficial effect:
1. the invention provides compared with razaxaban bulk drug synthetic method and the use 1-ethyl mentioned in WO0147919-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) use as the synthetic method of condensing agent, N'N-carbonyl dimidazoles (CDI) is cheap, and the cost of razaxaban is obviously reduced.
2. in the most preferred reaction method of the present invention, through screening the molar yield of this reactions steps obtained far above prior art document.
3. the present invention avoids using thionyl chloride, makes that production operation is easy, reaction conditions is gentle, is beneficial to suitability for industrialized production.
Embodiment:
Further illustrate the present invention by the following examples, but not as limitation of the present invention.
Synthetic method according to WO0147919 patent obtains key intermediate: 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai, and example 1 to example 3 is shown in operation:
Example 1:
5.4g4-(4-aminophenyl)-3-morpholone mai is added in 250mL reaction flask, 8.5g (S) – 2-(2-oxiranylmethyl radical)-1H-isoindole-1,3-diketone, the mixed solution (V:V=9:1) of 140mL second alcohol and water, temperature rising reflux 12h.Filter, filter cake washing with alcohol.Drying obtains white solid 10.2g, is intermediate A, and molar yield is 92% (in 4-(4-aminophenyl)-3-morpholone mai).
Example 2:
3.6g intermediate a is added in 250ml reaction flask, 90mL tetrahydrofuran (THF), 2.9gN, N-carbonyl dimidazoles (CDI), the DMAP (DMAP) of catalytic amount, be warming up to 60 DEG C and stir 24h, decompression steams solvent, obtains yellow solid, adds 100ml methylene dichloride and 100ml water, stir molten rear separatory, water layer with 100ml dichloromethane extraction once after, merge organic layer, with being concentrated into dry white solid 3.3g after anhydrous sodium sulfate drying, for intermediate b, molar yield is 87% (in intermediate A).
Example 3:
Add 4.2g intermediate b, 100mL ethanol in 250ml reaction flask, drip 10.2mL40% aqueous methylamine solution, evaporated under reduced pressure solvent after temperature rising reflux stirring 1h, obtains white solid.Add the ethanol solution hydrochloride of 100ml50%, stirring at room temperature, after 4 hours, is filtered and is obtained 2.8g white solid, be morpholone mai hydrochloride.Molar yield 86% (in intermediate B).
Example 4:
In 250ml reaction flask, add 1.6g5-chlorothiophene-2-carboxylic acid, 100ml DMF, be stirred to dissolving, add 1.6gN'N-carbonyl dimidazoles, stirring at room temperature 1 hour.Add 2.9g4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai, continue stirring 24 hours.Poured into by reaction solution in 100ml water, stir 2 hours, filter and obtain white solid, drying obtains 3.26g and is razaxaban, and molar yield is 75%.
Example 5:
In 250ml reaction flask, add 1.6g5-chlorothiophene dicarboxylic acid, 100ml DMF, be stirred to dissolving, add 1.6gN'N-carbonyl dimidazoles, stirring at room temperature 1 hour.Add 1g triethylamine, 3.3g4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai hydrochloride, continue stirring 24 hours.Poured into by reaction solution in 100ml water, stir 2 hours, filter and obtain white solid, drying obtains 3.7g and is razaxaban, and molar yield is 85%.
Following instance operation is identical with example 5, and reaction raw materials, feed ratio, reaction solvent, reaction times, temperature of reaction are variant, and experimental result sees the following form:
The operation steps of example 11 is as follows:
Add 4.5g intermediate B, 100mL ethanol in 250ml reaction flask, drip 10.2mL40% aqueous methylamine solution, evaporated under reduced pressure solvent after temperature rising reflux stirring 1h, obtains white solid.Add the ethanolic soln that 100ml contains 1.52gL-amygdalic acid, stirring at room temperature, after 4 hours, is filtered and is obtained 4.0g4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai L-mandelate.
In 250ml reaction flask, add 0.8g5-chlorothiophene-2-carboxylic acid, 100ml DMF, be stirred to dissolving, add 0.8gN'N-carbonyl dimidazoles, stirring at room temperature 1 hour.Add 2.2g4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai L-mandelate, continue stirring 24 hours.Poured into by reaction solution in 100ml water, stir 2 hours, filter and obtain white solid, drying obtains 1.964g razaxaban, and molar yield is 92%.
