A kind of synthetic method of razaxaban related substances diaminesTechnical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of synthesis side of razaxaban related substances diaminesMethod.
Background technology
Razaxaban (rivaroxaban, 2) is the first oral Xa factors developed jointly by Bayer and Johson ＆ JohnsonDirect inhibitor, clinic are mainly used for preventing hip joint or the phlebothrombosis of knee replacements patient, and 2008 in CanadaIt is listed with European Union, 2009 in Discussion on Chinese Listed.
Razaxaban chemistry is entitled：The entitled 5- of chemistry is chloro-N-[[(5S) -2- oxos -3- [4- (3- oxo -4- morpholinyls) -Phenyl] -1,3- oxazolidine -5- bases] methyl] -2- thenoyl amines, structural formula is：
2
To study and control the quality of razaxaban, need to prepare it in relation to substance product as a contrast.According to razaxabanStructure feature and Straub be equal to 2001 autograph Substituted oxazolidinones and their useSynthesis technology may disclosed in the European patent WO0147919 of in the field of blood coagulationThere are several impurity, report some impurity synthesis modes, but has no the structure and synthetic method of diamines.
Invention content
The purpose of the present invention is to provide a kind of structures of razaxaban related substances diamines, can be used as and study and control profitCut down the reference substance of husky class.
Another object of the present invention is to provide a kind of synthetic method of razaxaban related substances diamines, this method operationSimplicity, raw material are easy to get, and diamines has good practicability.
One, the structural formula of razaxaban related substances：
Molecular weight：610.5
Molecular formula：C25H24Cl2N4O6S2。
Two, a kind of synthetic method of razaxaban related substances diamines, includes the following steps：
（1）3 2- of compound (2- (4- (5- ((5- chlorothiophene -2- formamidos) methyl) 2- oxooxazolidine -3- bases)Phenyl) amino) ethyoxyl) and acetic acid synthesis：
Razaxaban bulk pharmaceutical chemicals are added in bottle with two necks, are slowly added to glacial acetic acid, the 1 times of volume of 6 times of volumes successivelyWater and 3 times of volumes 35% concentrated hydrochloric acid.60 DEG C are heated under stirring, reaction solution gradually dissolves, insulation reaction 5 hours.It is coldBut to room temperature, filtering.The mashing of filter cake isopropanol washes 2 times to get white solid, spare；
（2）The synthesis of 5 5- chlorothiophene -2- formyl chlorides of compound：
Compound 5- chlorothiophene -2- formic acid is added in bottle with two necks, a drop pyridine is added and is catalyzed, is slowly added to protochlorideThe rate of charge of sulfone, wherein thionyl chloride and 5- chlorothiophene -2- formic acid is 1:1~1:Between 3, be heated to 80 DEG C under stirring, solid byIt gradually dissolves, insulation reaction 3 hours.It is cooled to room temperature, vacuum distillation removes extra thionyl chloride to get pale yellowish oil liquidBody；
（3）6 2- of compound (2- (the chloro- N- of 5- (4- (5- ((5- chlorothiophene -2- formamidos) methyl) 2- Yang Dai oxazolesAlkane -3- bases) phenyl) thiophene-2-carboxamide derivatives base) ethyoxyl) acetic acid synthesis：
Compound 3 in there-necked flask are dissolved with the dichloromethane of 3 ~ 10 times of volumes, the triethylamine of 2 ~ 6 times of moles are added,It is cooled to -20 DEG C ~ 0 DEG C.5- chlorothiophene -2- the formyl chlorides of 1 ~ 3 times of mole are slowly added dropwise, keep low-temp reaction 1 ~ 5 hour, soAfter be warmed to room temperature, react 1 ~ 5 hour, be quenched with water, then with dichloromethane extract 2 ~ 6 times.Combined dichloromethane phase, recycling are moltenAgent is to get faint yellow solid.
（4）7 2- of compound (2- (the chloro- N- of 5- (4- (5- ((5- chlorothiophene -2- formamidos) methyl) 2- Yang Dai oxazolesAlkane -3- bases) phenyl) thiophene-2-carboxamide derivatives base) ethyoxyl) chloroacetic chloride synthesis：
Compound 6 is added in bottle with two necks, dichloromethane dissolving is added, a drop pyridine and 0.5 ~ 4 times of mole is addedThionyl chloride, back flow reaction 3 hours, is cooled to room temperature, and vacuum distillation removes dichloromethane and extra thionyl chloride to obtain the final product, isBrown yellow oil liquid.
（5）The synthesis of razaxaban related substances diamines
The aqueous solution of 40% methylamine is extracted with dichloromethane, mutually drying is placed in there-necked flask obtained dichloromethane, whereinThe amount of methylamine is big excessive, is cooled to -20 DEG C ~ 0 DEG C.Compound 7 is dissolved in dichloro according to the ratio that w/v is 2 ~ 7 timesDichloromethane solution is made in methane.The solution that adds methylene chloride is slowly added dropwise into there-necked flask, keeps low-temp reaction 1 ~ 5 smallWhen, it is then warmed to room temperature, reacts 1 ~ 5 hour.It is quenched with water.It is extracted 2 ~ 6 times with dichloromethane.Combined dichloromethane phase, recyclingSolvent obtains faint yellow solid.The solid is purified by column chromatography, eluent is dichloromethane：Methanol=100:1 to get toThe sterling of razaxaban related substances diamines.
