阅读说明：本技术 盐酸克林霉素杂质的制备方法 (Preparation method of clindamycin hydrochloride impurity ) 是由 李发光 王倩倩 黄畅 王玉芬 王琳琳 霍翔宏 王�琦 王利春 王晶翼 于 2019-06-04 设计创作，主要内容包括：本发明涉及盐酸克林霉素杂质的制备方法,属于药物领域。本发明所要解决的技术问题是现有技术中缺乏高效制备盐酸克林霉素杂质7-差向林可霉素和7-差向盐酸克林霉素对照品的方法。本发明提供了式Ⅱ所示盐酸克林霉素杂质中间体的制备方法：以式Ⅰ所示化合物和R<Sub>1</Sub>COOH为原料,经Mitsunobu取代反应制备得到,反应液中添加了胺和/或含氮芳香杂环化合物。本发明还进一步提供了7-差向林可霉素和7-差向盐酸克林霉素的完整合成方法：以林可霉素为原料,经过上硅保护基、选择性脱保护、Mitsunobu取代反应、水解反应得7-差向林可霉素,进一步氯代反应制备得到7-差向盐酸克林霉素。<Image he="232" wi="700" file="DDA0002084481160000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to a preparation method of clindamycin hydrochloride impurities, belonging to the field of medicines. The invention aims to solve the technical problem that a method for efficiently preparing clindamycin hydrochloride impurity 7-epimembrycin and 7-epimembrycin hydrochloride reference substances is lacked in the prior art. The invention provides a preparation method of a clindamycin hydrochloride impurity intermediate shown as a formula II: a compound of formula I and R 1 COOH is used as a raw material and is prepared through a Mitsunobu substitution reaction, and amine and/or a nitrogen-containing aromatic heterocyclic compound are/is added into reaction liquid. The invention further provides a complete synthesis method of the 7-epimembrycin and the 7-epimembrycin hydrochloride, which comprises the following steps: taking lincomycin as a raw material, carrying out silicon protecting group application, selective deprotection, Mitsunobu substitution reaction and hydrolysis reaction to obtain 7-epime lincomycin, and further carrying out chlorination reaction to prepare 7-epimeAdding clindamycin hydrochloride.)

1. The preparation method of the clindamycin hydrochloride impurity intermediate shown in the formula II is characterized by comprising the following steps: a compound of formula I and R₁COOH is used as a raw material and is prepared by Mitsunobu substitution reaction, and amine and/or a nitrogen-containing aromatic heterocyclic compound are also added into reaction liquid:

wherein R is₁Is optionally substituted aryl or alkyl;

R₂is composed ofWherein R is₃、R₄、R₅Independently selected from alkyl groups.

2. The method of claim 1, wherein:

the amine is a tertiary amine;

preferably, the amine is one or more than two of trimethylamine, triethylamine, triethanolamine, triallylamine and N, N-diisopropylethylamine;

and/or

The nitrogen-containing aromatic heterocyclic compound is a six-membered nitrogen-containing aromatic heterocyclic compound;

preferably, the six-membered nitrogen-containing aromatic heterocyclic compound is pyridine, 4-dimethylaminopyridine or a mixture thereof.

3. The process according to claim 1 or 2, characterized in that: r₁Is an optionally substituted 5-to 14-membered aryl or C₁～C₆Alkyl radical, R₃、R₄、R₅Independently selected from C₁～C₆An alkyl group; preferably, R₁Is optionally substituted phenyl or C₁～C₄Alkyl radical, R₃、R₄、R₅Independently selected from C₁～C₄An alkyl group; further preferably, R₁Is p-nitrophenyl, R₃、R₄、R₅Are all methyl.

4. The method according to any one of claims 1 to 3, wherein: the method comprises the following steps: a compound shown as a formula I and R₁COOH, a phosphine reagent and amine and/or a nitrogen-containing aromatic heterocyclic compound are added into a reaction solvent, then azodicarboxylic ester is slowly added, the temperature of the reaction liquid is controlled below 30 ℃, and the reaction is finished to obtain the clindamycin impurity intermediate shown in the formula II.

