CN104650057A - Rivaroxaban preparation method - Google Patents
Rivaroxaban preparation method Download PDFInfo
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Abstract
The invention relates to a rivaroxaban preparation method. The method is characterized in that 4-{4-[(4S)-5-(aminomethyl)-2-oxo-1,3-oxazolidinyl-3-yl]pheny}morpholine-3-one represented by formula II or its salt reacts with 5-chloro-thiophene-2-formic acid in an organic alkali-containing system in the presence of a condensing agent selected from 2,4,6-trichloro-1,3,5-triazine (TCT), 4,6-dimethoxy-2-chloro-1,3,5-triazine, 2-methoxy-4,6-dichloro-1,3,5-triazine, 4,6-dibenzyloxy-2-chloro-1,3,5-triazine and 4,6-diphenoxyl-2-chloro-1,3,5-triazine to prepare rivaroxaban. The method has the advantages of simple and practical operation, low cost, high yield, environmental protection, easily available raw materials, extremely great increase of the yield and the purity, and suitableness for large-scale industrial production.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of method preparing razaxaban.
Background technology
Deep venous thrombosis (DVT) is often formed at pelvis or deep veins of lower limb, and usual symptom is not obvious, but thrombus division flows into lung can cause pulmonary embolisms, serious caused death.DVT is common in surgical operation, long-term inpatients patient and long distance travelers.Razaxaban (formula I) is first, the whole world direct inhibitor of Xa by Bayer and Johson & Johnson's joint development, and it can be quick
Competitive inhibition Xa, inhibition thrombosis, reaches anticoagulation.In October, 2008, within 2009, U.S. FDA agreed to its clinical data significance, and the second half year in the same year visits auspicious appropriate in Discussion on Chinese Listed with trade(brand)name first in Canada and European Union's listing.Razaxaban oral administration biaavailability is high, liver and kidney tolerance good.Existing clinical being mainly used in is treated acute deep venous thrombosis (DVT), is prevented postoperative acute deep venous thrombosis.
Patent WO0147919 makes public for the first time chemical structure and the preparation method of razaxaban, and its synthetic route is as follows:
。
4-{4-in the method [(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base] phenyl } morpholine-3-ketone (II) and the chloro-thiophene of 5--2-formyl chloride (IV) react and prepare razaxaban (I) in pyridine.Pyridine toxicity is comparatively large, is very unfavorable for suitability for industrialized production as solvent.In addition, the method products obtained therefrom demand pole chromatography purification, is obviously also not suitable for industrial scale and produces.
Patent WO2005068456 also discloses a kind of method preparing razaxaban, first by 4-{4-[(5S)-5-(amino methyl)-2-oxo-1, 3-oxazolidine-3-base] phenyl } morpholine-3-ketone (II) is prepared into hydrochloride (Ⅸ), again hydrochloride (Ⅸ) is reacted in acetone and water equal solvent with the chloro-thiophene of 5--2-formyl chloride (IV), acid binding agent is done with mineral alkalis such as sodium carbonate, the method optimizes industrial process conditions, reduce cost, but this route has continued to use the chloro-thiophene of 5--2-formyl chloride, because formula IV needs by the chloro-thiophene of 5--2-formic acid (III) and sulfur oxychloride in situ preparation, larger to the infringement of equipment, therefore, this route exists obviously not enough.
Patent CN102746288, patent WO2012035057, patent WO2013053739 and WO2013098833 also all respectively to 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base] phenyl } salifie form of morpholine-3-ketone (II) and acid binding agent be optimized, but all do not depart from the constraint of the chloro-thiophene of 5--2-formyl chloride (IV).
Patent WO2013118130 disclose by 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base] phenyl } morpholine-3-ketone (II) and the chloro-thiophene of 5--2-formic acid (III), razaxaban (I) is prepared under boric acid and/or replacement or unsubstituted phenyl-boron dihydroxide catalysis, the method has abandoned the preparation of the acyl chlorides of formula IV, but boric acid and replacement or unsubstituted phenyl-boron dihydroxide price higher, and this reaction times is oversize, yield is not high, does not have cost advantage.
