CN105777738A - Rivaroxaban bulk drug and preparation method thereof - Google Patents
Rivaroxaban bulk drug and preparation method thereof Download PDFInfo
- Publication number
- CN105777738A CN105777738A CN201410784036.3A CN201410784036A CN105777738A CN 105777738 A CN105777738 A CN 105777738A CN 201410784036 A CN201410784036 A CN 201410784036A CN 105777738 A CN105777738 A CN 105777738A
- Authority
- CN
- China
- Prior art keywords
- razaxaban
- formula
- triethylamine
- rivaroxaban
- purity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a rivaroxaban bulk drug and a preparation method thereof. The rivaroxaban bulk drug is characterized in that the purity of rivaroxaban is not smaller than 99.5%, and the content of impurities represented by formula 1 is not greater than 0.1%. The preparation method of the rivaroxaban comprises the following steps: reacting hydrochloride of the compound represented by formula 1 with a toluene solution of 5-chlorothiophene-2-carbonyl chloride in an acetone and water mixed solution in the presence of triethylamine, and carrying out routine solid-liquid separation and drying to obtain crude rivaroxaban; and re-crystallizing the crude rivaroxaban by using a water and acetic acid mixed solvent to obtain purified rivaroxaban. The rivaroxaban prepared through using the preparation method has the advantages of high purity, low content of impurities, and suitableness for large scale production.
Description
Technical field
The invention provides a kind of razaxaban crude drug and preparation method thereof, relate to pharmaceutical chemical field.
Background technology
Razaxaban (Rivaroxaban) is first the oral direct Xa factor inhibitor in the whole world, Bayer/Johson & Johnson develop.Its molecular formula C19H18ClN3O5S, No. CAS: 366789-02-8, structural formula is as follows:
Razaxaban high selectivity and contestable suppress Xa factor that is free and that combine and prothrombin activity, extend activated partial thromboplastin time (PT) and prothrombin time (aPTT) with dose-dependent fashion.With fondaparinux sodium/heparin, razaxaban essential difference is in that it need not participate in by Antithrombin III, directly can reduce the activation of thrombin thus extend clotting time by antagonism Xa factor that is free and that combine, blood clot is not only formed with retardation by it, also can destroy established blood clot.In buttocks or knee replacement art process, Venous leg blood does not freely easily form thrombosis to heart adverse current, and razaxaban contributes to preventing the formation of this thrombosis and development further.
The preparation method of the publication number razaxaban that has been the patent report of CN200480040552.X and CN200610081919.3, its route is as follows:
The last recrystallization solvent of its report is glacial acetic acid, we in experiments it is found that formula one compound is as the intermediate in razaxaban preparation process, again as the impurity of razaxaban, cannot be removed by glacial acetic acid recrystallization, and it is wrapped in razaxaban, have a strong impact on the product quality of razaxaban.Additionally in the recrystallization process of razaxaban, it has been found that certain degraded, the acid degradation impurity of production two can occur razaxaban under the effect of glacial acetic acid, produce risk for final product quality.The patent disclosure of publication number WO2011080341 mixes with water with alcohols solvent, the method for recrystallization razaxaban, but the razaxaban purity obtained is not high, below 99%.Publication number many recrystallization methods that has been the patent disclosure of WO2011012321, including using methanol, acetone, acetonitrile, ethyl acetate, dimethyl sulfoxide, N, dinethylformamide equal solvent, in implementation process or there is the problem that organic solvent makes consumption big, exist and use dimethyl sulfoxide, N, dinethylformamide etc. two kind solvent, all works the mischief to environment.The patent that publication number is CN200680037076.5 also reports many recrystallization methods, employs oxolane, normal heptane equal solvent, but the quantity of solvent used is relatively big, inflammable and explosive and cost is high.The synthetic method of the razaxaban that publication number a kind of purity that has been the patent disclosure of CN201180005355.4 is higher, but it has used column chromatography purification, it is impossible to industrially large-scale production.Pertinent literature report triethylamine participates in the building-up process of razaxaban as acid binding agent, but after triethylamine once adds, it is easy to the yield causing the thick product of razaxaban is relatively low, and the impurity of formula one compound is higher.So groping a ripe razaxaban production technology thus to obtain highly purified razaxaban crude drug significant.
