CN103897025A - Preparation method of pidotimod - Google Patents
Preparation method of pidotimod Download PDFInfo
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- CN103897025A CN103897025A CN201210581095.1A CN201210581095A CN103897025A CN 103897025 A CN103897025 A CN 103897025A CN 201210581095 A CN201210581095 A CN 201210581095A CN 103897025 A CN103897025 A CN 103897025A
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Abstract
The invention provides an improved preparation method of pidotimod. According to the improved preparation method, a mixed anhydride method is adopted, and the improved preparation method comprises the following steps: under alkaline conditions, enabling L-pyroglutamic acid, ethyl chloroformate and L-thiazolidine-4-carboxylic acid to react, then acidifying, refining and devitrifying to prepare pidotimod. The method has the advantages of simplicity and convenience in operation, high yield and high product purity, and is more suitable for industrial production.
Description
Technical field
The invention belongs to the synthetic field of medicine, be specifically related to a kind of preparation method of pidotimod.
Background technology
Pidotimod (pidotimod), chemistry (R)-3-[(S by name)-(5-oxygen-2-pyrrolidyl) carbonyl]-thiazolidyl-4-formic acid, developed by Italian Poli chemical industrial company in the later stage eighties, and in 1993 with trade(brand)name Polimod in Italian Initial Public Offering, respiratory tract and urinary tract infection etc. [Immunomodulator agent for cognition disorders[J] the .Drugs Fut that grows and repeatedly show effect as inhibition tumor cell, 1994,19 (12): 1133-1134.], structural formula is as follows:
Pidotimod is a kind of brand-new chemosynthesis immunopotentiating agent, has the features such as toxin immunity, oxidation-resistance, irritation, anti-infection property; Nonspecific immune reaction can be promoted, specific immune response can be promoted again.Clinically all obtain gratifying result for preventing and treating respiratory tract infection (RRI), the chronic bronchitis etc. that children show effect repeatedly, so this compound has very important effect aspect medical.
In prior art, it synthetic mainly contains following several method:
In patent CN 102167727A, by Cys and paraformaldehyde or formaldehyde reaction generation L-thiazolidine-4-carboxylic acid, then carry out esterification generation L-thiazolidine-4-carboxylicesters, then carry out condensation reaction with L-Glutimic acid, through hydrolysis, acidifying obtains pidotimod again.The method complex operation, solvent for use kind is many, and toxicity is large, and condensation reaction condition harshness, needs to reflux, and pyroreaction easily causes that product impurity increases.Reaction formula is as follows:
Dan Shiming, Yu Shuqin, An Lufan " synthesizing of immunopotentiating agent pidotimod " Chinese Journal of New Drugs, 2000,9(11), 764-765] in, synthetic L-thiazolidine-4-carboxylic acid take Cys as raw material, prepare pidotimod with the ester condensation of L-Glutimic acid Pentachlorophenol again, use distilled water recrystallization, but yield is only 69%.Reaction formula is as follows:
The L-Glutimic acid pentachloro-phenolic ester that the method relates to, synthetic operation is loaded down with trivial details, and reagent pentachlorophenol toxicity is larger, and the active ester that nitrogen replaces is unstable; Condensation reaction solvent for use is DMF, and boiling point is high, is difficult to recycle, and cost is higher, is unfavorable for large production.
In addition, Li Xiu treasure, king's Yun, Shang Zhicai, Yu Qingsen, " the synthetic improvement of immunopotentiating agent pidotimod " chemistry world, the 9th phase in 2005,555-557] in mention and use mixed solvent Virahol: methyl alcohol=6:4 to refine pidotimod, two kinds of alcohols of mixed solvent are all little to pidotimod solvability, cause refining yield low, only 51%, and cost is higher.
Summary of the invention
The object of the present invention is to provide a kind of easy and simple to handle, yield is high, be more suitable for the preparation method of the large improved pidotimod of producing, and a kind for the treatment of process of, yield high, product purity high pidotimod little to environmental influence is provided simultaneously.
The present invention by lot of experiments, has finally obtained the technical scheme that realizes as follows the object of the invention, takes mixed anhydride method to prepare pidotimod take L-Glutimic acid and L-thiazolidyl-4-carboxylic acid as raw material.
