CN104817550B - A kind of preparation method of razaxaban - Google Patents
A kind of preparation method of razaxaban Download PDFInfo
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- CN104817550B CN104817550B CN201510275587.1A CN201510275587A CN104817550B CN 104817550 B CN104817550 B CN 104817550B CN 201510275587 A CN201510275587 A CN 201510275587A CN 104817550 B CN104817550 B CN 104817550B
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- razaxaban
- acid amides
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- 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 kind of preparation method of razaxaban, category pharmaceutical chemistry synthesis field.The method is by the carboxylic acid of 5 chlorothiophene 2 [(s) 2,3 dihydroxypropyls] acid amides is under triphenylphosphine, the catalysis of imidazoles and Iod R obtains the carboxylic acid of 5 chlorothiophene 2 [hydroxypropyl of (s) 3 iodine 2] acid amides, the carboxylic acid of 5 chlorothiophene 2 { (R) 2 hydroxyl 3 [4 (base of 3 oxomorpholin 4) phenyl amino] propyl group } acid amides is obtained with 4 (4 aminophenyl) 3 morpholine reactive ketone again, CO is finally passed through2Reaction obtains razaxaban.The method does not use expensive and poisonous raw material, and low production cost, production security is high, and the pollution produced to environment is small, is suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis field, it is related to a kind of preparation method of razaxaban.
Background technology
Razaxaban (Rivaroxaban), chemical name is the chloro- N- of 5- ({ (5S) -2- oxos -3- [4- (3- oxos
Quinoline -4- bases) phenyl] -1,3-oxazoles quinoline -5- bases } methyl) thiophene-2-carboxamide derivatives, structural formula is as follows：
Razaxaban is that Bayer and Johson ＆ Johnson develop jointly, in September And October, 2008 respectively plus take
Big and European Union obtains listing approval, trade name Xarelto.In China, the sale of in June, 2009 razaxaban official listing, business
The name of an article is auspicious appropriate to visit.Up to the present, razaxaban gets the Green Light in global more than 100 country, and by Beyer Co., Ltd super
75 countries are crossed successfully to list.Razaxaban is the inhibitor of the factor Xa of the high selectivity with Orally active, its quilt
For treating thrombus, including palsy.With at present clinically compared with widely used traditional anticoagulant, razaxaban have with
Lower feature：It has bioavilability high, and treatment spectrum of disease is wide, convenient oral, is in invertibity knot with Xa factor without hepatotoxicity wind agitation
Close, bleeding event is low, the advantage without the monitoring of conventional coagulation function turns into eager clinical demand, comes for clinician
Say, also implying that can simplify postoperative anticoagulant therapy.
WO00147919 discloses a kind of preparation method of razaxaban, and its synthetic route is as follows：
The method is by (S)-N- glycidols phthalimide (I) and 4- (4- aminophenyls) morpholine -3- ketone
(II) reaction obtain 2- [(2R) -2- hydroxyls -3- [[4- (3- oxo -4- morpholinyls) phenyl] amino] propyl group] -1H- iso-indoles -
1,3 (2H)-diketone (III).Then, with phosgene equivalent by (III) be converted into 2- [[(5S) -2- oxos -3- [4- (3- oxos -
4- morpholinyls) phenyl] -5- oxazoles alkyl] methyl] -1H- iso-indoles -1,3 (2H)-diketone (IV).Removal phthalimide
Protection group obtains 4- [4- [(5S) -5- (aminomethyl) -2- carbonyl -3- oxazolidinyls] phenyl] -3- morpholines ketone (V), finally and 5-
Chlorothiophene -2- carbonyls chlorine (VI) reaction obtains razaxaban.The impurity that the method is produced is not readily separated removal, and some raw materials are difficult
Reclaim, be unsuitable for industrialized production.
