CN104926807A - Rivaroxaban related substance 'diamine' and synthesis method thereof - Google Patents
Rivaroxaban related substance 'diamine' and synthesis method thereof Download PDFInfo
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- CN104926807A CN104926807A CN201510304496.6A CN201510304496A CN104926807A CN 104926807 A CN104926807 A CN 104926807A CN 201510304496 A CN201510304496 A CN 201510304496A CN 104926807 A CN104926807 A CN 104926807A
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- chlorothiophene
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- KGFYHTZWPPHNLQ-AWEZNQCLSA-N O=C(c([s]1)ccc1Cl)NC[C@@H](CN1c(cc2)ccc2N(CCOC2)C2=O)OC1=O Chemical compound O=C(c([s]1)ccc1Cl)NC[C@@H](CN1c(cc2)ccc2N(CCOC2)C2=O)OC1=O KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 description 1
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- 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
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Abstract
The invention belongs to the technical field of medicines, and discloses the structure and a synthesis method of a rivaroxaban related substance 'diamine'. The synthesis method comprises the following steps: (1) under the premise that rivaroxaban is used as an initial raw material, conducting hydrolysis on morpholine ketone ring to obtain a compound 3; (2) under the premise that 5-chlorothiophene-2-formic acid and sulfoxide chloride are used as initial raw material, carrying out synthesis to obtain 5-chlorothiophene-2-formyl chloride, namely a compound 5; (3) condensing the compound 3 and the compound 5 to create a compound 6; (4) condensing the compound 6 with methylamine to obtain the rivaroxaban related substance 'diamine'. The synthesis method has the advantages that the raw materials are easy to obtain, and the operation is simple. A synthesis route of the rivaroxaban related substance 'diamine' is shown in the description.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of synthetic method of razaxaban related substances " diamines ".
Background technology
Razaxaban (rivaroxaban, 2) is the direct inhibitor of first oral Xa factor developed jointly by Bayer and Johson & Johnson, the clinical phlebothrombosis being mainly used in prevention hip joint or knee replacements patient.The razaxaban of Beyer Co., Ltd's exploitation goes on the market on the ground such as European Union and Canada for 2008, and in June, 2009, within 2011, in U.S.'s listing, in the whole world, more than 50 countries went on the market so far at Chinese official listing.
Razaxaban is the novel anticoagulant that Beyer Co., Ltd goes through research and development in 10 years, is first the direct Xa factor inhibitor in the whole world.It can directly suppress to be Xa factor that is free or bonding state in high selectivity ground, and produce anticoagulation, have bioavailability high, disease therapy spectrum is wide, and dose-effect relationship is stable, convenient oral, the feature that bleeding risk is low.As novel anticoagulant, razaxaban is by oral absorption, and lasting medicine, can only take medicine once in one day, and it is treated window width and monitors without the need to conventional coagulation function.These advantages make razaxaban become the new lover of resisting cardiovascular and disease in the blood system.
According to IMS Health data presentation, within 2008, the global antithrombotic reagent market sales revenue is 18,000,000,000 dollars, and increase by 16% on a year-on-year basis, 2009 annual growths are 7.95%, reach 19,500,000,000 dollars.Razaxaban is expected to become the new cookle level new drug of cardiovascular field after clopidogrel.Thomson Reuters is predicted, the sales volume to this medicine in 2015 will reach 3,200,000,000 dollars.Wide market.
Razaxaban chemistry is by name: the chemistry chloro-N-of 5-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidine-5-base] methyl]-2-thenoyl amine by name, and its structural formula is:
At present, the research about razaxaban technique is very active, and Chinese patent discloses and authorizes just more than ten.For studying and controlling the quality of razaxaban, need to prepare its related substance product in contrast.According to several impurity that the constitutional features of razaxaban and Straub equal calendar year 2001 synthesis technique may have disclosed in the European patent WO0147919 of autograph Substituted oxazolidinones and their usein the field of blood coagulation, report some impurity synthesis modes, one of the important impurity of razaxaban is " diamines " according to the literature, but document does not provide structure and the synthetic method of " diamines ".According in the quality standard of razaxaban, the absorption peak position of " diamines " HPLC and our result of study, the chemical structure that we provide " diamines " and synthetic method.
Summary of the invention
The object of the present invention is to provide structure and the synthetic method of the razaxaban related substances of one " diamines ", for study and the quality controlling razaxaban lays the foundation.
