CN106008492B - A kind of synthetic method of razaxaban - Google Patents
A kind of synthetic method of razaxaban Download PDFInfo
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- CN106008492B CN106008492B CN201610657886.6A CN201610657886A CN106008492B CN 106008492 B CN106008492 B CN 106008492B CN 201610657886 A CN201610657886 A CN 201610657886A CN 106008492 B CN106008492 B CN 106008492B
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- 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
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Abstract
The invention discloses a kind of synthetic methods of razaxaban, comprising: 1) alkali is added in the organic solvent A containing 3- morpholone, then above-mentioned mixed solution is added dropwise to containing Isosorbide-5-Nitrae-in the organic solvent A of difluorobenzene, reaction obtains compound (I)；2) compound (I), (S) -3- amino -1,2-PD and alkali are added into organic solvent B, and temperature reaction obtains compound (II)；3) compound (II) reacts to obtain key intermediate compound (III) with containing hydrobromic acid solution；4) key intermediate compound (III) obtains compound (IV) by cyclization, and compound (IV) obtains compound (V) through aminolysis；Finally, compound (V) reacts to obtain razaxaban with the chloro- 2- thiophene chloride of 5-, this patent route is short, and high income, by-product is few, and strong operability, process costs are low, avoids being suitble to industrialized production using expensive Metal Palladium and hazardous reagents.
Description
Technical field
The present invention relates to a kind of medical material medicine and its synthetic methods, specifically disclose a kind of synthesis side of razaxaban
Method.
Background technique
The entitled chloro- N- of 5- ({ (5S) -2- oxo -3- [4- (3- oxo -4- morpholinyl) the phenyl] -1,3- of razaxaban chemistry
Oxazolidine -5- base }-methyl) -2- thenoyl amine, structural formula is as follows:
。
Razaxaban is global first Xa factor inhibitor that can directly take orally, for preventing and treating the medicine of phlebothrombosis
Object is particularly suitable for treatment myocardial infarction, angina pectoris etc..
The razaxaban synthetic route reported at present, common synthetic route has several following both at home and abroad:
Route one: the route that Beyer Co., Ltd announces in the patent document CN1262551 that China obtains authorization is as follows:
The shortcomings that above-mentioned route, is to prepare intermediate b(4-(4- aminophenyl) -3- morpholone) synthesis difficulty it is big, yield
It is low, it is needed in the process using to expensive palladium metal, the cost of raw material is high, while producing and using hydrogen, and relative risk is larger；
Racemization by-product can be generated in the reaction of intermediate b and III, and key intermediate compound c is caused to be not readily separated, above-mentioned two aspect
Make process operability poor, process costs are high, are not suitable for industrialized production.
Route two: the route that Beyer Co., Ltd announces in another patent document CN101821260 that China obtains authorization
It is as follows:
It is to prepare that intermediate b synthesis difficulty is big, and yield is low the shortcomings that above-mentioned route, is needed in the process using to expensive
Palladium metal, the cost of raw material is high, while producing and using hydrogen, and relative risk is larger；Intermediate b(4-(4- aminophenyl) -3-
Morpholone) and the reaction of (R)-epoxychloropropane in can generate racemization by-product, cause key intermediate compound c to be not easy point
From above-mentioned two aspect makes process operability poor, and process costs are high, are not suitable for industrialized production.
It is reported in Chinese patent (CN201310080291), parafluorobenzoic acid ethyl ester generates benefit through multistep reaction and cuts down sand
Class, reaction route are as follows:
4-(3- carbonyl-the 4- for having used sodium azide in reaction, having reduced the safety of operation, and prepared in route
Quinoline base) ethyl benzoate is to need column chromatography for separation, it is unfavorable for industrialized production.
It is reported in Chinese patent (CN201110330009.5), razaxaban is generated through multistep reaction to bromo-iodobenzene, instead
Answer route as follows:
The shortcomings that above-mentioned route is: 1) compound 5 slough needs in the reaction process of the benzyl protecting group of amino
Using to expensive palladium metal, the cost of raw material is high, while producing and using hydrogen, and relative risk is larger；2) compound 2 carries out
Annulation is using having arrived triphosgene, and relative risk is larger；3) (S)-epoxychloropropane and dibenzylamine can generate in reaction
Racemization by-product causes midbody compound 1 to be not readily separated, and above-mentioned two aspect makes process operability poor, and process costs are high,
Be not suitable for industrialized production.
Summary of the invention
Above-mentioned existing in the prior art various to solve the problems, such as, the present invention provides a kind of synthesis sides of razaxaban
Method, this method raw material is easy to get, easy to operate, and route is short, and high income, by-product is few, and process costs are low, avoids using expensive gold
Belong to palladium and hazardous reagents, is suitble to industrialized production.