WO2003000256 discloses a kind of preparation for preparing razaxaban as raw material with benzene methoxy acyl group paranitroanilinum
Method, its synthetic route is as follows：
Wherein, a:(1) .n-BuLi (2) butyric acid-R- glycidyl esters (3) .NH4Cl/H2O；b:(1) phthalyls
Amine, DEAD/PPh3；(2).NH2NH2·H2O, ethanol；(3) .5- chlor-2-thiophenecar-boxylic acids, EDC/HOBT；c:Zn/HCl；EDC：1-
Ethyl-(3- dimethylaminos third class) carbodiimide；HOBT：1- hydroxyl -1H- BTAs xH2O。
The method by benzene methoxy acyl group paranitroanilinum (I) n-BuLi catalysis under with butyric acid-R- glycidyl esters
Reaction generation product (II), then generates product in the presence of diethyl azodiformate with the reaction of 5- chlor-2-thiophenecar-boxylic acids
(III), there is reduction reaction finally by zinc/hydrochloric acid and generate product (IV), (IV) continues to react final that target product profit cuts down sand
Class.Although the method step is few, however it is necessary that the middle n-BuLi used and diethyl azodiformate are all more expensive, benzene feedstock first
Oxygen acyl group paranitroanilinum is not also common, and n-BuLi, hydrazine hydrate higher, the uncomfortable industrialized production of danger.
WO2004060887 discloses a kind of preparation method of razaxaban, and its synthetic route is as follows：
Wherein, a：1,2-2 hydroxypropylamine hydrochloric acid；b：HBr；c：4- (4- aminophenyls) -3 morpholones；d：Phosgene (light
Gas) or phosgene analog.
There is nucleophilic addition generation 5- with 5- chlorothiophene -2- formyl chlorides (I) and 1,2-2 hydroxypropylamines hydrochloric acid in the method
Chlorothiophene -2- carboxylic acids-[(s) -2,3- dihydroxypropyls]-acid amides (II), by bromination reaction generation 5- chlorothiophene -2- carboxylic acids -
[the bromo- 2- hydroxypropyls of (s) -3-]-acid amides (III), then with trimethylpyridine as catalyst and 4- (4- aminophenyls) -3 morpholones
Reaction generation 5- chlorothiophenes -2- { (R) -2- hydroxyls -3- [4- (3- oxomorpholin -4- bases) phenyl amino]-propyl group } acid amides (IV),
Last and phosgene (phosgene) or phosgene analog cyclization generation target product razaxaban.The method has used HBr, front three
Yl pyridines and phosgene, trimethylpyridine are less commonly used, and price is higher, and hydrobromic acid is strongly corrosion liquid, phosgene (phosgene)
Strong toxicity, is unfavorable for industrialized production.
The content of the invention
The purpose of the present invention is directed to the deficiency of above-mentioned preparation method, there is provided a kind of preparation method of razaxaban, should
Method does not use expensive and poisonous raw material, and low production cost, production security is high, and the pollution produced to environment is small,
It is suitable for industrialized production.
Technical scheme is as follows：A kind of preparation method of razaxaban, it is characterised in that comprise the steps：
(1) 5- chlorothiophenes -2- carboxylic acids-[(s) -2,3- dihydroxypropyls]-acid amides under triphenylphosphine, the catalysis of imidazoles and
Iod R carries out obtaining 5- chlorothiophene -2- carboxylic acids-[the iodo- 2- hydroxypropyls of (s) -3-]-acid amides (intermediate I)；
(2) 5- chlorothiophenes -2- carboxylic acids-[the iodo- 2- hydroxypropyls of (s) -3-]-acid amides and 4- (4- aminophenyls) -3- morpholines
Reactive ketone obtains 5- chlorothiophene -2- carboxylic acids { (R) -2- hydroxyls -3- [4- (3- oxomorpholin -4- bases) phenyl amino]-propyl group } acyl
Amine (intermediate II)；
(3) 5- chlorothiophenes -2- carboxylic acids { (R) -2- hydroxyls -3- [4- (3- oxomorpholin -4- bases) phenyl amino]-propyl group } acyl
Amine and CO2Reaction obtains razaxaban.Its synthetic route is as follows：
Comprise the following steps that：
(1) 5- chlorothiophene -2- carboxylic acids-[(s) -2,3- dihydroxypropyls]-acid amides is dissolved in organic solvent, addition iodine,
Triphenylphosphine and imidazoles, react 2~6 hours at 30~60 DEG C；It is post-treated after the completion of reaction to obtain intermediate I；
(2) mixed solvent in water and organic solvent adds intermediate I and 4- (4- aminophenyls) -3- morpholones, heating
Back flow reaction 5~20 hours, is down to room temperature, obtains the reaction solution containing intermediate II；
(3) 20~40 DEG C of temperature control, CO is continually fed into the reaction solution to (2)2Gas to product is separated out, post-treated to get profit
Cut down husky class.
The organic solvent of the step (1) is any one in dichloromethane, chloroform, toluene.