5. The method of claim 4, wherein:

the phosphine reagent is a triarylphosphine; preferably, the phosphine reagent is triphenylphosphine;

and/or

The azodicarboxylic acid ester is diisopropyl azodicarboxylate, diethyl azodicarboxylate or a mixture thereof;

and/or

The reaction solvent is one or more than two of toluene, dichloromethane and tetrahydrofuran;

and/or

Before adding the azodicarboxylic acid ester, controlling the temperature of the reaction liquid below 30 ℃; preferably, before adding the azodicarboxylic acid ester, the temperature of the reaction liquid is controlled to be 10-30 ℃;

and/or

The concentration (g: ml) of the compound represented by the formula I in the reaction solvent is (1:2) to (1: 100);

preferably, the concentration of the compound of formula I in the reaction solvent (g: ml) is 1: 30;

and/or

A compound of formula I: r₁COOH: phosphine reagent: azodicarboxylate: the molar ratio of the amine and/or the nitrogen-containing aromatic heterocyclic compound is 1: (1-5): (1-5): (1-5): (1-5); preferably, the compounds of formula I: r₁COOH: phosphine reagent: azodicarboxylate: the molar ratio of the amine and/or the nitrogen-containing aromatic heterocyclic compound is 1:2:2:2: 2.

6. A preparation method of clindamycin hydrochloride impurities shown in a formula IV is characterized by comprising the following steps: comprises one or more than two steps of the following steps a-d:

a. protecting the hydroxyl group of compound 1 with a silicon reagent to give compound 2:

wherein R is₂Is composed ofR₃、R₄、R₅Independently selected from alkyl; preferably, R₃、R₄、R₅Independently selected from C1-C6 alkyl; further preferably, R₃、R₄、R₅Independently selected from C1-C4 alkyl; most preferably, R₃、R₄、R₅Are both methyl;

b. selectively removing the silicon protecting group of the compound 2 in the presence of acid to obtain a compound shown as a formula I:

c. the preparation method of any one of claims 1 to 5, wherein the intermediate of formula II is prepared;

d. and (3) carrying out hydrolysis reaction on the intermediate of the formula II to obtain the clindamycin hydrochloride impurity shown in the formula IV:

preferably, the acid in the step b is one or more of formic acid, acetic acid and propionic acid; further preferably, the acid of step b is acetic acid.

7. A preparation method of clindamycin hydrochloride impurities shown in a formula III is characterized by comprising the following steps: the method comprises the following steps:

e. the preparation method of claim 6, obtaining the clindamycin hydrochloride impurity shown as the formula IV;

f. preparing the clindamycin hydrochloride impurity shown in the formula IV into hydrochloride, and performing chlorination reaction to obtain the clindamycin hydrochloride impurity shown in the formula III:

8. the method of claim 7, wherein: the chlorination reaction in the step f is specifically as follows: adding a chloroform solution of triphosgene into a mixed solvent of chloroform and N, N-dimethylformamide, fully reacting to generate a Vilsmeier reagent, adding a hydrochloride of the formula IV, and finishing the reaction to obtain the triphosgene.

9. A clindamycin hydrochloride impurity intermediate represented by formula ii or a salt thereof:

wherein R is₁Is optionally substituted aryl or alkyl;

R₂is composed ofR₃、R₄、R₅Independently selected from alkyl groups.

10. The clindamycin hydrochloride impurity intermediate as claimed in claim 9, which is characterized in that: r₁Is an optionally substituted 5-to 14-membered aryl or C₁～C₆Alkyl radical, R₃、R₄、R₅Independently selected from C1-C6 alkyl; preferably, R₁Is optionally substituted phenyl or C₁～C₄Alkyl radical, R₃、R₄、R₅Independently selected from C1-C4 alkyl; further preferably, R₁Is p-nitrophenyl, R₃、R₄、R₅Are all methyl.

11. Use of the clindamycin hydrochloride impurity intermediate of claim 9 or 10 in the preparation of 7-epimeric clindamycin hydrochloride shown in formula III and/or 7-epimeric clindamycin shown in formula IV.