The method realizes as follows:
Mixed anhydride method is prepared pidotimod: L-Glutimic acid in organic solvent A, temperature control T
1, add alkali B and Vinyl chloroformate, stirring reaction time t
1after, add L-thiazolidyl-4-carboxylic acid, continue temperature control T
1stirring reaction time t
2after, temperature of reaction is risen to room temperature, by reaction solution evaporated under reduced pressure, in residue, add solvent C, add concentrated hydrochloric acid acidifying, in temperature T
2stirring and crystallizing t
3, filter, be drying to obtain pidotimod crude product;
Refining: crude product is dissolved by mixed solvent D and E reflux, a small amount of insoluble impurity of filtering while hot, slow cooling is to temperature T
3stirring and crystallizing t
4, filter, dry, obtain pidotimod.
Reaction equation is as follows:
Wherein, described organic solvent A is at least one in anhydrous tetrahydro furan, Isosorbide-5-Nitrae-dioxane, toluene, preferably tetrahydrofuran (THF);
Described alkali B is at least one in sodium carbonate, salt of wormwood, Trimethylamine 99, triethylamine, diisopropyl ethyl amine, preferably sodium carbonate;
The consumption of described Vinyl chloroformate is and L-Glutimic acid mol ratio=1～2:1, preferably 1.1:1;
Described temperature T
1for-20～5 ℃, preferably-5～5 ℃;
Described time t
1be 2～30min, preferably 5～10min;
Described time t
2be 10～60min, preferably 15～20min;
Described solvent C is aqueous ethanolic solution, and concentration is 10-90%, preferably 30-60%;
Described temperature T
2for-20～20 ℃, preferably-10～10 ℃;
Described time t
3be 1～20h, preferably 4～8h;
If treating process is used merely purified water, the solubleness of pidotimod is large, and crystallization yield is low; If use merely alcohols, the solubleness of pidotimod is too small, causes solvent load large, increases refining cost.So grope by test, obtain the good mixed solvent of above-mentioned refining effect.
Wherein, in described mixed solvent, D is the purified water large to pidotimod solvability, in mixed solvent, E is alcohols little to pidotimod solvability, can be miscible with water, at least one in particular methanol, ethanol, n-propyl alcohol, Virahol, its consumption is pidotimod crude product: D:E=1:1～5:5～10(w/v/v), preferably pidotimod crude product: purified water: n-propyl alcohol=1:2:5(w/v/v);
Described temperature T
3for-10～10 ℃, preferably-10～0 ℃;
Described time t
4be 4～20h, preferably 4～8h;
The present invention has following significant advantage compared with literature method:
(1) this method is selected raw material L-thiazolidyl-4-carboxylic acid and L-Glutimic acid, and low price is easily bought, and is applicable to suitability for industrialized production;
(2) reaction process can be carried out without separation and purification continuously, has reduced the loss of raw material and product, has improved yield, and greatly must reduce industrial production cost;
(3) this legal system is fast for pidotimod speed of response, provides alkaline environment with mineral alkali, reaction conditions gentleness, easy controlled operation;
(4) this process for purification product purity is high, and yield is up to more than 90%;
(5) the refining mixed solvent of selecting is purified water and alcohols, guarantees, under the prerequisite of quality product, improved yield, and cost to be low.
Embodiment
In order to understand better the content of patent of the present invention, further illustrate technical scheme of the present invention below by specific embodiment, but these embodiment do not limit the present invention.
The preparation of embodiment 1 pidotimod
In three mouthfuls of round-bottomed flasks of dry 2000mL, add L-Glutimic acid 50.0g (0.375mol) and anhydrous tetrahydro furan 700ml, stir, be cooled to-5～5 ℃, add sodium carbonate 39.7g (0.375mol), temperature control-5～5 ℃ drip Vinyl chloroformate 40.7g (0.375mol), dropwise, after insulated and stirred reaction 20min, add L-thiazolidyl-4-carboxylic acid 49.9g (0.375mol), continue after ℃ stirring reaction 20min of temperature control-5～5, temperature of reaction is risen to room temperature, by reaction solution evaporated under reduced pressure, toward the ethanol 200ml that adds 50% in residue, stirring is all dissolved it, temperature control-20～-10 ℃ drip concentrated hydrochloric acid 30ml, dropwise, insulated and stirred crystallization 8h, filter, dry, obtain pidotimod crude product 76.7g, yield 83.73%,
Refining of pidotimod
In three mouthfuls of round-bottomed flasks of 2000mL, add above-mentioned gained pidotimod crude product 50.0g, and mixed solvent purified water 150mL and n-propyl alcohol 450ml, stirring heating, is back to solid entirely molten, a small amount of insolubles of filtering while hot, filtrate slow cooling was to-10～0 ℃ of stirring and crystallizing 8 hours, filter n-propyl alcohol 50mL × 2 washing leaching cake, 60～70 ℃/-0.095MPa vacuum-drying of filter cake 12 hours, obtain pidotimod 45.4g, refining yield: 90.8%, HPLC:99.91% is maximum single assorted: 0.06%.
