CN105777734A - Synthetic method of rivaroxaban intermediate - Google Patents
Synthetic method of rivaroxaban intermediate Download PDFInfo
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- CN105777734A CN105777734A CN201410795271.0A CN201410795271A CN105777734A CN 105777734 A CN105777734 A CN 105777734A CN 201410795271 A CN201410795271 A CN 201410795271A CN 105777734 A CN105777734 A CN 105777734A
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- 0 CC(CC(*)CC1)C1C(CC1)=CC=C1*1C2(CC2)C[*+]CC1 Chemical compound CC(CC(*)CC1)C1C(CC1)=CC=C1*1C2(CC2)C[*+]CC1 0.000 description 1
- URLKBWYHVLBVBO-UHFFFAOYSA-N Cc1ccc(C)cc1 Chemical compound Cc1ccc(C)cc1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention provides a synthetic method of a rivaroxaban intermediate (V). The method comprises the following steps: carrying out a reaction on a compound (II) in the presence of triphenylphosphine and an azo compound to obtain a compound (III), and carrying out a reaction on the compound (III) in an amine (ammonia) solution to obtain the rivaroxaban intermediate (V) which is 4-(4-((5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-yl)phenyl)morpholine-3-one or salt thereof. The new method provided by the invention has the advantages of mild reaction conditions, simple operation, convenience for purification, low production cost, environmental protection, and suitableness for industrial production.
Description
Technical field
The present invention relates to the synthetic method of anticoagulation medicine Rivaroxaban intermediate, more particularly to Rivaroxaban intermediate 4-(4-((5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base) phenyl) morpholine-3-ketone and the synthetic method of salt thereof.
Background technology
Razaxaban (Rivaroxaban), chemical name is the chloro-N-of 5-(((5S)-2-oxo-3-(4-(3-oxo-4-morpholinyl) phenyl)-1,3-oxazolidine-5-base) methyl-2-thenoyl amine, its structure as shown in the formula (I):
Razaxaban (Rivaroxaban) is the selective anticoagulation medicine a kind of novel, high researched and developed by Bayer A.G, and English name is Xarelto, and obtains EU Committee's license listing in September, 2008.Razaxaban contestable suppresses Xa factor that is free and that combine and prothrombin activity, extend prothrombin time (PT) and activated partial thromboplastin time (APTT) in a dose-dependent manner, be used for preventing hip joint and knee prosthesis postoperative patient person's DVT (DVT) and the formation of pulmonary embolism (PE).Along with the clinical practice of razaxaban, the demand of razaxaban will be gradually increased.
European patent WO0147919 and WO2005068456 discloses with compound 4-(4-aminophenyl)-morpholine-3-ketone and 2-((2S)-2-Oxyranyle-methyl)-1-H-iso-indoles-1,3 (2H)-diketone are the method that initiation material prepares Rivaroxaban, and reactions steps is as follows:
This synthetic method has a problem in that raw material 2-((2S)-2-Oxyranyle-methyl)-1-H-iso-indoles-1,3 (2H)-diketone used is prepared by (S)-2-polychlorinated dibenzo-furans and phthalimide.It is known that (S)-2-polychlorinated dibenzo-furans is toxic articles, industrial use is much limited.
Patent WO2011080341 discloses a 4-(4-aminophenyl protected with benzyloxycarbonyl group)-morpholine-3-ketone route as initiation material:
Chiral centre in this route azoles ring is introduced by (R)-Glycidyl butyrate, although avoids using poisonous polychlorinated dibenzo-furans, but has used toxic reagent mesyl chloride afterwards.Subsequent reactions tert-butylamine replaces, and the product of generation is condensed with 5-chlorothiophene carboxylic acid chloride again, removes the tert-butyl group the most under strongly acidic conditions and obtains razaxaban.The step of whole piece route is more, and yield is on the low side, and cost of material is high, is not suitable for industrialized production.
Patent WO2013098833 also discloses that one with 4-(4-aminophenyl)-morpholine-3-ketone route as initiation material:
Although this route also utilizes (R)-Glycidyl butyrate to introduce the chiral centre in azoles ring, avoid using poisonous polychlorinated dibenzo-furans, but used again toxic reagent mesyl chloride simultaneously, and the yield relatively low (70% ~ 75%) preparing compound III from compound II, cause cost of material higher.
Summary of the invention
It is an object of the present invention to provide a kind of synthesis Rivaroxaban intermediate 4-(4-((5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base) phenyl } morpholine-3-ketone and the method for salt thereof, reaction condition is gentle, simple to operate, be easy to purifying, low production cost, environmentally friendly and applicable industrialized production.
