CN114989159A - Synthetic method of rivaroxaban - Google Patents
Synthetic method of rivaroxaban Download PDFInfo
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- CN114989159A CN114989159A CN202210807327.4A CN202210807327A CN114989159A CN 114989159 A CN114989159 A CN 114989159A CN 202210807327 A CN202210807327 A CN 202210807327A CN 114989159 A CN114989159 A CN 114989159A
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- 229960001148 rivaroxaban Drugs 0.000 title claims abstract description 54
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 title claims abstract description 54
- 238000010189 synthetic method Methods 0.000 title claims description 8
- 238000000034 method Methods 0.000 claims abstract description 26
- -1 4- [4- [ (5S) -5- (aminomethyl) -2-carbonyl-3-oxazolidinyl ] phenyl ] -3-morpholinone hydrochloride Chemical compound 0.000 claims abstract description 15
- 239000012043 crude product Substances 0.000 claims abstract description 15
- QZLSBOVWPHXCLT-UHFFFAOYSA-N 5-chlorothiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)S1 QZLSBOVWPHXCLT-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000007670 refining Methods 0.000 claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 230000009471 action Effects 0.000 claims abstract description 5
- 238000006482 condensation reaction Methods 0.000 claims abstract description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 44
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 24
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000004537 pulping Methods 0.000 claims description 6
- GPIQOFWTZXXOOV-UHFFFAOYSA-N 2-chloro-4,6-dimethoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(OC)=N1 GPIQOFWTZXXOOV-UHFFFAOYSA-N 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000007821 HATU Substances 0.000 claims description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 22
- 230000008569 process Effects 0.000 abstract description 15
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 abstract description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 abstract description 8
- 230000002829 reductive effect Effects 0.000 abstract description 7
- 238000001308 synthesis method Methods 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000006257 total synthesis reaction Methods 0.000 abstract description 2
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- 239000002994 raw material Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 5
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 230000015271 coagulation Effects 0.000 description 5
- 238000005345 coagulation Methods 0.000 description 5
- 229960002897 heparin Drugs 0.000 description 5
- 229920000669 heparin Polymers 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 108010074860 Factor Xa Proteins 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 108090000190 Thrombin Proteins 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 239000003055 low molecular weight heparin Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229960004072 thrombin Drugs 0.000 description 3
- 108090000935 Antithrombin III Proteins 0.000 description 2
- 102100022977 Antithrombin-III Human genes 0.000 description 2
- GZSRYJHKUBISLJ-ZDUSSCGKSA-N NC[C@H]1CN(C(O1)=C=O)C1=CC=C(C=C1)N1C(COCC1)=O Chemical compound NC[C@H]1CN(C(O1)=C=O)C1=CC=C(C=C1)N1C(COCC1)=O GZSRYJHKUBISLJ-ZDUSSCGKSA-N 0.000 description 2
- 230000002429 anti-coagulating effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229940127215 low-molecular weight heparin Drugs 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- VQNDBXJTIJKJPV-UHFFFAOYSA-N 2h-triazolo[4,5-b]pyridine Chemical compound C1=CC=NC2=NNN=C21 VQNDBXJTIJKJPV-UHFFFAOYSA-N 0.000 description 1
- 108010029144 Factor IIa Proteins 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 230000001858 anti-Xa Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 229960005348 antithrombin iii Drugs 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002550 fecal effect Effects 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- KANJSNBRCNMZMV-ABRZTLGGSA-N fondaparinux Chemical compound O[C@@H]1[C@@H](NS(O)(=O)=O)[C@@H](OC)O[C@H](COS(O)(=O)=O)[C@H]1O[C@H]1[C@H](OS(O)(=O)=O)[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O[C@@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O4)NS(O)(=O)=O)[C@H](O3)C(O)=O)O)[C@@H](COS(O)(=O)=O)O2)NS(O)(=O)=O)[C@H](C(O)=O)O1 KANJSNBRCNMZMV-ABRZTLGGSA-N 0.000 description 1
- 229960001318 fondaparinux Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a synthesis method of rivaroxaban, which comprises the steps of carrying out condensation reaction on 4- [4- [ (5S) -5- (aminomethyl) -2-carbonyl-3-oxazolidinyl ] phenyl ] -3-morpholinone hydrochloride and 5-chloro-thiophene-2-carboxylic acid under the action of a condensing agent to generate 5-chloro-nitrogen- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophene-carboxamide, namely rivaroxaban crude product, and refining to obtain rivaroxaban. In the synthesis method, thionyl chloride and oxalyl chloride which are seriously polluted and dangerous in the using process are abandoned, and a warm and easily-treated condensing agent is used for reaction, so that the total synthesis yield is improved, the pollution is reduced, the process route is more environment-friendly, and the industrial mass production is easier.
