CN105820161A - Synthetic method of rivaroxaban intermediate 5-hydroxy methyl oxazolidinone derivative - Google Patents
Synthetic method of rivaroxaban intermediate 5-hydroxy methyl oxazolidinone derivative Download PDFInfo
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- CN105820161A CN105820161A CN201510008716.0A CN201510008716A CN105820161A CN 105820161 A CN105820161 A CN 105820161A CN 201510008716 A CN201510008716 A CN 201510008716A CN 105820161 A CN105820161 A CN 105820161A
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Abstract
The invention provides a synthetic method of a rivaroxaban intermediate 5-hydroxy methyl oxazolidinone derivative, and concretely provides a method for preparing a rivaroxaban intermediate (I). The synthetic method comprises the following steps: 1) a compound (II) and a compound (III) are subjected to a reaction in the presence of alkali to obtain a compound (IV); and 2) the compound (IV) and (R)-glycidyl butyrate are subjected to a reaction in the presence of alkali to obtain the rivaroxaban intermediate (I), which is 4-(4-((5S)-5-(hydroxy methyl)-2-oxo-1, 3-oxazolidine-3-yl)phenyl)morpholine-3-ketone. The provided novel method has the advantages of mild reaction condition, simple operation, convenient purification, and low production cost, and is suitable for industrial production.
Description
Technical field
The present invention relates to the synthetic method of anticoagulation medicine Rivaroxaban intermediate, synthetic method more particularly to Rivaroxaban intermediate 4-(4-((5S)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidine-3-base) phenyl) morpholine-3-ketone.
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 JIUYUE, 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 deep venous thrombosis (DVT) and the formation of pulmonary infarction (PE).Along with the clinical practice of razaxaban, the demand of razaxaban will be gradually increased.
The committed step of razaxaban synthesis is exactly the introducing of the circulus of substituted 5-methyloxazolidinone.The most existing multiple synthetic method is in the news.
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.
It addition, aromatic series amido is after COOR3 protection forms carbamate, reacts with (R)-Glycidyl butyrate under the effect of alkali and generate the method for 5-hydroxymethyl oxazolidone ring also by wide coverage.
In document report, R3 is saturated alkyl, the substituted alkyl of aryl and aryl.As patent WO2011080341 discloses a 4-(4-aminophenyl protected with benzyloxycarbonyl group)-morpholine-3-ketone route as initiation material:
In this route, aromatic amine is protected by benzyloxycarbonyl group, and the chiral centre in azoles ring is introduced by (R)-Glycidyl butyrate, it is to avoid use poisonous polychlorinated dibenzo-furans.But on the low side through the yield of the reaction of compound (VII) generation compound (I) by compound (II), the yield of two-step reaction is respectively 86% and 80%, and the cost of material ultimately resulting in whole synthetic route is higher, is not suitable for industrialized production.
Summary of the invention
It is an object of the present invention to provide a kind of synthesis Rivaroxaban intermediate 4-(4-((5S)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidine-3-base) phenyl } method of morpholine-3-ketone, reaction condition is gentle, simple to operate, be easy to purification, yield high, low production cost, is suitable for industrialized production.
For reaching object above, the present invention provides techniques below scheme:
One prepares the method for Rivaroxaban intermediate (I), it is characterised in that including:
1) compound (II) reacts with compound (III) in the presence of base and obtains compound (IV)；
2) compound (IV) reacts with (R)-Glycidyl butyrate in the presence of base and obtains in the middle of razaxaban (I), i.e. 4-(4-((5S)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidine-3-base) phenyl) morpholine-3-ketone.
Wherein, X is leaving group.R1 and R2 is respectively selected from hydrogen, the alkyl of C1-C10 and the substituted hydrocarbon radical of C1-C10.R1 and R2 can be the same or different.
Further, the X in step 1) is selected from halogen and the structure of logical formula V:
The definition of R1 and R2 is with claim 1.
Alkali in step 1) is selected from organic base or inorganic base.Organic base bag is selected from tertiary amine, pyridine and substituted pyridine.Tertiary amine is preferably triethylamine, N-methylmorpholine and N, N-diisopropyl ethyl amine.Substituted pyridines is preferably 2,6-lutidines, 2,4,6-trimethylpyridine and 4-(N, N-dimethylamino) pyridine.Inorganic base is preferably alkali carbonate, alkali metal hydrogencarbonate and alkali metal hydroxide.
Further, step 2) in alkali selected from tert-butyl alcohol lithium, n-BuLi, lithium diisopropyl amido, LHMDS, Feldalat NM and Sodium ethylate.
The present invention also provides for the compound of a kind of logical formula (IV):
Wherein, R1 and R2 is respectively selected from hydrogen, the alkyl of C1-C10 and the substituted hydrocarbon radical of C1-C10.R1 and R2 can be the same or different.
Although, aromatic series amido forms carbamate through COOR3 protection and reacts the method for generation 5-hydroxymethyl oxazolidone ring under the effect of alkali with (R)-Glycidyl butyrate also by wide coverage.But the R3 used in document is saturated alkyl, the substituted alkyl of aryl and aryl.The structure that R3 is allyl deriv that the present invention uses, the yield of two-step reaction, all more than 90%, the most all improves a lot.
