CN110606865A - Preparation method of clindamycin hydrochloride impurity - Google Patents
Preparation method of clindamycin hydrochloride impurity Download PDFInfo
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Abstract
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 R1COOH 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.
Description
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:
EXAMPLE 1 Compound 2-A
Adding 50.07g of lincomycin hydrochloride (compound 1) and 500ml of pyridine into a three-necked bottle at room temperature, and stirring to obtain a uniform semitransparent solution; then placing the three-necked bottle in an ice-water bath for cooling, controlling the internal temperature to be 2-10 ℃, dropwise adding 75.0ml of hexamethyldisilazane, when the solution turns white and turbid, dropwise adding 86.0ml of trimethylchlorosilane, controlling the internal temperature to be not more than 10 ℃ by using the ice-water bath, removing the ice-water bath after the charging is finished, and slowly heating the system to room temperature for reacting for 8 hours;
during the reaction, TLC plate detection (dichloromethane to methanol volume ratio of 10:1) was performed until no reaction material existed, the reaction solution was poured into 1500ml dichloromethane, after stirring and clarification, the organic phase was washed with 500ml water for 3 times, dried with 75.05g anhydrous sodium sulfate, filtered and dried to obtain 75.91g of yellow oily substance, and separated by column chromatography (n-hexane to ethyl acetate volume ratio of 12:1) to obtain the title compound 2-A (69.31g, yield: 89%).
MS(m/z):695.3[M+1]+
1H NMR(400MHz,CDCl3)δ7.82(d,J＝8.9Hz,1H),5.17(d,J＝5.6Hz,1H),4.43(d,J＝2.4Hz,1H),4.19(dd,J＝9.4,5.6Hz,1H),4.16-4.07(m,2H),3.96(d,J＝9.3Hz,1H),3.70(dd,J＝9.4,3.3Hz,1H),3.60(s,1H),3.15(q,J＝4.0Hz,1H),2.96(dd,J＝10.7,4.5Hz,1H),2.36(s,3H),2.08(s,2H),2.06-2.03(m,1H),1.97-1.89(m,2H),1.58(d,J＝4.1Hz,3H),1.31-1.20(m,5H),0.89(t,J＝6.9Hz,3H),0.14(s,9H),0.13(s,9H),0.10(s,9H),0.07(s,9H)。
EXAMPLE 2 Compound 3
69.31g of Compound 2-A was mixed with 1400ml of methanol at room temperature, dissolved by stirring, and then 70ml of 80% acetic acid solution was slowly added thereto with the internal temperature controlled not to exceed 30 ℃ and the reaction was stirred for 18 hours, and after completion of the reaction was confirmed by TLC plate detection, the reaction solution was spin-dried at 30 ℃, 600ml of dichloromethane was added, the organic phase was washed with 100ml of aqueous sodium bicarbonate solution having a pH of 8.0 for 3 times, and finally dried, filtered and concentrated to obtain the title compound 3(55.52g, yield: 90%).
MS(m/z):623.3[M+1]+
1H NMR(400MHz,CDCl3)δ7.44(d,J＝9.8Hz,1H),5.22(d,J＝5.6Hz,1H),4.34(td,J＝9.7,5.0Hz,1H),4.17(dd,J＝9.5,5.6Hz,1H),4.14–4.08(m,1H),4.02(d,J＝9.5Hz,1H),3.81(d,J＝2.1Hz,1H),3.60(dd,J＝9.5,2.4Hz,1H),3.23–3.13(m,1H),3.09(s,1H),3.01(dd,J＝10.9,3.8Hz,1H),2.40(s,3H),2.10(s,3H),2.08–1.94(m,3H),1.90–1.80(m,1H),1.38-1.25(m,4H),1.22-1.12(m,3H),0.95-0.82(m,3H),0.19(s,9H),0.17–0.13(m,18H)。
EXAMPLE 3-1 Compound 4
Dissolving 50g of compound 3 in 1500ml of toluene at room temperature, respectively adding 48.45g of triphenylphosphine, 26.80g of p-nitrobenzoic acid and 27ml of triethylamine, stirring uniformly, slowly adding 32.18g of DIAD, controlling the temperature of a reaction solution to be within 30 ℃, stirring for 20 hours, detecting by a TLC plate, after confirming that the reaction is finished, adding 400ml of a sodium bicarbonate aqueous solution with the pH of 8.0 into the reaction solution, stirring for 0.5 hour, standing for layering, and taking an organic phase; the organic phase was washed with purified water and dried to give a yellow viscous solid, which was then directly added to 400ml of a mixed solvent (volume ratio of n-hexane to ethyl acetate 7:1), stirred at room temperature for 2 hours, filtered to remove the filter cake, and the filtrate was concentrated to give the title compound 4(45g, yield 72%).