Summary of the invention
It is an object of the invention to provide the razaxaban crude drug that a kind of industrialized great production obtains, its purity is more than 99.5%, with the content of up-to-date style one impurity below 0.1%.
As preferably, this razaxaban crude drug, its purity is more than 99.7%, containing content≤0.06% of formula one impurity.
The preparation method that it is a further object to provide above-mentioned razaxaban crude drug.
In order to achieve the above object, the technical scheme is that and be achieved in that: a) toluene solution being reaction dissolvent formula one compound hydrochloride Yu 5-chlorothiophene-2-formyl chloride with the mixed solution of acetone Yu water reacts in the presence of triethyl amine, by conventional solid-liquid separation with dry, obtain razaxaban crude product；
B) by the mixed solvent recrystallization of razaxaban crude product water Yu acetic acid, razaxaban fine work is obtained.
As reaction dissolvent in step a), 5-7 times of the quality that the consumption (quality) of acetone is water.
As a kind of optimal way, with the mixed solution of acetone and water for reaction dissolvent in step a), the toluene solution of formula one compound hydrochloride and 5-chlorothiophene-2-formyl chloride reacts in the presence of triethyl amine, wherein triethylamine is that gradation joins in reaction system, the number of times of described addition triethylamine is 2-4 time, more preferably 2 times.It is 2/3rds of the triethylamine amount that altogether adds as the amount adding triethylamine in a kind of optimal way step a) first.
Mol ratio as 5-chlorothiophene-2-formyl chloride in a kind of more optimization method 5-chlorothiophene-2-formyl chloride solution Yu formula one compound hydrochloride is 1: 1～1.5: 1, with mass ratio for formula one compound hydrochloride 0.75-1.25 times of the consumption of triethylamine, reaction temperature is 0-35 DEG C.
As purity >=95% of razaxaban crude product, content≤3% of formula one impurity in a kind of optimal way razaxaban preparation method.
As a kind of optimization method, in the described mixed solvent of step b), water is 1: 20～1: 1 with the mass ratio of glacial acetic acid, it is preferred that the mass ratio of water and glacial acetic acid is 1: 4～1: 3.
Mass ratio as mixed solvent used by recrystallization in a kind of optimal way step b) with razaxaban crude product is 5: 1～6.7: 1,
Maximum temperature as a kind of optimal way step b) recrystallization process is 90-100 DEG C, and the final temperature of cooling crystallization is 15-20 DEG C.
It is static crystallize as Crystallization Process in a kind of optimal way step b).
The purity detecting that this patent relates to adopts high performance liquid chromatography, detection wavelength is 250nm, test instrunment is HP-1200, chromatographic condition: chromatographic column octadecylsilane chemically bonded silica is filler (5um, 4.6mm × 250mm), mobile phase A: 0.79g ammonium carbonate is dissolved in 1000ml water, add triethylamine 2ml, adjust pH value to 9.0 with formic acid, make mobile phase A.Mobile phase B: acetonitrile.Mobile phase speed is 0.7ml/min, and according to the form below carries out gradient elution:
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100 | 0 |
| 2 | 75 | 25 |
| 38 | 30 | 70 |
| 40 | 95 | 5 |
Purity detecting: razaxaban sample acetonitrile is configured the solution into about 0.5mg/ml, formula one compound control product are configured the contrast solution into about 0.5ug/ml, just the formula two compound control product configuration contrast solution into about 0.5ug/ml.Detection collection of illustrative plates according to razaxaban, according to area normalization method, calculates the purity of razaxaban；Detection collection of illustrative plates according to razaxaban, formula one compound compare collection of illustrative plates with formula two compound, calculate the content of razaxaban Chinese style one compound and formula two compound according to external standard method.Beneficial effects of the present invention:
1) razaxaban prepared according to the present invention, by the mixed solvent of water Yu glacial acetic acid, razaxaban is carried out recrystallization, product purity can reach more than 99.5%, and formula one impurity is below 0.1%, even with improve further its purity can >=99.7% and content≤0.06% containing formula one impurity, the content of formula two impurity also declines to a great extent；
2) join in reactant liquor by triethylamine gradation, make reaction yield increase to some extent, and reduce formula one compound and be mixed into the risk of final products.
