CN106008492A - Synthetic method for rivaroxaban - Google Patents
Synthetic method for rivaroxaban Download PDFInfo
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- CN106008492A CN106008492A CN201610657886.6A CN201610657886A CN106008492A CN 106008492 A CN106008492 A CN 106008492A CN 201610657886 A CN201610657886 A CN 201610657886A CN 106008492 A CN106008492 A CN 106008492A
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Abstract
The invention discloses a synthetic method for rivaroxaban. The synthetic method comprises the following steps: 1) adding alkali in an organic solvent A containing 3-morpholinone, then dropping a mixture in the organic solvent A containing 1,4-p-difluorobenzene, reacting the materials to obtain a compound (I); 2) adding the compound (I), (S)-3-amino-1,2-propylene glycol and alkali in an organic solvent B, heating the materials for a reaction to obtain a compound (II); 3) reacting the compound (II) and a solution containing hydrobromic acid to obtain a key intermediate compound (III); and 4) performing cyclization on the key intermediate compound (III) to obtain a compound (IV), performing aminolysis on the compound (IV) to obtain a compound (V); and finally, reacting the compound (V) and 5-chlorine-2-thiophenecarbonyl chloride to obtain rivaroxaban. The synthetic method of the invention has the advantages of short route, high yield, less by-product, strong operationality and low technological cost, avoids usage of metal palladium and danger reagents with high price, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of medical material medicine and synthetic method thereof, specifically disclose the synthesis side of a kind of razaxaban
Method.
Background technology
The razaxaban chemistry chloro-N-of entitled 5-({ (5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-
Oxazolidine-5-base }-methyl)-2-thenoyl amine, structural formula is as follows:
。
Razaxaban is first the Xa factor inhibitor that can be directly administered orally in the whole world, is used for preventing and treating venothrombotic medicine
Thing, is particularly suited for treating myocardial infarction, angina pectoris etc..
The razaxaban synthetic route of report at present, the most common synthetic route has following several:
Route one: the route that Beyer Co., Ltd announces in China obtains the patent documentation CN1262551 authorized is as follows:
The shortcoming of above-mentioned route is to prepare intermediate b(4-(4-aminophenyl)-3-morpholone) synthesize difficulty greatly, yield is low,
During need to use expensive palladium metal, the cost of raw material is high, and production and application hydrogen simultaneously, relative risk is bigger；In
Can produce racemization by-product in the reaction of mesosome b and III, cause key intermediate compound c to be not readily separated, above-mentioned two aspects are equal
Making process operability poor, process costs is high, is not suitable for industrialized production.
Route two: the route that Beyer Co., Ltd announces in China obtains another patent documentation CN101821260 authorized
As follows:
The shortcoming of above-mentioned route is to prepare that intermediate b synthesis difficulty is big, and yield is low, during need to use expensive porpezite
Belonging to, the cost of raw material is high, and production and application hydrogen simultaneously, relative risk is bigger；Intermediate b(4-(4-aminophenyl)-3-morpholine
Ketone) and the reaction of (R)-epoxychloropropane in can produce racemization by-product, cause key intermediate compound c to be not readily separated, on
Stating two aspects all makes process operability poor, and process costs is high, is not suitable for industrialized production.
Reporting in Chinese patent (CN201310080291), parafluorobenzoic acid ethyl ester generates profit through multistep reaction and cuts down sand
Class, reaction scheme is as follows:
Reaction is used Hydrazoic acid,sodium salt, has reduced the safety of operation, and the 4-(3-carbonyl-4-morpholinyl of preparation in route)
Ethyl benzoate is to need column chromatography for separation, is unfavorable for industrialized production.
Chinese patent (CN201110330009.5) reports, bromo-iodobenzene is generated razaxaban through multistep reaction, instead
Answer route as follows:
The shortcoming of above-mentioned route is: 1) compound 5 needs to use in carrying out sloughing the course of reaction of the benzyl protecting group of amino
To expensive palladium metal, the cost of raw material is high, and production and application hydrogen simultaneously, relative risk is bigger；2) compound 2 carries out cyclization
Reaction is to use to have arrived triphosgene, and relative risk is bigger；3) (S)-epoxychloropropane and dibenzylamine, can produce racemization in reaction
By-product, causes midbody compound 1 to be not readily separated, and above-mentioned two aspects all make process operability poor, and process costs is high, uncomfortable
Close industrialized production.
Summary of the invention
For solving various problems present in above-mentioned prior art, the invention provides the synthesis side of a kind of razaxaban
Method, the method raw material is easy to get, simple to operate, and route is short, and yield is high, and by-product is few, and process costs is low, it is to avoid use expensive gold
Belong to palladium and hazardous reagents, be suitable for industrialized production.