Description
Technical Field
The invention relates to the technical field of organic synthesis of medicines, in particular to a synthetic method for producing rivaroxaban.
Background
Rivaroxaban is a novel anticoagulant drug developed by Bayer companies for 10 years, is the first direct Xa factor inhibitor in the world, Xa factor is the junction of extrinsic and intrinsic coagulation pathways, and rivaroxaban, which is a key point in the coagulation process, can directly inhibit the activity of Xa factor with high selectivity, thereby inhibiting the generation of thrombin and the formation of thrombus.
Factor Xa, which is the junction of the intrinsic and extrinsic coagulation pathways, plays a key role in the coagulation process and is therefore considered to be a very important target in the development of new anticoagulants. Many researches show that the single inhibition of the Xa factor can more effectively prevent coagulation, the curative effect can be predicted, the therapeutic window is wide, the normal hemostatic process is not influenced, and in addition, the Xa factor is directly inhibited theoretically, and rebound is not caused after the medicine is stopped. Therefore, factor Xa is selected as the target of action, which may produce better clinical effect and controllable influence on the blood coagulation process.
The pharmacokinetic study of rivaroxaban shows that the rivaroxaban has a rapid onset of action and can rapidly reach the peak plasma concentration 2-4 hours after administration. The absolute bioavailability is as high as 80-100%. Moreover, the maximum effect of inhibiting the Xa factor can be obtained 1-4 hours after the medicine is taken, and the anti-Xa activity can be maintained for a long time which is up to 24 hours.
Rivaroxaban is essentially different from heparin, low molecular weight heparin, indirect factor Xa inhibitors such as fondaparinux, etc. in that heparin, etc. needs to bind to antithrombin iii (atiii) in order to generate anti-factor Xa activity without direct effect on factor Xa, which leads to osteoporosis and the potential risk of heparin-mediated thrombocytopenia in long-term use. Rivaroxaban, however, does not require the involvement of ATIII and can directly antagonize free and bound factor Xa. And rivaroxaban is an oral preparation, is convenient to use, does not need to monitor aPTT at regular intervals like heparin or monitor Xa factor like low molecular heparin, and costs extra inspection cost.
Rivaroxaban as a factor Xa inhibitor (FXaI) has the following advantages over DTI: xa is a better target compared with thrombin, and the anticoagulation effect is small, so that the safety is high; FXaI is proved to be positively correlated to the curative effect and the dosage by a plurality of researches, but does not increase the bleeding risk; FXaI is less likely than DTI to cause thrombin rebound after withdrawal; strong anticoagulant effect, such as selective FXaIfondaparinux to Xa factor: the inhibition ratio of factor IIa (which is proportional to the anticoagulant effect) is 4:1, whereas low molecular weight heparin is 1.5:1 and normal heparin is only 1: 1.
Studies have shown that rivaroxaban does not accumulate after multiple doses. The half-life period of the compound in healthy young subjects is 5-9 hours, and the half-life period of the compound in old subjects is 11-13 hours. Rivaroxaban is cleared by both the feces and kidneys, approximately 2/3 being metabolically degraded, then half of it is cleared by the kidneys and the other half by the fecal route. The remaining 1/3 were cleared directly through the kidney in the prototype. The rivaroxaban prototype is the most important compound in human plasma, and no major or active circulating metabolite has been found
The price of the raw material medicine is continuously increased due to the large domestic market demand of rivaroxaban at present, so that the provision of a rapid, simple and efficient synthetic route becomes urgent.
