CN110054621A - A kind of preparation method of Rivaroxaban intermediate - Google Patents
A kind of preparation method of Rivaroxaban intermediate Download PDFInfo
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- CN110054621A CN110054621A CN201910402112.2A CN201910402112A CN110054621A CN 110054621 A CN110054621 A CN 110054621A CN 201910402112 A CN201910402112 A CN 201910402112A CN 110054621 A CN110054621 A CN 110054621A
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- C07—ORGANIC CHEMISTRY
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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
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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Abstract
The present invention provides a kind of preparation methods of Rivaroxaban intermediate compound of formula I, including Formula II compound is dissolved in organic solvent, with C3‑4Alkyl primaquine is that ammonia source carries out ammonolysis reaction, obtains compound of formula I.Safer, economic, simple and direct, environmental-friendly, the suitable industrialization of preparation method of the invention
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, and in particular to a kind of preparation method of Rivaroxaban intermediate.
Background technique
Razaxaban (Rivaroxaban) is the novel anticoagulation medicine researched and developed by Beyer Co., Ltd, is a kind of highly selective
Xa factor inhibitor oral drugs.Razaxaban energy high selectivity and contestable inhibit Xa that is free and combining because
Son and prothrombin activity, for preventing hip joint and knee prosthesis postoperative patient person deep vein thrombosis (DVT) and pulmonary embolism
(PE) formation, it can also be used to prevent non-valve artrial fibrillation patient cerebral apoplexy and non-central nervous system embolism, reduce
The risk of coronary syndrome recurrence.Razaxaban is listed in Canada for the first time in September, 2008.Then it is more than in the whole world
120 countries are granted.The chemical name of razaxaban is the chloro- N- of 5- (((5S) -2- oxo -3- (4- (3- oxomorpholin -4-
Base) phenyl) -1,3- oxazoline -5- base) methyl) thiophene-2-carboxamide derivatives (CAS:366789-02-8), chemical structural formula is such as
Under:
United States Patent (USP) US7157456B2, which is disclosed, prepares razaxaban by amine intermediate (compound of formula I) shown in following formula
Synthetic route.
In the prior art, the imide compound that intermediate compound of formula I mainly passes through Formula II exists in methylamine gas
Under conditions of carry out aminolysis acquisition.However, the synthetic route of existing methylamine aminolysis is primarily present following deficiency:
1) it is gas under methylamine normal pressure, and mixes with air and can form explosive mixture, leads to the peace of industrialized production
Full blast danger is higher, and methylamine exhaust gas pollutes the environment in production process, is unfavorable for environmental protection；
2) closed pressure resistant reaction kettle need to be used using methylamine gas aminolysis, it is more demanding to production equipment, restrict production capacity
It improves；
3) use methylamine aminolysis when methylamine dosage be typically larger than 50 equivalents, need after reaction by filtering, neutralization,
The complicated procedures of forming such as extraction, washing remove large excess of methylamine residual, and entire process flow is relatively complicated, and yield is lower, production
Higher cost；
4) higher using impurity formula III compounds content in the intermediate compound of formula I of methylamine aminolysis technique acquisition, no
Easily removal, is unfavorable for controlling the quality of subsequent razaxaban bulk pharmaceutical chemicals.
Therefore, in order to overcome the shortcomings of existing synthesis technology, safer, economic, simple and direct, environment need to be developed
Intermediate compound of formula I that is friendly, being suitble to industrialized method to be used to produce high quality.
Summary of the invention
The insufficient, safer, economic, simple of existing synthesis technology is overcome the object of the present invention is to provide a kind of
Preparation method that is victory, environmental-friendly, being suitble to industrialized Rivaroxaban intermediate compound of formula I.
The preparation method of compound of formula I of the invention the following steps are included:
Formula II compound is dissolved in organic solvent, with C3-4Alkyl primaquine is that ammonia source carries out ammonolysis reaction, obtains Formulas I
Close object
Preparation method according to the present invention, wherein C3-4Alkyl primaquine can be n-butylamine or n-propylamine.
Preparation method according to the present invention, wherein the organic solvent is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, just
One of butanol, tert-butyl alcohol are a variety of, preferably ethyl alcohol.
Preparation method according to the present invention, wherein the Formula II compound (quality, g) and the organic solvent (volume,
ML mass volume ratio) is 1:5-10, preferably 1:6.
Preparation method according to the present invention, wherein the Formula II compound and C3-4The molar ratio of alkyl primaquine is 1:8-
15, preferably 1:11.
Preparation method according to the present invention, wherein the ammonolysis reaction 60-100 DEG C at a temperature of carry out, preferably exist
It is carried out at a temperature of 75-80 DEG C.
Preparation method according to the present invention, wherein after the ammonolysis reaction, reaction solution is cooled to 0-10 DEG C, it is excellent
0-5 DEG C is selected, is stirred, filtering obtains compound of formula I.
