CN114685316A

CN114685316A - MOC-L-valine synthesis process

Info

Publication number: CN114685316A
Application number: CN202210442464.2A
Authority: CN
Inventors: 王玉琴; 刘文庆; 詹玉进
Original assignee: Genchem & Genpharm Changzhou Co ltd
Current assignee: Genchem & Genpharm Changzhou Co ltd
Priority date: 2022-04-25
Filing date: 2022-04-25
Publication date: 2022-07-01

Abstract

The invention relates to the technical field of organic synthesis of medical intermediates, in particular to a synthesis process of MOC-L-valine, which comprises the steps of sequentially adding water and an acid-binding agent into a reaction kettle, starting stirring, controlling the temperature of the kettle to be not higher than 20 ℃, adding L-valine, and stirring until all solids are dissolved; controlling the internal temperature of the reaction kettle to be 5-20 ℃, adding N-succinimidyl methyl carbonate in batches under stirring, controlling the temperature, finishing the reaction when the L-valine is less than or equal to 2%, adding a solvent after the reaction is finished, adjusting the acid, layering, washing, concentrating, crystallizing, and separating to obtain the target product MOC-L-valine. Compared with the prior art, the method has the characteristics of safety, environmental protection, mild reaction conditions, easy operation and high purity of the prepared product, and is suitable for industrial mass production.

Description

MOC-L-valine synthesis process

Technical Field

The invention relates to the field of synthesis of medical intermediates, in particular to a synthesis process of MOC-L-valine.

Background

MOC-L-valine is an abbreviation for (S) -2- ((methoxycarbonyl) amino) -3-methylbutyric acid, CAS: 74761-42-5, the chemical structure is as follows:

MOC-L-valine is a key intermediate of antiviral drugs such as Daclatasvir (Daclatatasvir), Ledipasvir (Ledipasvir), Velpatasvir (Velpatasvir) and the like.

Hepatitis c is a viral disease that can cause inflammation of the liver, leading to diminished liver function or liver failure. Most patients infected with hepatitis c have no symptoms until liver damage becomes apparent. Genotype 3 hepatitis c is the second most common genotype after genotype 1 hepatitis c worldwide and is considered one of the most refractory genotype diseases.

Daclatasvir (Daclatasvir) is a pan-genotype NS5A replication complex inhibitor and has double antiviral effects of inhibiting RNA replication and virus assembly. In vitro studies, Daklinza has a potent antiviral effect across genotypes 1-6 of hepatitis C virus. FDA approval for marketing in the united states at 24 days 7-2015, in combination with sofosbuvir for the treatment of genotype 3 chronic hepatitis c adult patients, Daklinza is the first drug to prove safe and effective for the treatment of genotype 3 hepatitis c virus infection without the need for co-use with interferon or ribavirin, which are also two FDA approved drugs for the treatment of hepatitis c virus infection. The structural formula of daclatasvir is as follows:

ledipasvir (Ledipasvir) is a NS5A protease inhibitor developed by gillied science, which also binds to NS5A and prevents hepatitis c virus replication. The compound preparation (havini) of sofosbuvir and ledipasvir is approved in 10 months and 10 days in 2014 and is used for treating chronic hepatitis C. Harvoni was the first approved full oral anti-hepatitis C regimen for treatment of genotype I hepatitis C infection that did not require combination with interferon or ribavirin. The Harvoni dual scheme does not contain interferon or ribavirin, the tolerance is improved, only one tablet needs to be orally taken once every day, and the medicine taking convenience of patients is greatly improved. After marketing, Harvoni has become the gold standard for a full oral anti-hepatitis C regimen. Harvoni became one of the globally marketable products immediately after coming out, and the market potential has been spotlighted. The chemical structural formula of ledipasvir is as follows:

the vipatavir is a novel pan-genotypic hepatitis C drug developed by Jilidscience, and is a compound tablet consisting of NS5B inhibitor sofosbuvir and NS5A inhibitor vipatavir (velpatasvir, VEL), and is orally taken once a day. Epclusa is approved by the FDA and the European Union respectively for treating adult patients infected with gene 1-6 type hepatitis C virus in 2016, can be used for patients without liver cirrhosis or compensated liver cirrhosis alone, and can also be used for treating patients with uncompensated liver cirrhosis by combining with ribavirin. The vipatavir has good curative effect in patients with various genotypes, is expected to avoid genotyping test and improves the cure rate of patients with hepatitis C. The chemical structural formula is as follows:

the above products are heavy pounds of bomb drugs sold worldwide in a scale of over billions of dollars, and therefore the industrial production process for developing MOC-L-valine, which is a common intermediate, has extremely high market value.

