CN107400118B

CN107400118B - Preparation method of esomeprazole intermediate

Info

Publication number: CN107400118B
Application number: CN201710758716.1A
Authority: CN
Inventors: 袁建栋; 黄仰青; 顾家宁
Original assignee: XINTAI PHARMACEUTICAL (SUZHOU) CO Ltd
Current assignee: Borui Pharmaceutical (Suzhou) Co., Ltd
Priority date: 2017-08-29
Filing date: 2017-08-29
Publication date: 2020-07-28
Anticipated expiration: 2037-08-29
Also published as: CN107400118A

Abstract

The invention provides an improved preparation method of esomeprazole intermediate, namely, mufelazole, which comprises the steps of condensing 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride and 5-methoxy-2-mercapto-1H-benzimidazole serving as starting materials under an alkaline condition, wherein the specific conditions are that the equivalent ratio of E L2, E L3 and sodium hydroxide is 1:1.05:2.05, a mixed solvent with the mass ratio of ethanol to acetone being 3:1 is used as a reaction solvent, and the reaction temperature is 40-45 ℃.

Description

Preparation method of esomeprazole intermediate

Technical Field

The invention belongs to the field of medicines, relates to esomeprazole, and particularly relates to a preparation method of an esomeprazole intermediate.

Background

Omeprazole is a proton pump inhibitor of gastric parietal cells, can specifically inhibit gastric acid secretion, and is a first choice medicine for treating acid-related diseases such as gastric ulcer, duodenal ulcer and gastroesophageal reflux disease (GERD). Omeprazole is a sulfoxide compound, the sulfur atom is the stereocenter of the omeprazole, and the omeprazole is a racemic mixture of two enantiomers of the omeprazole. Esomeprazole is an S-optical isomer of omeprazole, is less subject to hepatic metabolism, has fewer side effects than omeprazole, is the first optically pure Proton Pump Inhibitor (PPI) in the world, and pharmaceutically acceptable salts include sodium salts and magnesium salts.

The chemical name of esomeprazole is 5-methoxy-2- ((S) - ((4-methoxy-3, 5-dimethyl-2-pyridyl) methyl) sulfinyl-1H-benzimidazole, and the structural formula is as follows:

the medicinal esomeprazole sodium has excellent solubility in water, can be used as an injection preparation, is particularly suitable for patients who cannot be orally administered, is marketed in Europe in 2003, is approved to be marketed in the United states by FDA in 2007, and is marketed in China by SFDA in 2009.

In a plurality of reports, two main ways for obtaining esomeprazole are asymmetric oxidation and resolution, wherein the former is a product selectively generating a single configuration by adopting an asymmetric oxidation method, and the latter is a method for synthesizing omeprazole firstly and then synthesizing the esomeprazole with the single configuration by a resolution method. Compared with the two methods, the yield of the resolution is only half of that of the asymmetric oxidation, the R-omeprazole with the other configuration obtained by the resolution cannot be utilized, the waste is caused, and the production cost is far higher than that of the asymmetric oxidation synthesis.

In the prior art, the following routes for preparing esomeprazole are mainly disclosed:

the amine used in this route is triethylamine, the salt formation is carried out in a mixed solvent of butanone and toluene, and diethyl ether is also used. According to a series of amine comparison experiments, triethylamine has obvious disadvantages compared with diisopropylethylamine with better effect, butanone smell is heavier, price is higher, diethyl ether is extremely flammable and explosive, and the route is not suitable for industrial production due to comprehensive consideration of the factors.

The other route is as follows:

this route is preferred to oxidize to sulfoxide and then replace the nitro group para to the pyridine ring with methoxy group, since the cost of this asymmetric synthesis is mainly due to the series of ligands and oxidizing reagents used in the asymmetric oxidation step, and it is generally desirable to have a costly reaction step placed after this, which is more economical. In addition, the similarity of the two compounds before and after the nitro group is replaced is very high, and a small amount of nitro compound which cannot completely react is difficult to remove cleanly, so that the nitro compound is a potential main impurity in the product. But the total yield is lower, and the purity and the ee value of the obtained product are lower.