MS(m/z):772.3[M+1]+
1H NMR(400MHz,CDCl3)δ8.32(d,J＝8.8Hz,2H),8.17(d,J＝8.8Hz,2H),7.68(d,J＝10.7Hz,1H),5.56(q,J＝6.2Hz,1H),5.15(d,J＝5.5Hz,1H),4.53(t,J＝10.2Hz,1H),4.14(dd,J＝9.5,5.5Hz,1H),3.93(d,J＝9.9Hz,1H),3.78(d,J＝2.0Hz,1H),3.54(dd,J＝9.5,2.3Hz,1H),3.26(dd,J＝7.2,4.8Hz,1H),3.05(dd,J＝10.8,3.9Hz,1H),2.42(s,3H),2.20–1.98(m,3H),1.92(d,J＝10.1Hz,1H),1.72(s,3H),1.35–1.32(m,3H),1.31–1.24(m,3H),1.15(d,J＝6.2Hz,1H),0.91(t,J＝6.8Hz,3H),0.20(s,9H),0.12(s,9H),0.10(s,9H)。
EXAMPLE 3-2 Compound 4
Dissolving 0.551g of compound 3 in 30ml of dichloromethane at room temperature, respectively adding 0.475g of triphenylphosphine, 0.320g of p-nitrobenzoic acid and 0.3ml of diisopropylethylamine, and uniformly stirring; 0.4ml of DIAD was added thereto, the internal temperature was controlled to 30 ℃ or less, and after stirring for 20 hours, the title compound 4 was obtained by the isolation method of example 3-1 (yield 67%).
The mass spectrum and hydrogen spectrum data were substantially the same as in example 3-1.
EXAMPLES 3-3 Compound 4
After 0.506g of Compound 3 was dissolved in 30ml of tetrahydrofuran at room temperature, 0.433g of triphenylphosphine, 0.271g of p-nitrobenzoic acid and 0.2ml of pyridine were added, followed by stirring to homogeneity, 0.3ml of DIAD was added, the internal temperature was controlled to 30 ℃ or less, and after stirring for 20 hours, the title compound 4 was obtained by the isolation method of example 3-1 (yield 60%).
The mass spectrum and hydrogen spectrum data were substantially the same as in example 3-1.
Example 47-Difference Lincomycin (Compound of formula IV)
Dissolving 20g of compound 4 in 500ml of methanol at room temperature, adding 18.43g of potassium carbonate, controlling the internal temperature within 30 ℃, stirring for 20 hours, detecting by a TLC plate, confirming that the raw materials are completely reacted, spin-drying the reaction liquid to obtain a yellow viscous solid, directly adding 200ml of ultrapure water and 300ml of ethyl acetate, stirring for 10 minutes, standing for layering, adjusting the pH of the aqueous phase to 10 by using a 2N KOH solution, extracting for 2 times by using 300ml of ethyl acetate, combining the organic phases, spin-drying to obtain a crude product, and eluting by column chromatography (the volume ratio of dichloromethane to methanol is 15:1) to obtain the title compound IV (9.10g, yield 86%, HPLC purity 98.4%).
