CN106565680A - Tedizolid impurity and preparing method thereof - Google Patents
Tedizolid impurity and preparing method thereof Download PDFInfo
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- CN106565680A CN106565680A CN201610967445.6A CN201610967445A CN106565680A CN 106565680 A CN106565680 A CN 106565680A CN 201610967445 A CN201610967445 A CN 201610967445A CN 106565680 A CN106565680 A CN 106565680A
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- azoles amine
- specially azoles
- impurity
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
The invention relates to a tedizolid impurity and a preparing method thereof, and belongs to the technical field of drug synthesis. The tedizolid impurity exists in the following tedizolid steps, and please see the steps in the specification, wherein X is fluorine, chlorine, bromine, iodine, tosylate or methanesulfonate, and R is organic boronic acid organic borate ester; and please see the structural formula of the impurity in the specification. The tedizolid impurity is of great significance in deep surveying of the tedizolid. The invention further provides a preparing method which is simple in process.
Description
Technical field
The present invention relates to one kind specially azoles amine impurity and preparation method thereof, belongs to technical field of medicine synthesis.
Background technology
Specially azoles amine (Tedizolid) is resisted by the oxazolidinone that Ka Bisite (Cubist) drugmaker develops
Raw element.Specially azoles amine obtains U.S. FDA approval and lists in the U.S. in June, 2014, trade name Sivextro.The medicine is first
The Er Dai oxazolidinone antibiotic of individual acquisition FDA approvals, compares with generation product Linezolid, and Sivextro is to some antibacterials
Vitro inhibition activity want high 2-8 times, safety is also increased to a certain extent.Because compound Tedizolid does not also have
There is the Chinese translation of standard, therefore its transliteration is " specially azoles amine " by the applicant's here.
The preparation method of specially azoles amine has been reported research, and patent CN200480037612 is reported with CN200980140144
The road specially synthetic method of azoles amine.
Patent CN201080014363 reports the impurity in Tedizolid Phosphate building-up process and limit handling.But mesh
Front patent is only controlled to the impurity in Tedizolid Phosphate building-up process, to the impurity in specially azoles amine building-up process
Without control.
Specially further investigation of the azoles amine process contaminants to specially azoles amine is significant, but has no in prior art that this is miscellaneous
The open report of matter, the structural formula of the impurity are as follows：
The content of the invention
It is an object of the invention to provide one kind specially azoles amine impurity, rationally, raw material is easy to get its synthetic route, simple to operate
Easy, the further investigation to specially azoles amine is significant；Invention also provides a kind of preparation method of process is simple.
Specially azoles amine impurity of the present invention, among being present in the synthesis step of following specially azoles amine：
Wherein X is fluorine, chlorine, bromine, iodine, p-toluenesulfonic esters or methanesulfonates, and R is organic boronic or organic boric acid ester；Institute
The structural formula for stating impurity is as follows：
Mass content of the impurity in specially azoles amine is 0.1-5%.
The preparation method of described specially azoles amine impurity, by compound V with compound VI depositing in catalyst, alkali and solvent
React under the conditions of uniform temperature under, obtain specially azoles amine impurity, reaction equation is as follows：
The catalyst be Palladous chloride., palladium, double (dibenzalacetone) palladiums, tetrakis triphenylphosphine palladium, [1,1 '-it is bis-
(diphenylphosphine) ferrocene] palladium chloride, double (tricyclohexyl phosphine) palladium chlorides or double (triphenylphosphine) palladium chlorides.
The alkali be tert-butyl alcohol lithium, sodium tert-butoxide, potassium tert-butoxide, Lithium hydrate, sodium hydroxide, potassium hydroxide, sodium carbonate,
One or more in potassium carbonate, cesium carbonate, cesium fluoride, potassium acetate or potassium phosphate, preferably potassium carbonate or sodium tert-butoxide.
The solvent be water, methanol, ethanol, isopropanol, the tert-butyl alcohol, dioxane, tetrahydrofuran, ether, dichloromethane,
One or more in acetone, positive butanone, dimethylbenzene, toluene, DMF or dimethyl sulfoxide, preferably dioxy
One or more in six rings, tetrahydrofuran, toluene or water.
The temperature of the reaction is 30～180 DEG C, preferably 70～120 DEG C.
The molar ratio of the compound V and compound VI is 1:0.5-2, preferably 1：1.0-1.5.
The Y is fluorine, chlorine, bromine, iodine, p-toluenesulfonic esters or methanesulfonates, preferably bromine or iodine.
The R is organic boronic or organic boric acid ester, such as boric acid, trimethyl borate, boric acid diethylester, boric acid dipropyl,
Boric acid diisopropyl ester, that alcohol ester of boric acid piece or the pungent amylalcohol ester of boric acid, preferably boric acid or boric acid piece that alcohol ester.