The third route is as follows:

regarding the synthesis of the precursor of esomeprazole sodium, the synthetic routes of the Wufelazole are numerous, the same point lies in that the Wufelazole sodium is subjected to substitution reaction with the pyridine derivative through mercaptobenzimidazole, and the difference lies in that the leaving groups of the pyridine derivative are different, the sequence of the reaction of the groups at the para-position of the pyridine ring is different, and the like. The main synthetic route is as follows:

1. the compound is synthesized by methoxy mercapto benzimidazole and nitropyridine chloride in one step, and two steps of reaction are actually carried out, wherein one step is substitution of mercapto compound and chloride, and the other step is substitution of nitro group at para position of pyridine ring by methoxy. The generated Wufelazole is easy to leave a small amount of intermediate with nitro group at para position of pyridine ring, has physical properties similar to those of the Wufelazole and is not easy to purify.

2.

The pyridine derivative used for synthesizing the Wufelazole is p-methoxypyridine mesylate, and hydroxyl is made into mesylate which is a good leaving group and can successfully generate substitution reaction with mercaptomethoxybenzimidazole under the action of alkali. However, the synthesis of the p-methoxypyridine methanesulfonate needs to use highly toxic and corrosive methane sulfonyl chloride or methane sulfonic anhydride, which is not environment-friendly and is not suitable for industrial production.

3.

2-chloromethyl-3, 5-dimethyl-4-chloropyridine is condensed with 2-mercapto-5-methoxy-1-hydrobenzimidazole, and then chlorine is replaced by methoxy under the action of sodium methoxide to obtain the Wufelazole.

4.

In the synthetic process of the route, in order to neutralize one molecule of hydrochloric acid, the inventor uses 2 molar equivalent of sodium hydroxide as an acid-binding agent, the heating reflux is carried out for 3 hours, the reaction is incomplete, the effect of prolonging the reaction time is not achieved, and then 0.1eq of 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride is supplemented, the 5-methoxy-2-mercapto-1H-benzimidazole is completely reacted, but T L C shows that unknown impurity points are generated in the reaction liquid.

Through the above experiments, the technical personnel of the invention find that the reaction can not be completely carried out under the condition of equivalent material proportion, and after 0.1eq 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride is supplemented, the reaction is completely carried out, but more impurities are generated in the reaction, and the high-purity Wufelazole can be obtained by two-time crystallization. Aiming at the existing defects, the technical personnel of the invention optimizes the process in the links of the mixture ratio of the reaction raw materials, the selection of the reaction solvent, the reaction temperature and the like.

Disclosure of Invention

The invention aims to provide an improved preparation method of esomeprazole intermediate, namely, mufelrazole (E L1). The synthetic route of the method is as follows:

compared with E L3, E L2 has large polarity and poor solubility, and a small amount of residual E L3 is easier to remove in a crystallization solvent, in the synthesis process of E L1, the technical personnel of the invention use equivalent material proportion, but the reaction is not complete, and when the E L3 is supplemented to 1:1.1eq, the reaction is complete, but more impurities are generated in the reaction and are difficult to remove, so the technical personnel of the invention further grope the material proportion, and the experimental results are shown in Table 1:

TABLE 1

The T L C result shows that when the ratio of the raw materials is 1:1.03, E L2 cannot completely react, E L3 is increased to 1.05 equivalent, E L2 completely reacts, a small amount of unknown impurities are generated, when the amount of E L3 is increased to 1.07 equivalent, the impurities are obviously increased, and the yield is reduced, and the technical personnel determine that the equivalent ratio of E L2 to E L3 to NaOH is 1:1.05: 2.05.

The reaction solvent used in the literature is an ethanol aqueous solution, the solubility of the two raw materials is good, but the post-treatment is complex, after the reaction is finished, the ethanol needs to be distilled off and then extracted by ethyl acetate, the ethanol and water are mixed and azeotroped, the ethanol and the water are not easy to be distilled off, and part of products can remain in an aqueous phase in the ethyl acetate extraction process, so that the yield is influenced. Other solvents are considered to be used, inorganic salt can be directly filtered and removed after the reaction, the post-treatment is simplified and the reaction yield is improved on the premise of ensuring the normal reaction. The reaction solvents were examined and the results are shown in table 2 below:

TABLE 2

The post-treatment modes of the above reactions are as follows: after the reaction is finished, the temperature of the reaction solution is reduced to room temperature, then the reaction solution is filtered, sodium chloride generated in the reaction is filtered out, the filtrate is decompressed, concentrated and evaporated to remove the solvent, and the residue is crystallized by ethyl acetate.