The preparation of embodiment 2 pidotimods
In three mouthfuls of round-bottomed flasks of dry 2000mL, add L-Glutimic acid 50.0g (0.375mol) and anhydrous tetrahydro furan 700ml, stir, be cooled to-20～-10 ℃, add sodium carbonate 39.7g (0.375mol), temperature control-20～-10 ℃ drip Vinyl chloroformate 40.7g (0.375mol), dropwise, after insulated and stirred reaction 10min, add L-thiazolidyl-4-carboxylic acid 49.9g (0.375mol), continue after ℃ stirring reaction 20min of temperature control-5～5, temperature of reaction is risen to room temperature, by reaction solution evaporated under reduced pressure, toward the ethanol 200ml that adds 60% in residue, stirring is all dissolved it, temperature control-20～-10 ℃ drip concentrated hydrochloric acid 30ml, dropwise, insulated and stirred crystallization 20h, filter, dry, obtain pidotimod crude product 71.8g, yield 78.38%,
Refining of pidotimod
In three mouthfuls of round-bottomed flasks of 1000mL, add above-mentioned gained pidotimod crude product 50.0g, and mixed solvent purified water 50mL and ethanol 300ml, stirring heating, is back to solid entirely molten, a small amount of insolubles of filtering while hot, filtrate slow cooling was to-10～0 ℃ of stirring and crystallizing 4 hours, filter ethanol 50mL × 2 washing leaching cake, 60～70 ℃/-0.095MPa vacuum-drying of filter cake 12 hours, obtain pidotimod 46.0g, refining yield: 92.0%, HPLC:99.90% is maximum single assorted: 0.04%.
The preparation of embodiment 3 pidotimods
In three mouthfuls of round-bottomed flasks of dry 2000mL, add L-Glutimic acid 50.0g (0.375mol) and anhydrous tetrahydro furan 700ml, stir, be cooled to-20～-10 ℃, add Trimethylamine 99 24.3g (0.412mol), temperature control-20～-10 ℃ drip Vinyl chloroformate 40.7g (0.412mol), dropwise, after insulated and stirred reaction 10min, add L-thiazolidyl-4-carboxylic acid 49.9g (0.375mol), continue after ℃ stirring reaction 20min of temperature control-5～5, temperature of reaction is risen to room temperature, by reaction solution evaporated under reduced pressure, toward the ethanol 200ml that adds 30% in residue, stirring is all dissolved it, temperature control-20～-10 ℃ drip concentrated hydrochloric acid 30ml, dropwise, insulated and stirred crystallization 16h, filter, dry, obtain pidotimod crude product 72.9g, yield 79.59%,
Refining of pidotimod
In three mouthfuls of round-bottomed flasks of 2000mL, add above-mentioned gained pidotimod crude product 50.0g, and mixed solvent purified water 150mL and n-propyl alcohol 550ml, stirring heating, is back to solid entirely molten, a small amount of insolubles of filtering while hot, filtrate slow cooling was to-10～0 ℃ of stirring and crystallizing 8 hours, filter n-propyl alcohol 50mL × 2 washing leaching cake, 60～70 ℃/-0.095MPa vacuum-drying of filter cake 12 hours, obtain pidotimod 45.2g, refining yield: 90.6%, HPLC:99.91% is maximum single assorted: 0.06%.