The research on the synthesis method of rivaroxaban reported in the literature is more, the research content mainly focuses on the synthesis of oxazolidinone, the use of various protective groups and the like, and the invention mainly researches the amidation reaction of 4- [4- [ (5S) -5- (aminomethyl) -2-carbonyl-3-oxazolidinyl ] phenyl ] -3-morpholone and 5-chlorothiophene-2-carboxylic acid to generate rivaroxaban. The reaction is reported to be carried out by reacting 5-chlorothiophene-2-carboxylic acid with thionyl chloride or oxalyl chloride to generate 5-chlorothiophene-2-formyl chloride, and then reacting the 5-chlorothiophene-2-carboxylic acid with 4- [4- [ (5S) -5- (aminomethyl) -2-carbonyl-3-oxazolidinyl ] phenyl ] -3-morpholinone to generate rivaroxaban. In the invention, thionyl chloride and oxalyl chloride which are seriously polluted and dangerous in the using process are abandoned, and a mild and easily-treated condensing agent is used for reaction, so that the total synthesis yield is improved, the pollution is reduced, the process route is more environment-friendly, and the industrial mass production is easier.
Disclosure of Invention
The invention provides a simple synthetic method of rivaroxaban. The synthetic method provided by the invention has the advantages of green and environment-friendly raw materials, low cost, simplicity and easiness in operation, high yield, simplified steps for obtaining rivaroxaban, improved yield and powerful support for large-scale industrial production of rivaroxaban.
In order to achieve the purpose, the invention provides the following technical scheme:
a method for synthesizing and refining rivaroxaban is characterized in that under the action of a condensing agent, 4- [4- [ (5S) -5- (aminomethyl) -2-carbonyl-3-oxazolidinyl ] phenyl ] -3-morpholinone hydrochloride and 5-chlorothiophene-2-carboxylic acid are subjected to condensation reaction to generate 5-chloro-nitrogen- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophene-carboxamide, a rivaroxaban crude product is obtained after filtration and drying, and rivaroxaban is obtained after refining;
wherein the condensation reaction condition is at least one of D Dicyclohexylcarbodiimide (DCC)/triethylamine, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU)/N, N-Diisopropylethylamine (DIPEA), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)/4-Dimethylaminopyridine (DMAP), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT)/N-methylmorpholine, 1-N-propylphosphoric anhydride (T3P)// 4-Dimethylaminopyridine (DMAP), and the like; the reaction solvent is one of NN-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and acetonitrile, and the refining method of the rivaroxaban crude product is one of methanol pulping, acetonitrile pulping, NN-Dimethylformamide (DMF) crystallization, NN-Dimethylformamide (DMF)/water crystallization and dimethyl sulfoxide (DMSO)/acetonitrile crystallization.
(1) Synthesis of rivaroxaban crude product
Reacting 4- [4- [ (5S) -5- (aminomethyl) -2-carbonyl-3-oxazolidinyl ] phenyl ] -3-morpholinone hydrochloride with 5-chlorothiophene-2-carboxylic acid in a proper solvent by using a condensing agent to generate a rivaroxaban crude product, crystallizing by using a proper mixed solvent, and filtering to obtain a rivaroxaban refined product.
The invention takes 4- [4- [ (5S) -5- (aminomethyl) -2-carbonyl-3-oxazolidinyl ] phenyl ] -3-morpholone hydrochloride and 5-chlorothiophene-2-carboxylic acid as initial raw materials, synthesizes a rivaroxaban crude product by using a condensing agent, and obtains a rivaroxaban finished product after refining. The method for synthesizing and refining rivaroxaban is simple, convenient and easy to operate, and has the advantages of high yield and mild reaction conditions compared with the existing synthetic route; the synthetic method of rivaroxaban can obtain a high-yield and high-purity product, and meanwhile, the product is dissolved and crystallized by a simple mixed solvent, so that the overall yield is improved, the pollution is reduced, and the harm in production operation is reduced. The method has mild reaction conditions and cheap raw materials, and is suitable for industrial large-scale production.
In the synthesis method of the present invention, preferably, the condensation reaction condition in step (1) is at least one of Dicyclohexylcarbodiimide (DCC)/triethylamine, 2- (7-azabenzotriazole) -N, N' -tetramethyluronium Hexafluorophosphate (HATU)/N, N-Diisopropylethylamine (DIPEA), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)/4-Dimethylaminopyridine (DMAP), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT)/N-methylmorpholine, 1-N-propylphosphoric anhydride (T3P)/4-Dimethylaminopyridine (DMAP), and the like, and is preferably Dicyclohexylcarbodiimide (DCC)/triethylamine.