Example 12:
In 250ml reaction flask, add 1.6g5-chlorothiophene-2-carboxylic acid, 3.2g4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai, 100ml DMF, is stirred to dissolving, add 2.1g N, N'-dicyclohexylcarbodiimide, stirring at room temperature 48 hours, pours in 100ml water by reaction solution, stir 2 hours, filtration obtains white solid, and drying obtains 3.1g and is razaxaban, and molar yield is 71%.
Example 13:
In 250ml reaction flask, add 1.6g5-chlorothiophene-2-carboxylic acid, 3.2g4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai hydrochloride, 1.15g diisopropylethylamine, 100ml DMF, be stirred to dissolving, add 2.1g N, N'-dicyclohexylcarbodiimide, stirring at room temperature 48 hours, reaction solution is poured in 100ml water, stir 2 hours, filtration obtains white solid, and drying obtains 3.4g and is razaxaban, and molar yield is 78%.
Following instance operation is identical with example 13, and reaction raw materials, feed ratio, reaction solvent, reaction times, reaction temperature are variant, and experimental result sees the following form:
Claims (2)
1. the synthetic method of a razaxaban, it is characterized in that, step is as follows: 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai L-mandelate and 5-chlorothiophene-2-carboxylic acid react under the effect of condensing agent N'N-carbonyl dimidazoles, wherein the usage quantity of condensing agent N'N-carbonyl dimidazoles is 1-2 times of 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai L-mandelate molar weight, the mol ratio of 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai L-mandelate and 5-chlorothiophene-2-carboxylic acid is 1:1, the reaction solvent that reaction uses is DMF, temperature of reaction is 0-70 DEG C, reaction times is 2-48 hour.
2. a synthetic method for razaxaban, is characterized in that, step is as follows: in 250ml reaction flask, adds 1.6g 5-chlorothiophene-2-carboxylic acid, 100ml DMF, is stirred to dissolving, adds 1.6g N'N-carbonyl dimidazoles, stirring at room temperature 1 hour; Add 3.2g 4-[4-[(5S)-5-(amino methyl)-2-oxo-3-oxazolidinyl] phenyl]-3-morpholone mai L-mandelate, continue stirring 24 hours, reaction solution is poured in 100ml water, stir 2 hours, filter and obtain razaxaban.
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| CN104031036A (en) * | 2014-05-16 | 2014-09-10 | 南通常佑药业科技有限公司 | Method for preparing rivaroxaban |
| CN104098558B (en) * | 2014-07-22 | 2016-07-06 | 常州市第四制药厂有限公司 | Amides compound and preparation method thereof |
| CN105777732B (en) * | 2014-12-15 | 2019-03-19 | 深圳翰宇药业股份有限公司 | A kind of synthetic method and its application of Rivaroxaban intermediate |
| JP7339754B2 (en) * | 2019-03-27 | 2023-09-06 | ダイト株式会社 | Method for producing intermediates |
| CN114105970A (en) * | 2022-01-05 | 2022-03-01 | 安徽悦康凯悦制药有限公司 | Preparation method of rivaroxaban |
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| DE10300111A1 (en) * | 2003-01-07 | 2004-07-15 | Bayer Healthcare Ag | Process for the preparation of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5-yl} methyl ) -2-thiophenecarboxamide |
| DE102004002044A1 (en) * | 2004-01-15 | 2005-08-04 | Bayer Healthcare Ag | manufacturing |
| DE102005047558A1 (en) * | 2005-10-04 | 2008-02-07 | Bayer Healthcare Ag | Combination therapy of substituted oxazolidinones for the prophylaxis and treatment of cerebral circulatory disorders |
| DE102005048824A1 (en) * | 2005-10-10 | 2007-04-12 | Bayer Healthcare Ag | Treatment and prophylaxis of microangiopathies |
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Inventor after: Ge Zhimin Inventor after: Li Dongqing Inventor after: Xu Xuerong Inventor after: Wu Yanpeng Inventor after: Zhang Hong Inventor after: Chen Lin Inventor after: Yang Lei Inventor before: Ge Zhimin Inventor before: Xu Xuerong Inventor before: Wu Yanpeng Inventor before: Zhang Hong Inventor before: Chen Lin Inventor before: Yang Lei |
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Address after: 100176 No. 6, Hongda Middle Road, Beijing economic and Technological Development Zone, Beijing, Daxing District Patentee after: Yuekang Pharmaceutical Group Co., Ltd. Address before: 100176 No. 6, Hongda Middle Road, Beijing economic and Technological Development Zone, Beijing, Daxing District Patentee before: YOUCARE PHARMACEUTICAL GROUP CO., LTD. |