5- chlorothiophene -2- carboxylic acids-[(s) -2,3- dihydroxypropyls]-acid amides, I in the step (1)2, triphenylphosphine and
The mol ratio of imidazoles is 1：1.05~1.5：1.0~1.4：1.8~2.2.
The post processing of the step (1) is：Washed 1-2 times using saturated sodium bicarbonate solution, then use saturation thiosulfuric acid
Sodium solution is washed 1 time, collects organic phase, and vacuum distillation, centrifugation obtains intermediate I.
The mixed solvent of the step (2), can be tetrahydrofuran/purified water, ethanol/purified water, methyl alcohol/purified water
Any one, purified water in the mixed solvent：The proportioning (v/v) of organic solvent is=1：7~10.
5- chlorothiophene -2- carboxylic acids-[(s) -2,3- dihydroxypropyls]-acid amides and 4- (4- aminobenzenes in the step (2)
Base) -3- morpholones mol ratio be 1：1.0~1.1.
CO in the step (3)2Be passed through the time for 4~12 hours.
The post processing of the step (3) is：Filtering, Washing of Filter Cake, drying, then through recrystallizing and refining, obtains high-purity
Razaxaban.
Compared to the method in WO2004060887, innovative point of the invention is as follows：
A. hydrobromic acid is strongly corrosion liquid, volatile and have very big toxicity, is unfavorable for industrialized production.The present invention is adopted
Use I2And catalysis is carried out by triphenylphosphine and imidazoles replace HBr, the substitution reaction of hydroxyl is easier to make for, improve reaction
Yield, simultaneously because iodine is solid material is easier to store and transport than HBr, the security that improve in production process, have
Beneficial to industrialized production；
B. the iodine substituent after step (1) treatment, active stronger compared to bromine substituent, it is easier to 4- (4- aminobenzenes
Base) -3- morpholones carry out substitution reaction, therefore be relatively easy to by being heated to reflux under mixed solvent and reacted
Mesosome II, it is not necessary to use trimethylpyridine；
C. phosgene (phosgene) strong toxicity, is unfavorable for industrialized production.The present invention is by CO2It is passed through the mixed of water and organic solvent
Slow ring is carried out in bonding solvent and reaction obtains razaxaban, safer, cost is lower.
D. method of step (2)-(3) using treating different things alike, simplifies post-processing step, saves cost, more conducively industry
Metaplasia is produced.
The beneficial effects of the invention are as follows：Razaxaban preparation method of the invention compared with the method for above-mentioned document report,
Avoid using expensive and hypertoxic raw material, reduce production cost, improve the security of production, reduce environment
Pollution is produced, with good industrial prospect.
Specific embodiment
The present invention is further illustrated below by example.Example of the invention be only used for explanation the present invention and to
Go out, be not limitation of the present invention.So, this hair is belonged to simple modifications of the invention under the premise of the method for the present invention
Bright protection domain.
Embodiment 1：
(1) by 5- chlorothiophene -2- carboxylic acids-[(s) -2,3- dihydroxypropyls]-acid amides 8.6kg addition reactors, add
Toluene 52L, opens stirring, adds iodine 10kg, triphenylphosphine 11.6kg, imidazoles 5kg, and intensification is heated to 45 DEG C, and insulation reaction 4 is small
When, washed twice with 25L saturated sodium bicarbonate solutions respectively after being down to room temperature, then washed with 25L saturated sodium thiosulfate solution
Once, organic phase is collected, vacuum distillation, centrifugation obtains 5- chlorothiophene -2- carboxylic acids-[the iodo- 2- hydroxypropyls of (s) -3-]-acid amides
(intermediate I)；
(2) by 64L ethanol, 7L purified waters addition reactor, stirring is opened, the intermediate I obtained by reaction is walked in addition
And 4- (4- aminophenyls) -3- morpholone 7.27kg, heating reflux reaction 12 hours is down to room temperature, obtains 5- chlorothiophene -2- carboxylics
Sour { (R) -2- hydroxyls -3- [4- (3- oxomorpholin -4- bases) phenyl amino]-propyl group } acid amides (intermediate II)；
(3) 30 DEG C of temperature control, CO is passed through in the product to (2)2Gas, gradually separates out a large amount of solids, is continually fed into 8 small
Shi Hou, filters to obtain white solid, and filter cake absolute ethanol washing obtains 11.6kg razaxaban crude products after drying.Tied again with acetic acid
Crystalline substance, is washed, vacuum drying with purified water and ethanol respectively, obtains razaxaban fine work about 9.9Kg, total recovery 62.2%.