Only ethanol is used as a reaction solvent, the reaction can be completely carried out, and after the reaction solution is cooled to room temperature, the inorganic salt can be removed completely by filtering, and can not remain in the final product; when a mixed solvent of ethanol and ethyl acetate is used as a reaction solvent, the ethyl acetate has poor solubility to inorganic salts, and sodium hydroxide added in the reaction and sodium chloride generated in the reaction process are quickly agglomerated into large blocks in the presence of the ethyl acetate, so that the reaction cannot be carried out; when a mixed solvent of ethanol and acetone is used as the reaction solvent, the reaction may not proceed completely when the mass ratio is 1:1, the reaction may proceed completely when the mass ratio is 3:1 and 5:1, and the yield is high when the mass ratio of ethanol to acetone is 3:1, and therefore, it is finally decided to use a mixed solution of ethanol and acetone in a mass ratio of 3:1 as the reaction solvent.

The skilled artisan also examined the effect of reaction temperature on the reaction, with the results shown in Table 3:

TABLE 3

The research personnel of the invention investigate the influence of different reaction temperatures on the reaction, when the reaction temperature is higher than 45 ℃, the reaction can be completely carried out, but relatively more impurities affect the product yield, when the reaction temperature is 40-45 ℃, the reaction can be completely carried out for 3h, the generated impurities are not obviously shown on T L C, the yield is higher, when the reaction temperature is lower than 40 ℃, the reaction is not completely carried out, and the reaction condition of prolonging the reaction time is not obviously improved.

And finally determining the reaction conditions of condensation of E L2 and E L3 to generate the Wufela azole (E L1) by combining the experimental results, wherein the equivalent ratio of E L2, E L3 and sodium hydroxide is 1:1.05:2.05, a mixed solvent of ethanol and acetone in a mass ratio of 3:1 is used as a reaction solvent, and the reaction temperature is 40-45 ℃.

After the synthesis process of the Wufelazole is optimized, technicians synthesize a batch of E L1 according to the determined process, the yield is about 94%, and the purity is over 95% by HP L C.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The present disclosure is further illustrated and described with reference to specific examples, which, however, are not to be construed as limiting or restricting the scope of the invention.

Example 1

Adding 12.0kg of absolute ethyl alcohol into a reaction kettle, stirring, adding 1.09kg of sodium hydroxide (27.25mol, 2.05eq), stirring for 30min, controlling the internal temperature to be 20-25 ℃, sequentially adding E L.40 kg (13.32mol, 1.00eq), E L.10 kg (13.96mol, 1.05eq), and 4.0kg of acetone, heating the reaction solution to the internal temperature of 40-45 ℃, reacting for 3h, monitoring the disappearance of E L point by T L C, completely reacting, reducing the internal temperature of the reaction solution to 25-30 ℃, stirring for 30min, filtering to remove insoluble substances, washing a filter cake once by using 1.5kg of acetone, decompressing and concentrating the filtrate (bath temperature of 40-45 ℃), adding 13.2kg of ethyl acetate into the residue, reducing the temperature to 0-5 ℃, stirring for 3h, filtering, washing the filter cake once by using 1.5kg of ethyl acetate at the temperature of 0-10 ℃, vacuum drying at the temperature of 40-45 ℃ for 8-10 hours, obtaining an intermediate (E L.3614 kg), and measuring the yield of the HP 3695%.

Claims

1. A preparation method of an esomeprazole intermediate, namely mufelrazole E L1 is characterized by comprising the following steps:

adding absolute ethyl alcohol into a reaction kettle, stirring, adding sodium hydroxide, stirring for 30min, controlling the internal temperature to be 20-25 ℃, sequentially adding E L2, E L3 and acetone, heating the reaction liquid to the internal temperature of 40-45 ℃, reacting for 3h, completely reacting, reducing the internal temperature of the reaction liquid to 25-30 ℃, stirring for 30min, filtering to remove insoluble substances, washing a filter cake once with acetone, concentrating the filtrate under reduced pressure, adding ethyl acetate into the residue, reducing the temperature to 0-5 ℃, stirring for 3h, filtering, drying, condensing E L2 and E L3 to generate the Wufilazol E L1, wherein the equivalent ratio of E L2, E L3 and sodium hydroxide is 1:1.05:2.05, and a mixed solvent with the mass ratio of the ethyl alcohol and the acetone being 3:1 is used as a reaction solvent.