3) technique is simple, it is possible to large-scale industrial production.
4) used by, recrystallization solvent is less, without two kind solvents, and environmentally friendly.
Accompanying drawing explanation
Fig. 1: the HPLC network for location of razaxaban
Fig. 2: the HPLC network for location of formula one compound
Fig. 3: the HPLC network for location of formula two compound
Fig. 4: the HPLC figure of the razaxaban sample that embodiment 1 prepares
Fig. 5: the razaxaban sample that embodiment 1 prepares1H-NMR schemes
Detailed description of the invention
The technical scheme of various embodiments of the present invention will be carried out clear, complete description below, it is clear that described embodiment is only a part of embodiment of the present invention, rather than whole embodiments.Based on the embodiment in the present invention, all other embodiments that those of ordinary skill in the art are obtained under the premise not making creative work, broadly fall into the scope that the present invention protects.
Embodiment 1
The purified water 12.1g of metering, acetone 76.7g, triethylamine 8g, formula one compound hydrochloride 12.1g (36.9mmol) are joined in reaction bulb, cooling is about to 10 DEG C, the toluene solution 87g (48.1mmol) of the 5-chlorothiophene-2-formyl chloride of 10% is dripped between 5-15 DEG C, the triethylamine into 4g is added after dropwising, continue to react 2 hours in this temperature range, filter, obtain solid.The purified water of solid 85g is washed and is filtered, dry, obtains razaxaban crude product 16.0g, yield 99.4%, purity 99.5%, the content 0.06% of formula one compound.
In reaction bulb, add the glacial acetic acid of 64g and the mixed solvent of 16g purified water composition, open stirring, the razaxaban crude product obtained is put into, heating is to 95-100 DEG C, solid dissolves, and filters, and filtrate stands, it is cooled to 15-20 DEG C, filter, obtain solid, the purified water washing of solid 123g, filter, obtain razaxaban tide product.
Above-mentioned tide product are dried, obtains razaxaban 13g, yield 86.1%.Fusing point: 232-233 DEG C, purity: 99.9%, formula one impurity content 0.01%, formula two impurity content 0.01%.The HPLC figure of its sample is shown in Fig. 4, its1Fig. 5 is shown in by H-NMR collection of illustrative plates.1H-NMR (500MHz, DMSO-d6): δ (ppm)=3.61 (t, 2), 3.71 (t, 2), 3.86 (m, 1), 4.18 (m, 1), 3.97 (t, 2), 4.20 (m, 3), 4.85 (m, 1), 7.18 (d, 1), 7.40 (t, 2), 7.56 (m, 2), 7.69 (d, 1), 3.97 (t, 1)
Embodiment 2
The purified water 12.1g of metering, acetone 76.7g, triethylamine 10g, formula one compound hydrochloride 12.1g (36.9mmol) are joined in reaction bulb, cooling is about to 15 DEG C, the toluene solution 87g (48.1mmol) of the 5-chlorothiophene-2-formyl chloride of 10% is dripped between 10-20 DEG C, the triethylamine into 5g is added after dropwising, continue to react 2 hours in this temperature range, filter, obtain solid.The purified water of solid 85g is washed and is filtered, dry, obtains razaxaban crude product 14.9g, yield 92.5%, purity 99.4%, the content 0.07% of formula one compound.