The synthetic method of a kind of razaxaban, comprises the steps:
1) alkali is joined in the organic solvent A containing 3-morpholone, then above-mentioned mixed solution is added dropwise to containing Isosorbide-5-Nitrae-right
In the organic solvent A of difluorobenzene, reaction obtains compound (I)；
2) compound (I), alkali are with (S)-3-amino-1,2-PD in organic solvent B, and temperature reaction obtains compound
(II)；
3) compound (II) obtains key intermediate compound (III) with reacting containing hydrogen bromide solution；
4) key intermediate compound (III) obtains compound (IV) through cyclization, and compound (IV) obtains compound through amine solution
(V)；Finally, compound (V) 2-chloro-with 5-thiophene chloride reacts and obtains razaxaban.
Wherein, one or more during organic solvent A described in step 1) is oxolane, toluene and dioxane.
Wherein, one or more during alkali described in step 1) is sodium hydrogen, Sodium ethylate and potassium tert-butoxide.
Wherein, Isosorbide-5-Nitrae described in step 1)-be to difluorobenzene, 3-morpholone and alkali molar ratio (1.0 ~ 10.0:1.0:
1.0 ~ 2.0).
Wherein, step 2) described in organic solvent B be oxolane, dichloromethane, N, N '-dimethyl Methanamide and acetic acid
One or more in ethyl ester.
Wherein, step 2) described in alkali be one or more in triethylamine, sodium hydroxide and sodium carbonate.
Wherein, step 2) described in compound (I), (S)-3-amino-1,2-PD and alkali molar ratio be 1.0:
1.0~2.0:1.0~2.0。
Wherein, hydrobromic acid solution described in step 3) is hydrogen bromide acetic acid solution.
The present invention compared with prior art has the advantage that
This patent route is short, and by-product is few, and purity can reach 99.8%, and yield is high, and total recovery can reach 56%, and post processing is simple,
Avoiding using the special reagents such as expensive Metal Palladium and hazardous reagents, process costs is cheap, easy and simple to handle, is suitable for industry metaplasia
Produce.
It is embodied as situation
Further illustrate the present invention by the following examples.
Embodiment one: the preparation of compound (I)
Under the conditions of 10 DEG C, 3-morpholone (50.01g, 0.49mol) is added in oxolane (100mL), stirring.Add in batches
Enter sodium hydrogen (60%, 23.74g, 0.59mol), finish, be warming up to room temperature reaction after reacting 30 minutes to reaction completely, reacted
Liquid, stand-by.
Under the conditions of 10 DEG C, the reactant liquor that above-mentioned reaction obtains is dropped to containing Isosorbide-5-Nitrae-to difluorobenzene (67.31g,
In tetrahydrofuran solution 0.59mol), finishing and warm naturally to room temperature, insulation reaction heats up 68 DEG C of back flow reaction extremely after 3 hours
Completely.It is cooled to room temperature after reaction completely, and adds 500mL water, agitation and filtration, it is dried, obtains compound (I) off-white color solid
81.38g, yield 92.7%, HPLC purity 98.89%.
Embodiment two: the preparation of compound (II)
Under room temperature, by embodiment one compound (I) (80.00g, 0.41mol) that obtains of reaction and triethylamine (49.67g,
0.49mol) add in oxolane (200mL), stirring.Add (S)-3-amino-1,2-PD (41.08g, 0.45mol),
Finish, be warming up to 68 DEG C of extremely reactions and completely, be cooled to room temperature, and add 600mL water, agitation and filtration, it is dried, obtains compound
(II) off-white color solid 98.77g, yield 90.5%, HPLC purity 97.58%.
Embodiment three: the preparation of compound (III)
Under room temperature, embodiment two gained compound (II) (90.00g, 0.38mol) is added in oxolane (400mL), stirs
Mix.Dropping hydrogen bromide acetic acid solution (40%, 204.53g, 1.01mol), finishes, and room temperature reaction is complete, adds 800mL water, and will
Reaction system moves to ice-water bath, is cooled to 0 DEG C, dropping sodium hydroxide solution to system pH most about 7.0, and a large amount of solids are analysed
Go out, agitation and filtration, be dried, obtain compound (III) off-white color solid 105.36g, yield 94.7%, HPLC purity 98.26%.