MS(m/z):407.2[M+1]+
1H NMR(400MHz,CDCl3)δ7.99(d,J＝8.9Hz,1H),5.35(d,J＝5.5Hz,1H),5.19(s,1H),4.40(q,J＝6.3Hz,1H),4.13(dd,J＝10.0,5.4Hz,1H),4.04(d,J＝10.2Hz,1H),3.84(t,J＝9.5Hz,1H),3.71–3.58(m,2H),3.18(dd,J＝7.1,4.5Hz,1H),3.02(dd,J＝10.4,4.9Hz,1H),2.94–2.56(m,2H),2.38(s,3H),2.14(s,3H),2.10–1.98(m,3H),1.97–1.81(m,2H),1.37–1.23(m,4H),1.19(d,J＝6.4Hz,3H),0.88(t,J＝6.6Hz,3H)。
Example 57 Difference clindamycin hydrochloride (Compound of formula III)
Dissolving 7.81g of compound IV in 100ml of absolute ethanol at room temperature, adding 12ml of 8M ethanol hydrochloride solution, stirring for 10 hours, and spin-drying to obtain 8.50g of hydrochloride of the compound IV; adding 10.0ml of chloroform and 7.0ml of DMF into a three-necked bottle, uniformly stirring, and cooling in an ice-water bath; adding 10.13g of triphosgene into 25.0ml of chloroform for full dissolution, slowly dropwise adding into a three-necked bottle, controlling the internal temperature to be not more than 5 ℃, reacting for 0.5 hour, adding 7.40g of hydrochloride of a compound IV in batches, and reacting for 1.5 hours under heat preservation; after the reaction solution is yellow clear solution, moving a reaction system to a room temperature environment, reacting for 0.5 hour, then heating to 40 ℃, reacting for 0.5 hour, then heating to 60 ℃, reacting for 20 hours, then moving the reaction to an ice-water bath, cooling, controlling the internal temperature not to exceed 20 ℃, dropwise adding a 50% sodium hydroxide aqueous solution to adjust the pH to be more than 11.0, stirring for 2 hours at room temperature, then moving to the ice-water bath to cool, adding 3N concentrated hydrochloric acid to adjust the pH to be less than 1.0, then heating to room temperature, standing for layering, removing a water layer, extracting an organic phase with 50ml of dilute hydrochloric acid with the pH of 1.0, and then combining the water phases; the aqueous phase was adjusted to a pH of >11.0, the aqueous phase was extracted with 50ml of dichloromethane, the organic phases were combined, washed, dried, filtered, concentrated and eluted by column chromatography (dichloromethane to methanol volume ratio 20:1) to give 5.02g of a yellow solid, dissolved in 15ml of ethanol, dissolved in 9.5ml of 8M ethanol hydrochloride solution, stirred at room temperature for 2 hours, concentrated at 40 ℃ to give 5.40g of a yellow solid, dissolved, stirred, left to stand at room temperature and filtered to give the title compound iii (3.54g, yield 47%, HPLC purity 98.7%).
MS(m/z):425.1[M+1]+
1H NMR(400MHz,DMSO)δ9.78(s,1H),9.08(d,J＝9.6Hz,1H),7.55(s,1H),7.43(s,1H),7.30(s,1H),5.17(d,J＝5.5Hz,1H),4.64(td,J＝9.9,2.4Hz,1H),4.41(dd,J＝6.7,2.6Hz,1H),4.26(s,1H),4.12–3.84(m,2H),3.75(s,1H),3.68–3.56(m,1H),3.40(s,1H),3.30(dd,J＝10.1,2.8Hz,1H),2.84(s,3H),2.29–2.15(m,2H),2.11–1.98(m,4H),1.49–1.35(m,5H),1.27(tt,J＝12.9,6.5Hz,2H),0.87(t,J＝7.2Hz,3H)。
13C NMR(101MHz,DMSO)δ167.61,89.27,70.93,69.95,68.09,67.89,67.63,60.65,59.23,53.30,36.04,35.59,34.84,20.93,19.29,14.31,13.66。
DEPT135 spectrum of compound III containing 4 secondary carbons at 20.46ppm, 34.37ppm, 35.12ppm and 60.18ppm, respectively; contains 9 tertiary carbons, 35.57ppm, 52.83ppm, 58.76ppm, 67.16ppm, 67.42ppm, 67.62ppm, 69.48ppm, 70.46ppm and 88.80ppm respectively; contains 1 quaternary carbon and is 167.14 ppm.
Compound iii ir spectrum, details are given in the table below:
high resolution Mass Spectrometry of Compound III, M/z 425.1859[ M + H [)]+，m/z 447.1678[M+Na]+。
Comparative example 1 preparation of Compound 4 without addition of amine and/or Nitrogen-containing heteroaromatic Compound
0.805g of Compound 3 was dissolved in 30ml of toluene at room temperature, 0.690g of triphenylphosphine and 0.437g of p-nitrobenzoic acid were added to the solution, the mixture was stirred uniformly, 0.51ml of DIAD was added thereto, the internal temperature was controlled to 30 ℃ or less, and after stirring for 20 hours, the reaction was carried out on a TLC plate to find that the starting material disappeared, the reaction was disordered, and Compound 4 was not produced.
As can be seen from comparative example 1, the target product could not be obtained without adding the amine and/or the nitrogen-containing heteroaromatic compound; the compound 4 can be prepared by adding amine or nitrogen-containing aromatic heterocyclic compounds (such as TEA, DIPEA and pyridine) in the embodiments 3-1, 3-2 and 3-3 respectively, and has high yield.
Having described embodiments of the present invention, the foregoing description is intended to be exemplary, not exhaustive, and not limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.
Claims (11)
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.
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