Summary of the invention
The object of the present invention is to provide a kind of method preparing razaxaban, the method overcomes prior art Problems existing, as avoided the problems such as the in situ preparation of the acyl chlorides of noxious solvent pyridine and formula IV, method of the present invention practicality simple to operate, low cost, high yield and environmental protection, raw material is easy to get, aftertreatment is simple, yield and purity greatly improve, and is applicable to large-scale industrial production.
For realizing object of the present invention, provide following embodiment.
In one embodiment, one of the present invention prepares the method for razaxaban (I), comprise by 4-{4-[(5S)-5-(amino methyl)-2-oxo-1, 3-oxazolidine-3-base] phenyl } morpholine-3-ketone or its salt (formula II compound), be selected from 2, 4, 6-tri-chloro-1, 3, 5-triazine (TCT), 4, 6,-dimethoxy-2-chloro-1, 3, 5-triazine (CDMT), 2-methoxyl group-4, 6-bis-chloro-1, 3, 5-triazine, 4, 6,-two Bian oxygen base-2-chloro-1, 3, 5-triazine and 4, 6,-two phenoxy group-2-chloro-1, 3, under the existence of the condensing agent of 5-triazine, in containing the system of organic bases, react obtained with the chloro-thiophene-2-carboxylic acid of the 5-of formula III, reaction formula is as follows:
。
In the above-described embodiment, method of the present invention, described 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base] phenyl } salt of morpholine-3-ketone comprises inorganic acid salt or organic acid salt, wherein, described inorganic acid salt comprises hydrochloride, vitriol, sulphite, phosphoric acid salt, phosphite or nitrate, preferably salt hydrochlorate; Described organic acid salt comprises formate, acetate, propionic salt, trifluoroacetate, mesylate, benzene sulfonate, tosilate, mandelate, oxalate, maleate, succinate, fumarate, malate, Citrate trianion, tartrate, lactic acid salt, benzoate, naphthalene diacid salt or succinate, preferable formic acid salt.
In the above-described embodiment, method of the present invention, described organic bases comprises triethylamine, diethylamine, diisopropylethylamine, N-methylmorpholine, N-methylcyclohexylamine or N, N-dimethyl aminopyridine, preferred N-methylmorpholine (NMM) or triethylamine.
In the above-described embodiment, method of the present invention, also comprise reaction solvent further, described reaction solvent comprises methyl-sulphoxide, N, dinethylformamide, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, acetonitrile, propionitrile, ethyl acetate, Iso Butyl Acetate, n-butyl acetate or their mixing, preferred DMF, methylene dichloride or their mixture.
In the above-described embodiment, method of the present invention, described condensing agent is 2,4,6-tri-chloro-1,3,5-triazines (TCT), 4,6,-dimethoxy-2-chloro-1,3,5-triazines (CDMT) or 2-methoxyl group-4,6-bis-chloro-1,3,5-triazine, is more preferably 2, and 4,6-tri-chloro-1,3,5-triazines (TCT) or 4,6,-dimethoxy-2-chloro-1,3,5-triazines.
In above-mentioned embodiment, the mol ratio of condensing agent and formula II compound is at least 1.01:1, and the mol ratio of organic bases and formula II compound is at least 1.01:1.
In one embodiment, a kind of method preparing razaxaban of the present invention, comprising:
By 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base] phenyl } morpholine-3-ketone (II) or its salt, under the existence of condensing agent and organic bases, in reaction solvent, chloro-thiophene-2-carboxylic acid (III) reacts and obtains with 5-, and wherein, described condensing agent is 2,4,6-tri-chloro-1,3,5-triazine (TCT), 4,6 ,-dimethoxy-2-chloro-1,3,5-triazine (CDMT) or 2-methoxyl group-4,6-bis-chloro-1,3,5-triazine.Reaction formula is as follows:
。
In above-mentioned specific embodiments, method of the present invention, wherein, 4,6,-dimethoxy-2-chloro-1,3,5-triazines (CDMT) is 2,4,6-tri-chloro-1, one of derivative of 3,5-triazine (TCT), the class both preparing peptide bond commonly uses coupling agent, can be bought by commercial sources.