The currently reported synthesis methods of MOC-L-valine are all obtained by reacting L-valine with methyl chloroformate. Acid-binding agents and solvents used in different documents vary. Acid-binding agents used in the reaction include sodium hydroxide (U.S. patent US2017/253614, 2017), triethylamine (chinese patent CN105949085, 2016), sodium carbonate and sodium bicarbonate (U.S. patent US2013/115194,2013 and CN109232612,2019). The solvents used in the reaction are tetrahydrofuran (european patent EP2513113, 2018) and EP2730572, 2015), dioxane (chinese patent CN112898219, 2021) and world patent WO2012/83170, 2012), ethyl acetate and toluene (US 2010/215618,2010), ethanol (chinese patent CN 949085, 2016).

As methyl chloroformate is adopted in the above processes, the methyl chloroformate has pungent odor and belongs to the control of dangerous chemicals with high toxicity. Therefore, the search for a more environmentally friendly and safe process is a general consensus in the industry at present, and is also a technical problem to be solved by those skilled in the art.

Disclosure of Invention

The technical problem to be solved by the invention is as follows: provides a green, environment-friendly, efficient and safe MOC-L-valine synthesis process. The method has the characteristics of simple operation, environment-friendly process and the like.

In order to solve the above problems, the technical solution provided by the present invention is as follows:

a synthesis process of MOC-L-valine comprises sequentially adding water and an acid binding agent into a reaction kettle, stirring, controlling the temperature of the kettle to be not higher than 20 ℃, adding L-valine, and stirring until solids are completely dissolved; controlling the internal temperature of the reaction kettle to be 5-20 ℃, adding N-succinimidyl methyl carbonate in batches under stirring, controlling the temperature, finishing the reaction when the L-valine is less than or equal to 2%, adding a solvent after the reaction is finished, adjusting the acid, layering, washing, concentrating, crystallizing, and separating to obtain a target product MOC-L-valine; the specific reaction formula is as follows:

adjusting the pH value to 2-3 by using sulfuric acid, wherein a large amount of solid salt generated in the acid adjusting process is not dissolved, heating to 23-28 ℃, stirring to completely dissolve the salt, and using petroleum ether as a crystallization solvent for crystallization.

Furthermore, the usage amount of the N-succinimidyl methyl carbonate is 1 to 1.5 times of the molar weight of the L-valine.

Preferably, the amount of N-succinimidyl methyl carbonate used is 1 to 1.2 times the molar amount of L-valine.

Further, the acid-binding agent is selected from one or more of liquid caustic soda, sodium carbonate and sodium bicarbonate; the usage amount of the acid-binding agent is 1-3.5 times of the molar weight of the L-valine.

Preferably, the use amount of the acid-binding agent is 1.2-1.5 times of the molar weight of the L-valine.

Further, the solvent is one or more selected from ethyl acetate, tetrahydrofuran and toluene.

Furthermore, the using amount of the solvent is 3-6 times of the mass of the L-valine.

Preferably, the amount of the solvent used is 4 to 5 times the mass of L-valine.

Further, the temperature control reaction temperature is 10-60 ℃, and the reaction time is 2-3 hours.

Preferably, the temperature-controlled reaction temperature is 10-20 ℃, and the reaction time is 2-3 hours.

Preferably, the temperature-controlled reaction temperature is 50-60 ℃, and the reaction time is 2-3 hours.

Compared with the prior art, the synthesis process of MOC-L-valine has the characteristics of safety, environmental protection, mild reaction conditions, easy operation and high purity of the prepared product, and is suitable for industrial mass production.

The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for obvious errors in the formula.

Drawings

FIG. 1 is a hydrogen spectrum of MOC-L-valine obtained in accordance with an embodiment of the present invention.

Detailed Description

The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.