The invention provides a kind of synthesis Rivaroxaban intermediate 4-(4-((5S)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidine-3-base) phenyl } method of morpholine-3-ketone.Reaction condition in this method is gentle, and reaction temperature is generally carried out under room temperature or lower temperature；Simple to operate and be easy to purification, simple filtration can be obtained by the product that purity is the highest after completion of the reaction；Yield is high, two step yields all at yield more than 90%, low production cost, be suitable for industrialized production.
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)
In the three neck round bottom of 250 ml fills, add compound II(15.0 g, 78.0 mmol), water (200 ml) and sodium bicarbonate (13.1 g, 156 mmol), it is cooled to 0 ~ 5 DEG C, temperature control 5 ~ 10 DEG C, is slowly added dropwise compound IIIa(10.0 g, 82.8 mmol).Drip and finish, be warming up to room temperature, continuous stirring 3 ~ 4 hours.After HPLC follows the tracks of reaction completely, filtering, filter cake washes with water, obtains compound (IVa) 20.7 after drying
G, yield 96.1%.
1H
NMR (400MHz, d6-DMSO): 9.78 (s, 1H), 7.40 (d,
J=8.0Hz, 2H), 7.25 (d, J=8.0Hz, 2H), 6.05-5.86 (s, 1H), 5.35-5.31 (m, 1H),
5.23-5.18 (m, 1H), 4.64-4.56 (m, 2H), 4.15 (s, 2H), 3.96-3.87 (m, 2H),
3.68-3.62 (m, 2H). LC-MS (ESI): m/z 277.
Step 2)
Compound IVa(20.2 g is added in the three neck round bottom of 250 ml fills, 73.0 mmol), (R)-Glycidyl butyrate (11.6 g, 80.3 mmol) and oxolane (190 ml) and, slow tert-butyl alcohol lithium (11.7 g at 20 ~ 30 DEG C, 146 mmol), and react 12 ~ 14 hours at this temperature.After HPLC follows the tracks of reaction completely, the hydrochloric acid with 3% regulates pH=6.5 ~ 7.0, and at 35 DEG C, decompression removes major part oxolane, filters, and filter cake washes with water, obtains compound (I) 19.6 g, yield 91.8% after drying.LC-MS (ESI): m/z 293.
Embodiment 2:
Step 1)
In the three neck round bottom of 250 ml fills, add compound II(15.0 g, 78.0 mmol), triethylamine (8.68 g, 85.8 mmol) and dichloromethane (150 ml), it is cooled to 0 ~ 5 DEG C, temperature control 5 ~ 10 DEG C, is slowly added dropwise compound IIIb(12.75 g, 85.8 mmol).Drip and finish, be warming up to room temperature, continuous stirring 3 ~ 4 hours.After HPLC follows the tracks of reaction completely, filtering, filter cake washes with water, obtains compound (IVb) 22.5 after drying
G, yield 94.8%.
1H NMR
(400MHz, d6-DMSO): 9.78 (s, 1H), 7.40 (d,
J=8.0Hz, 2H), 7.25 (d, J=8.0Hz, 2H), 6.05-5.86 (s, 1H), 4.64-4.56 (m, 2H), 4.15
(s, 2H), 3.96-3.87 (m, 2H), 3.68-3.62 (m, 2H), 1.82 (s, 3H), 1.74 (s, 3H).
LC-MS (ESI): m/z 305.
Step 2)
Compound IVa(22.0 g is added in the three neck round bottom of 250 ml fills, 72.3 mmol), (R)-Glycidyl butyrate (11.5 g, 79.5 mmol) and oxolane (190 ml) and, hexane solution (34.7 ml of the n-BuLi of 2.5mol/L it are slowly added dropwise at-80 ~-70 DEG C, 86.8 mmol), drip and finish, temperature is slowly increased to room temperature, and reacts 3 ~ 4 hours at this temperature.After HPLC follows the tracks of reaction completely, embracing and react with ammonium chloride solution cancellation, and regulate pH=6.5 ~ 7.0 with the hydrochloric acid of 3%, at 35 DEG C, decompression removes major part oxolane, filters, and filter cake washes with water, obtains compound (I) 19.2 after drying
G, yield 90.2%.LC-MS
(ESI): m/z 293.
Embodiment 3:
Step 1)
Compound II(15.0 g is added in the three neck round bottom of 250 ml fills, 78.0 mmol), compound IIIc(15.3 g, 89.7 mmol), triethylamine (9.47 g, 93.6 mmol), 4-(N, N-dimethylamino) pyridine (0.5 g) and dichloromethane (150 ml).It is warming up to backflow, continuous stirring 3 ~ 4 hours.After HPLC follows the tracks of reaction completely, filter, filter cake water and washing with alcohol, obtain compound (IVc) 21.2 g, yield 93.7% after drying.