The preparation of embodiment 4 pidotimods
In three mouthfuls of round-bottomed flasks of dry 2000mL, add L-Glutimic acid 50.0g (0.375mol) and anhydrous 1, 4-dioxane 700ml, stir, be cooled to-20～-10 ℃, add Trimethylamine 99 22.1g (0.375mol), temperature control-20～-10 ℃ drip Vinyl chloroformate 40.7g (0.375mol), dropwise, after insulated and stirred reaction 10min, add L-thiazolidyl-4-carboxylic acid 49.9g (0.375mol), continue after ℃ stirring reaction 20min of temperature control-5～5, temperature of reaction is risen to room temperature, by reaction solution evaporated under reduced pressure, toward the ethanol 200ml that adds 30% in residue, stirring is all dissolved it, temperature control-20～-10 ℃ drip concentrated hydrochloric acid 30ml, dropwise, insulated and stirred crystallization 8h, filter, dry, obtain pidotimod crude product 71.4g, yield 78.17%,
Refining of pidotimod
In three mouthfuls of round-bottomed flasks of 2000mL, add above-mentioned gained pidotimod crude product 50.0g, and mixed solvent purified water 150mL and Virahol 450ml, stirring heating, is back to solid entirely molten, a small amount of insolubles of filtering while hot, filtrate slow cooling was to-10～0 ℃ of stirring and crystallizing 14 hours, filter Virahol 50mL × 2 washing leaching cake, 60～70 ℃/-0.095MPa vacuum-drying of filter cake 12 hours, obtain pidotimod 46.5g, refining yield: 92.6%, HPLC:99.02% is maximum single assorted: 0.21%.
The preparation of embodiment 5 pidotimods
In three mouthfuls of round-bottomed flasks of dry 2000mL, add L-Glutimic acid 50.0g (0.375mol) and anhydrous tetrahydro furan 700ml, stir, be cooled to-5～5 ℃, add sodium carbonate 43.7g (0.412mol), temperature control-5～5 ℃ drip Vinyl chloroformate 44.7g (0.412mol), dropwise, after insulated and stirred reaction 10min, add L-thiazolidyl-4-carboxylic acid 49.9g (0.375mol), continue after ℃ stirring reaction 20min of temperature control-5～5, temperature of reaction is risen to room temperature, by reaction solution evaporated under reduced pressure, toward the ethanol 200ml that adds 60% in residue, stirring is all dissolved it, temperature control-20～-10 ℃ drip concentrated hydrochloric acid 30ml, dropwise, insulated and stirred crystallization 6h, filter, dry, obtain pidotimod crude product 77.6g, yield 84.72%,
Refining of pidotimod
In three mouthfuls of round-bottomed flasks of 1000mL, add above-mentioned gained pidotimod crude product 50.0g, and mixed solvent purified water 100mL and n-propyl alcohol 250ml, stirring heating, is back to solid entirely molten, a small amount of insolubles of filtering while hot, filtrate slow cooling was to-10～0 ℃ of stirring and crystallizing 8 hours, filter n-propyl alcohol 50mL × 2 washing leaching cake, 60～70 ℃/-0.095MPa vacuum-drying of filter cake 12 hours, obtain pidotimod 47.8g, refining yield: 95.6%, HPLC:99.94% is maximum single assorted: 0.04%.
The preparation of embodiment 6 pidotimods
In three mouthfuls of round-bottomed flasks of dry 2000mL, add L Pyrrolidonecarboxylic acid 50.0g (0.375mol) and anhydrous 1, 4-dioxane 700ml, stir, be cooled to-5～5 ℃, add salt of wormwood 62.1g (0.45mol), temperature control-5～5 ℃ drip Vinyl chloroformate 48.8g (0.45mol), dropwise, after insulated and stirred reaction 10min, add L-thiazolidyl-4-carboxylic acid 49.9g (0.375mol), continue after ℃ stirring reaction 20min of temperature control-5～5, temperature of reaction is risen to room temperature, by reaction solution evaporated under reduced pressure, toward the ethanol 200ml that adds 60% in residue, stirring is all dissolved it, temperature control-20～-10 ℃ drip concentrated hydrochloric acid 30ml, dropwise, insulated and stirred crystallization 6h, filter, dry, obtain pidotimod crude product 73.4g, yield 80.13%,
Refining of pidotimod
In three mouthfuls of round-bottomed flasks of 2000mL, add above-mentioned gained pidotimod crude product 50.0g, and mixed solvent purified water 250mL and ethanol 500ml, stirring heating, is back to solid entirely molten, a small amount of insolubles of filtering while hot, filtrate slow cooling to 0～10 ℃ stirring and crystallizing 20 hours, filter ethanol 50mL × 2 washing leaching cake, 60～70 ℃/-0.095MPa vacuum-drying of filter cake 12 hours, obtain pidotimod 45.6g, refining yield: 91.2%, HPLC:99.88% is maximum single assorted: 0.04%.
