CN114920786A

CN114920786A - Preparation method of clindamycin amide isomer

Info

Publication number: CN114920786A
Application number: CN202210612476.5A
Authority: CN
Inventors: 蒋祖艳; 王晓东; 刘健; 曾嘉斌; 刘梦楠; 郑亚东
Original assignee: Xinyu Pharmaceutical Co ltd
Current assignee: Xinyu Pharmaceutical Co ltd
Priority date: 2022-05-31
Filing date: 2022-05-31
Publication date: 2022-08-19

Abstract

The invention discloses a preparation method of a clindamycin amide isomer in the technical field of pharmaceutical chemicals, wherein the clindamycin amide isomer is prepared by reacting a lincomycin alpha-amino isomer serving as a raw material with a chlorinated reagent in the presence of a catalyst; the catalyst is N, N' -dimethylthiourea, and the chlorinated reagent is N-chlorosuccinimide. The preparation method of the invention takes lincomycin alpha-amino isomer as a reaction substrate, has mild reaction conditions, short reaction time and high purity of the obtained product, can be up to more than 99 percent, and has important significance for researching and controlling the quality of clindamycin hydrochloride finished products, and the obtained product has high purity and can be selectively chlorinated, under the condition that a catalyst N, N' -dimethylthiourea and a chlorinated reagent N-chlorosuccinimide exist.

Description

Preparation method of clindamycin amide isomer

Technical Field

The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of a clindamycin amide isomer.

Background

Chemical name of Clindamycin Hydrochloride (Clindamycin Hydrochloride): 6- (1-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamide) -1-thio-7 (S) -chloro-6, 7, 8-trideoxy-L-threo-alpha-D-galactooctapyranoside hydrochloride, which is a lincosamide antibiotic, is a 7-deoxy-7-chloro derivative of lincomycin.

Clindamycin was first synthesized in 1966 by magelein et al replacing the hydroxyl group at position 7 in the lincomycin molecule with chlorine, and was first introduced into the united states by the U.S. Puqiang corporation in the first 70 s and then introduced into European countries such as the uk. Compared with lincomycin, clindamycin has wide antibacterial spectrum and strong antibacterial activity which is 4-8 times of that of lincomycin, is more completely absorbed by gastrointestinal tract and is not influenced by food, and has low adverse reaction. The clindamycin hydrochloride has quick action, no first-pass effect, difficult loss of medicine content and reliable curative effect. Has high antibacterial activity against gram-positive bacteria such as Staphylococcus (including penicillin-resistant strains), Streptococcus, Corynebacterium diphtheriae, Bacillus anthracis, etc. The antibacterial agent also has good antibacterial activity on gram-negative anaerobic bacteria, and the bacteroides comprise bacteroides fragilis, clostridium, peptococcus, peptostreptococcus, perfringens and the like, and most of the bacteroides are highly sensitive to clindamycin hydrochloride. Gram-negative aerobic bacteria include haemophilus influenzae, neisseria and mycoplasma, all resistant to clindamycin hydrochloride. The clindamycin hydrochloride has no cross drug resistance with penicillin, chloramphenicol, cephalosporins and tetracyclines, has partial cross drug resistance with macrolides, and has complete cross drug resistance with lincomycin. The action mechanism is that the peptide chain is prevented from being prolonged by combining with bacterial ribosome 50S subunit, thereby inhibiting the protein synthesis of bacterial cells, and the peptide chain is a bacteriostatic agent, but has bactericidal effect on certain bacteria at high concentration. Since the market of China, clindamycin hydrochloride has definite curative effect and stable quality, is accepted by the market and is already received in Chinese pharmacopoeia. Clindamycin hydrochloride is an oral preparation, and also an injection is on the market, so the development prospect is very wide.

Any substance that affects the purity of a drug is referred to as an impurity, and in general, an impurity refers to a chemical other than a drug that is introduced or produced during production and storage. The impurities in the drug quality standard refer to impurities brought by the production process and raw auxiliary materials in the drug produced according to the specified process and the specified raw auxiliary materials approved by the national drug administration and supervision, or degradation products generated in the storage process and confirmed by stability experiments. The impurities in the drug quality standard do not include new impurities generated by changing the production process or changing raw and auxiliary materials, and also do not include infiltrated or polluted foreign substances. The pharmaceutical manufacturing enterprises change the production process or the raw and auxiliary materials, and bring new impurities to revise the original quality standard, and the revisions of the original quality standard should be legally declared and approved to the related pharmaceutical supervision and management departments.