In reaction bulb, add the glacial acetic acid of 60g and the mixed solvent of 20g purified water composition, open stirring, the razaxaban crude product obtained is put into, heating is to 90-95 DEG C, solid dissolves, and filters, and filtrate stands crystallize, it is cooled to 15-20 DEG C, filter, obtain solid, the purified water washing of solid 123g, filter, obtain razaxaban tide product.
Above-mentioned tide product are dried, obtains razaxaban 12.8g, yield 85.9%.Fusing point: 231-232 DEG C, purity: 99.9%, formula one impurity content 0.01%, formula two impurity content 0.01%.
Embodiment 3
The purified water 12.1g of metering, acetone 60.5g, triethylamine 8g, formula one compound hydrochloride 12.1g (36.9mmol) are joined in reaction bulb, cooling is about to 0 DEG C, the toluene solution 100.3g (55.4mol) of the 5-chlorothiophene-2-formyl chloride of 10% is dripped between 0-10 DEG C, after dropwising, add triethylamine 7.125g, continue to react 1 hour in this temperature range, add triethylamine 2g, continue to react 2 hours in this temperature range, filter, obtain solid.The purified water of solid 85g is washed and is filtered, dry, obtains razaxaban crude product 14.8g, yield 91.9%, purity 99.5%, the content 0.06% of formula one compound.
The glacial acetic acid of 56g and the mixed solution of 24g purified water is added in reaction bulb, opening stirring, put into by the razaxaban crude product obtained, heating is to 85-90 DEG C, solid dissolves, filtering, filtrate is cooled to 15-20 DEG C, filters, obtain solid, the purified water washing of solid 123g, filters, obtains razaxaban tide product.
Above-mentioned tide product are dried, obtains razaxaban 12.3g, yield 83.1%.Fusing point: 230-231 DEG C, purity: 99.9%, formula one impurity content 0.01%, formula two impurity content 0.02%.
Embodiment 4
The purified water 12.1g of metering, acetone 84.7g, triethylamine 8g, formula one compound hydrochloride 12.1g (36.9mmol) are joined in reaction bulb, cooling is about to 10 DEG C, the toluene solution 66.8g (36.9mmol) of the 5-chlorothiophene-2-formyl chloride of 10% is dripped between 5-15 DEG C, the triethylamine into 1.075g is added after dropwising, continue to react 2 hours in this temperature range, filter, obtain solid.The purified water of solid 85g is washed and is filtered, dry, obtains razaxaban crude product 12.76g, yield 79.3%, purity 96.0%, and the content of formula one impurity is 2.8%.
In reaction bulb, add the glacial acetic acid of 37.5g and the mixed solvent of 37.5g purified water composition, open stirring, the razaxaban crude product obtained is put into, heating is to 95-100 DEG C, solid dissolves, and filters, filtrate stirring and crystallizing, it is cooled to 0-5 DEG C, filter, obtain solid, the purified water washing of solid 123g, filter, obtain razaxaban tide product.
Above-mentioned tide product are dried, obtains razaxaban 9.8g, yield 76.8%.Fusing point: 231-233 DEG C, purity: 99.5%, formula one impurity content 0.1%, formula two impurity content 0.1%.
Embodiment 5
The purified water 12.1g of metering, acetone 76.7g, triethylamine 6g, formula one compound hydrochloride 12.1g (36.9mmol) are joined in reaction bulb, the toluene solution 87g (48.1mmol) of the 5-chlorothiophene-2-formyl chloride of 10% is dripped between 20-30 DEG C, the triethylamine into 2g is added after dropwising, continue to react 1 hour in this temperature range, then the triethylamine into 2g is added again, continue to react 1 hour in this temperature range, then the triethylamine into 2g is added, continue to react 1 hour in this temperature range, filter immediately, obtain solid.The purified water of solid 85g is washed and is filtered, dry, obtains razaxaban crude product 15.6g, yield 96.9%, purity 99.2%, and the content of formula one impurity is 0.5%.