The preparation of embodiment 7 pidotimods
In three mouthfuls of round-bottomed flasks of dry 2000mL, add L-Glutimic acid 50.0g (0.375mol) and anhydrous tetrahydro furan 700ml, stir, be cooled to-20～-10 ℃, add triethylamine 75.9g (0.75mol), temperature control-20～-10 ℃ drip Vinyl chloroformate 81.3g (0.75mol), dropwise, after insulated and stirred reaction 10min, add L-thiazolidyl-4-carboxylic acid 49.9g (0.375mol), continue after ℃ stirring reaction 20min of temperature control-5～5, temperature of reaction is risen to room temperature, by reaction solution evaporated under reduced pressure, toward the ethanol 200ml that adds 60% in residue, stirring is all dissolved it, temperature control-20～-10 ℃ drip concentrated hydrochloric acid 30ml, dropwise, insulated and stirred crystallization 2h, filter, dry, obtain pidotimod crude product 70.9g, yield 77.40%,
Refining of pidotimod
In three mouthfuls of round-bottomed flasks of 2000mL, add above-mentioned gained pidotimod crude product 50.0g, and mixed solvent purified water 150mL and Virahol 400ml, stirring heating, is back to solid entirely molten, a small amount of insolubles of filtering while hot, filtrate slow cooling was to-10～0 ℃ of stirring and crystallizing 14 hours, filter Virahol 50mL × 2 washing leaching cake, 60～70 ℃/-0.095MPa vacuum-drying of filter cake 12 hours, obtain pidotimod 46.2g, refining yield: 92.4%, HPLC:99.04% is maximum single assorted: 0.20%.
The preparation of embodiment 8 pidotimods
In three mouthfuls of round-bottomed flasks of dry 2000mL, add L-Glutimic acid 50.0g (0.375mol) and anhydrous tetrahydro furan 700ml, stir, be cooled to-5～5 ℃, add diisopropyl ethyl amine 77.5g (0.600mol), temperature control-5～5 ℃ drip Vinyl chloroformate 65.1g (0.600mol), dropwise, after insulated and stirred reaction 10min, add L-thiazolidyl-4-carboxylic acid 49.9g (0.375mol), continue after ℃ stirring reaction 20min of temperature control-5～5, temperature of reaction is risen to room temperature, by reaction solution evaporated under reduced pressure, toward the ethanol 200ml that adds 90% in residue, stirring is all dissolved it, temperature control-20～-10 ℃ drip concentrated hydrochloric acid 30ml, dropwise, insulated and stirred crystallization 4h, filter, dry, obtain pidotimod crude product 69.7g, yield 76.09%.
The preparation of embodiment 9 pidotimods
In three mouthfuls of round-bottomed flasks of dry 2000mL, add L-Glutimic acid 50.0g (0.375mol) and anhydrous 1, 4-dioxane 700ml, stir, be cooled to-5～5 ℃, add salt of wormwood 56.9g (0.412mol), temperature control-5～5 ℃ drip Vinyl chloroformate 44.7g (0.412mol), dropwise, after insulated and stirred reaction 5min, add L-thiazolidyl-4-carboxylic acid 49.9g (0.375mol), continue after ℃ stirring reaction 20min of temperature control-5～5, temperature of reaction is risen to room temperature, by reaction solution evaporated under reduced pressure, toward the ethanol 200ml that adds 60% in residue, stirring is all dissolved it, temperature control-20～-10 ℃ drip concentrated hydrochloric acid 30ml, dropwise, insulated and stirred crystallization 8h, filter, dry, obtain pidotimod crude product 75.7g, yield 82.64%.