Technical Field

The invention relates to a preparation method of clindamycin hydrochloride impurities, belonging to the field of medicines.

Background

Chemical name of Clindamycin Hydrochloride (Clindamycin Hydrochloride): 6- (1-methyl-trans-4-propyl-L-2-pyrrolidine carboxamido) -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. Since the market of China, clindamycin hydrochloride has definite curative effect and stable quality, is accepted by the market and is received in Chinese pharmacopoeia. Clindamycin hydrochloride is available in the market as injection besides oral preparation, and has a very wide development prospect.

The 7-epimeric clindamycin hydrochloride is a byproduct obtained by 7-site chlorination SN1 in the clindamycin hydrochloride synthesis process; the 7-epimembrin is residual impurities of the lincomycin or impurities generated in the reaction process when the lincomycin is used as a raw material to synthesize the clindamycin hydrochloride. Both 7-epimeric clindamycin hydrochloride and 7-epimeric clindamycin can remain in a final clindamycin hydrochloride product to influence the product quality, and 7-epimeric clindamycin (in a free state) is determined in Chinese pharmacopoeia, and the standard limit is 1.5%. The structural formulas of the two impurities are as follows:

the chinese patent applications CN101891778A, CN102702279A, and CN103172683A all report about the impurity 7-epimeric clindamycin hydrochloride, but do not disclose the synthesis method of the impurity. In addition, the residual quantity of 7-epimembricin hydrochloride and 7-epimembricin in the clindamycin hydrochloride raw material medicines is small, and the cost for obtaining reference substances with enough quantity and quality by a preparative chromatography method is very high; therefore, the method for preparing the high-purity 7-epi-clindamycin hydrochloride and the 7-epi-clindamycin is provided, the impurity reference substance is obtained, the quality of the raw material medicine is controlled, and the method has important significance for the research and control of the quality of the clindamycin hydrochloride finished product.

Disclosure of Invention

The invention aims to provide a preparation method of clindamycin hydrochloride impurity-7-epimeddium clindamycin hydrochloride and 7-epimeddium clindamycin so as to solve the problem that the prior art lacks a method for efficiently preparing the impurity reference substance.

The method provided by the invention takes lincomycin as a raw material, and 7-epimembrin is obtained by silicon protecting group application, selective deprotection, Mitsunobu substitution reaction and hydrolysis reaction; further carrying out chlorination reaction and other processes to prepare the 7-epimeddium clindamycin hydrochloride.

In the Mitsunobu substitution reaction, the inventors have come to mindIt has been found, in addition, that the tertiary amine function, which is present due to the reactants themselves, reacts with R₁The COOH salt formation interferes with the Mitsunobu substitution reaction, the yield of the step can be improved by adding amine and/or a nitrogen-containing aromatic heterocyclic compound, and if the amine and/or the nitrogen-containing aromatic heterocyclic compound are not added, the target product cannot be obtained.

Moreover, the inventor finds that the crude product prepared by the Mitsunobu substitution reaction has high purity, can be directly used for the next reaction, does not need an intermediate purification operation step, has simple and convenient process, and is beneficial to industrial production.

The invention comprises the following aspects:

in a first aspect, the invention provides a preparation method of a clindamycin hydrochloride impurity intermediate shown as a formula II:

a compound of formula I and R₁COOH is used as a raw material and is prepared by Mitsunobu substitution reaction, and amine and/or a nitrogen-containing aromatic heterocyclic compound are added into reaction liquid:

wherein R is₁Is optionally substituted aryl or alkyl;

R₂is composed ofWherein R is₃、R₄、R₅Independently selected from alkyl groups.