In reaction bulb, add the glacial acetic acid of 80g and the mixed solvent of 4g purified water composition, open stirring, the razaxaban crude product obtained is put into, heating is to 90-100 DEG C, solid dissolves, and filters, filtrate stirring and crystallizing, it is cooled to 10-15 DEG C, filter, obtain solid, the purified water washing of solid 120g, filter, obtain razaxaban tide product.
Above-mentioned tide product are dried, obtains razaxaban 13.2g, yield 84.6%.Fusing point: 230-232 DEG C, purity: 99.7%, formula one impurity content 0.06%, formula two impurity content 0.01%.
Embodiment 6
The purified water 12.1g of metering, acetone 76.7g, triethylamine 9g, formula one compound hydrochloride 12.1g (36.9mmol) are joined in reaction bulb, the toluene solution 65g (35.9mmol) of the 5-chlorothiophene-2-formyl chloride of 10% is dripped between 30-35 DEG C, after dropwising, the triethylamine into 3g is added after dropwising, continue to react 2 hours in this temperature range, filter, obtain solid.The purified water of solid 85g is washed and is filtered, dry, obtains razaxaban crude product 12.9g, yield 80.2%, purity 95.0%, and the content of formula one impurity is 3%.
The glacial acetic acid of 52.43g and the mixed solvent of 34g water is added in reaction bulb, opening stirring, put into by the razaxaban crude product obtained, heating is to 95-100 DEG C, solid dissolves, filtering, filtrate is cooled to 15-20 DEG C, filters, obtain solid, the purified water washing of solid 123g, filters, obtains razaxaban tide product.
Above-mentioned tide product are dried, obtains razaxaban 12.0g, yield 93.0%.Fusing point: 230-232 DEG C, purity: 99.5%, formula one impurity content 0.1%, formula two impurity content 0.1%.
Embodiment 7 (matched group)
The purified water 12.1g (36.9mmol) of metering, acetone 76.7g, triethylamine 12g, formula one compound hydrochloride 12.1g are joined in reaction bulb, the toluene solution 87g of the 5-chlorothiophene-2-formyl chloride of 10% is dripped between 30-35 DEG C, after dropwising, continue to react 2 hours in this temperature range, filter, obtain solid.The purified water of solid 85g is washed and is filtered, dry, obtains razaxaban crude product 12g, yield 74.5%, purity 95%, formula one impurity content 5%.
Adding the glacial acetic acid of 80g in reaction bulb, open stirring, put into by the razaxaban crude product obtained, heating is to 95-100 DEG C, solid dissolves, and filters, and filtrate is cooled to 15-20 DEG C, filters, obtain solid, the purified water washing of solid 123g, filter, obtain razaxaban tide product.
Above-mentioned tide product are dried, obtains razaxaban 11.2g, yield 93.3%.Fusing point: 230-231 DEG C, purity: 99.5%, formula one impurity content 0.13%, formula two impurity content 0.12%.
The above, it it is only presently preferred embodiments of the present invention, not the present invention is done any pro forma restriction, any those skilled in the art, without departing within the scope of technical solution of the present invention, when the technology contents of available the disclosure above makes few modifications or is modified to the Equivalent embodiments of equivalent variations, in every case it is the content without departing from technical solution of the present invention, according to any simple modification, equivalent variations and modification that above example is made by the technical spirit of the present invention, all still fall within the scope of inventive technique scheme.
Claims (10)
1. a razaxaban crude drug, it is characterised in that purity >=99.5% of described razaxaban and content≤0.1% of formula one impurity,
2. a kind of razaxaban crude drug according to claim 1, it is characterised in that purity >=99.7% of described razaxaban and content≤0.06% of formula one impurity.
3. the method for the razaxaban prepared described in claim 1, it is characterised in that comprise the steps of
A) with the mixed solution of acetone and water for reaction dissolvent, the toluene solution of formula one compound hydrochloride and 5-chlorothiophene-2-formyl chloride reacts in the presence of triethyl amine, and product is by conventional solid-liquid separation and dries, and obtains razaxaban crude product；
B) by the mixed solvent recrystallization of razaxaban crude product water Yu acetic acid, razaxaban fine work is obtained.