The structural formula of razaxaban related substances " diamines " provided by the invention is as follows:
Molecular weight: 610.5
Molecular formula: C
25h
24cl
2n
4o
6s
2
The synthetic method of razaxaban related substances " diamines " of the present invention, comprises the steps:
(1) 2-(2-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-Yang Dai oxazolidine-3-base) phenyl) amino) oxyethyl group) synthesis of acetic acid (compound 3):
In bottle with two necks, add razaxaban, slowly add successively volume ratio be 3 ~ 9:0.5 ~ 4:0.5 ~ 6 Glacial acetic acid, water and 35% concentrated hydrochloric acid.Under stirring, be heated to 30 ~ 100 DEG C, insulation reaction 3 ~ 10 hours.Be cooled to room temperature, filter.The making beating of filter cake Virahol washes 2 times, obtains compound as white solid 3.
(2) synthesis of 5-chlorothiophene-2-formyl chloride (compound 5):
In bottle with two necks, add 5-chlorothiophene-2-formic acid, not solubilizing agent or add dissolution with solvents, solvent for use is methylene dichloride, tetrahydrofuran (THF), acetonitrile, ether, acetone, ethyl acetate, and the amount of solvent for use is 1 ~ 30 times of 5-chlorothiophene-2-formic acid quality; Add a pyridine and do catalysis, slowly add sulfur oxychloride, wherein the feed ratio of sulfur oxychloride and 5-chlorothiophene-2-formic acid is 1 ~ 10:1, and be heated to 20 ~ 80 DEG C under stirring, solid dissolves gradually, insulation reaction 2 ~ 6 hours.Be cooled to room temperature, underpressure distillation removing more than sulfur oxychloride, obtain the compound 5 of pale yellowish oil liquid;
(3) synthesis of 2-(2-(the chloro-N-of 5-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-Yang Dai oxazolidine-3-base) phenyl) thiophene-2-carboxamide derivatives base) oxyethyl group) acetic acid (compound 6):
Compound 3 is added in there-necked flask, add dissolution with solvents, solvent for use is methylene dichloride, tetrahydrofuran (THF), acetone, acetonitrile, ether, ethyl acetate, N, dinethylformamide, 2 ~ 30 times that the amount of solvent for use is the quality that feeds intake, add triethylamine, the molar weight of triethylamine is 1 ~ 6 times of compound 3, is cooled to-30 DEG C ~ 5 DEG C.Slow dropping 5-chlorothiophene-2-formyl chloride, the molar weight of 5-chlorothiophene-2-formyl chloride is that 1 ~ 5 times of compound 3 keeps-30 DEG C ~ 5 DEG C reactions 0.1 ~ 5 hour, then room temperature is risen to, react 0.1 ~ 5 hour, cancellation, cancellation reagent is water, methyl alcohol, ethanol, propyl alcohol, and extract 2 ~ 6 times, extraction agent is methylene dichloride, ethyl acetate, tetrahydrofuran (THF).Merge organic phase, recycling design, obtains faint yellow solid compound 6.
(4) synthesis of razaxaban related substances " diamines ":
With the aqueous methylamine solution of dichloromethane extraction 40%, methylene dichloride uses anhydrous sodium sulfate drying mutually, stand-by.Compound 6 is added in there-necked flask, add dissolution with solvents, solvent for use is methylene dichloride, tetrahydrofuran (THF), ethyl acetate, acetonitrile, acetone, N, dinethylformamide, ether, the quantity of solvent added is 3 ~ 20 times of reactant weight, slowly DCC or CDI is added under ice bath, the molar weight of DCC or DCI added is 1 ~ 10 times of (2-(the chloro-N-of 5-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-oxygen is for oxazolidine-3-base) phenyl) thiophene-2-carboxamide derivatives base) oxyethyl group) acetic acid, room temperature is risen to after adding, react 0.5 ~ 10 hour, then the dichloromethane solution of methylamine is added.React 1 ~ 30 hour under room temperature.Decompression and solvent recovery, obtain light yellow solid, by this solid through silica column purification, eluent used is sherwood oil and ethyl acetate or methylene dichloride and methyl alcohol, eluent ratio is ethyl acetate: sherwood oil=5:1 ~ 100 or methyl alcohol: methylene dichloride=1:30 ~ 300, obtains razaxaban related substances " diamines ".
Razaxaban related substances " diamines " of the present invention, can as the crucial reference substance of monitoring razaxaban amount.
The synthetic method of razaxaban related substances " diamines " of the present invention, has raw material and is easy to get, simple to operate, has good practicality, can produce good economic benefit and social benefit.
