CN109824617A - A kind of Linezolid impurity M1Z1 and its preparation method and application - Google Patents

Abstract

The invention discloses a kind of Linezolid degradation impurity M1Z1, as shown in Equation 1.In addition, also disclosing the synthetic method of the impurity, the method includes being starting material with compound 2, its final products is obtained through elimination reaction.Linezolid degradation impurity M1Z1 of the invention may be used as the reference substance of drug quality control and its research.

Description

A kind of Linezolid impurity M1Z1 and its preparation method and application

Technical field

The invention belongs to but be not limited to field of medicinal chemistry, in particular to a kind of Linezolid impurity M1Z1 and its Preparation method and purposes.

Background technique

Linezolid (linezolid), entitled Isosorbide-5-Nitrae-dihydro -1,6- dimethyl -4- (3- nitrotoleune) -3, the 5- pyrrole of chemistry Pyridine dicarboxyl -2 [4- (benzhydryl) -1- piperazinyl] ethyl methyl esters dihydrochloride, is a kind of lipophilic third generation dihydro pyrrole Pyridine class and the calcium ion binary channels retarding agent for having L-type, T-type concurrently.

The medicine still has some adverse reactions in clinical application at present, and if it is related with impurity, up for studying and tracking Relevant research report, but pass through the quality of strict control Linezolid, it improves quality standard and is expected to reduce the bad of the drug Reaction.

Summary of the invention

It is the general introduction to the theme being described in detail herein below.This general introduction is not the protection model in order to limit claim It encloses.

Inventor developed a kind of Linezolid impurity and its production method, the Linezolid obtained by this method is miscellaneous Matter purity is more than 99%, and reaction preparation condition is simple (being raw material with commercially common Linezolid starting material), and technique Stablize, it is easily operated.

The present invention provides a kind of Linezolid impurity M1Z1, chemical structure is as shown in Equation 1:

On the other hand, the present invention provides the synthetic method of Linezolid impurity M1Z1 a kind of, include the following steps:

Elimination reaction occurs for compound 2, obtains Linezolid impurity M1Z1 i.e. compound 1；

In the synthetic method of the application, wherein the compound 2 can be compound 2 ' or compound 2 " or The mixture of person's compound 2 ' and compound 2 ":

In the synthetic method of the application, wherein elimination reaction is in aprotic organic solvent and in weak base, high temperature Lower progress.

In above-mentioned synthetic method, wherein the aprotic organic solvent is dimethylformamide, that is, DMF, diformazan One of yl acetamide, dioxane and toluene, it is preferable that be dimethylformamide.

In above-mentioned synthetic method, wherein the weak base be weak base be triethylamine, potassium phthalimide, pyridine, Or diisopropyl ethyl amine (DIPEA), it is preferable that be triethylamine.

In above-mentioned synthetic method, wherein the molar ratio of the compound 2 and weak base is 1:3-6.

In above-mentioned synthetic method, wherein the mass volume ratio of the compound 2 and aprotic organic solvent is 1:5- 10；(unit g:mL).

In above-mentioned synthetic method, wherein the high temperature of the generation elimination reaction is 85~120 DEG C, it is preferable that is 100~115 DEG C.

In above-mentioned synthetic method, optionally, using heating so that compound 2 is dissolved in aprotic organic solvent, Here, the temperature of heating for dissolving is 50~90 DEG C, it is preferable that is 65~85 DEG C.

In a kind of synthetic method of the application, which includes will be molten in the addition dimethylformamide of compound 2 Then triethylamine or potassium phthalimide is added and heat up 85~95 DEG C, stirring in solution；It is anti-to be performed under heating conditions elimination It answers；The reaction system is added to the water by end of reaction, and then stirring adds methylene chloride (DCM), water phase is abandoned in liquid separation, will have Machine is mutually concentrated under reduced pressure, and obtains Linezolid degradation impurity i.e. compound 1.

In above-mentioned synthetic method, wherein the triethylamine or potassium phthalimide of the compound 2 and addition Molar ratio is 1:3-6；

The mass volume ratio of the compound 2 and the DMF being added are 1:5-10；(unit g:mL)；

The mass volume ratio of the compound 2 and the water being added is 1:5-10；(unit g:mL)；

The mass volume ratio of the compound 2 and the extractant DCM being added are 1:10-20；(unit g:mL).

The third aspect, the present invention provides above-mentioned Linezolid impurity M1Z1 in Linezolid bulk pharmaceutical chemicals or its preparation Purposes in quality research or quality control as reference substance.

Invention resulting product purity is higher, and the five-membered ring of product can be destroyed by overcoming traditional dehalogenate technique Structure.

Other features and advantages of the present invention will be illustrated in the following description, also, partly becomes from specification It obtains it is clear that understand through the implementation of the invention.The objectives and other advantages of the invention can be by specification and power Specifically noted structure is achieved and obtained in sharp claim.

Specific embodiment

It, hereinafter will be to the embodiment of the present invention for the purposes, technical schemes and advantages of the application are more clearly understood It is described in detail.It should be noted that in the absence of conflict, the features in the embodiments and the embodiments of the present application can With mutual any combination.

In the embodiment of the present application, reagent used is all commercially to buy.

Bruker-400MHz Nuclear Magnetic Resonance (solvent DMSO, TMS are internal standard)

The instrument model of MS: Waters ACQUITY UPLC H-Class；

Carbon-13 nmr spectra (¹³C-NMR): III -400M nuclear magnetic resonance chemical analyser of Bruker Avance；100MHz, solvent: DMSO-d₆。

The instrument model of HPLC: Agilent 1260

The testing conditions of HPLC are as follows:

Chromatographic column: welch vltimate XB-C18 (3 μm, 4.6mm × 250mm)；

Detector: UV,

Detection wavelength: 254nm；

Column temperature: 40 DEG C；

Flow velocity: 0.8mL/min；

Sample volume: 10 μ L.