In the synthesis method of the present invention, preferably, the reaction solvent in step (1) is one of NN-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), and acetonitrile; dimethyl sulfoxide (DMSO) is preferred.
In the synthetic method of the present invention, preferably, the refining method of the rivaroxaban crude product in the step (1) is one of methanol pulping, acetonitrile pulping, NN-Dimethylformamide (DMF) crystallization, NN-Dimethylformamide (DMF)/water crystallization, and dimethyl sulfoxide (DMSO)/acetonitrile crystallization. Preferably Dimethylsulfoxide (DMSO)/acetonitrile.
Compared with the prior art, the synthesis and refining method of rivaroxaban disclosed by the invention has the following positive effects:
the process route takes 4- [4- [ (5S) -5- (aminomethyl) -2-carbonyl-3-oxazolidinyl ] phenyl ] -3-morpholone hydrochloride and 5-chlorothiophene-2-carboxylic acid as starting raw materials, synthesizes a rivaroxaban crude product by using a condensing agent, and obtains a rivaroxaban fine product after refining. Compared with the original process, the synthesis process route has the advantages of high yield and mild reaction conditions; moreover, the method has the advantages of cheap raw materials, simple post-treatment and mild reaction conditions, and is suitable for industrial scale-up production.
Detailed Description
For the sake of simplicity and clarity, descriptions of well-known techniques are omitted appropriately below to avoid unnecessary detail affecting the description of the present solution. The synthesis and purification method of rivaroxaban according to the present invention will be further described with reference to the preferred examples, which particularly illustrate that the compound 4- [4- [ (5S) -5- (aminomethyl) -2-carbonyl-3-oxazolidinyl ] phenyl ] -3-morpholinone hydrochloride can be conveniently obtained by the related patents (see the synthesis methods CN201010212502 and CN 1906191); 5-chlorothiophene-2-carboxylic acid is commercially available, and further NN-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), N-methylmorpholine and hydrochloric acid are also commercially available.
Example 1
15.26g of dimethyl sulfoxide (DMSO)) was charged into a reaction flask, stirring was turned on, and 1.16g of 4- [4- [ (5S) -5- (aminomethyl) -2-carbonyl-3-oxazolidinyl ] phenyl ] -3-morpholinone hydrochloride and 0.5g of 5-chlorothiophene-2-carboxylic acid were added. The temperature was reduced to 0 ℃ and 0.6g of 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT)) and 0.5g N-methylmorpholine were added to the reaction mixture. After the addition, the reaction was carried out at 3 ℃ for 90 minutes, and the progress of the reaction was monitored by TLC, and the reaction was completed when the starting material, 4- [4- [ (5S) -5- (aminomethyl) -2-carbonyl-3-oxazolidinyl ] phenyl ] -3-morpholinone hydrochloride, was consumed. After completion of the reaction, 23.20g (1.20 g hydrochloric acid +22.00g purified water) of dilute hydrochloric acid was added dropwise to the reaction mixture while keeping the temperature at 10 ℃. After the dripping is finished, stirring is carried out for 2 hours at the temperature of 20 ℃, heat preservation is finished, and the rivaroxaban crude product (1.2 g, yield 78.60%) is obtained after suction filtration, washing and drying.
3.50g of dimethyl sulfoxide DMSO is added into a reaction bottle, stirring is started, 1.20g of rivaroxaban crude product is added, and stirring is carried out until the rivaroxaban crude product is dissolved. After the solution was cleared, 7.0g of acetonitrile was added to the above reaction solution. After the dropwise addition, the temperature is reduced to 25 ℃ and the temperature is kept for 2 hours. Filtering, washing and drying at 100 ℃ for 2 hours to obtain a rivaroxaban competitive product with a melting point of 229.9-235.5 ℃ (purity of 99.7% and yield of 93.1%).
Example 2
10.96g of dimethylformamide (NN-Dimethylformamide (DMF)) were placed in a reaction flask, stirring was turned on, and 1.16g of 4- [4- [ (5S) -5- (aminomethyl) -2-carbonyl-3-oxazolidinyl ] phenyl ] -3-morpholinone hydrochloride and 0.5g of 5-chlorothiophene-2-carboxylic acid were added. Cooling to 0 deg.C, adding Dicyclohexylcarbodiimide (DCC), and dropping triethylamine at 5 deg.C or below. After the addition was completed, the reaction was carried out at 0 ℃ for 60 minutes, and the progress of the reaction was monitored by TLC, and the reaction was completed when the starting material, 4- [4- [ (5S) -5- (aminomethyl) -2-carbonyl-3-oxazolidinyl ] phenyl ] -3-morpholinone hydrochloride, was consumed. After the reaction was completed, insoluble matter was filtered, and the reaction solution was concentrated to obtain a crude rivaroxaban product (1.2 g, yield 78.60%).