The present invention compared with prior art, has the advantages that：
Specially azoles amine impurity of the present invention, can as reference substance in specially azoles amine quality research impurity it is qualitative fixed
Quantity research is used, and controls content of the crude drug about material, it is ensured that the quality of crude drug；Synthetic route of the present invention is reasonable, raw material
It is easy to get, operational approach easy steps are few, the further investigation to specially azoles amine is significant.
Description of the drawings
Fig. 1 is the hydrogen spectrum of specially azoles amine impurity I；
Fig. 2 is the mass spectrum of specially azoles amine impurity I.
Specific embodiment
With reference to embodiment, the present invention is further illustrated, but which is not intended to limit the enforcement of the present invention.
It is raw materials used to be commercially available prod.
Embodiment 1
Nitrogen is protected, add in reaction bulb bromo- 2- (2- methyl -2H- tetrazolium -5- bases) pyridines of 5- (10g,
41.6mmol), (6- (2- methyl -2H- tetrazolium -5- bases) pyridin-3-yl) boric acid (8.5g, 41.6mmol), [1,1 '-bis- (hexichol
Base phosphine) ferrocene] palladium chloride (304mg, 0.416mmol), potassium carbonate (11.5g, 83.2mmol) and 20mL tetrahydrofurans with
The mixture (1 of water:1, V/V) 30 DEG C, are warming up to, stirring reaction 4 hours, TLC detection reactions are completed, and are added 20ml water, are filtered
Obtain specially azoles amine impurity I 12.6g.
Embodiment 2
Nitrogen is protected, add in reaction bulb bromo- 2- (2- methyl -2H- tetrazolium -5- bases) pyridines of 5- (21g,
62.4mmol), (6- (2- methyl -2H- tetrazolium -5- bases) pyridin-3-yl) that alcohol ester of boric acid piece (11.9g, 41.6mmol), double
(triphenylphosphine) palladium chloride (292mg, 0.416mmol), sodium tert-butoxide (6.2g, 83.2mmol) and 30mL toluene, are warming up to
110 DEG C, stirring reaction 5 hours, TLC detection reactions are completed, and filter to obtain specially azoles amine impurity I 11.9g.
Embodiment 3
Nitrogen is protected, add in reaction bulb iodo- 2- (2- methyl -2H- tetrazolium -5- bases) pyridines of 5- (11.9g,
41.6mmol), (6- (2- methyl -2H- tetrazolium -5- bases) pyridin-3-yl) boric acid (4.25g, 20.8mmol), [1,1 '-bis- (two
Phenylphosphine) ferrocene] palladium chloride (304mg, 0.416mmol), sodium tert-butoxide (8.0g, 83.2mmol) and 20mL dioxies six
Ring, is warming up to 80 DEG C, stirring reaction 2 hours, and TLC detection reactions are completed, and filter to obtain specially azoles amine impurity I 12g.
Embodiment 4
Nitrogen is protected, and the iodo- 2- methyl -2H- tetrazoliums -5- bases of 5- are added in reaction bulb) pyridine (11.9g, 41.6mmol),
(6- (2- methyl -2H- tetrazolium -5- bases) pyridin-3-yl) boric acid (8.5g, 41.6mmol) (25.6g, 83.2mmol), double (triphens
Base phosphine) palladium chloride (416mg, 0.416mmol), sodium tert-butoxide (8.0g, 83.2mmol) and 40mL dimethyl sulfoxide, it is warming up to
180 DEG C, stirring reaction 3 hours, TLC detection reactions are completed, and filter to obtain specially azoles amine impurity I 11g.
Embodiment 5
Nitrogen is protected, and the iodo- 2- methyl -2H- tetrazoliums -5- bases of 5- are added in reaction bulb) pyridine (11.9g, 41.6mmol),
(6- (2- methyl -2H- tetrazolium -5- bases) pyridin-3-yl) boric acid (8.5g, 41.6mmol) (12.8g, 62.4mmol), double (triphens
Base phosphine) palladium chloride (416mg, 0.416mmol), cesium carbonate (27g, 83.2mmol) and 40mL ethanol, 60 DEG C are warming up to, are stirred
Reaction 2 hours, TLC detection reactions are completed, and filter to obtain specially azoles amine impurity I 10g.
Embodiment 6
Nitrogen is protected, add in reaction bulb bromo- 2- (2- methyl -2H- tetrazolium -5- bases) pyridines of 5- (10g,
41.6mmol), (R) -3- (the fluoro- 4- of 3- (4,4,5,5- tetramethyl -1,3,2- dioxo bora -2- bases) phenyl) -5- (methylol)
Oxazole -2- ketone (14g, 41.6mmol), [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride (304mg, 0.416mmol), carbon
Sour potassium (11.5g, 83.2mmol) and the anhydrous THF of 20mL, are warming up to 70 DEG C, stirring reaction 4 hours, and TLC detection reactions are completed.Subtract
Pressure concentration, gained grease are beaten with first alcohol and water (4: 1, V/V), are vacuum dried to obtain off-white powder, liquid phase analysis specially azoles
Amine impurity I contents are 3.6%.