Impurities of a drug are generally associated with a particular drug and originate from several sources:

1. from lysozymes, catalysts, etc. commonly used in pharmaceutical production processes;

2. reaction raw materials which are not completely reacted and exist, reaction initial compounds, synthetic intermediate products, byproducts and other substances related to the synthetic process;

3. oxidation, decomposition, hydrolysis products in the storage process;

4. optical isomers in chiral compounds;

5. multiple crystalline forms of a drug;

6. the animal and plant medicine extract contains small molecules such as alkaloid volatile oil and organic acid as effective components, and impurities such as protein, tanned matter, starch, resin, etc. with large molecular weight;

7. attenuating substances in radiopharmaceuticals;

8. proteins aberrantly expressed in bioengineered products;

9. heavy metals and inorganic salts.

Drug impurities can be classified into the following chemical classes and characteristics: organic impurities, inorganic impurities, organic volatile impurities. The method can be divided into the following parts according to sources: related substances (including precursors, intermediates, by-products, degradation products and the like of chemical reactions), other impurities, foreign impurities and the like; according to the structural relationship, the impurities can be divided into: other steroids, other alkaloids, geometric isomers, optical isomers, polymers, and the like; according to toxicity, the impurities can be divided into toxic impurities and common impurities, wherein the common impurities are impurities without obvious adverse biological effects under the existence amount, and the toxic impurities are impurities with strong adverse biological effects.

Clindamycin hydrochloride mainly contains the following impurities: dehydroclindamycin, clindamycin B, epimeddium clindamycin, clindamycin amide hydrochloride isomer and the like. Wherein the clindamycin amide hydrochloride isomer is an impurity derived from the alpha-amino isomer of the lincomycin in the lincomycin hydrochloride through chlorination reaction; the lincomycin alpha-amino isomer is lincomycin residual impurities or impurities generated in the reaction process when lincomycin is used as a raw material to synthesize clindamycin hydrochloride. The clindamycin amide hydrochloride isomer may remain in a clindamycin hydrochloride final product to influence the product quality, and the clindamycin amide isomer (in a free state) is only loaded into a European pharmacopoeia impurity list as a potential organic impurity at present and is controlled to be 0.5% according to a single impurity limit.

Clindamycin hydrochloride and injection thereof have more adverse reactions in clinical application, the adverse reactions generated in the clinical application of the medicine are related to the pharmacological activity of the medicine, and also have great relation with impurities in the medicine, the clindamycin hydrochloride can be directly used for preparing clindamycin hydrochloride amide isomers, but the purity is very low, the extraction and purification cost is very high, a high-purity target substance is not easy to obtain, in addition, the residual quantity of the clindamycin hydrochloride amide isomers in clindamycin hydrochloride raw medicine is small, and the cost for preparing a reference substance with enough quantity and quality by a chromatographic method is very high. For this reason we propose a process for the preparation of isomers of clindamycin amides to solve the above mentioned problems.

Disclosure of Invention

The invention aims to provide a preparation method of a clindamycin amide isomer, which solves the problems in the background technology.

In order to solve the technical problems, the invention adopts the following technical scheme:

a preparation method of a clindamycin amide isomer is disclosed, wherein the clindamycin amide isomer is prepared by reacting a lincomycin alpha-amino isomer serving as a raw material with a chlorinated reagent in the presence of a catalyst;

the catalyst is N, N' -dimethylthiourea, and the chlorinated reagent is N-chlorosuccinimide.

Preferably, the molar ratio of the lincomycin alpha-amino isomer to the N, N' -dimethylthiourea is 1: (0.01-0.5).

Preferably, the molar ratio of the lincomycin alpha-amino isomer to the N, N' -dimethylthiourea is 1: (0.1-0.3).

Preferably, the mol ratio of the lincomycin alpha-amino isomer to the chlorinated reagent is 1: (0.5-2).

Preferably, the molar ratio of the lincomycin alpha-amino isomer to the chlorinated reagent is 1: (0.8-1.5).

Preferably, the reaction solvent is at least one of dichloromethane, dichloroethane and chloroform.

Preferably, the reaction temperature is from 10 ℃ to 65 ℃.

Preferably, the reaction temperature is from 15 ℃ to 30 ℃.

Preferably, the reaction time is 1 to 5 hours.

Compared with the prior art, the invention has the beneficial effects that:

1. the preparation method of the invention takes lincomycin alpha-amino isomer as a reaction substrate, has mild reaction conditions and short reaction time in the presence of a catalyst N, N' -dimethylthiourea and chlorinated reagent N-chlorosuccinimide, can carry out selective chlorination, and the obtained product has high purity which can reach more than 99 percent, is used for controlling the quality of the raw material medicine, and has important significance for the research and control of the quality of clindamycin hydrochloride finished products.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.