In above-mentioned specific embodiments, method of the present invention, described 4-{4-[(5S)-5-(amino methyl)-2-oxo-1, 3-oxazolidine-3-base] phenyl } salt of morpholine-3-ketone comprises inorganic acid salt or organic acid salt, wherein, described inorganic acid salt comprises hydrochloride, vitriol, sulphite, phosphoric acid salt, phosphite or nitrate etc., preferably salt hydrochlorate, described organic acid salt comprises formate, acetate, propionic salt, trifluoroacetate, mesylate, benzene sulfonate, tosilate, mandelate, oxalate, maleate, succinate, fumarate, malate, Citrate trianion, tartrate, lactic acid salt, benzoate, naphthalene diacid salt or succinate etc., preferable formic acid salt.
In above-mentioned specific embodiments, method of the present invention, described organic bases comprises triethylamine, diethylamine, diisopropylethylamine, N-methylmorpholine, N-methylcyclohexylamine or N, N-dimethyl aminopyridine, preferred N-methylmorpholine (NMM), triethylamine or their mixture.
In above-mentioned specific embodiments, method of the present invention, described solvent comprises methyl-sulphoxide, N, dinethylformamide, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, acetonitrile, propionitrile, ethyl acetate, Iso Butyl Acetate, n-butyl acetate or their mixture, preferred DMF, methylene dichloride or their mixture.
In above-mentioned specific embodiments, the mol ratio of condensing agent and formula II compound is at least 1.01:1, and the mol ratio of organic bases and formula II compound is at least 1.01:1.
In a preferred embodiment, a kind of method preparing razaxaban of the present invention, comprising:
By 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base] phenyl } morpholine-3-ketone (II) or its hydrochloride or formate, under the existence of condensing agent and organic bases N-methylmorpholine (NMM) or triethylamine, at reaction solvent N, react with the chloro-thiophene-2-carboxylic acid of 5-(III) in dinethylformamide, methylene dichloride or its mixed solvent and obtain, wherein, described condensing agent is 2,4,6-tri-chloro-1,3,5-triazine (TCT) or 4,6 ,-dimethoxy-2-chloro-1,3,5-triazine (CDMT).
The method preparing razaxaban provided by the invention is with TCT and CDMT of cheapness for condensing agent, and reaction yield is high, and purity is high, also there is not the problem of racemization, and aftertreatment is simple, reduces cost, is applicable to large-scale commercial production.
Embodiment
Following examples are used for illustrating further and understanding the present invention, but do not limit the scope of the invention with this.
embodiment 1
Get 1L three-necked bottle, by chloro-for 26.0g 5-thiophene-2-carboxylic acid, 50.0g 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base] phenyl } morpholine-3-keto hydrochloride and 33.0gCDMT be suspended in 450mL N, in dinethylformamide, ice-water bath stirs lower dropping 40.0g NMM and 50.0mL N, the mixing solutions of dinethylformamide composition, dropwises rear continuation stirring 1 hour, is then warmed up to stirring at room temperature 1.5 hours in 20 minutes.Stop stirring, be added in water by reaction solution and pull an oar, ice bath crystallization, filter, decompression drying obtains white solid 63.25g, yield 95.2%, HPLC 99.82%, ee>99.9%.
embodiment 2
Get 500mL three-necked bottle, by 5.2g 5-chlor-2-thiophenecar-boxylic acid, 10.0g4-{4-[(5S)-5-(amino methyl)-2-oxo-1, 3-oxazolidine-3-base] phenyl } morpholine-3-ketone formate and 33.0gCDMT be suspended in 120mL N, in dinethylformamide, ice-water bath stirs lower dropping 6.8g NMM and 30.0mL N, the mixing solutions of dinethylformamide composition, rear continuation stirring 1 hour is dropwised in 20 minutes, then be warmed up to stirring at room temperature 2 hours to stop stirring, reaction solution is added in water and pulls an oar, ice bath crystallization, filter, decompression drying obtains white solid 12.3g, yield 94.8%, HPLC 99.72%, ee>99.9%.