Chemical purity：99.9% (HPLC conditions：Chromatographic column is Dicel Chiralpak IC (250 × 4.6mm, 5 μm)；
Mobile phase is 0.1% trifluoroacetic acid solution-acetonitrile (50:50)；Detection wavelength is 250nm；Column temperature is 40 DEG C；Flow velocity is 1.0ml/
min)。
IR (KBr, cm- 1):3354,3074,29362868,1737,16691647,15461518,14281411,
12201121,829.
1H NMR (400MHz, DMSO-d6)δ(ppm)：3.60 (2H, t), 3.69 (2H, t), 3.844.17 (2H, dd),
3.96 (2H, t), 4.18 (2H, s), 4.83 (1H, m), 7.147.64 (2H, d), 7.36-7.55 (4H, AA ' BB '), 8.89 (1H,
t)。
ESI-MSm/z：436[M+H]+,458[M+Na]+。
Embodiment 2：
(1) by 5- chlorothiophene -2- carboxylic acids-[(s) -2,3- dihydroxypropyls]-acid amides 5.0kg addition reactors, add
Dichloromethane 30L, opens stirring, adds iodine 6kg, triphenylphosphine 6kg, imidazoles 3kg, and intensification is heated to 40 DEG C, and insulation reaction 4 is small
When, washed twice with 20L saturated sodium bicarbonate solutions respectively after being down to room temperature, then washed with 20L saturated sodium thiosulfate solution
Once, organic phase is collected, vacuum distillation, centrifugation obtains 5- chlorothiophene -2- carboxylic acids-[the iodo- 2- hydroxypropyls of (s) -3-]-acid amides
(intermediate I)；
(2) by 50L tetrahydrofurans, 6L purified waters addition reactor, stirring is opened, the centre obtained by reaction is walked in addition
Body I and 4- (4- aminophenyls) -3- morpholone 4.2kg, heating reflux reaction 10 hours are down to room temperature, obtain 5- chlorothiophenes -2-
Carboxylic acid { (R) -2- hydroxyls -3- [4- (3- oxomorpholin -4- bases) phenyl amino]-propyl group } acid amides (intermediate II)；
(3) 30 DEG C of temperature control, CO is passed through in the product to (2)2Gas, gradually separates out a large amount of solids, is continually fed into 8 small
Shi Hou, filters to obtain white solid, and filter cake absolute ethanol washing obtains 6.8kg razaxaban crude products after drying.Tied again with acetic acid
Crystalline substance, is washed, vacuum drying with purified water and ethanol respectively, obtains razaxaban fine work about 5.8Kg, and total recovery 62.6%, chemistry is pure
Degree：99.8%.
Claims (9)
1. a kind of preparation method of razaxaban, it is characterized in that,
(1) 5- chlorothiophenes -2- carboxylic acids-[(s) -2,3- dihydroxypropyls]-acid amides is under triphenylphosphine, the catalysis of imidazoles and iodine is anti-
Should carry out obtaining 5- chlorothiophene -2- carboxylic acids-[the iodo- 2- hydroxypropyls of (s) -3-]-acid amides；
(2) 5- chlorothiophenes -2- carboxylic acids-[the iodo- 2- hydroxypropyls of (s) -3-]-acid amides and 4- (4- aminophenyls) -3- morpholones are anti-
5- chlorothiophene -2- carboxylic acids { (R) -2- hydroxyls -3- [4- (3- oxomorpholin -4- bases) phenyl amino]-propyl group } acid amides should be obtained；
(3) 5- chlorothiophenes -2- carboxylic acids { (R) -2- hydroxyls -3- [4- (3- oxomorpholin -4- bases) phenyl amino]-propyl group } acid amides and
CO2Reaction obtains razaxaban；
Specifically include following steps：
(1) 5- chlorothiophene -2- carboxylic acids-[(s) -2,3- dihydroxypropyls]-acid amides is dissolved in organic solvent, adds iodine, triphen
Base phosphine and imidazoles, react 2~6 hours at 30~60 DEG C；After the completion of reaction it is post-treated obtain 5- chlorothiophene -2- carboxylic acids-[(s) -
The iodo- 2- hydroxypropyls of 3-]-acid amides；
(2) mixed solvent in water and organic solvent adds 5- chlorothiophene -2- carboxylic acids-[the iodo- 2- hydroxypropyls of (s) -3-]-acid amides
And 4- (4- aminophenyls) -3- morpholones, heating reflux reaction 5~20 hours is down to room temperature, obtains containing 5- chlorothiophenes -2-
The reaction solution of carboxylic acid { (R) -2- hydroxyls -3- [4- (3- oxomorpholin -4- bases) phenyl amino]-propyl group } acid amides；
(3) 20~40 DEG C of temperature control, CO is continually fed into the reaction solution to (2)2Gas to product is separated out, and post-treated getting profit cuts down sand
Class.