The present invention uses the C under normal temperature and pressure for liquid3-4Alkyl primaquine replaces methylamine by ammonia source, and high temperature and pressure is avoided to set
Standby use, process safety are improved；The dosage for reducing ammonia, simplifies process flow；Reaction yield is improved, is had
Effect reduces production cost；Product is easy to purify, and effectively reduces the content of impurity formula III compound, improves product matter
Amount.
Specific embodiment
The following example further explains the present invention, still, they and be not meant to limit the scope of the invention or
It limits.
Facility information and use condition used in the present invention are as follows:
HPLC chromatogram condition are as follows: instrument: high performance liquid chromatograph is equipped with UV detector；Chromatographic column: C18 4.6 ×
250mm,5μm；Mobile phase: phosphate buffer solution-acetonitrile of pH=3.0；Detection wavelength: 245nm；Flow velocity: 0.8mL/min；
Column temperature: 30 DEG C；Sampling volume: 10 μ L；Runing time: 60min；Dilution: acetonitrile-water-phosphoric acid (100:900:1).
The information of primary raw material used in the embodiment of the present invention is as follows:
Embodiment 1
Formula II compound (42.1g), ethyl alcohol (252mL), n-butylamine (47.2g, 8eq) are put into reaction flask, are warming up to 75
~80 DEG C, insulation reaction 8~12 hours, after reaction, reaction solution is cooled to 0~5 DEG C, insulated and stirred 1 hour, by institute
Solid filtering is obtained, filter cake dries to obtain intermediate compound of formula I (23.3g), purity (HPLC) after being eluted with ethyl alcohol (20mL)
99.57%, yield 80%.
The characterize data of intermediate compound of formula I made from embodiment 1 is as follows: mp:149-151 DEG C；[α]20 D(C=
0.01g/mL, water)=- 59.4 °；TOF-MS(ES+): 292.16 [M+H]；1H NMR (DMSO-d6, 400MHz) and δ: 7.56 (d, J
=8.8Hz, 2H), 7.41 (d, J=8.8Hz, 2H), 4.93~4.88 (m, 2H), 4.18 (s, 2H), 4.15 (m, 1H), 4.16
(d, J=8.8Hz, 1H), 3.98~3.92 (m, 3H), 3.71 (t, J=5.2Hz, 2H), 3.14~3.10 (m, 2H)；13C NMR
(DMSO-d6, 100MHz) and δ: 166.16,153.98,137.34,136.57,126.03,118.70,70.84,67.87,
63.63,49.17,47.45,42.32.
Embodiment 2 is to embodiment 9
Change according to the operating process of embodiment 1 in the case where the inventory (42.1g) of Formula II compound remains unchanged
Become solvent and its dosage, the dosage of n-butylamine and reaction temperature, as a result sees such as the following table 1.
Table 1
| Embodiment number | Solvent and dosage | The dosage of n-butylamine | Reaction temperature | Yield |
| 2 | Ethyl alcohol (252mL) | 64.9g(11eq) | 75~80 DEG C | 88% |
| 3 | Ethyl alcohol (252mL) | 88.5g(15eq) | 75~80 DEG C | 86% |
| 4 | Ethyl alcohol (421mL) | 64.9g(11eq) | 75~80 DEG C | 84% |
| 5 | Methanol (252mL) | 64.9g(11eq) | 60~65 DEG C | 78% |
| 6 | Normal propyl alcohol (252mL) | 64.9g(11eq) | 75~80 DEG C | 83% |
| 7 | Isopropanol (252mL) | 64.9g(11eq) | 75~80 DEG C | 82% |
| 8 | N-butanol (252mL) | 64.9g(11eq) | 95~100 DEG C | 85% |
| 9 | The tert-butyl alcohol (252mL) | 64.9g(11eq) | 75~80 DEG C | 81% |
As shown in Table 1, embodiment 2 is optimum process condition.
Through detecting, the characterize data of intermediate compound of formula I made from embodiment 2 to embodiment 9 and embodiment 1 are made
Intermediate compound of formula I characterize data it is consistent.
Embodiment 10: under above-mentioned optimum process condition, n-butylamine is replaced with n-propylamine
Formula II compound (42.1g), ethyl alcohol (252mL), n-propylamine (64.9g, 11eq) are put into reaction flask, are warming up to
75~80 DEG C, insulation reaction 20~24 hours, after reaction, reaction solution is cooled to 0~5 DEG C, it insulated and stirred 1 hour, will
Obtained solid filtering, filter cake dry to obtain intermediate compound of formula I (23.9g), purity (HPLC) after being eluted with ethyl alcohol (10mL)
99.8%, yield 82%.
Through detecting, intermediate made from the characterize data of intermediate compound of formula I made from embodiment 10 and embodiment 1
The characterize data of compound of formula I is consistent.
Above embodiments are only a part of the preferred embodiment of the present invention, are said from technological layer, to the implementation
Several optimizations also should be regarded as within the scope of the present invention in step.
