CN104844588A - Synthetic method for rivaroxaban related substance diamine - Google Patents

Synthetic method for rivaroxaban related substance diamine Download PDF

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CN104844588A
CN104844588A CN201510129320.1A CN201510129320A CN104844588A CN 104844588 A CN104844588 A CN 104844588A CN 201510129320 A CN201510129320 A CN 201510129320A CN 104844588 A CN104844588 A CN 104844588A
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chlorothiophene
add
diamines
synthesis
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CN104844588B (en
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郑继宇
孙长山
孙铁民
李为理
张文涛
于曜荧
王世杰
秦培红
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LIAONING HAOHUSHI PHARMACEUTICAL CO Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14Heterocyclic 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a rivaroxaban related substance diamine which can be used as a reference substance to research and control rivaroxaban. The preparation method is simple, and the raw materials are easily available. The structural formula of the diamine is shown as follows: FORMULA shown in the description and the formula is C25H24CL2N4O4S2, and the molecular weight is 610.5. The rivaroxaban related substance diamine provided by the invention can be used as a reference substance for monitoring impurities of the rivaroxaban. The synthetic method for the rivaroxaban related substance diamine provided by the invention is simple to operate, has excellent practicality, and can bringrelatively good economic and social benefits.

Description

A kind of synthetic method of razaxaban related substances diamines
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), be the direct inhibitor of the 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, within 2008, in Canada and European Union's listing, 2009 in Discussion on Chinese Listed.
Razaxaban chemistry is by name: 5-by name is chloro-for chemistry n-[[(5 s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidine-5-base] methyl]-2-thenoyl amine, its structural formula is:
2
For studying and controlling the quality of razaxaban, need to prepare its related substance product in contrast.According to the constitutional features of razaxaban and Straub equal 2001 disclosed in the European patent WO0147919 of autograph Substituted oxazolidinones and their use in the field of blood coagulation synthesis technique may have several impurity, report some impurity synthesis modes, but have no structure and the synthetic method of diamines.
Summary of the invention
The object of the present invention is to provide a kind of structure of razaxaban related substances diamines, can as studying and controlling the reference substance of razaxaban.
Another object of the present invention, be to provide a kind of synthetic method of razaxaban related substances diamines, the method is easy and simple to handle, and raw material is easy to get, and diamines has good practicality.
One, the structural formula of razaxaban related substances:
Molecular weight: 610.5
Molecular formula: C 25h 24cl 2n 4o 6s 2.
Two, a synthetic method for razaxaban related substances diamines, comprises the steps:
(1) compound 32-(2-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-Yang Dai oxazolidine-3-base) phenyl) amino) oxyethyl group) synthesis of acetic acid:
In bottle with two necks, add razaxaban bulk drug, slowly add the concentrated hydrochloric acid of the Glacial acetic acid of 6 times of volumes, the water of 1 times of volume and 35% of 3 times of volumes successively.Be heated to 60 DEG C under stirring, reaction solution dissolves gradually, insulation reaction 5 hours.Be cooled to room temperature, filter.The making beating of filter cake Virahol washes 2 times, obtains white solid, for subsequent use;
(2) compound 5the synthesis of 5-chlorothiophene-2-formyl chloride:
In bottle with two necks, add compound 5-chlorothiophene-2-formic acid, add a pyridine and do catalysis, slowly add sulfur oxychloride, wherein the feed ratio of sulfur oxychloride and 5-chlorothiophene-2-formic acid is between 1:1 ~ 1:3, be heated to 80 DEG C under stirring, solid dissolves gradually, insulation reaction 3 hours.Be cooled to room temperature, underpressure distillation removes unnecessary sulfur oxychloride, obtains pale yellowish oil liquid;
(3) compound 6the 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 in there-necked flask 3, dissolve with the methylene dichloride of 3 ~ 10 times of volumes, add the triethylamine of 2 ~ 6 times of molar weights, be cooled to-20 DEG C ~ 0 DEG C.5-chlorothiophene-2-the formyl chloride of slow dropping 1 ~ 3 times of molar weight, keeps low-temp reaction 1 ~ 5 hour, then rises to room temperature, react 1 ~ 5 hour, go out with shrend, then use dichloromethane extraction 2 ~ 6 times.Combined dichloromethane phase, recycling design, obtains faint yellow solid.
(4) compound 7the 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) Acetyl Chloride 98Min.:
Compound is added in bottle with two necks 6, add methylene dichloride and dissolve, add the sulfur oxychloride of a pyridine and 0.5 ~ 4 times of molar weight, back flow reaction 3 hours, is cooled to room temperature, and underpressure distillation removes methylene dichloride and unnecessary sulfur oxychloride and get final product, and is brown yellow oil liquid.