2. a kind of preparation method of razaxaban as claimed in claim 1, it is characterized in that, the organic solvent of the step (1)
It is any one in dichloromethane, chloroform, toluene.
3. a kind of preparation method of razaxaban as claimed in claim 1, it is characterized in that, 5- chlorothiophenes in the step (1)-
2- carboxylic acids-[(s) -2,3- dihydroxypropyls]-acid amides, I2, triphenylphosphine and imidazoles mol ratio be 1：1.05~1.5：1.0~
1.4：1.8~2.2.
4. a kind of preparation method of razaxaban as claimed in claim 1, it is characterized in that, the post processing of the step (1) is：
Washed 1-2 times using saturated sodium bicarbonate solution, then washed 1 time with saturated sodium thiosulfate solution, collect organic phase, decompression is steamed
Evaporate, be centrifuged, obtain 5- chlorothiophene -2- carboxylic acids-[the iodo- 2- hydroxypropyls of (s) -3-]-acid amides.
5. a kind of preparation method of razaxaban as claimed in claim 1, it is characterized in that, the mixed solvent of the step (2),
For tetrahydrofuran/purified water, ethanol/purified water, methyl alcohol/purified water any one, purified water in the mixed solvent：It is organic
Volume ratio=1 of solvent：7~10.
6. a kind of preparation method of razaxaban as claimed in claim 1, it is characterized in that, 5- chlorothiophenes in the step (2)-
The mol ratio of 2- carboxylic acids-[(s) -2,3- dihydroxypropyls]-acid amides and 4- (4- aminophenyls) -3- morpholones is 1：1.0~
1.1。
7. the preparation method of a kind of razaxaban as described in any one in claim 1-6, it is characterized in that, the step
(3) CO in2Be passed through the time for 4~12 hours.
8. the preparation method of a kind of razaxaban as described in any one in claim 1-6, it is characterized in that, the step
(3) post processing is：Filtering, Washing of Filter Cake, drying, then through recrystallizing and refining, obtains high-purity razaxaban.
9. a kind of preparation method of razaxaban as claimed in claim 8, it is characterized in that, the Washing of Filter Cake uses anhydrous second
Alcohol.
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| CN105440028B (en) * | 2015-12-07 | 2018-03-13 | 石家庄康贺威药业有限公司 | A kind of razaxaban compound and preparation method thereof |
| CN106008490B (en) * | 2016-01-11 | 2019-01-04 | 南京生命能科技开发有限公司 | A kind of new crystal of razaxaban and preparation method thereof |
| CN109553611A (en) * | 2017-09-23 | 2019-04-02 | 齐鲁制药有限公司 | The preparation method and purposes of Rivaroxaban intermediate |
| CN108061767B (en) * | 2017-12-06 | 2020-07-21 | 重庆华邦制药有限公司 | Method for separating and measuring rivaroxaban intermediate and related impurities thereof by HP L C method |
| CN112110910B (en) * | 2019-06-19 | 2024-03-19 | 上海特化医药科技有限公司 | Method for preparing rivaroxaban intermediate and method for preparing rivaroxaban from rivaroxaban intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2013156936A1 (en) * | 2012-04-16 | 2013-10-24 | Ranbaxy Laboratories Limited | Process for the preparation of rivaroxaban and intermediates thereof |
| WO2015011617A1 (en) * | 2013-07-23 | 2015-01-29 | Ranbaxy Laboratories Limited | Process for the preparation of rivaroxaban |
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| WO2013156936A1 (en) * | 2012-04-16 | 2013-10-24 | Ranbaxy Laboratories Limited | Process for the preparation of rivaroxaban and intermediates thereof |
| WO2015011617A1 (en) * | 2013-07-23 | 2015-01-29 | Ranbaxy Laboratories Limited | Process for the preparation of rivaroxaban |
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