The present invention comprises the following steps:
1) formula (II) is reacted with phthalimide in the presence of triphenylphosphine and azo-compound and is obtained compound (III):
2) formula (III) is reacted in amine (ammonia) solution and is obtained in the middle of razaxaban (V), i.e. 4-(4-((5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base) phenyl) morpholine-3-ketone or its salt:
Wherein in step 1) azo-compound selected from following compound:
With
Further, in said structure, R is selected from alkyl, replaces alkyl, aromatic radical, substituted aromatic base；R1 and R2 is selected from alkyl, replacement alkyl, aromatic radical, substituted aromatic base, R1 and R2 can be the same or different, it is also possible to is collectively forming circulus.Alkyl is selected from the alkyl of C1-C10.Solvent in step 1) is selected from aprotic solvent, preferably ethers, esters, halogenated alkane, aromatic hydrocarbons, substituted arene, DMF, DMA and acetonitrile etc..
Step 2) reaction carry out in amine (ammonia) solution.Further, amine (ammonia) solution is selected from methylamine, ethamine, the mixed solution that hydrazine hydrate, monomethylhydrazine are formed with water or organic solvent.Further, organic solvent is selected from fatty alcohol, preferably methyl alcohol, ethanol, isopropanol.
Detailed description of the invention
In order to further appreciate that the present invention, below in conjunction with embodiment, the preferred embodiment of the invention is described, but it is to be understood that these describe simply as further illustrating the features and advantages of the present invention rather than limiting to the claimed invention.
The effect of the present invention is described with specific embodiment below, but protection scope of the present invention is not limited by the following examples.
Below with reference to embodiment, technical scheme and produced technique effect thereof are described further, but the most therefore limit the present invention among described scope of embodiments.
Embodiment 1: step 1)
(R)-4-[4-(5-methylol-2-oxo-oxazoline-3-base)-phenyl]-morpholine-3-ketone (Formula II compound is added in the three neck round bottom of 250 ml fills, 5 g, 17.1 mmol), oxolane (75 ml), triphenylphosphine (5.38g, 20.5mmol) with phthalimide (3.02g, 20.5mmol), mixture it is stirred at room temperature 5 minutes.It is slowly added to diethyl azodiformate (3.58g, 20.5 mmol) with the time of 30 minutes, continues stirring 2 ~ 3 hours.Filter and be dried, obtain compound (III) 6.63g, yield 92%.
1H NMR (300MHz, d6-DMSO): 3.71
(s,2H),3.92-4.0(m,5H),4.2-4.25(m,3H),
4.95(m,1H),7.40(d,2H),7.54(d,2H),7.9(d,4H)
Embodiment 2: step 1)
(R)-4-[4-(5-methylol-2-oxo-oxazoline-3-base)-phenyl]-morpholine-3-ketone (Formula II compound is added in the three neck round bottom of 250 ml fills, 5 g, 17.1 mmol), oxolane (75 ml), triphenylphosphine (5.38g, 20.5mmol) with phthalimide (3.02g, 20.5mmol), mixture it is stirred at room temperature 5 minutes.It is slowly added to diisopropyl azodiformate (4.15g, 20.5 mmol) with the time of 30 minutes, continues stirring 2 ~ 3 hours.Filter and be dried, obtain compound (III) 6.7g, yield 93%.
Embodiment 3: step 1)
(R)-4-[4-(5-methylol-2-oxo-oxazoline-3-base)-phenyl]-morpholine-3-ketone (Formula II compound is added in the three neck round bottom of 250 ml fills, 5 g, 17.1 mmol), acetonitrile (75 ml), triphenylphosphine (5.38g, 20.5mmol) with phthalimide (3.02g, 20.5mmol), mixture it is stirred at room temperature 5 minutes.It is slowly added to azodicarbonyldipiperidine (5.17g, 20.5 mmol) with the time of 30 minutes, continues stirring 2 ~ 3 hours.Filter and be dried, obtain compound (III) 6.4g, yield 89%.
Embodiment 4: step 1)
(R)-4-[4-(5-methylol-2-oxo-oxazoline-3-base)-phenyl]-morpholine-3-ketone (Formula II compound is added in the three neck round bottom of 250 ml fills, 5 g, 17.1 mmol), N, dinethylformamide (75 ml), triphenylphosphine (5.38g, 20.5mmol) with phthalimide (3.02g, 20.5mmol), mixture it is stirred at room temperature 5 minutes.It is slowly added to azodicarbonamide (3.53g, 20.5 mmol) with the time of 30 minutes, continues stirring 2 ~ 3 hours.Filter and be dried, obtain compound (III) 6.5g, yield 90%
Embodiment 5: step 2)
Compound (III) (3.0g is added in the three neck round bottom of 100 ml, 7. 1 mmol), 25% methylamine water solution (3.89g) and ethanol (22.5ml), it is warming up to 60 ~ 70 DEG C react 2 ~ 3 hours, it is cooled to room temperature, add concentrated hydrochloric acid and adjust pH value 1 ~ 2, filter, obtain the hydrochloride 1.98g of razaxaban midbody compound V, yield 85%.