4. method according to claim 3, it is characterized in that in step a), the mol ratio of 5-chlorothiophene-2-formyl chloride and formula one compound hydrochloride is 1: 1～1.5: 1, the consumption of triethylamine is 0.75-1.42 times of formula one compound hydrochloride quality, and reaction temperature is 0-35 DEG C.
5. method according to claim 4, it is characterised in that triethylamine described in step a) divides 2-4 time and joins in reaction system；Preferably divide and join in reaction system for 2 times.
6. method according to claim 5, it is characterised in that add quality is the total addition of triethylamine 2/3rds of triethylamine first.
7. the method according to any one of claim 3～6, it is characterised in that purity >=95% of the razaxaban crude product that step a) obtains, content≤3% of formula one impurity.
8. method according to claim 3, it is characterised in that in the described mixed solvent of step b), water is 1: 20～1: 1 with the mass ratio of glacial acetic acid, the mass ratio of described mixed solvent and razaxaban crude product is 5: 1～6.7: 1.
9. method according to claim 3, it is characterised in that in described mixed solvent, water is 1: 4～1: 3 with the mass ratio of glacial acetic acid, and the maximum temperature of recrystallization process is 90-100 DEG C, and the final temperature of cooling crystallization is 15-20 DEG C.
10. method according to claim 9, it is characterised in that described Crystallization Process is static crystallize.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410784036.3A CN105777738A (en) | 2014-12-16 | 2014-12-16 | Rivaroxaban bulk drug and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410784036.3A CN105777738A (en) | 2014-12-16 | 2014-12-16 | Rivaroxaban bulk drug and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105777738A true CN105777738A (en) | 2016-07-20 |
Family
ID=56374813
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410784036.3A Pending CN105777738A (en) | 2014-12-16 | 2014-12-16 | Rivaroxaban bulk drug and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105777738A (en) |
Cited By (3)
| 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 |
| CN111721858A (en) * | 2020-06-03 | 2020-09-29 | 杭州华东医药集团新药研究院有限公司 | Method for determining genotoxic impurities in rivaroxaban |
| CN115536651A (en) * | 2021-12-15 | 2022-12-30 | 陕西汉江药业集团股份有限公司 | Preparation method of rivaroxaban |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145698A (en) * | 2013-03-01 | 2013-06-12 | 江西同和药业有限责任公司 | Preparation method of Rivaroxaban midbody and novel synthetic method of Rivaroxaban |
| CN103833724A (en) * | 2012-11-20 | 2014-06-04 | 上海医药工业研究院 | Preparation method of 5-penphene-2-formyl chloride |
| WO2014096214A1 (en) * | 2012-12-21 | 2014-06-26 | Farma Grs, D.O.O. | A process for preparation of rivaroxaban |
| CN104016975A (en) * | 2014-06-27 | 2014-09-03 | 深圳翰宇药业股份有限公司 | Preparation method of rivaroxaban |
| CN104031036A (en) * | 2014-05-16 | 2014-09-10 | 南通常佑药业科技有限公司 | Method for preparing rivaroxaban |
| CN104109158A (en) * | 2013-04-16 | 2014-10-22 | 上海医药工业研究院 | Rivaroxaban purification method |
| CN104193739A (en) * | 2014-09-11 | 2014-12-10 | 北京诺泓医药科技有限公司 | 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 |
| CN105669662A (en) * | 2014-11-21 | 2016-06-15 | 北大方正集团有限公司 | Synthetic method for rivaroxaban |
-
2014
- 2014-12-16 CN CN201410784036.3A patent/CN105777738A/en active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103833724A (en) * | 2012-11-20 | 2014-06-04 | 上海医药工业研究院 | Preparation method of 5-penphene-2-formyl chloride |