embodiment 3
Get 5L three-necked bottle, by chloro-for 104g 5-thiophene-2-carboxylic acid, 108gCDMT, 178.0g 4-{4-[(5S)-5-(amino methyl)-2-oxo-1, 3-oxazolidine-3-base] phenyl } morpholine-3-ketone is suspended in 1.5L N, in dinethylformamide, ice-water bath stirs 1 hour, 62.4gNMM and 280mL N is dripped in 20 minutes, dinethylformamide mixed solution, then maintain ice-water bath and stir 1 hour, then stirring at room temperature 1 hours stops stirring, reaction solution is added in water and pulls an oar, ice bath crystallization, filter, decompression drying obtains white solid 252g, yield 94.7%, HPLC 99.70%, ee>99.9%.
embodiment 4
Get 1L three-necked bottle, by chloro-for 26.0g 5-thiophene-2-carboxylic acid, 50.0g4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base] phenyl } morpholine-3-keto hydrochloride and 10.3gTCT be suspended in 450mL N, in dinethylformamide, ice-water bath stirs lower dropping 40.0g NMM and 50.0mL N, the mixing solutions of dinethylformamide composition, dropwises rear continuation stirring 1 hour, is then warmed up to stirring at room temperature 1 hours in 20 minutes.Stop stirring, be added in water by reaction solution and pull an oar, ice bath crystallization, filter, decompression drying obtains white solid 62.01g, yield 93.2%, HPLC 99.43%, ee>99.9%.
embodiment 5
Get 2L three-necked bottle, by chloro-for 54g 5-thiophene-2-carboxylic acid, 53.3gCDMT, 80.0gNMM is suspended in 500.0mL methylene dichloride and 100.0mL N, in dinethylformamide mixed solvent, ice-water bath stirs 1 hour, add several times in 20 minutes 100.0g 4-{4-[(5S)-5-(amino methyl)-2-oxo-1, 3-oxazolidine-3-base] phenyl } morpholine-3-keto hydrochloride powder, after reinforced, ice-water bath stirs 40 minutes, be warmed up to stirring at room temperature 1.5 hours, by reaction solution and 2L methylene dichloride, 3L water fully mixes, separate organic phase, aqueous phase 1L dichloromethane extraction twice, merge organic phase, 2 times are washed again with 3L saturated sodium bicarbonate aqueous solution, 5L washes 1 time, organic phase anhydrous sodium sulfate drying 2 hours, then filter, evaporate to dryness obtains crude product 122.3g, yield 92.2%, HPLC 97.2%, ee>99.9%.
embodiment 6
Get 500mL three-necked bottle, by chloro-for 5.2g 55-thiophene-2-carboxylic acid, 10.0g4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base] phenyl } morpholine-3-keto hydrochloride and 33.0gCDMT be suspended in 120mL N, in dinethylformamide, ice-water bath stirs lower dropping 6.8g triethylamine and 30.0mL N, the mixing solutions of dinethylformamide composition, dropwises rear continuation stirring 1 hour, is then warmed up to stirring at room temperature in 20 minutes.HPLC monitoring 10.0g4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base] phenyl } the complete stopping stirring of morpholine-3-keto hydrochloride reaction, reaction solution is added in water and pulls an oar, ice bath crystallization, filter, decompression drying obtains white solid 11.5g, yield 86.5%, HPLC 99.65%, ee>99.9%.
Claims (11)
1. the method for the razaxaban of a preparation formula I, comprise by the 4-{4-of formula II [(5S)-5-(amino methyl)-2-oxo-1, 3-oxazolidine-3-base] phenyl } morpholine-3-ketone (II) or its salt, be selected from 2, 4, 6-tri-chloro-1, 3, 5-triazine (TCT), 4, 6,-dimethoxy-2-chloro-1, 3, 5-triazine, 2-methoxyl group-4, 6-bis-chloro-1, 3, 5-triazine, 4, 6,-two Bian oxygen base-2-chloro-1, 3, 5-triazine and 4, 6,-two phenoxy group-2-chloro-1, 3, under the existence of the condensing agent of 5-triazine, in containing the system of organic bases, react obtained with the chloro-thiophene-2-carboxylic acid of the 5-of formula III,
。
2. method according to claim 1, described salt comprises inorganic acid salt or organic acid salt.
3. method according to claim 2, described inorganic acid salt comprises hydrochloride, vitriol, sulphite, phosphoric acid salt, phosphite or nitrate.