FIG. 1 is a schematic representation of the structure of the amide isomers of clindamycin according to the invention;

FIG. 2 is a schematic structural diagram of a lincomycin alpha-amino isomer in the present invention;

FIG. 3 is a plot of the peaks of the clindamycin amide isomers according to the invention;

FIG. 4 is a HPLC chromatogram of the purity of the amide isomer of clindamycin prepared in accordance with example 1 of the present invention;

FIG. 5 is a HPLC chromatogram of the isomer purity of clindamycin amide prepared according to example 2 of the invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

A preparation method of a clindamycin amide isomer is characterized in that the clindamycin amide isomer is prepared by reacting a lincomycin alpha-amino isomer serving as a raw material with a chlorinated reagent in the presence of a catalyst;

the lincomycin alpha-amino isomer is shown in figure 2:

wherein the catalyst is N, N' -dimethylthiourea; the chlorinated reagent is N-chlorosuccinimide;

the clindamycin amide isomers are shown in figure 1.

Example 1

Preparation of clindamycin amide isomers:

weighing lincomycin alpha-amino isomer (200g,0.49mol) and N, N' -dimethylthiourea (10g,0.1mol) to dissolve in 500mL of dichloromethane, adding N-chlorosuccinimide (58.8g,0.44mol) at 20 ℃, stirring for 2 hours to carry out heat preservation reaction, detecting that the raw materials are reacted completely in TLC (thin layer chromatography), adding 200mL of dichloromethane and water into the reaction system respectively, separating an organic phase, extracting an aqueous phase once by using 100mL of dichloromethane, combining the organic phases, drying sodium sulfate, filtering, concentrating to obtain 146.2g of target product clindamycin amide isomer, wherein the yield is 78%, the HPLC purity is 99%, and the corresponding graph is shown in figure 2:

the integration data is as follows:

example 2

Preparation of clindamycin amide isomers:

weighing lincomycin alpha-amino isomer (200g,0.49mol) and N, N' -dimethylthiourea (10g,0.1mol) to be dissolved in 500mL of dichloromethane, adding N-chlorosuccinimide (58.8g,0.44mol) at 20 ℃, stirring for 4 hours to carry out heat preservation reaction, detecting that the raw materials are reacted completely in TLC (thin layer chromatography), adding dichloromethane and water to the reaction system for 200mL respectively, separating an organic phase, extracting an aqueous phase once by using 100mL of dichloromethane, combining the organic phases, drying with sodium sulfate, filtering, and concentrating to obtain 129.7g of target product clindamycin amide isomer, wherein the yield is 69.2%, the HPLC purity is 96.5%, and the corresponding spectrum is shown in figure 3:

the integration data is as follows:

example 3:

preparation of clindamycin amide isomers:

weighing lincomycin alpha-amino isomer (200g,0.49mol) and N, N' -dimethylthiourea (10g,0.1mol) to dissolve in 500mL of dichloromethane, adding N-chlorosuccinimide (65.4g,0.49mol) at 20 ℃, carrying out heat preservation reaction while stirring for 2, carrying out TLC (thin layer chromatography) controlled detection on the completion of the reaction of raw materials, adding dichloromethane and water 200mL respectively into the reaction system, separating an organic phase, extracting an aqueous phase once by using 100mL of dichloromethane, combining the organic phases, drying with sodium sulfate, filtering, and concentrating to obtain 121.8g of target product clindamycin amide isomer, wherein the yield is 65.0%, and the HPLC purity is 95.7%.

In the description herein, references to the description of "one embodiment," "an example," "a specific example," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

The foregoing shows and describes the general principles, principal features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed.

Claims

1. The preparation method of the clindamycin amide isomer is characterized in that the clindamycin amide isomer is prepared by reacting a lincomycin alpha-amino isomer serving as a raw material with a chlorinated reagent in the presence of a catalyst;

2. The method for preparing the amide isomer of clindamycin according to claim 1, wherein the molar ratio of the alpha-amino isomer of lincomycin to the N, N' -dimethylthiourea is 1: (0.01-0.5).

3. A process for preparing a clindamycin amide isomer according to claim 2, wherein the molar ratio of the lincomycin α -amino isomer to the N, N' -dimethylthiourea is 1: (0.1-0.3).

4. The preparation method of clindamycin amide isomer according to claim 1, wherein the molar ratio of the lincomycin alpha-amino isomer to the chlorinated reagent is 1: (0.5-2).

5. A preparation method of clindamycin amide isomer according to claim 4, wherein the molar ratio of the lincomycin alpha-amino isomer to the chlorinated reagent is 1: (0.8-1.5).

6. A process for preparing a clindamycin amide isomer according to any one of claims 1 to 5, wherein the reaction solvent is at least one of dichloromethane, dichloroethane and chloroform.

7. The process for preparing the isomer of clindamycin amide according to claim 1, wherein the reaction temperature is 10-65 ℃.

8. A process for preparing a clindamycin amide isomer according to claim 7, characterized in that the reaction temperature is 15-30 ℃.

9. The process for the preparation of a clindamycin amide isomer according to claim 1, characterized in that the reaction time is 1-5 hours.