A kind of synthetic method of razaxaban, includes the following steps:
1) alkali is added in the organic solvent A containing 3- morpholone, then above-mentioned mixed solution is added dropwise to containing 1,
For 4- in the organic solvent A of difluorobenzene, reaction obtains compound (I)；
2) in organic solvent B, temperature reaction obtains compound for compound (I), alkali and (S) -3- amino -1,2-PD
(II)；
3) compound (II) reacts to obtain key intermediate compound (III) with containing hydrogen bromide solution；
4) key intermediate compound (III) obtains compound (IV) by cyclization, and compound (IV) obtains chemical combination through aminolysis
Object (V)；Finally, compound (V) reacts to obtain razaxaban with the chloro- 2- thiophene chloride of 5-.
Wherein, organic solvent A described in step 1) is one of tetrahydrofuran, toluene and dioxane or a variety of.
Wherein, alkali described in step 1) is one of sodium hydrogen, sodium ethoxide and potassium tert-butoxide or a variety of.
Wherein, Isosorbide-5-Nitrae-described in step 1) to difluorobenzene, 3- morpholone and alkali molar ratio be (1.0 ~ 10.0:1.0:
1.0 ~ 2.0).
Wherein, organic solvent B described in step 2 is tetrahydrofuran, methylene chloride, N, N '-dimethyl formamide and acetic acid
One of ethyl ester is a variety of.
Wherein, alkali described in step 2 is one of triethylamine, sodium hydroxide and sodium carbonate or a variety of.
Wherein, compound described in step 2 (I), (S) -3- amino -1,2-PD and alkali molar ratio are 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 has the advantage that compared with prior art
This patent route is short, and by-product is few, and purity can reach 99.8%, and high income, total recovery can reach 56%, post-processing letter
It is single, it avoids using special reagents such as expensive Metal Palladiums and hazardous reagents, process costs are cheap, and it is easy to operate, it is suitble to industry
Metaplasia produces.
Situation is embodied
The present invention is further illustrated 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 tetrahydrofuran (100mL), stirring.Point
It criticizes and sodium hydrogen (60%, 23.74g, 0.59mol) is added, finish, reaction is warming up to room temperature reaction to fully reacting after 30 minutes, obtain
Reaction solution, for use.
Under the conditions of 10 DEG C, by the reaction solution that above-mentioned reaction obtains be added dropwise to containing Isosorbide-5-Nitrae-to difluorobenzene (67.31g,
It in tetrahydrofuran solution 0.59mol), finishes and warms naturally to room temperature, 68 DEG C of back flow reactions are heated up after insulation reaction 3 hours extremely
Completely.It is cooled to room temperature after fully reacting, and 500mL water is added, agitation and filtration is dry, obtains compound (I) off-white powder
81.38g, yield 92.7%, HPLC purity 98.89%.
Embodiment two: the preparation of compound (II)
At room temperature, by embodiment one react obtained compound (I) (80.00g, 0.41mol) and triethylamine (49.67g,
It 0.49mol) is added in tetrahydrofuran (200mL), stirring.(S) -3- amino -1,2-PD (41.08g, 0.45mol) is added,
It finishes, is warming up to 68 DEG C to fully reacting, is cooled to room temperature, and 600mL water is added, agitation and filtration is dry, obtains compound
(II) off-white powder 98.77g, yield 90.5%, HPLC purity 97.58%.
Embodiment three: the preparation of compound (III)
At room temperature, two gained compound (II) (90.00g, 0.38mol) of embodiment is added in tetrahydrofuran (400mL),
Stirring.It being added dropwise hydrogen bromide acetic acid solution (40%, 204.53g, 1.01mol), finishes, completely, 800mL water is added in room temperature reaction, and
Reaction system is moved into ice-water bath, is cooled to 0 DEG C, sodium hydroxide solution is added dropwise to system pH most 7.0 or so, a large amount of solid analysis
Out, agitation and filtration, it is dry, obtain compound (III) off-white powder 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)。
Example IV: 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 added portionwise
Potassium tert-butoxide (22.44g, 0.20mol), finishes, and reaction is warming up to room temperature reaction to fully reacting after 30 minutes, is reacted
Liquid, for use.
Under the conditions of 10 DEG C, by the reaction solution that above-mentioned reaction obtains be added dropwise to containing Isosorbide-5-Nitrae-to difluorobenzene (22.81g,
It in tetrahydrofuran solution 0.20mol), finishes and warms naturally to room temperature, 68 DEG C of back flow reactions are heated up after insulation reaction 3 hours extremely
Completely.It is cooled to room temperature after fully reacting, and 500mL water is added, agitation and filtration is dry, obtains compound (I) off-white powder
18.40g, yield 95.3%, HPLC purity 98.23%.