Comparative example 1
Isopropanol (250mL) is put into 500mL autoclave, is cooled to 0~5 DEG C, it is extremely full to be passed through methylamine gas (170.5g)
With, then by Formula II compound (42.1g) investment reaction flask, be warming up to 35~40 DEG C, insulation reaction 4 hours, be cooled to 0~5
DEG C, it adds and is passed through methylamine gas to being saturated, be warming up to 35~40 DEG C, insulation reaction 20~24 hours, after controlling qualification in TLC, drop
Temperature is to 0~5 DEG C, insulated and stirred 1 hour, filtering, and filter cake and isopropanol (100mL) are put into reaction flask, stir 1 at room temperature
Hour, filtering obtains compound of formula I crude product.Above-mentioned crude product and isopropanol (100mL) are put into reaction flask, are cooled to 0~5 DEG C,
HCl gas is passed through to pH≤1, ventilation finishes, insulated and stirred 1 hour, it is warming up to 70~75 DEG C, insulated and stirred 1 hour, then
30~35 DEG C are cooled to, insulated and stirred 1 hour, filtering, filter cake drying put into above-mentioned dry product and methylene chloride (200mL) anti-
Bottle is answered, 20% NaOH aqueous solution is added dropwise at room temperature, adjusts pH value 7~8, stirring is to dissolved clarification, stratification, and water layer is with two
Chloromethanes (200mL) extracts primary, merging organic layer, and decompression precipitation takes off and isopropanol (100mL) is added after doing, stirs at room temperature
It mixes 2 hours, filters, drying obtains intermediate compound of formula I (21.2g), purity (HPLC) 99.19%, yield 73%.
Through detecting, intermediate formula made from the characterize data of intermediate compound of formula I made from comparative example 1 and embodiment 1
The characterize data of Compound I is consistent.
1 purity of test example is investigated
The purity data of above-described embodiment and the intermediate compound of formula I of comparative example preparation is as shown in table 2 below.
Table 2
| Serial number | Purity | Impurity formula III compound | Other maximum contaminants |
| Comparative example 1 | 99.19% | 0.50% | 0.14% |
| Embodiment 1 | 99.57% | 0.19% | 0.07% |
| Embodiment 2 | 99.92% | 0.02% | 0.03% |
| Embodiment 3 | 99.83% | 0.03% | 0.05% |
| Embodiment 4 | 99.92% | 0.02% | 0.02% |
| Embodiment 5 | 99.38% | 0.01% | 0.23% |
| Embodiment 6 | 99.72% | 0.13% | 0.02% |
| Embodiment 7 | 99.66% | 0.15% | 0.05% |
| Embodiment 8 | 99.34% | 0.13% | 0.17% |
| Embodiment 9 | 99.56% | 0.25% | 0.08% |
| Embodiment 10 | 99.83% | 0.02% | 0.07% |
As shown in Table 2, the purity of intermediate compound of formula I obtained according to embodiments of the present invention is than made from comparative example 1
The purity is high of intermediate compound of formula I；Impurity formula III chemical combination in intermediate compound of formula I obtained according to embodiments of the present invention
The content of object wants much lower compared to the content of impurity formula III compound in intermediate compound of formula I made from comparative example 1；And
According to embodiments of the present invention in intermediate compound of formula I obtained the content of other maximum contaminants also than in made from comparative example 1
The content of other maximum contaminants is low in mesosome compound of formula I.
Claims (7)
1. the preparation method of compound of formula I, comprising the following steps:
Formula II compound is dissolved in organic solvent, with C3-4Alkyl primaquine is that ammonia source carries out ammonolysis reaction, obtains compound of formula I
2. according to the method described in claim 1, wherein, C3-4Alkyl primaquine is n-butylamine or n-propylamine.
3. method according to claim 1 or 2, wherein the organic solvent is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropyl
One of alcohol, n-butanol, tert-butyl alcohol are a variety of, preferably ethyl alcohol.
4. method according to claim 1 or 2, wherein the quality volume of the Formula II compound and the organic solvent
Than for 1:5-10, preferably 1:6.
5. method according to claim 1 or 2, wherein the Formula II compound and C3-4The molar ratio of alkyl primaquine is 1:
8-15, preferably 1:11.
6. method according to claim 1 or 2, wherein the ammonolysis reaction 60-100 DEG C at a temperature of carry out, preferably
75-80 DEG C at a temperature of carry out.
7. method according to claim 1 or 2, wherein after the ammonolysis reaction, reaction solution is cooled to 0-10
DEG C, it preferably 0-5 DEG C, stirs, filtering obtains compound of formula I.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| DE19962924A1 (en) * | 1999-12-24 | 2001-07-05 | Bayer Ag | Substituted oxazolidinones and their use |
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2019
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- 2019-12-13 WO PCT/CN2019/125116 patent/WO2020181860A1/en active Application Filing
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| 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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Application publication date: 20190726 |