Claims (10)
1. one kind specially azoles amine impurity, it is characterised in that：Among the impurity is present in the synthesis step of following specially azoles amine：
Wherein X is fluorine, chlorine, bromine, iodine, p-toluenesulfonic esters or methanesulfonates, and R is organic boronic or organic boric acid ester；It is described miscellaneous
The structural formula of matter is as follows：
2. specially azoles amine impurity according to claim 1, it is characterised in that：Quality of the impurity in specially azoles amine contains
Measure as 0.1-5%.
3. the preparation method of the specially azoles amine impurity described in a kind of claim 1 or 2, it is characterised in that：By compound V and chemical combination
Thing VI is reacted in the presence of catalyst, alkali and solvent under the conditions of uniform temperature, obtains specially azoles amine impurity, reaction equation
It is as follows：
4. the preparation method of specially azoles amine impurity according to claim 3, it is characterised in that：Catalyst is Palladous chloride., vinegar
It is sour palladium, double (dibenzalacetone) palladiums, tetrakis triphenylphosphine palladium, [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride, double
(tricyclohexyl phosphine) palladium chloride or double (triphenylphosphine) palladium chlorides.
5. the preparation method of specially azoles amine impurity according to claim 3, it is characterised in that：Alkali is tert-butyl alcohol lithium, tertiary fourth
Sodium alkoxide, potassium tert-butoxide, Lithium hydrate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, potassium acetate or
One or more in potassium phosphate.
6. the preparation method of specially azoles amine impurity according to claim 3, it is characterised in that：Solvent is water, methanol, second
Alcohol, isopropanol, the tert-butyl alcohol, dioxane, tetrahydrofuran, ether, dichloromethane, acetone, positive butanone, dimethylbenzene, toluene, N, N-
One or more in dimethylformamide or dimethyl sulfoxide.
7. the preparation method of specially azoles amine impurity according to claim 3, it is characterised in that：The temperature of reaction be 30～
180℃。
8. the preparation method of specially azoles amine impurity according to claim 3, it is characterised in that：Compound V and compound VI
Molar ratio be 1:0.5-2.
9. the preparation method of specially azoles amine impurity according to claim 3, it is characterised in that：Y is fluorine, chlorine, bromine, iodine, right
Tosylate or methanesulfonates.
10. the preparation method of specially azoles amine impurity according to claim 3, it is characterised in that：R is organic boronic or organic
Borate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610967445.6A CN106565680A (en) | 2016-10-31 | 2016-10-31 | Tedizolid impurity and preparing method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610967445.6A CN106565680A (en) | 2016-10-31 | 2016-10-31 | Tedizolid impurity and preparing method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111920781A (en) * | 2020-08-24 | 2020-11-13 | 瑞阳制药有限公司 | Preparation method of tedizolid phosphate preparation for injection |
| CN111995616A (en) * | 2020-09-22 | 2020-11-27 | 宜宾市南溪区红光制药有限公司 | Tedizolid phosphate impurity and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102177156A (en) * | 2008-10-10 | 2011-09-07 | 特留斯治疗学公司 | Methods for preparing oxazolidinones and compositions containing them |
| CN102850340A (en) * | 2011-06-28 | 2013-01-02 | 中国科学院上海有机化学研究所 | Conjugated polymer or oligomer having narrow band gap characteristic and side chain stereoregularity, and its preparation method |
-
2016
- 2016-10-31 CN CN201610967445.6A patent/CN106565680A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102177156A (en) * | 2008-10-10 | 2011-09-07 | 特留斯治疗学公司 | Methods for preparing oxazolidinones and compositions containing them |
| CN102850340A (en) * | 2011-06-28 | 2013-01-02 | 中国科学院上海有机化学研究所 | Conjugated polymer or oligomer having narrow band gap characteristic and side chain stereoregularity, and its preparation method |
Non-Patent Citations (2)
| Title |
|---|
| BIN GUO ET AL.: "Solubility-Driven Optimization of （Pyridin-3-yl） Benzoxazinyl oxazolidinones to a Promising Antibacterial Agent", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 朱益忠等: "磷酸特地唑胺的合成新方法", 《应用化学》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111920781A (en) * | 2020-08-24 | 2020-11-13 | 瑞阳制药有限公司 | Preparation method of tedizolid phosphate preparation for injection |
| CN111920781B (en) * | 2020-08-24 | 2024-01-09 | 瑞阳制药股份有限公司 | Preparation method of injection terozolomide disodium salt preparation |
| CN111995616A (en) * | 2020-09-22 | 2020-11-27 | 宜宾市南溪区红光制药有限公司 | Tedizolid phosphate impurity and preparation method and application thereof |
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