The razaxaban related substances diamines of the present invention, can be as the reference substance of monitoring razaxaban impurity.
The synthetic method of the razaxaban related substances diamines of the present invention, raw material is easy to get, easy to operate, has real wellWith property, good economic benefit and social benefit can be generated.
Description of the drawings
Fig. 1 is the synthetic route of razaxaban related substances diamines.
Specific implementation mode
A kind of synthetic method of razaxaban related substances diamines, includes the following steps：
（1）, 3 2- of compound (2- (4- (5- ((5- chlorothiophene -2- formamidos) methyl) 2- oxooxazolidine -3- bases)Phenyl) amino) ethyoxyl) and acetic acid synthesis：
5g compounds 2 are added in the 250mL bottle with two necks equipped with thermometer and rotor, are slowly added to 50mL ice vinegar successivelyAcid, 15mL water and 30mL concentrated hydrochloric acids.60 DEG C are heated under stirring, reaction solution gradually dissolves, insulation reaction 5 hours.It is cooled to roomTemperature is filtered under diminished pressure.With 20mL isopropanols filter wash cake at twice.Then filter cake is placed in 50mL single port bottles and is beaten with 25mL isopropanolsIt washes and starches, is filtered under diminished pressure, filter wash cake obtains the white solids of 4.8g compounds 3 at twice with 20mL isopropanols.Yield 92.2%, HR-MS: Calcd for C19H20ClN3O6S 453.08, found 453.2。
（2）, 5 5- chlorothiophene -2- formyl chlorides of compound synthesis：
1.9g compound 5- chlorothiophene -2- formic acid is added in the 50mL bottle with two necks equipped with rotor and thermometer, is added onePyridine is dripped, 1.8g thionyl chlorides is slowly added to, 80 DEG C is heated under stirring, solid gradually dissolves, insulation reaction 3 hours.It is coolingTo room temperature, vacuum distillation removes extra thionyl chloride.2.1g 5- chlorothiophene -2- formyl chlorides are obtained, are pale yellowish oil liquidBody, it is spare.
（3）, 6 2- of compound (2- (the chloro- N- of 5- (4- (5- ((5- chlorothiophene -2- formamidos) methyl) 2- Yang Dai oxazolesAlkane -3- bases) phenyl) thiophene-2-carboxamide derivatives base) ethyoxyl) acetic acid synthesis：
4.8g compounds 3 are added in 100mL there-necked flasks, the dissolving of 25mL dichloromethane is added, 3.2g triethylamines, ice is addedIt is cooled to -5 DEG C or less under salt bath.The 10mL dichloromethane solutions of 2.1g compounds 5 are slowly added dropwise, temperature is kept in low-cost processIt≤- 5 DEG C, after being added dropwise to complete, is kept for -5 DEG C react 3 hours, is then slowly increased to room temperature, reacted 3 hours.50mL water quenchings are addedIt goes out.Three times with the extraction of 180mL dichloromethane（60mL×3）.Combined dichloromethane phase is recovered under reduced pressure solvent and obtains 5.2g compounds6 faint yellow solid.Yield 83.1%.HR-MS: Calcd for C24H21Cl2N3O7S2 597.02, found 597.1。
（4）, 7 2- of compound (2- (the chloro- N- of 5- (4- (5- ((5- chlorothiophene -2- formamidos) methyl) 2- Yang Dai oxazolesAlkane -3- bases) phenyl) thiophene-2-carboxamide derivatives base) ethyoxyl) chloroacetic chloride synthesis.
5.2g compounds 6 are added in the 100mL single port bottles equipped with rotor, 30mL dichloromethane is added, stir lower dissolving,A drop pyridine is added, 2g thionyl chlorides are heated to flowing back, and react 3 hours, are cooled to room temperature, and revolving removes dichloromethane and moreRemaining thionyl chloride.Obtain the brown yellow oil liquid of 5.3g compounds 7.
（5）, razaxaban related substances diamines synthesis：
With the methylamine water solution of 30mL dichloromethane extraction 40%, organic phase is dried with anhydrous sodium sulfate, for use.Equipped withThe dichloromethane solution for the methylamine being added in the 100mL there-necked flasks of rotor and thermometer is cooled to -5 DEG C under ice salt bath.It is slowThe slow 20mL dichloromethane solutions that 5.3g compounds 7 are added dropwise keep temperature≤- 5 DEG C during being added dropwise.- 5 are kept after being added dropwise to completeDEG C reaction 3 hours, be then slowly increased to room temperature, at room temperature react 3 hours.50mL water is added.It is extracted with 180mL dichloromethaneThree times（60mL×3）.Combined dichloromethane phase is recovered under reduced pressure dichloromethane and obtains 5.1g light yellow solids.The solid is passed throughSilica gel chromatography, eluent are dichloromethane：Methanol=100:1.Finally obtain 3g faint yellow solids, as razaxabanThe sterling of related substances compound diamines.Yield 57.3%.1H NMR (400 MHz, CDCl3)δ:3.50~4.07(m, 18H,OCH2, NCH2), 4.36(s, 2H, OCH2CO), 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 C25H24Cl2N4O6S2 611.05, found 611.0。