(5) synthesis of razaxaban related substances diamines
With the aqueous solution of dichloromethane extraction 40% methylamine, the methylene dichloride obtained mutually drying is placed in there-necked flask, and wherein the amount of methylamine is excessive greatly, is cooled to-20 DEG C ~ 0 DEG C.By compound 7the ratio being 2 ~ 7 times according to weightmeasurement ratio is dissolved in methylene dichloride makes dichloromethane solution.The solution that this added methylene chloride slowly drops in there-necked flask, keeps low-temp reaction 1 ~ 5 hour, then rises to room temperature, react 1 ~ 5 hour.Go out with shrend.With dichloromethane extraction 2 ~ 6 times.Combined dichloromethane phase, recycling design obtains faint yellow solid.By this solid through purification by column chromatography, elutriant is methylene dichloride: methyl alcohol=100:1, namely obtains the sterling of razaxaban related substances diamines.
Razaxaban related substances diamines of the present invention, can as the reference substance of monitoring razaxaban impurity.
The synthetic method of razaxaban related substances diamines of the present invention, raw material is easy to get, simple to operate, has good practicality, can produce good economic benefit and social benefit.
Accompanying drawing explanation
Fig. 1 is the synthetic route of razaxaban related substances diamines.
Embodiment
A synthetic method for razaxaban related substances diamines, comprises the steps:
(1), compound 32-(2-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-Yang Dai oxazolidine-3-base) phenyl) amino) oxyethyl group) synthesis of acetic acid:
5g compound is added in the 250mL bottle with two necks that thermometer and rotor are housed 2, slowly add 50mL Glacial acetic acid, 15mL water and 30mL concentrated hydrochloric acid successively.Be heated to 60 DEG C under stirring, reaction solution dissolves gradually, insulation reaction 5 hours.Be cooled to room temperature, filtration under diminished pressure.With 20mL Virahol filter wash cake at twice.Then filter cake is placed in 50mL single port bottle 25mL Virahol making beating wash, filtration under diminished pressure, with 20mL Virahol at twice filter wash cake obtain the white solid of 4.8g compound 3.Yield 92.2%, HR-MS:Calcd for C 19h 20clN 3o 6s 453.08, found 453.2.
(2), compound 5the synthesis of 5-chlorothiophene-2-formyl chloride:
In the 50mL bottle with two necks that rotor and thermometer are housed, add 1.9g compound 5-chlorothiophene-2-formic acid, add a pyridine, slowly add 1.8g sulfur oxychloride, be heated to 80 DEG C under stirring, solid dissolves gradually, insulation reaction 3 hours.Be cooled to room temperature, underpressure distillation removes unnecessary sulfur oxychloride.Obtaining 2.1g 5-chlorothiophene-2-formyl chloride, is pale yellowish oil liquid, for subsequent use.
(3), compound 6the 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:
4.8g compound is added in 100mL there-necked flask 3, add 25mL methylene dichloride and dissolve, add 3.2g triethylamine, under cryosel bath, be cooled to less than-5 DEG C.Slow dropping 2.1g compound 510mL dichloromethane solution, keep temperature≤-5 DEG C in low-cost process, after being added dropwise to complete, keep-5 DEG C react 3 hours, then slowly rise 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 5.2g compound 6faint yellow solid.Yield 83.1%.HR-MS: Calcd for C 24H 21Cl 2N 3O 7S 2597.02, found 597.1。
(4), compound 7the 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) Acetyl Chloride 98Min..
5.2g compound is added in the 100mL single port bottle that rotor is housed 6, add 30mL methylene dichloride, stir lower dissolving, add a pyridine, 2g sulfur oxychloride, be heated to backflow, react 3 hours, be cooled to room temperature, revolve and steam removing methylene dichloride and unnecessary sulfur oxychloride.Obtain 5.3g compound 7brown yellow oil liquid.
(5), the synthesis of razaxaban related substances diamines:
With the aqueous methylamine solution of 30mL dichloromethane extraction 40%, use anhydrous sodium sulfate drying organic phase, stand-by.In the 100mL there-necked flask that rotor and thermometer are housed, add the dichloromethane solution of the methylamine obtained, under cryosel bath, be cooled to-5 DEG C.Slow dropping 5.3g compound 720mL dichloromethane solution, keep temperature≤-5 DEG C in dropping process.Be added dropwise to complete rear maintenance-5 DEG C reaction 3 hours, then slowly rise to room temperature, at room temperature react 3 hours.Add 50mL water.With 180mL dichloromethane extraction three times (60mL × 3).Combined dichloromethane phase, reclaim under reduced pressure methylene dichloride obtains 5.1g light yellow solid.By this solid through silica gel chromatography, elutriant is methylene dichloride: methyl alcohol=100:1.Finally obtain 3g faint yellow solid, be the sterling of razaxaban related substances compound diamines.Yield 57.3%. 1H NMR (400 MHz, CDCl 3) δ:3.50~4.07(m, 18H, OCH 2, NCH 2), 4.36(s, 2H, OCH 2CO), 4.63(m, 2H, OCH), 6.59(s, 1H,NH), 6.66(d, 2H, ArH), 6.87(s, 1H, NH) , 7.24(m, 6H, ArH), 7.56(d, 2H, ArH), 7.66(d, 2H, ArH). HR-MS: Calcd for C 25H 24Cl 2N 4O 6S 2611.05, found 611.0。

Claims (2)

