CN106632594B - Method for synthesizing pidotimod - Google Patents
Method for synthesizing pidotimod Download PDFInfo
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- CN106632594B CN106632594B CN201611262917.4A CN201611262917A CN106632594B CN 106632594 B CN106632594 B CN 106632594B CN 201611262917 A CN201611262917 A CN 201611262917A CN 106632594 B CN106632594 B CN 106632594B
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- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06173—Dipeptides with the first amino acid being heterocyclic and Glp-amino acid; Derivatives thereof
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Abstract
The invention relates to a method for synthesizing pidotimod. Belongs to pure liquid phase synthesis; the method adopts L-thiazolidine-4-carboxylic ester or L-thiazolidine-4-carboxylic acid protected by carboxyl R group and pyroglutamic acid protected by nitrogen R1 to condense in the presence of boric acid substituted by R2 as a catalyst to form the target compound pidotimod shown in the general formula III. High purity products can also be obtained by recrystallization. The invention also discloses application of the boric acid substituted by R2 in synthesizing pidotimod. The method greatly shortens the synthesis period, avoids the mechanism of forming oxazolidinone by all the traditional polypeptide synthesis methods, thoroughly solves the racemization problem, and can recycle the catalyst, thereby greatly reducing the cost, having high yield and good product purity and being suitable for industrial production.
Description
Technical Field
The invention relates to a method for synthesizing pidotimod, belonging to the field of chemical drug synthesis.
Background
Pidotimod (Pidotimod) is chemically named as (4R) -3- [ [ (2S) -5-oxo-2-pyrrolidinyl ] carbonyl ] -4-thiazolidinecarboxylic acid, is a brand-new chemically synthesized immune promoter, and has the characteristics of antitoxicity, inoxidizability, anti-irritation, anti-infection and the like. The original research company is Poli chemical industry company in Italy, is used as an oral preparation on the market in 1993, is mainly used for preventing and treating recurrent respiratory tract infection (RRI) of children, chronic bronchitis and the like, and achieves satisfactory results, so the compound has very important function in the aspect of medicine.
The synthesis method of the compound is numerous, but some methods have high cost, inconvenient operation, high toxicity of an intermediate and poor stability; some methods have more severe conditions, are difficult to operate and have low total yield; some methods have simple operation and high yield, but the three wastes are required to be treated in the reaction process. Even though some methods are simple and convenient to operate and high in yield, the overall cost is very high due to the existence of racemization impurities. Meanwhile, the synthesis method mainly focuses on two aspects, namely, the traditional synthesis method, such as the improvement of the pidotimod synthesis process published by phyllostachys, etc. (china pharmacy, volume 23 of 2012, 1 year), wherein thionyl chloride and formaldehyde are condensed to form thiazolium alkanoic acid chloride, and then the thiazolium alkanoic acid chloride is condensed with pyroglutamic acid to form pidotimod. Pidotimod disclosed in Hukun et al (Chinese pharmaceutical industry impurities, 2009, 12) is synthesized by forming acyl chloride from thionyl chloride and thiazolealkanoic acid, and then synthesizing the pidotimod in the presence of an acid-binding agent, namely triethylamine. The improved synthesis of pidotimod, an immunopotentiator disclosed in Li Xiuzhen et al (the chemical world (9 th 2005)), uses acetyl chloride for acylation, and then reacts with pyroglutamic acid to produce pidotimod. CN102167727A discloses a method for synthesizing pidotimod, which comprises performing conventional condensation of thiazolealkanoic acid or ester and pyroglutamic acid to obtain pidotimod. The other methods still have a plurality of kinds, but are almost all established on the original reaction mechanism, or racemization is reduced, or the method is only simple and avoids other synthetic routes, so that the purposes of obtaining an authorized patent or a published article are achieved, the racemization problem is not really solved, and the purposes of improving the product quality and reducing the cost are achieved.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for synthesizing pidotimod, which has more reasonable synthetic route, eliminates racemate and greatly improves yield, aiming at the defects of the prior art.
The invention also discloses application of the boric acid substituted by R2.
The technical problem to be solved by the present invention is achieved by the following technical means. The invention relates to a method for synthesizing pidotimod, which is characterized by comprising the following steps: the method adopts L-thiazolidine-4-carboxylic ester or L-thiazolidine-4-carboxylic acid protected by carboxyl R group and pyroglutamic acid protected by nitrogen R1 to condense in the presence of boric acid substituted by R2 as a catalyst to form a target compound pidotimod shown in a general formula III:
r is selected from: H. otbu, Bn, cHX, Mpe, 2-ph1pr, TEGbn, Damb, Al, pNB, pTMSE, or Dmnb;
r1 is selected from: H. z, Boc, Cl-Z, Fmoc, oNBS, dNBS, Troc, Dts, pNZ, oNZ, NVOC, NPPOC, HFA, Ddz, Bpoc, Nps, Nsc, Bsmoc, alpha-Nsmoc, ivDde, Fmoc, MTT or Alloc;
r2 is selected from: various benzene rings, substituted benzene rings, furan, thiophene, imidazole or triazole.
The synthesis route diagram of the method of the invention is as follows:
the further preferable technical scheme of the synthesis method of pidotimod provided by the invention is as follows: the substituted benzene ring is preferably selected from 3-fluoro substituted, 3, 5-fluoro substituted, 3-chloro substituted, and trifluoromethyl substituted benzene ring.
The synthesis method of pidotimod provided by the invention further preferably comprises the following specific steps:
(1) uniformly stirring pyroglutamic acid protected by nitrogen R1, boric acid substituted by R2, an activated molecular sieve and an organic solvent; the activated molecular sieve is preferably an activated 4 a particle diameter molecular sieve; the organic solvent is preferably anhydrous dichloromethane or ethyl acetate;
(2) adding L-thiazolidine-4-carboxylic ester or L-thiazolidine-4-carboxylic acid protected by carboxyl R group, and continuously stirring for reaction;
(3) after the reaction is finished, filtering the reaction solution to obtain filtrate;
(4) when the raw materials use L-thiazolidine-4-carboxylate protected by carboxyl R group and pyroglutamic acid without nitrogen protection, the filtrate is hydrolyzed by sodium hydroxide or potassium hydroxide solution, then acid is directly used for regulating acid to a large amount of white precipitate, and crude pidotimod is obtained by filtering;
when the raw materials use L-thiazolidine-4-carboxylate protected by carboxyl R group and pyroglutamic acid protected by nitrogen R1 except H, the filtrate is washed by acid, alkali or alkaline salt, washed by saturated sodium chloride solution, and rotary evaporated to obtain solid, then the R1 protecting group is removed, then sodium hydroxide or potassium hydroxide solution is used for hydrolysis, the R group is removed, acid is directly used for adjusting acid to a large amount of white precipitate, and the crude pidotimod is obtained by filtration.
The further preferable technical scheme of the synthesis method of pidotimod provided by the invention is as follows: the molar ratio of pyroglutamic acid protected by raw material nitrogen R1, L-thiazolidine-4-carboxylic ester or L-thiazolidine-4-carboxylic acid protected by carboxyl R group and boric acid substituted by R2 is 0.8-1.5: 1: 0.05 to 0.3, preferably 1.1: 1: 0.1.
the further preferable technical scheme of the synthesis method of pidotimod provided by the invention is as follows: the ratio of the volume ml of the organic solvent to the amount mmol of the pyroglutamic acid protected by nitrogen R1 is 1-20: 1, preferably 7: 1; the ratio of the mol of the pyroglutamic acid protected by nitrogen R1 to the mass kg of the molecular sieve is 0.8-1.5: 1, preferably 1.1: 1; after the addition of the L-thiazolidine-4-carboxylate protected by the carboxyl R group, the reaction is preferably stirred at room temperature for 24 hours.
The further preferable technical scheme of the synthesis method of pidotimod provided by the invention is as follows: and after the reaction is finished, filtering the reaction solution by using kieselguhr or a sand core funnel, leaching the kieselguhr by using an organic solvent after the filtration, and combining the organic solvents to obtain a filtrate.
The further preferable technical scheme of the synthesis method of pidotimod provided by the invention is as follows: in the step (3): and washing the filtrate with dilute hydrochloric acid, sodium bicarbonate and saturated sodium chloride solution in sequence, drying the washed organic solvent solution with anhydrous magnesium sulfate, and performing rotary evaporation to obtain a solid crude product.
The further preferable technical scheme of the synthesis method of pidotimod provided by the invention is as follows: in the step (4): when removing the R1 protecting group, selecting a proper deprotection reagent to remove according to the difference of R1, wherein the deprotection reagent is selected from organic alkali, inorganic alkali, organic acid and inorganic acid, and washing with ethers, preferably diethyl ether, petroleum ether and isopropyl ether to obtain a solid product; when removing R group, selecting different deprotection reagents to remove according to the difference of R, wherein the deprotection reagents are selected from inorganic base, organic acid and inorganic acid, and acidifying to obtain crude pidotimod; the acidification operation is preferably concentrated hydrochloric acid.
The further preferable technical scheme of the synthesis method of pidotimod provided by the invention is as follows: in the step (4): and recrystallizing the crude product by using pure water to obtain the high-purity pidotimod product.
The invention also discloses an application of the boric acid substituted by R2, which is characterized in that the boric acid substituted by R2 is used
Used as a catalyst in the synthesis process of pidotimod, wherein R2 is selected from: various benzene rings, substituted benzene rings, furan, thiophene, imidazole or triazole; the synthesis method of pidotimod is the method in any one of the above technical schemes.
The method of the invention completely avoids the generating mechanism of the oxazole ketone racemate by adopting boric acid as a catalyst, and the reaction mechanism completely breaks away from the original traditional synthesis and activation principle and mechanism, thereby not only completely solving the racemization problem, but also greatly reducing the feeding of reaction materials and greatly improving the yield, and achieving the purpose of being suitable for industrial production. Meanwhile, the method greatly shortens the synthesis period and can recycle the catalyst.
Drawings
Fig. 1 is a chromatogram of the product pidotimod of the method of the invention.
Detailed Description
The following further description of the embodiments of the present invention is provided to further understand the present invention for those skilled in the art, and not to limit the present invention in any way. All organic solvents used in the experimental examples of the invention are subjected to anhydrous treatment, or commercial anhydrous reagents, and molecular sieves are subjected to strong heat activation.
r is selected from: H. otbu, Bn, cHX, Mpe, 2-ph1pr, TEGbn, Damb, Al, pNB, pTMSE, or Dmnb;
r1 is selected from: H. z, Boc, Cl-Z, Fmoc, oNBS, dNBS, Troc, Dts, pNZ, oNZ, NVOC, NPPOC, HFA, Ddz, Bpoc, Nps, Nsc, Bsmoc, alpha-Nsmoc, ivDde, Fmoc, MTT or Alloc;
r2 is selected from: various benzene rings, substituted benzene rings, furan, thiophene, imidazole or triazole.
The method comprises the following specific steps:
(1) uniformly stirring pyroglutamic acid protected by nitrogen R1, boric acid substituted by R2, an activated molecular sieve and an organic solvent; activated molecular sieves activated with a particle diameter of 4 a; the organic solvent is anhydrous dichloromethane or ethyl acetate;
(2) adding L-thiazolidine-4-carboxylic ester or L-thiazolidine-4-carboxylic acid protected by carboxyl R group, and continuously stirring for reaction;
(3) after the reaction is finished, filtering the reaction solution to obtain filtrate;
(4) when the raw materials use L-thiazolidine-4-carboxylate protected by carboxyl R group and pyroglutamic acid without nitrogen protection, the filtrate is hydrolyzed by sodium hydroxide or potassium hydroxide solution, then acid is directly used for regulating acid to a large amount of white precipitate, and crude pidotimod is obtained by filtering;
when the raw materials use L-thiazolidine-4-carboxylate protected by carboxyl R group and pyroglutamic acid protected by nitrogen R1 except H, the filtrate is washed by acid, alkali or alkaline salt, washed by saturated sodium chloride solution, and rotary evaporated to obtain solid, then the R1 protecting group is removed, then sodium hydroxide or potassium hydroxide solution is used for hydrolysis, the R group is removed, acid is directly used for adjusting acid to a large amount of white precipitate, and the crude pidotimod is obtained by filtration.
The molar ratio of pyroglutamic acid protected by raw material nitrogen R1, L-thiazolidine-4-carboxylic acid ester or L-thiazolidine-4-carboxylic acid protected by carboxyl R group and boric acid substituted by R2 is 0.8: 1: 0.05.
the ratio of the volume ml of the organic solvent to the amount mmol of the pyroglutamic acid protected by nitrogen R1 is 1: 1; the ratio of the amount mol of pyroglutamic acid protected by nitrogen R1 to the mass kg of the molecular sieve is 0.8: 1; after addition of the carboxy R group-protected L-thiazolidine-4-carboxylate, the reaction was stirred at room temperature for 24 hours.
In the step (3): and after the reaction is finished, filtering the reaction solution by using kieselguhr or a sand core funnel, leaching the kieselguhr by using an organic solvent after the filtration, and combining the organic solvents to obtain a filtrate.
In the step (3): and washing the filtrate with dilute hydrochloric acid, sodium bicarbonate and saturated sodium chloride solution in sequence, drying the washed organic solvent solution with anhydrous magnesium sulfate, and performing rotary evaporation to obtain a solid crude product.
In the step (4): when removing the R1 protecting group, selecting a proper deprotection reagent to remove according to the difference of R1, wherein the deprotection reagent is selected from organic alkali, inorganic alkali, organic acid and inorganic acid, and washing with ethers, preferably diethyl ether, petroleum ether and isopropyl ether to obtain a solid product; when removing R group, selecting different deprotection reagents to remove according to the difference of R, wherein the deprotection reagents are selected from inorganic base, organic acid and inorganic acid, and acidifying to obtain crude pidotimod; the acidification operation is preferably concentrated hydrochloric acid.
In the step (4): and recrystallizing the crude product by using pure water to obtain the high-purity pidotimod product.
the molar ratio of pyroglutamic acid protected by raw material nitrogen R1, L-thiazolidine-4-carboxylic acid ester or L-thiazolidine-4-carboxylic acid protected by carboxyl R group and boric acid substituted by R2 is 1.5: 1: 0.3;
volume ml of organic solvent with nitrogen R1oNBS, dNBS, Troc, Dts, pNZ, oNZ, NVOC, NPPOC, HFA, Ddz, Bpoc, Nps, Nsc, Bsmoc, α -Nsmoc, ivDde, Fmoc, MTT or Alloc;
r2 is selected from: various benzene rings, substituted benzene rings, furan, thiophene, imidazole or triazole.
The method comprises the following specific steps:
(1) uniformly stirring pyroglutamic acid protected by nitrogen R1, boric acid substituted by R2, an activated molecular sieve and an organic solvent; activated molecular sieves activated with a particle diameter of 4 a; the organic solvent is anhydrous dichloromethane or ethyl acetate;
(2) adding L-thiazolidine-4-carboxylic ester or L-thiazolidine-4-carboxylic acid protected by carboxyl R group, and continuously stirring for reaction;
(3) after the reaction is finished, filtering the reaction solution to obtain filtrate;
(4) when the raw materials use L-thiazolidine-4-carboxylate protected by carboxyl R group and pyroglutamic acid without nitrogen protection, the filtrate is hydrolyzed by sodium hydroxide or potassium hydroxide solution, then acid is directly used for regulating acid to a large amount of white precipitate, and crude pidotimod is obtained by filtering;
when the raw materials use L-thiazolidine-4-carboxylate protected by carboxyl R group and pyroglutamic acid protected by nitrogen R1 except H, the filtrate is washed by acid, alkali or alkaline salt, washed by saturated sodium chloride solution, and rotary evaporated to obtain solid, then the R1 protecting group is removed, then sodium hydroxide or potassium hydroxide solution is used for hydrolysis, the R group is removed, acid is directly used for adjusting acid to a large amount of white precipitate, and the crude pidotimod is obtained by filtration.
The molar ratio of pyroglutamic acid protected by raw material nitrogen R1, L-thiazolidine-4-carboxylic acid ester or L-thiazolidine-4-carboxylic acid protected by carboxyl R group and boric acid substituted by R2 is 0.8: 1: 0.05.
the ratio of the volume ml of the organic solvent to the amount mmol of the pyroglutamic acid protected by nitrogen R1 is 1: 1; the ratio of the amount mol of pyroglutamic acid protected by nitrogen R1 to the mass kg of the molecular sieve is 0.8: 1; after addition of the carboxy R group-protected L-thiazolidine-4-carboxylate, the reaction was stirred at room temperature for 24 hours.
In the step (3): and after the reaction is finished, filtering the reaction solution by using kieselguhr or a sand core funnel, leaching the kieselguhr by using an organic solvent after the filtration, and combining the organic solvents to obtain a filtrate.
In the step (3): and washing the filtrate with dilute hydrochloric acid, sodium bicarbonate and saturated sodium chloride solution in sequence, drying the washed organic solvent solution with anhydrous magnesium sulfate, and performing rotary evaporation to obtain a solid crude product.
In the step (4): when removing the R1 protecting group, selecting a proper deprotection reagent to remove according to the difference of R1, wherein the deprotection reagent is selected from organic alkali, inorganic alkali, organic acid and inorganic acid, and washing with ethers, preferably diethyl ether, petroleum ether and isopropyl ether to obtain a solid product; when removing R group, selecting different deprotection reagents to remove according to the difference of R, wherein the deprotection reagents are selected from inorganic base, organic acid and inorganic acid, and acidifying to obtain crude pidotimod; the acidification operation is preferably concentrated hydrochloric acid.
In the step (4): and recrystallizing the crude product by using pure water to obtain the high-purity pidotimod product.
the molar ratio of pyroglutamic acid protected by raw material nitrogen R1, L-thiazolidine-4-carboxylic acid ester or L-thiazolidine-4-carboxylic acid protected by carboxyl R group and boric acid substituted by R2 is 1.5: 1: 0.3;
the volume ml of the organic solvent and nitrogen R1 are prepared into a 10mmol% dichloromethane solution), 1kg of activated particle diameter 4A molecular sieve and 7L of anhydrous dichloromethane are put into a reaction kettle together, and stirred and reacted at room temperature for 2 hours, and then stirred vigorously for 10 minutes to ensure that all reactants are uniform.
2. While stirring, tert-butyl L-thiazolidine-4-carboxylate (1mol,189g) was slowly added to the mixture, and the mixture was stirred at room temperature for 24 hours to complete the reaction of all the tert-butyl L-thiazolidine-4-carboxylate and complete the detection reaction.
3. After the reaction is finished, the reaction solution is filtered by a sand core funnel with an organic filter membrane to remove the molecular sieve (which can be activated and reused), the sand core funnel and the molecular sieve are rinsed by 1L of dichloromethane, and the dichloromethane is combined.
4. Washing with 5% dilute hydrochloric acid aqueous solution, standing for layering, separating, washing three times in total (200 ml X3), washing with 10% saturated sodium bicarbonate aqueous solution, standing for layering, separating, washing three times in total (200 ml X3), washing with saturated sodium chloride solution, standing for layering, separating, and washing three times in total (200 ml X3). The washed dichloromethane solution was dried over anhydrous magnesium sulfate to a sandy anhydrous sodium sulfate solution and dried overnight. The next day, the product was rotary evaporated to give 395g of a solid crude product (which was oily when containing water).
5. 395g of the solid (or oil) was cleaved with 1.5L of a cleavage solution (95% TFA (trifluoroacetic acid): 2.5% DIS (dimethyl sulfide): 2.5% H2O (water)), and after 2 hours of reaction, the cleavage solution was added to 12L of ethyl glacial ether to precipitate a large amount of white precipitate, which was then washed by centrifugation to obtain a solid.
6. Putting the solid and 550ml of pure water into a round-bottom flask, heating to reflux, keeping the reflux for 1.5 hours, then cooling to 0-10 ℃, stirring, crystallizing, filtering, washing a filter cake with 200ml of ice water, drying, and drying to obtain 216g of white powdery solid pidotimod, wherein the yield is 72%, the melting point is 195.4-196.2 ℃, and the HPLC purity is more than 99.0%.
Example 7, synthesis of pidotimod experiment three:
1. putting pyroglutamic acid (1.1 mol,344.9 g) protected by Fmoc (fluorene methoxycarbonyl), 2-furanboronic acid (0.1 mol,11.2 g) into a 10mmol% dichloromethane solution, activated molecular sieve with particle diameter of 4A 1kg and anhydrous dichloromethane 7L into a reaction kettle, stirring at room temperature for reaction for 2 hours, and stirring strongly for 10 minutes to ensure that all reactants are uniform.
2. While stirring, tert-butyl L-thiazolidine-4-carboxylate (1mol,189g) was slowly added to the mixture, and the mixture was stirred at room temperature for 24 hours to complete the reaction of all the tert-butyl L-thiazolidine-4-carboxylate and complete the detection reaction.
3. After the reaction is finished, the reaction solution is filtered by a sand core funnel with an organic filter membrane to remove the molecular sieve (which can be activated and reused), the sand core funnel and the molecular sieve are rinsed by 1L of dichloromethane, and the dichloromethane is combined.
4. Washing with 5% dilute hydrochloric acid aqueous solution, standing for layering, separating, washing three times in total (200 ml X3), washing with 10% saturated sodium bicarbonate aqueous solution, standing for layering, separating, washing three times in total (200 ml X3), washing with saturated sodium chloride solution, standing for layering, separating, and washing three times in total (200 ml X3). The washed dichloromethane solution was dried over anhydrous magnesium sulfate to a sandy anhydrous sodium sulfate solution and dried overnight. The next day, rotary evaporation gave 498g of crude solid.
5. Placing 498g of solid in a 2L round-bottom flask, removing Fmoc groups by using 800ml of deprotection solution (the deprotection solution is 20% piperidine N, N-dimethylformamide solution), reacting for 2 hours, pouring the reaction solution into 3L of ice water, cooling in an ice bath, dropwise adding 37% concentrated hydrochloric acid at the temperature of-5-0 ℃, adjusting the pH value to 1.3, stirring at the temperature of 0-10 ℃, crystallizing for 7 hours, carrying out suction filtration, and washing a filter cake by using 500ml of pure water.
6. Putting the filter cake and 550ml of pure water into a round-bottom flask, heating to reflux, keeping refluxing for 1.5 hours, then cooling to 0-10 ℃, stirring, crystallizing, filtering, washing the filter cake with 200ml of ice water, drying, and drying to obtain white powdery solid which is 232g of pidotimod, wherein the yield is 77%, the melting point is 195.8-196.4 ℃, and the HPLC purity is more than 99.0%.
Claims (9)
1. A method for synthesizing pidotimod, which is characterized by comprising the following steps: the method adopts L-thiazolidine-4-carboxylate protected by carboxyl R group and pyroglutamic acid protected by nitrogen R1 to condense in the presence of 2-furanboronic acid as a catalyst to form a pidotimod intermediate shown in a general formula III, and the target compound pidotimod is obtained after deprotection:
r is selected from: otbu, Bn, cHX, Mpe, 2-phipr, TEGbn, Dmab, Al, pNB, pTMSE or Dmnb;
r1 is selected from: H. z, Boc, Cl-Z, Fmoc, oNBS, dNBS, Troc, Dts, pNZ, oNZ, NVOC, NPPOC, HFA, Ddz, Bpoc, Nps, Nsc, Bsmoc, alpha-Nsmoc, ivDde, Fmoc, MTT or Alloc.
2. The method for synthesizing pidotimod according to claim 1, wherein,
the method comprises the following specific steps:
(1) uniformly stirring pyroglutamic acid protected by nitrogen R1, 2-furanboronic acid, an activated molecular sieve and an organic solvent; the activated molecular sieve is an activated molecular sieve with a particle diameter of 4A; the organic solvent is anhydrous dichloromethane;
(2) adding L-thiazolidine-4-carboxylic ester protected by carboxyl R group, and continuously stirring for reaction;
(3) after the reaction is finished, filtering the reaction solution to obtain filtrate;
(4) when the raw materials use L-thiazolidine-4-carboxylate protected by carboxyl R group and pyroglutamic acid without nitrogen protection, the filtrate is hydrolyzed by sodium hydroxide or potassium hydroxide solution, then acid is directly used for regulating acid to a large amount of white precipitate, and crude pidotimod is obtained by filtering;
when the raw materials use L-thiazolidine-4-carboxylate protected by carboxyl R group and pyroglutamic acid protected by nitrogen R1 except H, the filtrate is washed by acid, alkali or alkaline salt, washed by saturated sodium chloride solution, and rotary evaporated to obtain solid, then the R1 protecting group is removed, then sodium hydroxide or potassium hydroxide solution is used for hydrolysis, the R group is removed, acid is directly used for adjusting acid to a large amount of white precipitate, and the crude pidotimod is obtained by filtration.
3. The method for synthesizing pidotimod according to claim 2, wherein: the molar ratio of pyroglutamic acid protected by raw material nitrogen R1, L-thiazolidine-4-carboxylic ester protected by carboxyl R group and 2-furanboronic acid is 0.8-1.5: 1: 0.05 to 0.3.
4. The method for synthesizing pidotimod according to claim 2, wherein: the ratio of the volume ml of the organic solvent to the amount mmol of the pyroglutamic acid protected by nitrogen R1 is 1-20: 1; the ratio of the mol of the pyroglutamic acid protected by nitrogen R1 to the mass kg of the molecular sieve is 0.8-1.5: 1.
5. the method for synthesizing pidotimod according to claim 4, wherein: after addition of the carboxy R group-protected L-thiazolidine-4-carboxylate, the reaction was stirred at room temperature for 24 hours.
6. The method for synthesizing pidotimod according to claim 2, wherein: the ratio of the volume ml of organic solvent to the amount mmol of pyroglutamic acid protected with nitrogen R1 was 7: 1; the ratio of the amount mol of pyroglutamic acid protected by nitrogen R1 to the mass kg of the molecular sieve is 1.1: 1; the molar ratio of pyroglutamic acid protected by raw material nitrogen R1, L-thiazolidine-4-carboxylic ester protected by carboxyl R group and 2-furanboronic acid is 1.1: 1: 0.1.
7. the method for synthesizing pidotimod according to claim 2, wherein in step (3): after the reaction is finished, filtering the reaction solution by using kieselguhr, leaching the kieselguhr by using an organic solvent after the filtration, and combining the organic solvents to obtain a filtrate; or filtering the reaction solution by using a sand core funnel, leaching by using an organic solvent after filtering, and combining the organic solvents to obtain a filtrate.
8. The method for synthesizing pidotimod according to claim 2, wherein in step (4): when the R1 protecting group is removed, a proper deprotection reagent is selected for removal according to the difference of R1, the deprotection reagent is selected from organic alkali, inorganic alkali, organic acid and inorganic acid, and then the solid product is obtained after washing by using ether, petroleum ether or isopropyl ether; when removing R group, selecting different deprotection reagents to remove according to the difference of R, wherein the deprotection reagents are selected from inorganic base, organic acid and inorganic acid, and acidifying to obtain crude pidotimod; concentrated hydrochloric acid is selected for acidification.
9. Use of 2-furanboronic acid as a catalyst in the synthesis of pidotimod, according to any one of claims 1 to 8.
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|---|---|---|---|---|
| CN102167727A (en) * | 2011-01-29 | 2011-08-31 | 浙江金立源药业有限公司 | Synthesis method of pidotimod |
| CN103059099A (en) * | 2013-01-03 | 2013-04-24 | 福州乾正药业有限公司 | Novel pidotimod crystal form and preparation method thereof |
| CN104447947A (en) * | 2014-11-18 | 2015-03-25 | 成都医路康医学技术服务有限公司 | Process for producing pidotimod |
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| CN102167727A (en) * | 2011-01-29 | 2011-08-31 | 浙江金立源药业有限公司 | Synthesis method of pidotimod |
| CN103059099A (en) * | 2013-01-03 | 2013-04-24 | 福州乾正药业有限公司 | Novel pidotimod crystal form and preparation method thereof |
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