The amine is a product obtained by replacing one or more hydrogen atoms in an ammonia molecule by alkyl, and comprises aliphatic amine and aromatic amine. In some embodiments of the invention, the amine and/or nitrogen-containing heteroaromatic compound is a tertiary amine and/or six-membered ring nitrogen-containing heteroaromatic compound;

preferably, the tertiary amine is one or more than two of trimethylamine, triethylamine, triethanolamine, triallylamine and N, N-diisopropylethylamine, and the six-membered ring nitrogen-containing aromatic heterocyclic compound is pyridine, 4-dimethylaminopyridine or a mixture thereof;

preferably, the amine and/or the nitrogen-containing aromatic heterocyclic compound is one or more of triethylamine, diisopropylethylamine and pyridine.

In some embodiments of the invention, R₁Is an optionally substituted 5-to 14-membered aryl or C₁～C₆Alkyl radical, R₃、R₄、R₅Independently selected from C₁～C₆An alkyl group; preferably, R₁Is optionally substituted phenyl or C₁～C₄Alkyl radical, R₃、R₄、R₅Independently selected from C₁～C₄An alkyl group; further preferably, R₁Is p-nitrophenyl, R₃、R₄、R₅Are all methyl.

In some embodiments of the invention, the preparation method comprises the steps of: a compound shown as a formula I and R₁COOH, a phosphine reagent and amine and/or a nitrogen-containing aromatic heterocyclic compound are added into a reaction solvent, then azodicarboxylic ester is slowly added, the temperature of the reaction liquid is controlled below 30 ℃, and the reaction is finished to obtain the clindamycin impurity intermediate shown in the formula II.

In some embodiments of the invention, the method of preparation satisfies at least one of the following:

the phosphine reagent is a triarylphosphine; preferably, the phosphine reagent is triphenylphosphine;

the azodicarboxylic acid ester is diisopropyl azodicarboxylate, diethyl azodicarboxylate or a mixture thereof;

the reaction solvent is one or more than two of toluene, dichloromethane and tetrahydrofuran;

before adding the azodicarboxylic acid ester, controlling the temperature of the reaction liquid below 30 ℃; preferably, the temperature of the reaction liquid is controlled to be 10-30 ℃;

the concentration (g: ml) of the compound represented by the formula I in the reaction solvent is (1:2) to (1: 100); preferred concentrations (g: ml) are 1: 30;

reaction reagents compounds of formula i: r₁COOH: phosphine reagent: azodicarboxylate: molar ratio of amine and/or nitrogen-containing aromatic heterocyclic compoundThe ratio is 1: (1-5): (1-5): (1-5): (1-5); preferably, the reaction reagent is a compound represented by formula I: r₁COOH: phosphine reagent: azodicarboxylate: the molar ratio of the amine and/or the nitrogen-containing aromatic heterocyclic compound is 1:2:2:2: 2.

In a second aspect, the invention provides a method for preparing clindamycin hydrochloride impurities shown in formula IV, which comprises one or more than two of the following steps:

a. protecting the hydroxyl group of compound 1 with a silicon reagent to give compound 2:

R₂is composed ofWherein R is₃、R₄、R₅Independently selected from alkyl;

b. selectively removing the silicon protecting group of the compound 2 in the presence of acid to obtain a compound shown as a formula I:

c. preparing an intermediate shown in a formula II according to the preparation method of the clindamycin hydrochloride impurity intermediate shown in the formula II;

d. and (3) carrying out hydrolysis reaction on the intermediate of the formula II to obtain the clindamycin hydrochloride impurity shown in the formula IV:

in some embodiments of the invention, R₃、R₄、R₅Independently selected from C₁～C₆An alkyl group; preferably, R₃、R₄、R₅Independently selected from C₁～C₄An alkyl group; most preferably, R₃、R₄、R₅Are all methyl.

In some embodiments of the present invention, the acid in step b is one or more of formic acid, acetic acid, and propionic acid; preferably, the acid of step b is acetic acid.