1. a razaxaban related substances diamines, is characterized in that: the structural formula of razaxaban related substances diamines:
Molecular formula: C 25h 24cL 2n 4o 6s 2, molecular weight is 610.5.
2. a synthetic method for razaxaban related substances diamines, is characterized in that comprising the steps:
(1) compound 32-(2-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-Yang Dai oxazolidine-3-base) phenyl) amino) oxyethyl group) synthesis of acetic acid:
Razaxaban bulk drug is added in bottle with two necks, slowly add the concentrated hydrochloric acid of 35% of the Glacial acetic acid of 6 times of volumes, the water of 1 times of volume and 3 times of volumes successively, 60 DEG C are heated under stirring, reaction solution dissolves gradually, and insulation reaction 5 hours, is cooled to room temperature, filter, the making beating of filter cake Virahol washes 2 times, obtains white solid, for subsequent use;
(2) compound 5the synthesis of 5-chlorothiophene-2-formyl chloride:
Compound 5-chlorothiophene-2-formic acid prepared by step (2) is added in bottle with two necks, add a pyridine and do catalysis, slowly add sulfur oxychloride, wherein the feed ratio of sulfur oxychloride and 5-chlorothiophene-2-formic acid is between 1:1 ~ 1:3, is heated to 80 DEG C under stirring, solid dissolves gradually, insulation reaction 3 hours, is cooled to room temperature, and underpressure distillation removes unnecessary sulfur oxychloride, obtaining, is pale yellowish oil liquid;
(3) compound 6the synthesis of 2-(2-(the chloro-N-of 5-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-oxo oxazolidine-3-base) phenyl) thiophene-2-carboxamide derivatives base) oxyethyl group) acetic acid:
Compound prepared by step (1) is added in there-necked flask 3, dissolve with the methylene dichloride of 3 ~ 10 times of volumes, add the triethylamine of 2 ~ 6 times of molar weights, be cooled to-20 DEG C ~ 0 DEG C, 5-chlorothiophene-2-the formyl chloride of slow dropping 1 ~ 3 times of molar weight, keeps low-temp reaction 1 ~ 5 hour, then rises to room temperature, react 1 ~ 5 hour, go out with shrend, with dichloromethane extraction 2 ~ 6 times, combined dichloromethane phase, decompression and solvent recovery, obtains faint yellow solid;
(4) compound 7the synthesis of 2-(2-(the chloro-N-of 5-(4-(5-((5-chlorothiophene-2-formamido-) methyl) 2-oxo oxazolidine-3-base) phenyl) thiophene-2-carboxamide derivatives base) oxyethyl group) Acetyl Chloride 98Min.:
Compound prepared by step (3) is added in bottle with two necks 6, add methylene dichloride and dissolve, add the sulfur oxychloride of a pyridine and 0.5 ~ 4 times of molar weight, back flow reaction 3 hours, is cooled to room temperature, and underpressure distillation removes methylene dichloride and unnecessary sulfur oxychloride and get final product, and is brown yellow oil liquid;
(5) synthesis of razaxaban related substances diamines
With the aqueous solution of dichloromethane extraction 40% methylamine, the methylene dichloride obtained the mutually dry amount being placed on wherein methylamine in there-necked flask, for excessive greatly, is cooled to-20 DEG C ~ 0 DEG C, prepared by step (4) by compound 7the ratio being 2 ~ 7 times according to weightmeasurement ratio is dissolved in methylene dichloride makes dichloromethane solution, the solution that this added methylene chloride slowly drops in there-necked flask, keep low-temp reaction 1 ~ 5 hour, then rise to room temperature, react 1 ~ 5 hour, go out with shrend, with dichloromethane extraction 2 ~ 6 times, combined dichloromethane phase, is spin-dried for and obtains faint yellow solid, by this solid through purification by column chromatography, obtain the sterling of razaxaban related substances diamines.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104926807A (en) * 2015-06-04 2015-09-23 沈阳药科大学 Rivaroxaban related substance 'diamine' and synthesis method thereof
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

Citations (2)

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Publication number Priority date Publication date Assignee Title
US20100273798A1 (en) * 2009-04-28 2010-10-28 Apotex Pharmachem Inc. Processes for the preparation of rivaroxaban and intermediates thereof
CN104098558A (en) * 2014-07-22 2014-10-15 常州市第四制药厂有限公司 Amide compound and preparation method thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100273798A1 (en) * 2009-04-28 2010-10-28 Apotex Pharmachem Inc. Processes for the preparation of rivaroxaban and intermediates thereof
CN104098558A (en) * 2014-07-22 2014-10-15 常州市第四制药厂有限公司 Amide compound and preparation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
国家食品药品监督管理局: "《国家食品药品监督管理局.利伐沙班片进口注册标准》", 31 December 2009, 中国医药科技出版社 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104926807A (en) * 2015-06-04 2015-09-23 沈阳药科大学 Rivaroxaban related substance 'diamine' and synthesis method thereof
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
CN106432218B (en) * 2015-12-18 2019-08-30 重庆植恩药业有限公司 Razaxaban impurity and its preparation method and application

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