A kind of synthetic method of razaxaban related substances diaminesTechnical 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 chemistryn-[[(5s)-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: C25h24cl2n4o6s2.
Two, a synthetic method for razaxaban related substances diamines, comprises the steps:
(1) compound32-(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) compound5the 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) compound6the 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 flask3, 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) compound7the 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 necks6, 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 compound7the 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), compound32-(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 housed2, 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 C19h20clN3o6s 453.08, found 453.2.
(2), compound5the 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), compound6the 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 flask3, 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 compound510mL 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 compound6faint yellow solid.Yield 83.1%.HR-MS: Calcd for C24H21Cl2N3O7S2597.02, found 597.1。
(4), compound7the 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 housed6, 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 compound7brown 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 compound720mL 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, 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 C25H24Cl2N4O6S2611.05, found 611.0。