Mobile phase: 0.1mol/L trifluoroacetic acid aqueous solution: 0.1mol/L trifluoroacetic acid acetonitrile solution

Embodiment 1

The preparation of Linezolid impurity M1Z1

Compound 2 ' (10.0g) is added in DMF (50ml) and is dissolved at 70 DEG C, triethylamine is added after dissolved clarification (10.0g) is warming up to 85 DEG C, magnetic agitation 10h, 90 DEG C of reaction temperature.After completion of the reaction, DCM is added in the reaction system (100ml) extraction, organic phase are concentrated under reduced pressure at 45 DEG C.Off-white powder (compound 1) 8.5g is obtained, molar yield: 96.04%.Mass spectrum m+1/z=279, HPLC purity is 99.5%.

Embodiment 2

The preparation of Linezolid impurity M1Z1

Compound 2 ' (10.0g) is added in DMF (50ml) and is dissolved at 70 DEG C, it is sub- that phthalyl is added after dissolved clarification Amine potassium (10.0g) is warming up to 90 DEG C, magnetic agitation 10h, 110 DEG C of reaction temperature.After completion of the reaction, water (100ml) is added to be quenched, to DCM (100ml) extraction is added in system, organic phase is concentrated under reduced pressure at 45 DEG C.Column chromatography for separation obtains off-white powder (chemical combination Object 1) 2.5g, molar yield: 96.04%.Mass spectrum m+1/z=279, HPLC purity is 99.1%.

Serial number	RT(min)	Peak area	Peak area %	Peak width (sec)	Peak height
						1.	50.020	59663	0.781	45.600	3372
2.	51.243	7571376	99.142	57.200	615596
						3.	54.950	5847	0.077	17.600	1110

Mp:297 DEG C；¹H-NMR(400MHz,DMSO-d₆) δ (ppm): 7.48~7.60 (d, 1H, AR-H), 7.2 (t, 1H, AR-H), 7.1 (d, 1H, AR-H), 4.9 (d, 2H ,-CH₂- N), 4.5 (m, 2H ,-CH₂), 3.75 (t, 4H ,-CH₂-O-CH₂), 2.9(t,4H,-CH₂-N-CH₂-)。

¹³C-NMR

The carbon atoms numbered of Linezolid impurity M1Z1

The carbon-13 nmr spectra data and ownership of Linezolid impurity M1Z1

Although embodiment disclosed by the application is as above, the content only for ease of understanding the application and use Embodiment is not limited to the application.Technical staff in any the application fields, is taken off not departing from the application Under the premise of the spirit and scope of dew, any modification and variation, but the application can be carried out in the form and details of implementation Scope of patent protection, still should be subject to the scope of the claims as defined in the appended claims.

Claims (10)

1. a kind of Linezolid impurity M1Z1, chemical structure are as shown in Equation 1:

2. the synthetic method of Linezolid impurity M1Z1 as described in claim 1, includes the following steps:

Elimination reaction occurs for compound 2, obtains Linezolid impurity M1Z1 i.e. compound 1；

3. the synthetic method of Linezolid impurity M1Z1 as claimed in claim 2, wherein 2 can be of compound Close the mixture of object 2 ' or compound 2 " or compound 2 ' and compound 2 ":

4. the synthetic method of Linezolid impurity M1Z1 as claimed in claim 2 or claim 3, wherein elimination reaction is non-proton It is carried out in organic solvent and under weak base, high temperature.

5. the synthetic method of Linezolid impurity M1Z1 as claimed in claim 4, wherein the aprotic organic solvent is One of dimethylformamide, that is, DMF, dimethyl acetamide, dioxane and toluene, it is preferable that be dimethylformamide.

6. the synthetic method of Linezolid impurity M1Z1 as claimed in claim 4, wherein the weak base is that weak base is three second Amine, potassium phthalimide, pyridine or diisopropyl ethyl amine (DIPEA), it is preferable that be triethylamine.

7. the synthetic method of Linezolid impurity M1Z1 as claimed in claim 4, wherein the height of the generation elimination reaction Temperature is 85~120 DEG C, it is preferable that is 100~115 DEG C.

8. the synthetic method of Linezolid impurity M1Z1 as claimed in claim 2, the synthetic method include that compound 2 is added It is dissolved in dimethylformamide, triethylamine or potassium phthalimide is then added and heat up 85~95 DEG C, stirring；It is heating Under the conditions of carry out elimination reaction；The reaction system is added to the water by end of reaction, then stirring adds methylene chloride, liquid separation Water phase is abandoned, organic phase is concentrated under reduced pressure, Linezolid degradation impurity i.e. compound 1 is obtained.

9. the synthetic method of Linezolid impurity M1Z1 as claimed in claim 8, wherein the compound 2 and the three of addition The molar ratio of ethamine or potassium phthalimide is 1:3-6；

The mass volume ratio of the compound 2 and the DMF being added are 1:-10；(unit g:mL)；

The mass volume ratio of the compound 2 and the water being added is 1:5-10；(unit g:mL)；

The mass volume ratio of the compound 2 and the extractant DCM being added are 1:10-20；(unit g:mL).

10. Linezolid impurity M1Z1 described in claim 1 Linezolid bulk pharmaceutical chemicals or its preparation quality research or Purposes in quality control as reference substance.