In a third aspect, the invention provides a preparation method of clindamycin hydrochloride impurity shown in formula III, which further comprises the following steps:

e. preparing the clindamycin hydrochloride impurity shown in the formula IV according to the preparation method of the clindamycin hydrochloride impurity shown in the formula IV;

f. preparing the clindamycin hydrochloride impurity shown in the formula IV into hydrochloride, and performing chlorination reaction to obtain the clindamycin hydrochloride impurity shown in the formula III:

in some embodiments of the invention, the chlorination reaction in step f is carried out under the following conditions: adding a chloroform solution of triphosgene into a mixed solvent of chloroform and N, N-dimethylformamide, fully reacting to generate a Vilsmeier reagent, adding a hydrochloride of the formula IV, and finishing the reaction to obtain the triphosgene.

In some embodiments of the invention, the silicon reagent in step a is a trialkyl halosilane and a hexaalkyldisilazane wherein the halogen group is selected from Cl, Br, or I, preferably Cl, and the alkyl group is preferably methyl.

In some embodiments of the invention, step a: and (3) applying a silicon protecting group, adding lincomycin hydrochloride (compound 1), trimethylchlorosilane, hexamethyldisilazane and pyridine into a three-necked bottle, reacting for 8 hours at 0-25 ℃, and carrying out post-treatment on the reaction liquid to obtain a compound 2. In some embodiments of the invention, step b: and (3) selective deprotection, namely adding the obtained compound 2 into a reaction bottle, adding methanol and acetic acid, reacting for 18 hours at the temperature of no more than 30 ℃, and carrying out post-treatment on the reaction liquid to obtain the compound shown in the formula I.

In some embodiments of the invention, step c: and (b) carrying out Mitsunobu substitution reaction, namely adding the compound I purified in the step (b) and toluene into a reaction bottle, adding triphenylphosphine, p-nitrobenzoic acid, amine and/or a nitrogen-containing aromatic heterocyclic compound and diisopropyl azodicarboxylate, reacting for 20 hours at the temperature of no more than 30 ℃, and concentrating the reaction solution to obtain the compound shown in the formula II.

In some embodiments of the invention, step d: and (c) performing hydrolysis reaction, namely dissolving the compound II obtained in the step (c) in methanol, adding potassium carbonate, stirring the mixture overnight at the temperature of the reaction solution not higher than 30 ℃, and performing post-treatment to obtain a compound IV, namely 7-epimeramycin.

In some embodiments of the invention, step f preferably employs a Vilsmeier reagent generated from triphosgene/DMF as the chlorinating reagent.

In some embodiments of the invention, step f: c, chlorination reaction, namely preparing the compound IV obtained in the step d into compound IV hydrochloride; adding chloroform, N-dimethylformamide and triphosgene into a reaction bottle, adding hydrochloride of a compound IV, reacting at 0-60 ℃, and performing post-treatment to obtain clindamycin hydrochloride impurities shown in a formula III.

Further preferably, in some embodiments of the present invention, the method for synthesizing clindamycin hydrochloride impurity comprises the following steps:

step a: stirring the compound 1 and pyridine in a three-neck flask until the compounds are basically dissolved at room temperature, sequentially adding hexamethyldisilazane and trimethylchlorosilane, and controlling the temperature of reaction liquid to be 2-10 ℃ by using an ice water bath; after the addition is finished, removing the ice water bath, and reacting for 8 hours at room temperature; extracting, drying, concentrating and carrying out column chromatography on the reaction solution to obtain a compound 2;

step b: under the condition of room temperature, after the compound 2 and methanol are stirred and dissolved, adding an acetic acid solution, reacting for 18 hours at the temperature of no more than 30 ℃, and washing, drying, filtering and concentrating the reaction solution to obtain a compound shown in a formula I;

step c: adding a compound shown in the formula I and toluene into a reaction bottle at room temperature, then sequentially adding triphenylphosphine, p-nitrobenzoic acid, amine and/or a nitrogen-containing aromatic heterocyclic compound and diisopropyl azodicarboxylate, uniformly stirring, controlling the temperature of the reaction solution to be not more than 30 ℃, and stirring for 20 hours; washing the reaction solution with sodium bicarbonate solution and purified water, and concentrating an organic phase to obtain a compound shown as a formula II;