Example 1:

adding 110g of water and 40g of liquid caustic soda with the mass fraction of 32% into a 500ml four-mouth bottle, starting stirring, controlling the temperature of a kettle to be not higher than 20 ℃, adding 35g of L-valine, and stirring until the solid is completely dissolved. Controlling the internal temperature of the reaction kettle to be 5-20 ℃, simultaneously adding 56.9g of N-succinimidyl methyl carbonate in batches, controlling the internal temperature of the reaction kettle to be 50-60 ℃ after the feeding is finished, and keeping the temperature and stirring for 2-3 h. The sampling is controlled in a middle way, and the L-valine is required to be less than or equal to 2 percent. Adding 160g of toluene into the reaction solution, cooling to below 15 ℃, dropwise adding sulfuric acid to adjust the pH to be 2-3, dissolving a large amount of solid salt, heating to 23-28 ℃, stirring to completely dissolve the salt, and removing a water layer to obtain an organic layer. The organic layer was washed three times with 15% saline, 40g each time. Controlling the internal temperature not to exceed 60 ℃, concentrating under reduced pressure until no liquid is distilled off, and continuously evacuating under reduced pressure for 2-3 h. And adding 120g of petroleum ether into the concentrate, heating to 68-75 ℃ for dissolving, slowly cooling to 20 ℃, separating out a large amount of solids, and continuously stirring for 1-2 hours. Filtering and rinsing with the mixed solution. And (3) drying the wet product at 45-50 ℃ by air blast for 12-18 h to obtain 46.5g of white solid with the purity of 99.92% and the yield of 89.0%.

Example 2:

adding 110g of water and 53g of sodium carbonate into a 500ml four-mouth bottle, starting stirring, controlling the temperature of a kettle to be not higher than 20 ℃, adding 35g of L-valine, and stirring until all solids are dissolved. Controlling the internal temperature of the reaction kettle to be 5-20 ℃, simultaneously adding 56.9g of N-succinimidyl methyl carbonate in batches, controlling the internal temperature of the reaction kettle to be 10-20 ℃ after the addition is finished, and stirring for 2-3 h under heat preservation. The sampling is controlled in a middle way, and the L-valine is required to be less than or equal to 2 percent. Adding 160g of ethyl acetate into the reaction solution, cooling to below 15 ℃, dropwise adding sulfuric acid to adjust the pH to be 2-3, dissolving a large amount of solid salt, heating to 23-28 ℃, stirring to completely dissolve the salt, and removing a water layer to obtain an organic layer. Washing the organic layer with 15% of salt water, controlling the internal temperature not to exceed 60 ℃, concentrating under reduced pressure until no liquid is distilled off, and continuing to evacuate under reduced pressure for 2-3 h. And adding 120g of petroleum ether into the concentrate, heating to 68-75 ℃ for dissolving, slowly cooling to 20 ℃, separating out a large amount of solids, and continuously stirring for 1-2 hours. Filtering and rinsing with the mixed solution. And (3) drying the wet product at 45-50 ℃ for 12-18 h by air blast to obtain 47.5g of white solid with the purity of 99.91% and the yield of 91.0%.

Example 3:

110g of water and 84g of sodium bicarbonate are added into a 500ml four-mouth bottle, stirring is started, the temperature of a kettle is controlled to be not higher than 20 ℃, 35g of L-valine is added, and stirring is carried out until all solids are dissolved. Controlling the internal temperature of the reaction kettle to be 5-20 ℃, simultaneously adding 56.9g of N-succinimidyl methyl carbonate in batches, controlling the internal temperature of the reaction kettle to be 10-20 ℃ after the addition is finished, and stirring for 2-3 h under heat preservation. The sampling is controlled in a middle way, and the L-valine is required to be less than or equal to 2 percent. Adding 160g of tetrahydrofuran into the reaction solution, cooling to below 15 ℃, dropwise adding sulfuric acid to adjust the pH to be 2-3, dissolving a large amount of solid salt, heating to 23-28 ℃, stirring to completely dissolve the salt, and removing a water layer to obtain an organic layer. Washing the organic layer with 15% of salt water, controlling the internal temperature not to exceed 60 ℃, concentrating under reduced pressure until no liquid is distilled off, and continuing to evacuate under reduced pressure for 2-3 h. Adding 120g of petroleum ether into the concentrate, heating to 68-75 ℃ for dissolving, slowly cooling to 20 ℃, separating out a large amount of solids, and continuously stirring for 1-2 hours. Filtering and rinsing with the mixed solution. And (3) drying the wet product at 45-50 ℃ by air blast for 12-18 h to obtain 48.3g of white solid with the purity of 99.90% and the yield of 92.5%.

Example 4:

adding 110g of water and 38g of sodium carbonate into a 500ml four-mouth bottle, starting stirring, controlling the temperature of a kettle to be not higher than 20 ℃, adding 35g of L-valine, and stirring until all solids are dissolved. Controlling the internal temperature of the reaction kettle to be 5-20 ℃, simultaneously adding 47.5g of N-succinimidyl methyl carbonate in batches, controlling the internal temperature of the reaction kettle to be 10-20 ℃ after the addition is finished, and stirring for 2-3 hours under heat preservation. The sampling is controlled in a middle way, and the L-valine is required to be less than or equal to 2 percent. Adding 105g of ethyl acetate into the reaction solution, cooling to below 15 ℃, dropwise adding sulfuric acid to adjust the pH to be 2-3, dissolving a large amount of solid salt, heating to 23-28 ℃, stirring to completely dissolve the salt, and removing a water layer to obtain an organic layer. Washing the organic layer with 15% of salt water, controlling the internal temperature not to exceed 60 ℃, concentrating under reduced pressure until no liquid is distilled off, and continuously evacuating under reduced pressure for 2-3 h. And adding 120g of petroleum ether into the concentrate, heating to 68-75 ℃ for dissolving, slowly cooling to 20 ℃, separating out a large amount of solids, and continuously stirring for 1-2 hours. Filtering and rinsing with the mixed solution. And (3) drying the wet product at 45-50 ℃ by air blast for 12-18 h to obtain 46.7g of white solid with the purity of 99.91% and the yield of 89.3%.

Example 5:

110g of water and 47.5g of sodium carbonate are added into a 500ml four-mouth bottle, stirring is started, the temperature of the kettle is controlled to be not higher than 20 ℃, 35g of L-valine is added, and the mixture is stirred until all solids are dissolved. Controlling the internal temperature of the reaction kettle to be 5-20 ℃, simultaneously adding 71.3g of N-succinimidyl methyl carbonate in batches, controlling the internal temperature of the reaction kettle to be 10-20 ℃ after the addition is finished, and stirring for 2-3 h under the condition of heat preservation. The sampling is controlled in a middle way, and the L-valine is required to be less than or equal to 2 percent. Adding 140g of ethyl acetate into the reaction solution, cooling to below 15 ℃, dropwise adding sulfuric acid to adjust the pH to be 2-3, dissolving a large amount of solid salt, heating to 23-28 ℃, stirring until the salt is completely dissolved, and removing a water layer to obtain an organic layer. Washing the organic layer with 15% of salt water, controlling the internal temperature not to exceed 60 ℃, concentrating under reduced pressure until no liquid is distilled off, and continuing to evacuate under reduced pressure for 2-3 h. And adding 120g of petroleum ether into the concentrate, heating to 68-75 ℃ for dissolving, slowly cooling to 20 ℃, separating out a large amount of solids, and continuously stirring for 1-2 hours. Filtering and rinsing with the mixed solution. And (3) drying the wet product at 45-50 ℃ by air blast for 12-18 h to obtain 46.8g of white solid with the purity of 99.92% and the yield of 89.4%.

Example 6:

110g of water and 87.8g of sodium bicarbonate are added into a 500ml four-mouth bottle, stirring is started, the temperature of a kettle is controlled to be not higher than 20 ℃, 35g of L-valine is added, and stirring is carried out until all solids are dissolved. Controlling the internal temperature of the reaction kettle to be 5-20 ℃, simultaneously adding 56.9g of N-succinimidyl methyl carbonate in batches, controlling the internal temperature of the reaction kettle to be 10-20 ℃ after the addition is finished, and stirring for 2-3 h under heat preservation. The sampling is controlled in a middle way, and the L-valine is required to be less than or equal to 2 percent. Adding 175g of tetrahydrofuran into the reaction solution, cooling to below 15 ℃, dropwise adding sulfuric acid to adjust the pH value to be 2-3, so that a large amount of solid salt is not dissolved, heating to 23-28 ℃, stirring the salt to be completely dissolved, and removing a water layer to obtain an organic layer. Washing the organic layer with 15% of salt water, controlling the internal temperature not to exceed 60 ℃, concentrating under reduced pressure until no liquid is distilled off, and continuously evacuating under reduced pressure for 2-3 h. Adding 120g of petroleum ether into the concentrate, heating to 68-75 ℃ for dissolving, slowly cooling to 20 ℃, separating out a large amount of solids, and continuously stirring for 1-2 hours. Filtering and rinsing with the mixed solution. And (3) drying the wet product at 45-50 ℃ by air blast for 12-18 h to obtain 48.1g of white solid with the purity of 99.90% and the yield of 92.1%.

Example 7:

adding 110g of water and 35g of sodium bicarbonate into a 500ml four-neck bottle, starting stirring, controlling the temperature of a kettle to be not higher than 20 ℃, adding 35g of L-valine, and stirring until all solids are dissolved. Controlling the internal temperature of the reaction kettle to be 5-20 ℃, simultaneously adding 66.5g of N-succinimidyl methyl carbonate in batches, controlling the internal temperature of the reaction kettle to be 30-40 ℃ after the feeding is finished, and keeping the temperature and stirring for 2-3 h. The sampling is controlled in a middle way, and the L-valine is required to be less than or equal to 2 percent. Adding 210g of tetrahydrofuran into the reaction solution, cooling to below 15 ℃, dropwise adding sulfuric acid to adjust the pH to be 2-3, dissolving a large amount of solid salt, heating to 23-28 ℃, stirring to completely dissolve the salt, and removing a water layer to obtain an organic layer. Washing the organic layer with 15% of salt water, controlling the internal temperature not to exceed 60 ℃, concentrating under reduced pressure until no liquid is distilled off, and continuing to evacuate under reduced pressure for 2-3 h. Adding 120g of petroleum ether into the concentrate, heating to 68-75 ℃ for dissolving, slowly cooling to 20 ℃, separating out a large amount of solids, and continuously stirring for 1-2 hours. Filtering and rinsing with the mixed solution. And (3) drying the wet product at 45-50 ℃ by air blast for 12-18 h to obtain 47.6g of white solid with the purity of 99.90% and the yield of 91.2%.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.

Claims

1. A synthesis process of MOC-L-valine is characterized in that water and an acid binding agent are sequentially added into a reaction kettle, stirring is started, the temperature of the kettle is controlled to be not higher than 20 ℃, L-valine is added, and the stirring is carried out until all solids are dissolved; controlling the internal temperature of the reaction kettle to be 5-20 ℃, adding N-succinimidyl methyl carbonate in batches under stirring, controlling the temperature, finishing the reaction when the L-valine is less than or equal to 2%, adding a solvent after the reaction is finished, adjusting the acid, layering, washing, concentrating, crystallizing, and separating to obtain a target product MOC-L-valine; the specific reaction formula is as follows:

2. The process for synthesizing MOC-L-valine according to claim 1, wherein the amount of N-succinimidyl methyl carbonate used is 1 to 1.5 times the molar amount of L-valine.

3. The process for synthesizing MOC-L-valine according to claim 2, wherein the amount of N-succinimidyl methyl carbonate used is 1 to 1.2 times the molar amount of L-valine.

4. The process for synthesizing MOC-L-valine according to claim 1, wherein the acid-binding agent is one or more selected from liquid caustic soda, sodium carbonate and sodium bicarbonate; the usage amount of the acid-binding agent is 1-3.5 times of the molar weight of the L-valine.

5. The process for synthesizing MOC-L-valine according to claim 4, wherein the amount of the acid-binding agent is 1.2 to 1.5 times of the molar amount of the L-valine.

6. The process for synthesizing MOC-L-valine according to claim 1, wherein the solvent is one or more selected from the group consisting of ethyl acetate, tetrahydrofuran and toluene; the using amount of the solvent is 3-6 times of the mass of the L-valine.

7. The process for synthesizing MOC-L-valine according to claim 6, wherein the amount of the solvent used is 4 to 5 times the mass of L-valine.

8. The process for synthesizing MOC-L-valine according to claim 1, wherein the temperature-controlled reaction temperature is 10-60 ℃ and the reaction time is 2-3 hours.

9. The process for synthesizing MOC-L-valine according to claim 8, wherein the temperature-controlled reaction temperature is 10-20 ℃ and the reaction time is 2-3 hours.

10. The process for synthesizing MOC-L-valine according to claim 8, wherein the temperature-controlled reaction temperature is 50-60 ℃ and the reaction time is 2-3 hours.