1H
NMR (400MHz, d6-DMSO): 9.78 (s, 1H), 7.40 (d,
J=8.0Hz, 2H), 7.25 (d, J=8.0Hz, 2H), 5.35-5.31 (m, 1H), 5.23-5.18 (m, 1H),
4.64-4.56 (m, 2H), 4.15 (s, 2H), 3.96-3.87 (m, 2H), 3.68-3.62 (m, 2H), 1.74 (s,
3H). LC-MS (ESI): m/z 291.
Step 2)
Compound IVa(20.0 g is added in the three neck round bottom of 250 ml fills, 68.9 mmol), (R)-Glycidyl butyrate (10.9 g, 75.8 mmol) and oxolane (190 ml) and, at 0 ~ 10 DEG C, be slowly added dropwise the tetrahydrofuran solution (82.7 of the hexamethyl silica-based amido lithium of 1mol/L
Ml, 82.7 mmol), drip and finish, temperature is slowly increased to room temperature, and reacts 5 ~ 6 hours at this temperature.After HPLC follows the tracks of reaction completely, embrace and react with ammonium chloride solution cancellation, and regulate pH=6.5 ~ 7.0 with the hydrochloric acid of 3%, at 35 DEG C, decompression removes major part oxolane, filters, filter cake water and washing with alcohol, obtain compound (I) 18.5 g, yield 91.9% after drying.LC-MS (ESI): m/z 293.
Claims (7)
1. the method preparing Rivaroxaban intermediate (I)
It is characterized in that:
1) compound (II) reacts with compound (III) in the presence of base and obtains compound (IV)；
2) compound (IV) reacts with (R)-Glycidyl butyrate in the presence of base and obtains in the middle of razaxaban (I), i.e. 4-(4-((5S)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidine-3-base) phenyl) morpholine-3-ketone；
Wherein, X is leaving group；
R1And R2It is respectively selected from hydrogen, the alkyl of C1-C10 and the substituted hydrocarbon radical of C1-C10；
R1And R2Can be the same or different.
2., according to claim 1, the X in step 1) is selected from halogen and the structure of logical formula V:
The definition of R1 and R2 is with claim 1.
3., according to claim 1, the alkali in step 1) is selected from organic base or inorganic base.
4., according to claim 3, organic base bag is selected from tertiary amine, pyridine and substituted pyridine；Tertiary amine is preferably triethylamine, N-methylmorpholine and N, N-diisopropyl ethyl amine；Substituted pyridines is preferably 2,6-lutidines, 2,4,6-trimethylpyridine and 4-(N, N-dimethylamino) pyridine.
5., according to claim 3, inorganic base is preferably alkali carbonate, alkali metal hydrogencarbonate and alkali metal hydroxide.
6. according to claim 1, step 2) in alkali selected from tert-butyl alcohol lithium, n-BuLi, lithium diisopropyl amido, LHMDS, Feldalat NM and Sodium ethylate.
7. lead to the compound of formula (IV):
Wherein, R1And R2It is respectively selected from hydrogen, the alkyl of C1-C10 and the substituted hydrocarbon radical of C1-C10；R1And R2Can be the same or different.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108059624A (en) * | 2016-11-08 | 2018-05-22 | 上海医药工业研究院 | It is used to prepare the preparation method of click azoles amine key intermediate |
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| US20050080081A1 (en) * | 2001-02-09 | 2005-04-14 | Alexander Straub | Substituted oxazolidinones and their use in the field of blood coagulation |
| CN1772751A (en) * | 1999-12-24 | 2006-05-17 | 拜耳医药保健股份公司 | Substituted oxazolidinones and their use in the field of blood coagulation |
| WO2008090570A1 (en) * | 2007-01-25 | 2008-07-31 | Panacea Biotec Ltd | Novel antimicrobials |
| CN102822167A (en) * | 2010-01-04 | 2012-12-12 | 埃南蒂亚有限公司 | Process for the preparation of rivaroxaban and intermediates thereof |
| CN103012389A (en) * | 2013-01-24 | 2013-04-03 | 中国药科大学 | Rivaroxaban intermediate preparation method |
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2015
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Patent Citations (5)
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| CN1772751A (en) * | 1999-12-24 | 2006-05-17 | 拜耳医药保健股份公司 | Substituted oxazolidinones and their use in the field of blood coagulation |
| US20050080081A1 (en) * | 2001-02-09 | 2005-04-14 | Alexander Straub | Substituted oxazolidinones and their use in the field of blood coagulation |
| WO2008090570A1 (en) * | 2007-01-25 | 2008-07-31 | Panacea Biotec Ltd | Novel antimicrobials |
| CN102822167A (en) * | 2010-01-04 | 2012-12-12 | 埃南蒂亚有限公司 | Process for the preparation of rivaroxaban and intermediates thereof |
| CN103012389A (en) * | 2013-01-24 | 2013-04-03 | 中国药科大学 | Rivaroxaban intermediate preparation method |
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| 符坚等: "利伐沙班合成工艺改进", 《安徽医药》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108059624A (en) * | 2016-11-08 | 2018-05-22 | 上海医药工业研究院 | It is used to prepare the preparation method of click azoles amine key intermediate |
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