1H NMR (500 MHz, DMSO-d 6): δ 9.00 (s, 1H), 7.23 – 7.15 (m, 2H), 6.58
– 6.50 (m, 2H), 5.10 (d, 1H), 4.80 (d, 1H), 4.47 – 4.36 (m, 2H), 4.18 (m,
2H), 4.04 – 3.86 (m, 2H), 3.80 (dd, 1H), 3.57 (dd,, 1H), 3.40 (dd, 1H), 3.28
(dd, 1H)。
Embodiment four: the preparation of compound (I)
Under the conditions of 10 DEG C, 3-morpholone (10.01g, 0.10mol) is added in toluene (50mL), stirring.It is dividedly in some parts tertiary fourth
Potassium alcoholate (22.44g, 0.20mol), finishes, and is warming up to room temperature reaction to reaction completely, obtains reactant liquor, treat after reacting 30 minutes
With.
Under the conditions of 10 DEG C, the reactant liquor that above-mentioned reaction obtains is dropped to containing Isosorbide-5-Nitrae-to difluorobenzene (22.81g,
In tetrahydrofuran solution 0.20mol), finishing and warm naturally to room temperature, insulation reaction heats up 68 DEG C of back flow reaction extremely after 3 hours
Completely.It is cooled to room temperature after reaction completely, and adds 500mL water, agitation and filtration, it is dried, obtains compound (I) off-white color solid
18.40g, yield 95.3%, HPLC purity 98.23%.
Embodiment five: the preparation of compound (II)
Under room temperature, by embodiment four compound (I) (18.00g, 0.09mol) that obtains of reaction and sodium carbonate (19.55g,
0.18mol) add in N ' dinethylformamide (30mL), stirring.Addition (S)-3-amido-1,2-propanediol (16.40g,
0.18mol), finish, be warming up to 80 DEG C of extremely reactions and completely, be cooled to room temperature, and add 600mL water, agitation and filtration, it is dried,
To compound (II) off-white color solid 23.23g, yield 94.6%, HPLC purity 98.63%.
Embodiment six: the preparation of compound (III)
Under room temperature, by embodiment five gained compound (II) (23.00g, 0.09mol) add to hydrogen bromide acetic acid solution (40%,
36.45g, 0.18mol), finish, room temperature reaction is complete, adds 200mL water, and reaction system is moved to ice-water bath, be cooled to 0
DEG C, dropping sodium hydroxide solution to system pH most about 7.0, a large amount of solids separate out, and agitation and filtration is dried, obtains compound
(III) off-white color solid 26.67g, yield 93.8%, HPLC purity 99.08%.
Embodiment seven: the preparation of razaxaban
Under the conditions of 0 DEG C, by embodiment three gained compound (III) (100.00g, 0.30mol) and triethylamine (30.77g,
0.36mol) add in dichloromethane (400mL), stirring.Dropping ethyl chloroformate (39.08g, 0.36mol), finishes, and insulation is anti-
After answering 1 hour, it is warming up to room temperature reaction complete, adds 800mL water, separatory, concentration, obtain compound (IV) off-white color solid
103.26g, yield 95.7%, HPLC purity 98.53%.
Under room temperature, compound obtained above (IV) (100.00g, 0.28mol) is added in oxolane (400mL),
Stirring.Disposably adding ammonia (by 25% conversion, 190.40g, 2.8mol), finish, room temperature reaction is complete, adds 800mL water,
Filter, be dried, obtain compound (V) white solid 80.54g, yield 98.2%, HPLC purity 98.53%.Without further
Process, be directly used in next step.
Under the conditions of 0 ~ 10 DEG C, by compound obtained above (V) (80.00g, 0.27mol) and triethylamine
(33.29g, 0.33mol) adds in dichloromethane (200mL), stirring.Dropping 5-chloro-2-thiophene chloride (53.77g,
0.30mol), finishing, room temperature reaction is complete, adds 800mL water, separatory, concentration, obtains razaxaban crude white solid
114.69g, yield 95.8%, HPLC purity 98.21%.
The addition of above-mentioned crude product is warming up to backflow to 400mL glacial acetic acid, is completely dissolved, and insulation is filtered, and filtrate moves to reaction
In Ping, it is naturally cooling to room temperature, is filtrated to get razaxaban highly finished product white solid 108.48g, yield 94.6%, HPLC purity
99.87%。
1H-NMR(DMSO): δ8.98-8.95(t,1H), δ7.69(d,1H), δ7.56(d,2H), δ7.40(d,
2H), δ7.19(d,1H), δ4.86-4.82(m,1H), δ4.21-4.17(m,3H), δ3.98-3.96(m,2H), δ
3.87-3.83(m,1H), δ3.72-3.70(m,2H), δ3.62-3.59(m,2H)。
The detection data of the title product that mass spectral analysis obtains are as follows: HR-MS (ESI): C19H18ClN3O5S molecular weight:
435.0656, [M+H]+Measured value: 435.0651.