step d: adding a compound shown as a formula II, methanol and potassium carbonate into a reaction bottle at room temperature, controlling the temperature of the reaction liquid to be not more than 30 ℃, stirring for 20 hours, washing the reaction liquid with water, extracting, concentrating and carrying out column chromatography to obtain a compound IV, namely 7-epimembrin;

step f: compound IV was converted to compound IV hydrochloride at room temperature. Adding chloroform and N, N-dimethylformamide into the reaction bottle, uniformly stirring, and cooling in an ice-water bath; then adding a chloroform solution of triphosgene into the system, and reacting for 0.5 hour at the temperature of not more than 5 ℃; adding compound IV hydrochloride in batches, and reacting for 1.5 hours at the temperature of not more than 5 ℃; the reaction system is sequentially reacted for 0.5 hour at room temperature and 40 ℃, finally moved to 60 ℃ for reaction for 20 hours, and the clindamycin hydrochloride impurity shown in the formula III is obtained through post-treatment.

In some embodiments of the invention, in the method for synthesizing clindamycin hydrochloride impurities, the molar ratio of clindamycin hydrochloride (compound 1), hexamethyldisilazane and trimethylchlorosilane in step a is 1:1:2 to 1:5:10, and preferably 1:3: 7.

In some embodiments of the present invention, in the method for synthesizing clindamycin hydrochloride impurities, the post-treatment in step a specifically comprises the following steps: and pouring the reaction solution into dichloromethane, washing an organic phase with water, drying, concentrating, eluting by column chromatography, and washing a product after elution to remove pyridine to obtain a compound 2. The eluent is n-hexane and ethyl acetate, and the volume ratio is 5:1-20: 1; the preferred volume ratio is 12: 1.

In some embodiments of the present invention, in the method for synthesizing clindamycin hydrochloride impurity, in step b, the concentration of the acetic acid solution is 36% to 98%, and preferably, the concentration of the acetic acid solution is 80%.

In some embodiments of the present invention, in the method for synthesizing clindamycin hydrochloride impurity, in step b, the temperature of the reaction solution is concentrated under reduced pressure to 25-40 ℃, preferably 30 ℃.

In some embodiments of the invention, in the method for synthesizing clindamycin hydrochloride impurities, in the step d, the molar ratio of the compound shown in the formula II to potassium carbonate is 1:1-1: 5; preferably in a molar ratio of 1: 1.5.

In some embodiments of the present invention, in the method for synthesizing clindamycin hydrochloride impurities, in step d, the post-treatment specifically comprises the following operation steps: concentrating the reaction solution under reduced pressure, layering by using a solvent, extracting, drying, concentrating, and eluting by using column chromatography to obtain a compound IV; the eluent is dichloromethane and methanol with the volume ratio of 5:1-30: 1; preferably in a volume ratio of 15: 1.

In some embodiments of the present invention, in the method for synthesizing clindamycin hydrochloride impurity, in step f, the specific method for synthesizing hydrochloride of compound IV is: stirring a mixture of the compound IV, hydrochloric acid ethanol and absolute ethyl alcohol for 10 hours at room temperature, and concentrating under reduced pressure to obtain a crude hydrochloride of the compound IV, wherein the volume ratio of the hydrochloric acid ethanol to the ethanol is 1:5-1: 20; preferably in a volume ratio of 1: 8.

In some embodiments of the present invention, in the method for synthesizing clindamycin hydrochloride impurity, in step f, the molar ratio of the crude hydrochloride of compound IV to triphosgene is 1:1-1: 5; preferably in a molar ratio of 1: 2.

In some embodiments of the present invention, in the method for synthesizing clindamycin hydrochloride impurities, in step f, the post-treatment comprises the following specific operation steps: cooling the reaction solution to below 20 ℃, adding a sodium hydroxide solution to adjust the pH to be more than 11.0, and stirring for 2 hours at room temperature; cooling the system below 10 deg.C, adding concentrated hydrochloric acid to adjust pH to less than 1.0, layering, extracting organic phase, adjusting pH of water phase to more than 11.0, extracting, drying, concentrating, and freezing for storage; finally, carrying out column chromatography elution, salifying and recrystallization on the crude product to obtain a compound III, wherein an eluent is dichloromethane and methanol in a volume ratio of 10:1-40: 1; preferably in a volume ratio of 20: 1.