1H
NMR(300MHzd6-DMSO):3.25(m,2H),3.72(m,2H),3.98(m,3H),4.42(m,3H),4.97(m,1H),7.42(d,2H),7.57(d,2H),8.44(s(br),3H)
Embodiment 6: step 2)
Compound (III) (3.0g is added in the three neck round bottom of 100 ml, 7. 1 mmol), the 35% hydrazine hydrate aqueous solution (4.5g) and methyl alcohol (22.5ml), it is warming up to 60 ~ 70 DEG C react 2 ~ 3 hours, it is cooled to room temperature, add concentrated hydrochloric acid and adjust pH value 1 ~ 2, filter, obtain the hydrochloride 1.8g of razaxaban midbody compound V, yield 81%.
Claims (7)
1. the method preparing Rivaroxaban intermediate (V)
It is characterized in that:
1) formula (II) is reacted with phthalimide in the presence of triphenylphosphine and azo-compound and is obtained compound (III):
2) formula (III) reaction obtains in the middle of razaxaban (V), i.e. 4-(4-((5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base) phenyl) morpholine-3-ketone or its salt:
。
2., according to claim 1, in step 1), azo-compound is selected from following compound:
With
Wherein, R is selected from alkyl, replacement alkyl, aromatic radical, substituted aromatic base；R1 and R2 is selected from alkyl, replacement alkyl, aromatic radical, substituted aromatic base, R1 and R2 can be the same or different, it is also possible to is collectively forming circulus.
3., according to claim 1, the solvent in step 1) is selected from aprotic solvent, preferably ethers, esters, halogenated alkane, aromatic hydrocarbons, substituted arene, DMF, DMF and acetonitrile etc..
4., according to claim 3, described alkyl is selected from the alkyl of C1-C10.
5. according to claim 1, step 2) reaction carry out in amine (ammonia) solution.
6., according to claim 5, amine (ammonia) solution is selected from methylamine, ethamine, the mixed solution that hydrazine hydrate, monomethylhydrazine are formed with water or organic solvent.
7., according to claim 6, organic solvent is selected from fatty alcohol, preferably methyl alcohol, ethanol and isopropanol.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110054621A (en) * | 2019-03-12 | 2019-07-26 | 浙江天宇药业股份有限公司 | A kind of preparation method of Rivaroxaban intermediate |
| CN112521380A (en) * | 2020-12-14 | 2021-03-19 | 哈尔滨珍宝制药有限公司 | Synthetic method of rivaroxaban intermediate A and application of rivaroxaban intermediate A in preparation of 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 |
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| CN1882539A (en) * | 2003-11-17 | 2006-12-20 | 惠氏公司 | Processes for the preparation of N-substituted phthalimides |
| CN1900074A (en) * | 1999-12-24 | 2007-01-24 | 拜耳医药保健股份公司 | Substituted oxazolidinones and their use in the field of blood coagulation |
| US20110160256A1 (en) * | 2008-06-26 | 2011-06-30 | Rouse Meagan B | Inhibitors of akt activity |
| WO2013098833A2 (en) * | 2011-09-08 | 2013-07-04 | Cadila Healthcare Limited | Processes and intermediates for preparing rivaroxaban |
| CN103965184A (en) * | 2014-04-18 | 2014-08-06 | 上海方楠生物科技有限公司 | Synthesis method for rivaroxaban intermediate |
-
2014
- 2014-12-22 CN CN201410795271.0A patent/CN105777734A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1900074A (en) * | 1999-12-24 | 2007-01-24 | 拜耳医药保健股份公司 | Substituted oxazolidinones and their use in the field of blood coagulation |
| CN1882539A (en) * | 2003-11-17 | 2006-12-20 | 惠氏公司 | Processes for the preparation of N-substituted phthalimides |
| US20110160256A1 (en) * | 2008-06-26 | 2011-06-30 | Rouse Meagan B | Inhibitors of akt activity |
| WO2013098833A2 (en) * | 2011-09-08 | 2013-07-04 | Cadila Healthcare Limited | Processes and intermediates for preparing rivaroxaban |
| CN103965184A (en) * | 2014-04-18 | 2014-08-06 | 上海方楠生物科技有限公司 | Synthesis method for rivaroxaban intermediate |
Non-Patent Citations (1)
| Title |
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| 王海燕等: "利伐沙班合成路线图解", 《中国药物化学杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110054621A (en) * | 2019-03-12 | 2019-07-26 | 浙江天宇药业股份有限公司 | A kind of preparation method of Rivaroxaban intermediate |
| CN112521380A (en) * | 2020-12-14 | 2021-03-19 | 哈尔滨珍宝制药有限公司 | Synthetic method of rivaroxaban intermediate A and application of rivaroxaban intermediate A in preparation of 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 |
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