The preparation of embodiment 10 pidotimods
In three mouthfuls of round-bottomed flasks of dry 2000mL, add L-Glutimic acid 50.0g (0.375mol) and anhydrous tetrahydro furan 700ml, stir, be cooled to-5～5 ℃, add sodium carbonate 43.7g (0.412mol), temperature control-5～5 ℃ drip Vinyl chloroformate 44.7g (0.412mol), dropwise, after insulated and stirred reaction 20min, add L-thiazolidyl-4-carboxylic acid 49.9g (0.375mol), continue after ℃ stirring reaction 60min of temperature control-5～5, temperature of reaction is risen to room temperature, by reaction solution evaporated under reduced pressure, toward the ethanol 200ml that adds 30% in residue, stirring is all dissolved it, temperature control-10～0 ℃ drips concentrated hydrochloric acid 30ml, dropwise, insulated and stirred crystallization 6h, filter, dry, obtain pidotimod crude product 73.5g, yield 80.24%,
Refining of pidotimod
In three mouthfuls of round-bottomed flasks of 500mL, add gained pidotimod crude product 50.0g, and mixed solvent purified water 50mL and methyl alcohol 150ml, stirring heating, is back to solid entirely molten, a small amount of insolubles of filtering while hot, filtrate slow cooling to 0～10 ℃ stirring and crystallizing 6 hours, filter methyl alcohol 50mL × 2 washing leaching cake, 60～70 ℃/-0.095MPa vacuum-drying of filter cake 12 hours, obtain pidotimod 46.4g, refining yield: 92.8%, HPLC:99.89% is maximum single assorted: 0.04%.
Claims (10)
1. a preparation method for pidotimod, step is as follows:
L-Glutimic acid joins in organic solvent A, controls temperature T
1for-20～5 ℃, add alkali B and Vinyl chloroformate, stirring reaction time t
1after being 2～30 minutes, add L-thiazolidyl-4-carboxylic acid, continue temperature control T
1stirring reaction time t
2after being 10～60 minutes, temperature of reaction is risen to room temperature, by reaction solution evaporated under reduced pressure, in residue, add solvent C aqueous ethanolic solution, add concentrated hydrochloric acid acidifying, in temperature T
2for-20～20 ℃ of stirring and crystallizing time t
3be 1～20 hour, filter, be drying to obtain pidotimod crude product; Wherein organic solvent A is at least one in tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, toluene, and alkali B is at least one in sodium carbonate, salt of wormwood, Trimethylamine 99, triethylamine, diisopropyl ethyl amine;
Crude product is dissolved by solvent D and E mixed solution reflux, a small amount of insoluble impurity of filtering while hot, slow cooling is to temperature T
3for-10～10 ℃ of stirring and crystallizing t
4be 4～20 hours, filter, dry, obtain pidotimod; Wherein in solvent, D is purified water, and solvent E is at least one in methyl alcohol, ethanol, n-propyl alcohol, Virahol, pidotimod crude product: D:E=1g:1～5ml:5～10ml.
2. the preparation method of pidotimod according to claim 1, is characterized in that organic solvent A is tetrahydrofuran (THF).
3. the preparation method of pidotimod according to claim 1, is characterized in that alkali B is sodium carbonate.
4. the preparation method of pidotimod according to claim 1, is characterized in that mol ratio Vinyl chloroformate: L-Glutimic acid=1～2:1.
5. the preparation method of pidotimod according to claim 1, is characterized in that mol ratio Vinyl chloroformate: L-Glutimic acid=1.1:1.
6. the preparation method of pidotimod according to claim 1, is characterized in that temperature T
1for-5～5 ℃.
7. the preparation method of pidotimod according to claim 1, is characterized in that time t
1it is 5～10 minutes.
8. the preparation method of pidotimod according to claim 1, is characterized in that time t
2it is 15～20 minutes.
9. the preparation method of pidotimod according to claim 1, is characterized in that aqueous ethanolic solution concentration is 10-90%.
10. the preparation method of pidotimod according to claim 1, is characterized in that aqueous ethanolic solution concentration is 30-60%.
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| CN104926922A (en) * | 2015-04-09 | 2015-09-23 | 常州工程职业技术学院 | Preparation method for pidotimod |
| CN105753938A (en) * | 2015-11-25 | 2016-07-13 | 天津中津药业股份有限公司 | Pidotimod crystal form as well as preparation method and application thereof |
| CN106632592A (en) * | 2016-11-23 | 2017-05-10 | 南京工业大学 | Preparation method of pidotimod |
| CN106749515A (en) * | 2016-11-28 | 2017-05-31 | 无锡福祈制药有限公司 | A kind of synthetic method of Pidotimod |
| CN108715598A (en) * | 2018-06-13 | 2018-10-30 | 峨眉山宏昇药业股份有限公司 | A kind of preparation method of Pidotimod |
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| CN108715598A (en) * | 2018-06-13 | 2018-10-30 | 峨眉山宏昇药业股份有限公司 | A kind of preparation method of Pidotimod |
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