The invention provides a clindamycin hydrochloride impurity intermediate or a salt thereof shown in a formula II:

R₁is optionally selected fromSubstituted aryl or alkyl; r₂Is composed ofWherein R is₃、R₄、R₅Independently selected from alkyl groups.

In some embodiments of the invention, R₁Is an optionally substituted 5-to 14-membered aryl or C1-C6 alkyl, R₃、R₄、R₅Independently selected from C₁～C₆An alkyl group.

Preferably, R₁Is optionally substituted phenyl or C₁～C₄Alkyl radical, R₃、R₄、R₅Independently selected from C1-C4 alkyl.

More preferably, R₁Is p-nitrophenyl, R₃、R₄、R₅Are all methyl.

The invention also provides application of the clindamycin hydrochloride impurity intermediate shown in the formula II in preparation of 7-epimeric clindamycin hydrochloride shown in the formula III and/or 7-epimeric clindamycin shown in the formula IV.

In the context of the present description, the following abbreviations have the following meanings; for undefined abbreviations, they have generally accepted meanings:

DMF ═ N, N-dimethylformamide

TMSCl ═ trimethylchlorosilane

(TMS)₂NH-hexamethyldisilazane

TEA ═ triethylamine

Py ═ pyridine

DIPEA ═ N, N-diisopropylethylamine

DIAD (diisopropyl azodicarboxylate)

Ph₃P ═ triphenylphosphine

MeOH ═ methanol

PhMe-toluene

AcOH ═ acetic acid

EtOH-HCl (hydrochloric acid) ethanol solution

The amine is a product obtained by replacing one or more hydrogen atoms in an ammonia molecule by alkyl, and comprises aliphatic amine and aromatic amine.

The invention provides a preparation method of clindamycin hydrochloride impurity-7-epimeric clindamycin hydrochloride, which mainly has the following beneficial effects:

1. the invention takes lincomycin as raw material, and can prepare 7-epimeddic clindamycin hydrochloride with the total yield of 23 percent through silicon protecting group application, selective deprotection, Mitsunobu substitution reaction, hydrolysis reaction and chlorination reaction. The synthesized high-purity 7-epimeric clindamycin hydrochloride can be used as an impurity standard substance in the detection and analysis of a clindamycin hydrochloride finished product, so that the accuracy of qualitative and quantitative analysis of impurities is improved, the control on the impurities is favorably enhanced, and the quality of the clindamycin hydrochloride finished product is improved.

2. The synthetic route of the clindamycin hydrochloride impurity provided by the invention can obtain 7-epimeddium clindamycin hydrochloride and also can obtain another impurity, namely 7-epimeddium clindamycin, and the route can synthesize the two impurities at the same time with higher yield, which is incomparable with the prior art.

3. The invention adopts Vilsmeier reagent generated by triphosgene/DMF as chlorination reagent, triphosgene as solid, and has stable property in the processes of production, transportation, storage and the like; in the reaction of the step f, the reaction activity of the triphosgene is far greater than that of chlorinated reagents such as phosphorus oxychloride and the like, so that the reaction can be carried out more thoroughly; compared with the use of phosphorus oxychloride and other chlorinating agents, the waste water generated by the reaction is reduced by half, the three-waste treatment cost is reduced, and the method is more suitable for industrial production.

4. The invention adopts the intermediate of the formula II to prepare the 7-epimembricin hydrochloride and the 7-epimembricin, not only can reduce the production cost, but also provides a method for efficiently preparing the impurity reference substance of the clindamycin hydrochloride, and solves the problems of low yield, high content of byproducts and impurities in the 7-epimembricin hydrochloride prepared by the prior art.

Detailed Description

The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.

The technical solution of the present invention is further illustrated by the following examples.

In a preferred embodiment of the present invention, the synthetic routes of 7-epimeric clindamycin hydrochloride and 7-epimeric clindamycin are as follows: