CN115043823A - A kind of synthetic method of emtricitabine - Google Patents

Abstract

The invention discloses a method for synthesizing emtricitabine. The ethylene glycol and butyryl chloride are mixed, and 2-hydroxyethyl butyrate is obtained by constant temperature reaction, then dimethyl sulfoxide and a catalyst are added, and the 2-hydroxyethyl butyrate is added. The hydroxyl group in the acid ester is oxidized to form an aldehyde group, and then 2,5-dihydroxy-1,4-dithiothiane is added, and the pH value of the system is adjusted simultaneously to obtain 2-butyrylmethoxy-5-acetoxy-1 , the four isomers of 3-oxathiolane, and then obtain the isomer whose chirality to the 2-position is R by splitting, and then add the 5-fluorocytosine protected by trimethylsilane to react to obtain an intermediate Add hydrochloric acid to the intermediate to adjust the pH of the system, after the hydrolysis reaction, recrystallize the hydrolyzed product through ethanol, separate and obtain the product of the (2R-5S)-configuration, and finally carry out deacidification through the ionic resin to obtain En Tricitabine. The synthesis method for emtricitabine simplifies the production process, shortens the production time, reduces the production cost, reduces the impurity content in the product, and improves the production quality of the emtricitabine.

Description

A kind of synthetic method of emtricitabine

technical field

The invention belongs to the technical field of drug synthesis, relates to a method for synthesizing a drug, in particular to a method for synthesizing emtricitabine.

Background technique

Emtricitabine is a new type of nucleoside reverse transcriptase inhibitor, which belongs to antiviral drugs. It is phosphorylated to 5'-triphosphate by cellular enzymes. Phosphate substrate competitively inhibits the activity of HIV-1 reverse transcriptase and binds to viral DNA resulting in chain termination, thereby inhibiting the virus.

The existing synthetic method of emtricitabine has the following shortcomings:

(1) the existing emtricitabine synthesis method has complicated technology in the actual production process, and the production time is longer, which causes the production cost to increase, and the final product impurity content is higher, causing the problem that the production quality of emtricitabine is lower ,Room for improvement;

(2) Glass instruments need to be used in the preparation and pretreatment of the reaction raw materials. The inner and outer surfaces of the glass instruments are easy to absorb dust and other impurities. If dust and other impurities enter the reactants, it is easy to cause the reactants to be polluted and ultimately affect the to product quality;

(3) During the preparation process of the reaction intermediate, gas with pungent odor, volatile organic compounds or other by-products that are harmful to the body will be produced, and the direct discharge will cause harm to the human body or the environment, and needs to be improved.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a synthetic method of emtricitabine, the production process is simplified, the production time is shortened, and the production cost is reduced.

Another object of the present invention is to provide a method for synthesizing emtricitabine, which can reduce the impurity content in the product and improve the production quality of emtricitabine.

Another object of the present invention is to provide a method for synthesizing emtricitabine, which can purify the waste gas generated in the reaction process and then discharge it, so as to avoid the harm caused by direct discharge to the human body and the environment.

In order to achieve the above-mentioned purpose, the solution of the present invention is:

A synthetic method of emtricitabine, comprising the steps:

Step 1, mix ethylene glycol and butyryl chloride, react at a constant temperature to obtain 2-hydroxyethyl butyrate, then add dimethyl sulfoxide and a catalyst, react at room temperature for 20 to 40 minutes, and mix the 2-hydroxyethyl butyrate in 2-hydroxyethyl butyrate. The hydroxyl group is oxidized to an aldehyde group, then 2,5-dihydroxy-1,4-dithiothiane is added, and acetic anhydride is used to adjust the pH of the system to 4.5-5 to obtain 2-butyrylmethoxy-5-acetyl Four isomers of oxy-1,3-oxathiolane, and then the isomer with the chirality of R at the 2-position is obtained by splitting, and then the 5-fluorocytosine protected by trimethylsilane is added to react , to obtain an intermediate;

In step 2, hydrochloric acid is added to the intermediate to adjust the pH of the system to 3.5-4. After the hydrolysis reaction, the hydrolyzed product is recrystallized by ethanol, and the product of (2R-5S)-configuration is obtained by separation. After deacidification, emtricitabine is obtained.

In the above step 1, the mixed molar ratio of ethylene glycol and butyryl chloride is 0.7-1.5:2, and the reaction is carried out at a constant temperature of 35-40 degrees Celsius for 4-9 minutes to obtain 2-hydroxyethyl butyrate.

In the above step 1, the molar ratio of the added dimethyl sulfoxide and 2-hydroxyethyl butyrate is 0.4 to 0.7:1, and the catalyst is selected from phosphorus pentoxide and triethylamine.

In the above step 1, the molar ratio of the added 2,5-dihydroxy-1,4-dithiothiane to 2-hydroxyethyl butyrate is 2-4:1.

In the above step 1, after adding 2,5-dihydroxy-1,4-dithiothiane, the water bath is kept at a constant temperature of 55 to 65 degrees Celsius, and the reaction is performed for 15 to 25 minutes to obtain 2-butyrylmethoxy-5-acetoxy - Four isomers of 1,3-oxathiolane.

In the above step 1, the molar ratio of the added trimethylsilane-protected 5-fluorocytosine to 2-hydroxyethyl butyrate is 1-2:1.

In the above step 1, after adding 5-fluorocytosine protected by trimethylsilane, heating to 70-90 degrees Celsius, and reacting for 40-60 minutes to obtain an intermediate.

In the above step 1, before the reaction, both the raw material and the reaction vessel are cleaned and dried.

In the above step 2, the temperature of the hydrolysis reaction is 86-95 degrees Celsius, and the high-temperature hydrolysis is performed for 70-85 minutes.

After adopting the above-mentioned scheme, the beneficial effect of the present invention compared with the prior art is:

(1) The present invention provides a method for synthesizing emtricitabine, wherein ethylene glycol is reacted with butyryl chloride to obtain 2-hydroxyethyl butyrate, and the hydroxyl group of 2-hydroxyethyl butyrate is oxidized with dimethyl sulfoxide. To form an aldehyde group, the compound first reacts with 2,5-dihydroxy-1,4-dithiothiane, and then reacts with acetic anhydride to obtain 2-butyrylmethoxy-5-acetoxy-1,3-oxygen Four isomers of thiolane, a pair of isomers with the chirality of R at the 2-position are obtained by splitting, react with 5-fluorocytosine protected by trimethylsilane to obtain a pair of isomers, hydrolyzed, It becomes hydrochloride, and then recrystallizes with ethanol to separate the product of (2R-5S)-configuration. Finally, deacidify it with ion resin to obtain emtricitabine solution, and then recrystallize the product for several times to obtain emtricitabine. Binjing simplifies the production process, shortens the production time and reduces the production cost;

(2) The present invention provides a method for synthesizing emtricitabine, which thoroughly cleans the glass instrument containing the raw materials, and performs drying treatment to prevent the moisture in the glass instrument from changing the concentration of the reactant added to the instrument and causing the reaction Inaccurate results, affecting product quality;

(3) The present invention provides a method for synthesizing emtricitabine. In the preparation process of the reaction intermediate, a waste gas treatment device is set to collect the irritating odor gas, volatile organic compounds or other by-products that are harmful to the body, and then A sufficient amount of the corresponding chemical absorption liquid is added to react with the collected waste gas, and the waste gas is fully treated into a gas or liquid that is harmless to the human body and the environment, so as to avoid the problem of direct discharge affecting the human body or the environment.

Detailed ways

Embodiments of the present invention are described in detail below.

The invention provides a method for synthesizing emtricitabine. First, all reaction raw materials and various instruments are prepared according to the technical process, and then the reaction is carried out step by step according to the requirements of the technical process to obtain a reaction intermediate, and then according to the requirements of the technical process, a reaction intermediate is obtained. The intermediate carries out the corresponding reaction to obtain the product, and finally the product is purified to obtain relatively pure emtricitabine, which is specifically composed of the following steps:

Step 1, preparation and pretreatment of reaction raw materials;

In the first step, the reactants and various chemical reaction devices that need to be used in the reaction process are prepared in advance, and part of the chemical reaction devices are pretreated, the reaction devices are cleaned, and the dust attached to the device is removed. The chemical reactants that need to be used in the process are mainly ethylene glycol, butyryl chloride, dimethyl sulfoxide, 2,5-dihydroxy-1,4-dithiothiane, acetic anhydride, and trimethylsilane-protected 5- Flucytosine, hydrochloric acid, ethanol, etc., the chemical reaction devices used in the reaction process mainly include flasks, beakers, pipettes, alcohol lamps, constant temperature water baths, etc. after drying and drying;

Step 2, the preparation of the reaction intermediate;

In the second step, firstly, ethylene glycol and butyryl chloride are mixed according to a molar ratio of 0.7 to 1.5:2, and then heated at a constant temperature of 35 to 40 degrees Celsius in a constant temperature water bath to react for 4 to 9 minutes to obtain 2-hydroxyethyl butyric acid ester, then add dimethyl sulfoxide, the molar ratio of dimethyl sulfoxide and 2-hydroxyethyl butyrate is 0.4~0.7:1, and add catalyst phosphorus pentoxide and triethylamine at the same time, and react at room temperature for 20~40 minutes , oxidize the hydroxyl group in 2-hydroxyethyl butyrate to aldehyde group, and then add 2,5-dihydroxy-1,4- Dithiothiane, at the same time adjust the pH of the system to 4.5-5 by acetic anhydride, the constant temperature of the water bath is 55-65 degrees Celsius, and the reaction is performed for 15-25 minutes to obtain 2-butyrylmethoxy-5-acetoxy-1,3- Four isomers of oxathiolane, and then obtain the isomer whose chirality at the 2-position is R, and then add 2-hydroxyethyl butyrate in a molar ratio of 1 to 2:1. Trimethylsilane-protected 5-fluorocytosine reaction, heated at 70-90 degrees Celsius, and reacted for 40-60 minutes to obtain an intermediate. During the reaction process, irritating odor gas, volatile organic compounds or other harmful substances to the body will be continuously generated. Harmful by-products, these gases, volatile organic compounds or other by-products that are harmful to the body are collected by the waste gas treatment device, which is convenient for centralized treatment;

Step 3, preparation of emtricitabine;

In the step 3, add hydrochloric acid to the reaction intermediate prepared in the step 2, adjust the pH of the system to 3.5-4, heat to 86-95 degrees Celsius at the same time, hydrolyze at high temperature for 70-85 minutes, and then regenerate the hydrolyzed product with ethanol. Crystallize, isolate the product with (2R-5S)-configuration, and finally deacidify it with ionic resin to obtain emtricitabine. The recrystallization process needs to be carried out 3 to 4 times. During the process, the impurities will be gradually washed away, and a relatively pure (2R-5S)-configuration product will be obtained; adding hydrochloric acid to the reaction intermediate will obtain an emtricitabine solution with impurities. It is necessary to repeat the recrystallization process for 3 to 4 times in the emtricitabine solution of the first batch. During the recrystallization process, the impurities are continuously washed into the solution, and finally relatively pure emtricitabine crystals are obtained, and the purity is greater than 99%;

In this step, the recrystallization process is to dissolve the produced product in a certain amount of hot ethanol solution, so that the dissolved solution is approximately in a saturated state. During the temperature drop of the solution, the product is continuously precipitated in the form of crystals, and then passed through The method of suction filtration separates the product crystals and leaves the impurities in the solution. Repeat the above process several times to obtain a relatively pure product.

Example 1

Step 1, ethylene glycol and butyryl chloride are mixed according to a molar ratio of 1:2, and the reaction is performed for 5 minutes at a constant temperature of 35 degrees Celsius in a constant temperature water bath to obtain 2-hydroxyethyl butyrate;

In step 2, dimethyl sulfoxide is added to 2-hydroxyethyl butyrate, and the molar ratio of dimethyl sulfoxide and 2-hydroxyethyl butyrate is 0.5:1, and the catalyst phosphorus pentoxide and trisulfate are added simultaneously. Ethylamine, react at room temperature for 25 minutes, oxidize the hydroxyl group in 2-hydroxyethyl butyrate to aldehyde group, and then add 2,5-dihydroxyl with a molar ratio of 2:1 to 2-hydroxyethyl butyrate -1,4-Dithiothiane, at the same time adjust the pH of the system to 4.5 by acetic anhydride, the water bath is kept at a constant temperature of 60 degrees Celsius, and the reaction is performed for 15 minutes to obtain 2-butyrylmethoxy-5-acetoxy-1,3-oxygen Four isomers of thiolane, and then split to obtain the isomer whose chirality is R at the 2-position, and then add trimethyl with a molar ratio of 1:1 to 2-hydroxyethyl butyrate Silane-protected 5-fluorocytosine reaction, heated to 75 degrees Celsius, and reacted for 45 minutes to obtain an intermediate. During the reaction, use a waste gas treatment device to treat the irritating odor gas, volatile organic compounds or other harmful to the body. By-products are collected and processed;

Step 3, add hydrochloric acid to the reaction intermediate prepared in step 2, adjust the pH of the system to 4, heat to 90 degrees Celsius at the same time, hydrolyze at high temperature for 85 minutes, and then recrystallize the hydrolyzed product by ethanol, and the recrystallization process needs to be carried out 3 times , the product of (2R-5S)-configuration is obtained by separation, and finally deacidification is carried out by ion resin to obtain emtricitabine.

The purity of the emtricitabine obtained in Example 1 was 99.2%.

Example 2

In step 1, ethylene glycol and butyryl chloride are mixed according to a molar ratio of 1.2:2, and the reaction is carried out at a constant temperature of 40 degrees Celsius in a constant temperature water bath for 8 minutes to obtain 2-hydroxyethyl butyrate;

In step 2, dimethyl sulfoxide is added to 2-hydroxyethyl butyrate, and the molar ratio of dimethyl sulfoxide and 2-hydroxyethyl butyrate is 0.6:1, and the catalyst phosphorus pentoxide and trisulfate are added simultaneously. Ethylamine, react at room temperature for 40 minutes, oxidize the hydroxyl group in 2-hydroxyethyl butyrate to aldehyde group, and then add 2,5-dihydroxyl with a molar ratio of 2:1 to 2-hydroxyethyl butyrate -1,4-Dithiothiane, at the same time adjust the pH of the system to 5 by acetic anhydride, the water bath is kept at a constant temperature of 65 degrees Celsius, and react for 20 minutes to obtain 2-butyrylmethoxy-5-acetoxy-1,3-oxygen Four isomers of thiolane, and then split to obtain the isomer whose chirality at the 2-position is R, and then add trimethyl with a molar ratio of 2-hydroxyethyl butyrate of 2:1 Silane-protected 5-fluorocytosine reaction, heated to 90 degrees Celsius, and reacted for 40 minutes to obtain an intermediate. During the reaction, use a waste gas treatment device to treat the irritating odor gas, volatile organic compounds or other harmful to the body. By-products are collected and processed;

Step 3, add hydrochloric acid to the reaction intermediate prepared in step 2, adjust the pH of the system to 4, heat to 95 degrees Celsius at the same time, hydrolyze at high temperature for 70 minutes, and then recrystallize the hydrolyzed product by ethanol, and the recrystallization process needs to be carried out 3 times , the product of (2R-5S)-configuration is obtained by separation, and finally deacidification is carried out by ion resin to obtain emtricitabine.

The purity of the emtricitabine obtained in Example 2 was 99.4%.

Example 3

In step 1, ethylene glycol and butyryl chloride are mixed according to a molar ratio of 0.8:2, and the reaction is carried out at a constant temperature of 40 degrees Celsius in a constant temperature water bath for 9 minutes to obtain 2-hydroxyethyl butyrate;

In step 2, dimethyl sulfoxide is added to 2-hydroxyethyl butyrate, and the molar ratio of dimethyl sulfoxide and 2-hydroxyethyl butyrate is 0.7:1, and the catalyst phosphorus pentoxide and trisulfate are added simultaneously. Ethylamine, react at room temperature for 20 minutes, oxidize the hydroxyl group in 2-hydroxyethyl butyrate to aldehyde group, and then add 2,5-dihydroxyl with a molar ratio of 4:1 to 2-hydroxyethyl butyrate -1,4-Dithiothiane, at the same time, adjust the pH of the system to 5 by acetic anhydride, the water bath is kept at a constant temperature of 60 degrees Celsius, and the reaction is performed for 25 minutes to obtain 2-butyrylmethoxy-5-acetoxy-1,3-oxygen Four isomers of thiolane, and then split to obtain the isomer whose chirality at the 2-position is R, and then add trimethyl with a molar ratio of 2-hydroxyethyl butyrate of 2:1 Silane-protected 5-fluorocytosine reaction, heated to 90 degrees Celsius, and reacted for 60 minutes to obtain an intermediate. During the reaction, use a waste gas treatment device to treat irritating odor gases, volatile organic compounds or other harmful to the body. By-products are collected and processed;

Step 3, add hydrochloric acid to the reaction intermediate prepared in step 2, adjust the pH of the system to 4, heat to 95 degrees Celsius at the same time, hydrolyze at high temperature for 85 minutes, and then recrystallize the hydrolyzed product by ethanol, and the recrystallization process needs to be carried out 3 times , the product of (2R-5S)-configuration is obtained by separation, and finally deacidification is carried out by ion resin to obtain emtricitabine.

The purity of the emtricitabine obtained in Example 3 was 99.4%.

Although the embodiments of the present invention have been shown and described above, it should be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. Embodiments are subject to variations, modifications, substitutions and variations.

Claims (9)

1. The method for synthesizing emtricitabine is characterized by comprising the following steps:

step 1, mixing ethylene glycol and butyryl chloride, reacting at constant temperature to obtain 2-hydroxyethyl butyrate, then adding dimethyl sulfoxide and a catalyst, reacting at normal temperature for 20-40 minutes, oxidizing hydroxyl in the 2-hydroxyethyl butyrate into aldehyde group, then adding 2, 5-dihydroxy-1, 4-dithiane, adjusting the pH value of a system to be 4.5-5 by using acetic anhydride to obtain four isomers of 2-butyrylmethoxy-5-acetoxyl-1, 3-oxathiolane, then splitting to obtain an isomer with chirality at 2-position being R, and then adding 5-fluorocytosine protected by trimethylsilane for reaction to obtain an intermediate;

and 2, adding hydrochloric acid into the intermediate, adjusting the pH value of the system to 3.5-4, after hydrolysis reaction, recrystallizing the hydrolysis product through ethanol, separating to obtain a product with a (2R-5S) -configuration, and finally performing deacidification treatment through ion resin to obtain the emtricitabine.

2. The method of claim 1, wherein: in the step 1, the mixing molar ratio of the ethylene glycol to the butyryl chloride is 0.7-1.5: 2, and the reaction is carried out for 4-9 minutes at a constant temperature of 35-40 ℃ to obtain the 2-hydroxyethyl butyrate.

3. The method of claim 1, wherein: in the step 1, the molar ratio of the added dimethyl sulfoxide to the 2-hydroxyethyl butyrate is 0.4-0.7: 1, and the catalyst is phosphorus pentoxide and triethylamine.

4. The method of claim 1, wherein: in the step 1, the molar ratio of the added 2, 5-dihydroxy-1, 4-dithiothiane to the 2-hydroxyethyl butyrate is 2-4: 1.

5. The method of claim 1, wherein: in the step 1, after the 2, 5-dihydroxy-1, 4-dithiothiane is added, the temperature of a water bath is kept constant at 55-65 ℃, and the reaction is carried out for 15-25 minutes to obtain four isomers of 2-butyrylmethoxy-5-acetoxyl-1, 3-oxathiolane.

6. The method of claim 1, wherein: in the step 1, the molar ratio of the 5-fluorocytosine protected by the added trimethylsilane to the 2-hydroxyethyl butyrate is 1-2: 1.

7. The method of claim 6, wherein: in the step 1, 5-fluorocytosine protected by trimethylsilane is added, heated to 70-90 ℃, and reacted for 40-60 minutes to obtain an intermediate.

8. The method of claim 1, wherein: in the step 1, before the reaction, the raw materials and the reaction vessel are cleaned and dried.

9. The method of claim 1, wherein: in the step 2, the temperature of the hydrolysis reaction is 86-95 ℃, and the hydrolysis is carried out for 70-85 minutes at high temperature.