4. method according to claim 2, described organic acid salt comprises formate, acetate, propionic salt, trifluoroacetate, mesylate, benzene sulfonate, tosilate, mandelate, oxalate, maleate, succinate, fumarate, malate, Citrate trianion, tartrate, lactic acid salt, benzoate, naphthalene diacid salt or succinate.
5. method according to claim 1, described salt is hydrochloride or formate.
6. method according to claim 1, described organic bases comprises triethylamine, diethylamine, diisopropylethylamine, N-methylmorpholine, N-methylcyclohexylamine, N, N-dimethyl aminopyridine or pyridine.
7. method according to claim 6, described organic bases is N-methylmorpholine or triethylamine.
8. method according to claim 1, also comprise reaction solvent, comprise methyl-sulphoxide, DMF, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, acetonitrile, propionitrile, ethyl acetate, Iso Butyl Acetate, n-butyl acetate or their mixture.
9. method according to claim 8, reaction solvent is DMF, methylene dichloride or their mixture.
10. method according to claim 1, described condensing agent is 2,4,6-tri-chloro-1,3,5-triazines (TCT), 4,6 ,-dimethoxy-2-chloro-1,3,5-triazines or 2-methoxyl group-4,6-bis-chloro-1,3,5-triazines.
11. methods according to claim 1, the mol ratio of condensing agent and formula II compound is at least 1.01:1, or the mol ratio of organic bases and formula II compound is at least 1.01:1.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108250193A (en) * | 2018-01-09 | 2018-07-06 | 江苏中邦制药有限公司 | The method that one kettle way prepares razaxaban |
| CN110172060A (en) * | 2018-12-27 | 2019-08-27 | 苏州二叶制药有限公司 | Razaxaban, synthesis and refining methd |
| CN114989159A (en) * | 2022-07-11 | 2022-09-02 | 天津力生制药股份有限公司 | Synthetic method of rivaroxaban |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110288294A1 (en) * | 2010-05-21 | 2011-11-24 | Michael Nonnenmacher | Preparation process for an inhibitor of a blood clotting factor |
| WO2012156983A1 (en) * | 2011-05-16 | 2012-11-22 | Symed Labs Limited | Processes 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 |
| WO2013098833A2 (en) * | 2011-09-08 | 2013-07-04 | Cadila Healthcare Limited | Processes and intermediates for preparing rivaroxaban |
| WO2013118130A1 (en) * | 2012-02-06 | 2013-08-15 | Symed Labs Limited | A 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-thiophene carboxamide |
| CN103360380A (en) * | 2013-03-13 | 2013-10-23 | 浙江天宇药业股份有限公司 | Synthesis method of rivaroxaban, and rivaroxaban intermediate and preparation thereof |
-
2013
- 2013-11-22 CN CN201310592103.7A patent/CN104650057B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110288294A1 (en) * | 2010-05-21 | 2011-11-24 | Michael Nonnenmacher | Preparation process for an inhibitor of a blood clotting factor |
| WO2012156983A1 (en) * | 2011-05-16 | 2012-11-22 | Symed Labs Limited | Processes 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 |
| WO2013098833A2 (en) * | 2011-09-08 | 2013-07-04 | Cadila Healthcare Limited | Processes and intermediates for preparing rivaroxaban |
| WO2013118130A1 (en) * | 2012-02-06 | 2013-08-15 | Symed Labs Limited | A 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-thiophene carboxamide |
| CN103360380A (en) * | 2013-03-13 | 2013-10-23 | 浙江天宇药业股份有限公司 | Synthesis method of rivaroxaban, and rivaroxaban intermediate and preparation thereof |
Non-Patent Citations (1)
| Title |
|---|
| 温飞，等: "三聚氯氰在催化有机合成中的应用", 《精细石油化工》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108250193A (en) * | 2018-01-09 | 2018-07-06 | 江苏中邦制药有限公司 | The method that one kettle way prepares razaxaban |
| CN110172060A (en) * | 2018-12-27 | 2019-08-27 | 苏州二叶制药有限公司 | Razaxaban, synthesis and refining methd |
| CN114989159A (en) * | 2022-07-11 | 2022-09-02 | 天津力生制药股份有限公司 | Synthetic method of rivaroxaban |
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