Embodiment five: the preparation of compound (II)
At room temperature, example IV is reacted compound (I) (18.00g, 0.09mol) and sodium carbonate (19.55g,
It 0.18mol) is added in N ' dinethylformamide (30mL), stirring.Addition (S) -3- amido-1,2-propanediol (16.40g,
0.18mol), it finishes, is warming up to 80 DEG C to fully reacting, is cooled to room temperature, and 600mL water is added, agitation and filtration is dry, obtains
To compound (II) off-white powder 23.23g, yield 94.6%, HPLC purity 98.63%.
Embodiment six: the preparation of compound (III)
At room temperature, five gained compound (II) (23.00g, 0.09mol) of embodiment is added to hydrogen bromide acetic acid solution
(40%, 36.45g, 0.18mol), finishes, and completely, 200mL water is added, and reaction system is moved to ice-water bath in room temperature reaction, drops
Sodium hydroxide solution is added dropwise to system pH most 7.0 or so to 0 DEG C in temperature, and a large amount of solids are precipitated, and agitation and filtration is dry, is changed
Close object (III) off-white powder 26.67g, yield 93.8%, HPLC purity 99.08%.
Embodiment seven: the preparation of razaxaban
Under the conditions of 0 DEG C, by three gained compound (III) (100.00g, 0.30mol) of embodiment and triethylamine (30.77g,
It 0.36mol) is added in methylene chloride (400mL), stirring.It is added dropwise ethyl chloroformate (39.08g, 0.36mol), finishes, heat preservation is anti-
After answering 1 hour, it is warming up to room temperature reaction completely, 800mL water is added, liquid separation, concentration obtain compound (IV) off-white powder
103.26g, yield 95.7%, HPLC purity 98.53%.
At room temperature, compound obtained above (IV) (100.00g, 0.28mol) is added in tetrahydrofuran (400mL),
Stirring.It is added at one time ammonium hydroxide (by 25% conversion, 190.40g, 2.8mol), is finished, completely, 800mL water is added in room temperature reaction,
Filtering, drying, obtain compound (V) white solid 80.54g, yield 98.2%, HPLC purity 98.53%.Without further
Processing is 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) is added in methylene chloride (200mL), stirring.The dropwise addition chloro- 2- thiophene chloride of 5- (53.77g,
0.30mol), it finishes, completely, 800mL water is added, liquid separation, concentration obtain razaxaban crude white solid in room temperature reaction
114.69g, yield 95.8%, HPLC purity 98.21%.
Above-mentioned crude product, which is added into 400mL glacial acetic acid, is warming up to reflux, is completely dissolved, and heat preservation filtering, filtrate moves to reaction
In bottle, it is naturally cooling to room temperature, razaxaban highly finished product white solid 108.48g, yield 94.6%, HPLC purity is obtained by filtration
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 for the title product that mass spectral analysis obtains is as follows: HR-MS (ESI): C19H18ClN3O5S molecular weight:
435.0656 [M+H]+Measured value: 435.0651.
Claims (8)
1. a kind of synthetic method of razaxaban, which comprises the steps of:
1) alkali is added in the organic solvent A containing 3- morpholone, it is right containing Isosorbide-5-Nitrae-to be then added dropwise to above-mentioned mixed solution
In the organic solvent A of difluorobenzene, reaction obtains compound (I)；
2) in organic solvent B, temperature reaction obtains compound for compound (I), alkali and (S) -3- amino -1,2-PD
(Ⅱ)；
3) compound (II) reacts to obtain key intermediate compound (III) with hydrogen bromide solution；
4) key intermediate compound (III) obtains compound (IV) by cyclization, and compound (IV) reacts with ammonia water to obtain chemical combination
Object (V)；Finally, compound (V) reacts to obtain razaxaban with the chloro- 2- thiophene chloride of 5-.
2. the method according to claim 1, wherein organic solvent A described in step 1) is tetrahydrofuran, toluene
With one of dioxane or a variety of.
3. the method according to claim 1, wherein alkali described in step 1) is sodium hydrogen, sodium ethoxide and the tert-butyl alcohol
One of potassium is a variety of.
4. the method according to claim 1, wherein 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.
5. the method according to claim 1, wherein organic solvent B described in step 2) is tetrahydrofuran, dichloro
Methane, N, one of N '-dimethyl formamide and ethyl acetate or a variety of.
6. the method according to claim 1, wherein alkali described in step 2) is triethylamine, sodium hydroxide and carbon
One of sour sodium is a variety of.
7. the method according to claim 1, wherein compound described in step 2) (I), amino -1 (S) -3-,
2- propylene glycol and alkali molar ratio are 1.0:1.0~2.0:1.0~2.0.
8. the method according to claim 1, wherein hydrobromic acid solution described in step 3) is that bromination acetate hydrogen is molten
Liquid.
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| 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 |
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| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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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. |