Claims (8)
1. the synthetic method of a razaxaban, it is characterised in that comprise the steps:
1) alkali is joined in the organic solvent A containing 3-morpholone, then above-mentioned mixed solution is added dropwise to containing Isosorbide-5-Nitrae-right
In the organic solvent A of difluorobenzene, reaction obtains compound (I)；
2) compound (I), alkali are with (S)-3-amino-1,2-PD in organic solvent B, and temperature reaction obtains compound
(II)；
3) compound (II) obtains key intermediate compound (III) with reacting containing hydrogen bromide solution；
4) key intermediate compound (III) obtains compound (IV) through cyclization, and compound (IV) obtains compound through amine solution
(V)；Finally, compound (V) 2-chloro-with 5-thiophene chloride reacts and obtains razaxaban.
Method the most according to claim 1, it is characterised in that organic solvent A described in step 1) is oxolane, toluene
With one or more in dioxane.
Method the most according to claim 1, it is characterised in that alkali described in step 1) is sodium hydrogen, Sodium ethylate and the tert-butyl alcohol
One or more in potassium.
Method the most according to claim 1, it is characterised in that Isosorbide-5-Nitrae described in step 1)-to difluorobenzene, 3-morpholone and
Alkali molar ratio is (1.0 ~ 10.0:1.0:1.0 ~ 2.0).
Method the most according to claim 1, it is characterised in that step 2) described in organic solvent B be oxolane, dichloro
Methane, N, one or more in N '-dimethyl Methanamide and ethyl acetate.
Method the most according to claim 1, it is characterised in that step 2) described in alkali be triethylamine, sodium hydroxide and carbon
One or more in acid sodium.
Method the most according to claim 1, it is characterised in that step 2) described in compound (I), (S)-3-amino-1,
2-propylene glycol and alkali molar ratio are 1.0:1.0 ~ 2.0:1.0 ~ 2.0.
Method the most according to claim 1, it is characterised in that hydrobromic acid solution described in step 3) is that hydrogen bromide acetic acid is molten
Liquid.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110003193A (en) * | 2019-04-02 | 2019-07-12 | 北京四环制药有限公司 | It is a kind of to prepare the razaxaban and preparation method thereof for being easy to crush |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013105100A1 (en) * | 2012-01-09 | 2013-07-18 | 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-thiophene-carboxamide and intermediates thereof |
| CN104016975A (en) * | 2014-06-27 | 2014-09-03 | 深圳翰宇药业股份有限公司 | Preparation method of rivaroxaban |
| CN104262335A (en) * | 2014-09-30 | 2015-01-07 | 常州市勇毅生物药业有限公司 | Preparation method of rivaroxaban |
| CN105566310A (en) * | 2014-10-15 | 2016-05-11 | 常州诺贝朗生物医药科技有限公司 | Rivaroxaban intermediate preparation method |
-
2016
- 2016-08-12 CN CN201610657886.6A patent/CN106008492B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013105100A1 (en) * | 2012-01-09 | 2013-07-18 | 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-thiophene-carboxamide and intermediates thereof |
| CN104016975A (en) * | 2014-06-27 | 2014-09-03 | 深圳翰宇药业股份有限公司 | Preparation method of rivaroxaban |
| CN104262335A (en) * | 2014-09-30 | 2015-01-07 | 常州市勇毅生物药业有限公司 | Preparation method of rivaroxaban |
| CN105566310A (en) * | 2014-10-15 | 2016-05-11 | 常州诺贝朗生物医药科技有限公司 | Rivaroxaban intermediate preparation method |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110003193A (en) * | 2019-04-02 | 2019-07-12 | 北京四环制药有限公司 | It is a kind of to prepare the razaxaban and preparation method thereof for being easy to crush |
| CN110003193B (en) * | 2019-04-02 | 2023-12-05 | 北京四环制药有限公司 | Rivaroxaban easy to crush and preparation method thereof |
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Address after: Room 201, building 4, No. 101, No. 1 Street, Qiantang New District, Hangzhou City, Zhejiang Province Patentee after: Zhejiang Heze Pharmaceutical Technology Co., Ltd Patentee after: Hangzhou hezekunyuan Pharmaceutical Co.,Ltd. Address before: 201, room 4, building 101, No. 1, 310018 Avenue, Hangzhou economic and Technological Development Zone, Zhejiang, China Patentee before: Zhejiang Heze Pharmaceutical Technology Co., Ltd Patentee before: Hangzhou hezekunyuan Pharmaceutical Co.,Ltd. |