Embodiment
Embodiment 1: the preparation of razaxaban related substances " diamines ":
(1) 2-(2-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-Yang Dai oxazolidine-3-base) phenyl) amino) oxyethyl group) synthesis of acetic acid (compound 3):
In the 250mL bottle with two necks that thermometer and rotor are housed, add 5g compound 2, slowly add 50mL Glacial acetic acid, 15mL water and 30mL concentrated hydrochloric acid successively.Under stirring, be heated to 60 DEG C, reaction solution dissolves gradually, insulation reaction 5 hours.Be cooled to room temperature, suction filtration.With 20mL Virahol filter wash cake at twice.Then filter cake is placed in 50mL single port bottle, with 25mL Virahol making beating wash, suction filtration, with 20mL Virahol at twice filter wash cake obtain the compound 3 of 4.8g white solid.Yield 92.2%, HR-MS:Calcd forC
19h
20clN
3o
6s 453.08, found 453.2.
(2) synthesis of 5-chlorothiophene-2-formyl chloride (compound 5):
In the 50mL bottle with two necks that rotor and thermometer are housed, add 1.9g 5-chlorothiophene-2-formic acid, add a pyridine, slowly add 1.8g sulfur oxychloride, under stirring, be heated to 80 DEG C, solid dissolves gradually, insulation reaction 3 hours.Be cooled to room temperature, underpressure distillation removes unnecessary sulfur oxychloride.Obtain the 5-chlorothiophene-2-formyl chloride of 2.1g pale yellowish oil.
(3) synthesis of (2-(the chloro-N-of 5-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-Yang Dai oxazolidine-3-base) phenyl) thiophene-2-carboxamide derivatives base) oxyethyl group) acetic acid (compound 6):
In 100mL there-necked flask, add 4.8g compound 3, add 25mL methylene dichloride and dissolve, add 3.2g triethylamine, under cryosel bath, be cooled to less than-5 DEG C.The 10mL dichloromethane solution of slow dropping 2.1g compound 5, keeps temperature≤-5 DEG C in dropping process, after being added dropwise to complete, keeping-5 DEG C to react 3 hours, then slowly rises to room temperature, react 3 hours.Add 50mL shrend to go out.With 180mL dichloromethane extraction three times (60mL × 3).Combined dichloromethane phase, decompression and solvent recovery obtains the compound 6 of 5.2g faint yellow solid.Yield 83.1%.HR-MS:Calcd for C
24H
21Cl
2N
3O
7S
2597.02,found 597.1。
(4) synthesis of razaxaban related substances " diamines ":
With the aqueous methylamine solution of 30mL dichloromethane extraction 40%, with anhydrous sodium sulfate drying.In the 250mL there-necked flask that thermometer and rotor are housed, add 5g compound 6, add 60mL methylene dichloride and dissolve, under ice bath, be cooled to less than 5 DEG C.Add the DCC of 4.8g, stir 5 minutes, then rise to room temperature, react 0.5 hour, add the dichloromethane solution of 30mL methylamine, react 15 hours under room temperature.Decompression and solvent recovery, obtains light yellow solid, and through silica gel chromatography, elutriant is methylene dichloride: methyl alcohol=100:1.Obtain 1.9g faint yellow solid, be razaxaban related substances " diamines ", purity >=98%, yield 38.2%.
1H-NMR(400MHz,CDCl
3)δ:3.51～4.08(m,18H,OCH
2,NCH
2),4.37(s,2H,OCH
2CO),4.64(m,2H,OCH),6.59(s,1H,NH),6.67(d,2H,ArH),6.87(s,1H,NH),7.25(m,6H,ArH),7.57(d,2H,ArH),7.67(d,2H,ArH).HR-MS:Calcd for C
25H
24Cl
2N
4O
6S
2611.05,found 611.1。
Claims (6)
1. the razaxaban related substances " diamines " Ru shown in (1):
（1）。
2. a synthetic method for razaxaban related substances " diamines " as claimed in claim 1, is characterized in that, comprise the steps:
(1) 2-(2-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-Yang Dai oxazolidine-3-base) phenyl) amino) oxyethyl group) synthesis of acetic acid:
With razaxaban bulk drug for starting raw material, heat with Glacial acetic acid, water and concentrated hydrochloric acid mixed solution, make its selective hydrolysis, to obtain final product;
(2) synthesis of 5-chlorothiophene-2-formyl chloride:
Make catalyzer with pyridine, sulfur oxychloride makes chlorizating agent, and 5-chlorothiophene-2-formic acid is made 5-chlorothiophene-2-formyl chloride;
(3) synthesis of 2-(2-(the chloro-N-of 5-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-Yang Dai oxazolidine-3-base) phenyl) thiophene-2-carboxamide derivatives base) oxyethyl group) acetic acid:
The 2-for preparing with step (1) (2-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-Yang Dai oxazolidine-3-base) phenyl) is amino) oxyethyl group) acetic acid is that 5-chlorothiophene-2-formyl chloride prepared by raw material and step (2) carries out acylation reaction, obtains 2-(2-(the chloro-N-of 5-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-Yang Dai oxazolidine-3-base) phenyl) thiophene-2-carboxamide derivatives base) oxyethyl group) acetic acid;
(4) synthesis of razaxaban related substances diamines:
2-(2-(the chloro-N-of 5-(4-(5-((5-chlorothiophene-2-formamido-) methyl) the 2-Yang Dai oxazolidine-3-base) phenyl) thiophene-2-carboxamide derivatives base) oxyethyl group) acetic acid prepared with step (3) is that raw material and methylamine carry out amidate action, obtains razaxaban related substances " diamines ".