| WO2014096214A1 (en) * | 2012-12-21 | 2014-06-26 | Farma Grs, D.O.O. | A process for preparation of rivaroxaban |
| CN103145698A (en) * | 2013-03-01 | 2013-06-12 | 江西同和药业有限责任公司 | Preparation method of Rivaroxaban midbody and novel synthetic method of Rivaroxaban |
| CN104109158A (en) * | 2013-04-16 | 2014-10-22 | 上海医药工业研究院 | Rivaroxaban purification method |
| CN104031036A (en) * | 2014-05-16 | 2014-09-10 | 南通常佑药业科技有限公司 | Method for preparing rivaroxaban |
| CN104016975A (en) * | 2014-06-27 | 2014-09-03 | 深圳翰宇药业股份有限公司 | Preparation method of rivaroxaban |
| CN104193739A (en) * | 2014-09-11 | 2014-12-10 | 北京诺泓医药科技有限公司 | 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 |
| CN105669662A (en) * | 2014-11-21 | 2016-06-15 | 北大方正集团有限公司 | Synthetic method for rivaroxaban |
Cited By (5)
| 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 |
| CN111721858A (en) * | 2020-06-03 | 2020-09-29 | 杭州华东医药集团新药研究院有限公司 | Method for determining genotoxic impurities in rivaroxaban |
| CN111721858B (en) * | 2020-06-03 | 2022-07-01 | 杭州华东医药集团新药研究院有限公司 | Method for determining genotoxic impurities in rivaroxaban |
| CN115536651A (en) * | 2021-12-15 | 2022-12-30 | 陕西汉江药业集团股份有限公司 | Preparation method of rivaroxaban |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105777738A (en) | Rivaroxaban bulk drug and preparation method thereof | |
| CN105418581A (en) | Preparation method of trelagliptin succinate | |
| Kormos et al. | Synthesis and enantiomeric recognition studies of a novel 5, 5-dioxophenothiazine-1, 9 bis (thiourea) containing glucopyranosyl groups | |
| CN102351847B (en) | Industrial method for refining esomeprazole sodium salt | |
| CN104387393A (en) | Preparation method of sitagliptin impurity | |
| CN109867685B (en) | Preparation method of clopidogrel hydrogen sulfate II type | |
| CN107056722A (en) | A kind of method for preparing Parecoxib Sodium | |
| CN103788010B (en) | Febuxostat intermediate and preparation method thereof | |
| CN104974105A (en) | Method of preparing 4-(4-aminophenyl)-3-morpholinone | |
| CN106883227B (en) | The method for preparing ergometrine by ergot fermentation waste | |
| CN108997377B (en) | Preparation method of E-type 7-ATCA | |
| CN102159576B (en) | Improved production method for adefovir dipivoxil | |
| CN102557980A (en) | Method for preparing high-purity capsaicine monomer by crystallization | |
| CN104557689A (en) | Method for preparing 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-formamide and hydrate thereof | |
| CN105085499B (en) | The Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture | |
| CN111116477B (en) | Synthesis process of doramelamine | |
| CN109438543B (en) | Preparation method of high-purity fluticasone furoate | |
| JP5501054B2 (en) | Method for producing 3,3-diaminoacrylic acid (1-diphenylmethylazetidin-3-yl) ester acetate | |
| CN105566296A (en) | Method for preparing dabigatran amidated impurities | |
| CN111763222A (en) | Intermediate for preparing edoxaban free base and preparation method and application thereof | |
| CN112409433B (en) | Preparation method of U18666A | |
| CN110256261A (en) | A kind of chiral separation method being used to prepare left-handed 2- amino-n-butyl alcohol | |
| CN105273030A (en) | Preparation method of high-purity difluprednate | |
| CN105237549A (en) | Synthetic method for sirolimus 40-ether derivative | |
| CN104402813A (en) | Novel method for synthesizing sorafenib |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160720 |
|
| RJ01 | Rejection of invention patent application after publication |