Adding 3.50g of dimethylformamide (NN-Dimethylformamide (DMF)) into a reaction bottle, starting stirring, adding 1.20g of rivaroxaban crude product, heating to an internal temperature of 75-80 ℃, and stirring until the rivaroxaban crude product is dissolved. After the solution was cleared, 7.20g of purified water was added to the above reaction solution. After the addition, the temperature is reduced to 25 +/-2 ℃, and the temperature is kept for 2 hours. And (5) after heat preservation, performing suction filtration, and drying at 70-100 ℃ for 8 hours. After drying, obtaining rivaroxaban competitive products with melting point of 230.5-236.8 ℃ (purity of 96.3% and yield of 91.3%)
The physical and chemical properties of rivaroxaban prepared by the method are as follows:
and (4) conclusion: the conventional process of rivaroxaban uses thionyl chloride or oxalyl chloride, has many side reactions, is high in pollution, is dangerous to operate and is not beneficial to industrial production; most of the raw materials of the process provided by the invention are completely reacted, a solid with higher purity can be obtained after elution and crystallization by using a mixed solvent, the yield is far higher than that of the conventional process, a green and environment-friendly process route is more beneficial to industrial production, and the synthesized rivaroxaban is consistent with physicochemical data reported in the document CN 1262551C.
It will be apparent to those skilled in the art that various changes and modifications can be made in the above embodiments without departing from the scope and spirit of the invention, and any simple modification and equivalent changes and modifications made to the above embodiments according to the technical spirit of the invention fall within the scope of the invention. And the invention is not limited to the example embodiments set forth in the description.
Claims (1)
1. A synthetic method of rivaroxaban is characterized in that under the action of a condensing agent, 4- [4- [ (5S) -5- (aminomethyl) -2-carbonyl-3-oxazolidinyl ] phenyl ] -3-morpholone hydrochloride and 5-chloro-thiophene-2-carboxylic acid are subjected to condensation reaction in a reaction solvent to generate 5-chloro-nitrogen- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophene-carboxamide, a rivaroxaban crude product is obtained after filtration and drying, and rivaroxaban crude product is obtained after refining
Wherein the condensing agent is at least one of Dicyclohexylcarbodiimide (DCC)/triethylamine, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU)/N, N-Diisopropylethylamine (DIPEA), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)/4-Dimethylaminopyridine (DMAP), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT)/N-methylmorpholine, 1-N-propylphosphoric anhydride (T3P)// 4-Dimethylaminopyridine (DMAP); the reaction solvent is one of NN-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and acetonitrile;
the refining method is one of methanol pulping, acetonitrile pulping, NN-Dimethylformamide (DMF) crystallization, NN-Dimethylformamide (DMF)/water crystallization and dimethyl sulfoxide (DMSO)/acetonitrile crystallization.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103360380A (en) * | 2013-03-13 | 2013-10-23 | 浙江天宇药业股份有限公司 | Synthesis method of rivaroxaban, and rivaroxaban intermediate and preparation thereof |
| CN104650057A (en) * | 2013-11-22 | 2015-05-27 | 重庆医药工业研究院有限责任公司 | Rivaroxaban preparation method |
| CN110172060A (en) * | 2018-12-27 | 2019-08-27 | 苏州二叶制药有限公司 | Razaxaban, synthesis and refining methd |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103360380A (en) * | 2013-03-13 | 2013-10-23 | 浙江天宇药业股份有限公司 | Synthesis method of rivaroxaban, and rivaroxaban intermediate and preparation thereof |
| CN104650057A (en) * | 2013-11-22 | 2015-05-27 | 重庆医药工业研究院有限责任公司 | Rivaroxaban preparation method |
| CN110172060A (en) * | 2018-12-27 | 2019-08-27 | 苏州二叶制药有限公司 | Razaxaban, synthesis and refining methd |
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