3. synthetic method as claimed in claim 2, is characterized in that: in step (1): the volume ratio of Glacial acetic acid, water and concentrated hydrochloric acid is 3 ~ 9:0.5 ~ 4:0.5 ~ 6, and temperature of reaction is between 30 ~ 100 DEG C, and the reaction times is between 3 ~ 10 hours.
4. synthetic method as claimed in claim 2 or claim 3, it is characterized in that: in step (2): solvent for use is methylene dichloride, tetrahydrofuran (THF), acetonitrile, ether, acetone, ethyl acetate or solvent-free, 1 ~ 30 times that the amount of solvent for use is the quality that feeds intake, the feed ratio of sulfur oxychloride and 5-chlorothiophene-2-formic acid is 1 ~ 10:1, temperature of reaction is between 20 ~ 80 DEG C, and the reaction times is 2 ~ 6 hours.
5., as the synthetic method of claim 2-4 as described in any one, it is characterized in that: in step (3): solvent for use is methylene dichloride, tetrahydrofuran (THF), acetone, acetonitrile, ether, ethyl acetate, N, dinethylformamide, 2 ~ 30 times that the amount of solvent for use is the quality that feeds intake, the molar weight adding triethylamine is 2-(2-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-Yang Dai oxazolidine-3-base) phenyl) is amino) oxyethyl group) 1 ~ 6 times of the molar weight of acetic acid, the molar weight of the 5-chlorothiophene-2-formyl chloride added is 2-(2-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-Yang Dai oxazolidine-3-base) phenyl) is amino) oxyethyl group) 1 ~ 5 times of the molar weight of acetic acid, temperature when dripping 5-chlorothiophene-2-formyl chloride is-30 DEG C ~ 5 DEG C, the low-temp reaction time is kept to be 0.1 ~ 5 hour, after rising to room temperature, the reaction times is 0.1 ~ 5 hour, cancellation reagent is water, methyl alcohol, ethanol, propyl alcohol, extraction agent is methylene dichloride, ethyl acetate, tetrahydrofuran (THF).
6. as the synthetic method of claim 2-5 as described in any one, it is characterized in that: in step (4): solvent for use is methylene dichloride, tetrahydrofuran (THF), ethyl acetate, acetonitrile, acetone, N, dinethylformamide, ether, the quantity of solvent added is 3 ~ 20 times of reactant weight, the condensing agent added is DCC or CDI, the molar weight of DCC or DCI added is 1 ~ 10 times of (2-(the chloro-N-of 5-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-oxygen is for oxazolidine-3-base) phenyl) thiophene-2-carboxamide derivatives base) oxyethyl group) acetic acid molar weight, room temperature reaction is risen to 0.5 ~ 10 hour after adding DCC or CDI, after adding methylamine solution, the room temperature lower reaction times is 1 ~ 30 hour, silica gel chromatography eluent used is sherwood oil and ethyl acetate or methylene dichloride and methyl alcohol, eluent ratio is ethyl acetate: sherwood oil=5:1 ~ 100 or methyl alcohol: methylene dichloride=1:30 ~ 300.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106432218A (en) * | 2015-12-18 | 2017-02-22 | 重庆植恩药业有限公司 | Rivaroxaban impurities and preparing method and application thereof |
| CN110818700A (en) * | 2019-11-15 | 2020-02-21 | 湖南九典制药股份有限公司 | Oxazolidone derivative and preparation method thereof |
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| CN106432218A (en) * | 2015-12-18 | 2017-02-22 | 重庆植恩药业有限公司 | Rivaroxaban impurities and preparing method and application thereof |
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| CN110818700A (en) * | 2019-11-15 | 2020-02-21 | 湖南九典制药股份有限公司 | Oxazolidone derivative and preparation method thereof |
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