CN102234313B - Method for synthesizing pidotimod - Google Patents
Method for synthesizing pidotimod Download PDFInfo
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- CN102234313B CN102234313B CN 201110235340 CN201110235340A CN102234313B CN 102234313 B CN102234313 B CN 102234313B CN 201110235340 CN201110235340 CN 201110235340 CN 201110235340 A CN201110235340 A CN 201110235340A CN 102234313 B CN102234313 B CN 102234313B
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- pidotimod
- filtered
- thiazolidine
- oven dry
- thick product
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- UUTKICFRNVKFRG-WDSKDSINSA-N (4R)-3-[oxo-[(2S)-5-oxo-2-pyrrolidinyl]methyl]-4-thiazolidinecarboxylic acid Chemical compound OC(=O)[C@@H]1CSCN1C(=O)[C@H]1NC(=O)CC1 UUTKICFRNVKFRG-WDSKDSINSA-N 0.000 title claims abstract description 32
- 229960001163 pidotimod Drugs 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title abstract description 7
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 47
- 239000000047 product Substances 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- DZLNHFMRPBPULJ-GSVOUGTGSA-N D-thioproline Chemical compound OC(=O)[C@H]1CSCN1 DZLNHFMRPBPULJ-GSVOUGTGSA-N 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 11
- 239000011230 binding agent Substances 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 239000012065 filter cake Substances 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- RMHPSSGICDJKDR-VKHMYHEASA-N (2s)-5-oxopyrrolidine-2-carbonyl chloride Chemical compound ClC(=O)[C@@H]1CCC(=O)N1 RMHPSSGICDJKDR-VKHMYHEASA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 238000010189 synthetic method Methods 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 238000005303 weighing Methods 0.000 claims description 4
- 239000013078 crystal Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 abstract description 4
- 238000001914 filtration Methods 0.000 abstract description 3
- 238000001035 drying Methods 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 4
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachlorophenol Chemical compound OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 206010057190 Respiratory tract infections Diseases 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000002434 immunopotentiative effect Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 241000710185 Mengo virus Species 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention relates to a method for synthesizing pidotimod, which comprises the following steps of: mixing L-thiazolidine-4-carboxylic acid and an acid binding agent in anhydrous acetone; dripping an anhydrous acetone solution of L-pyroglutamic acyl chloride; after the reaction is finished, filtering; dissolving a filter cake in water, acidifying, and filtering to obtain a coarse product; and drying the coarse product, and recrystallizing to obtain the pidotimod.
Description
Technical field
The present invention relates to a kind of preparation method of medical compounds, particularly a kind of synthetic method of immunopotentiating agent pidotimod.
Background technology
Pidotimod (pidotimod) is the eighties in 20th century by the research and development of Italian Poli industria chimica S.P.A company, getting permission listing in 1993 is used for clinical, it is a kind of immunopotentiating agent of synthetic, its similar is in dipeptides, and its chemical name is (R)-3-(S)-(5-oxo-2-pyrrolidyl) carbonyl]-tetrahydro-thiazoles-4-carboxylic acid.It has quick distribution, drainage, does not accumulate in vivo, and the advantages such as better tolerance can promote nonspecific immune reaction, can promote specific immune response again.At present, in the Asia, the listing of all a plurality of countries such as Europe, America, be mainly used in the curative effect that infects by promotion performance significant treatment bacterium (streptococcus pneumoniae, intestinal bacteria, Pseudomonas aeruginosa, Bacillus proteus etc.) and virus (influenza virus, hsv, myocarditis virus and mengo virus etc.) to body's immunity; The treatment of share the respiratory tract infection that suppressed repeatedly to show effect for cellular immunization concentration, Respiratory infections, urinary system infection etc. with antimicrobial drug.
According to the literature, the main synthetic method of pidotimod has two kinds:
1. generate L-thiazolidine-4-carboxylic acid with Cys and formaldehyde reaction, L-Glutimic acid and pentachlorophenol generation active ester, then L-thiazolidine-4-carboxylic acid reacts under the effect of triethylamine with the active ester of L-Glutimic acid in the DMF solvent and obtains.
The pentachlorophenol of the severe toxicity that the method adopts is as one of raw material, and is too high with production protection and three wastes processing requirements to equipment, adopted again high boiling DMF as solvent, and it is excessive to consume energy.Total recovery only has 27%, and is lower, so cost compare is high.Consider, not too be fit to suitability for industrialized production.
2.L-pyroglutamyl chlorine is dissolved in the acetone, and the sodium hydroxide solution of 2N is added drop-wise in the sodium hydroxide solution of L-thiazolidine under the ice bath-4-carboxylic acid simultaneously, PH is between 7.5 to 8.5 in control, uses the concentrated hydrochloric acid acidifying behind the concentrating under reduced pressure.Yield 49% behind the recrystallization.
L-pyroglutamyl chlorine needs and sodium hydroxide solution are added dropwise in the reaction system simultaneously in this method, need strict control rate of addition to keep system PH in the narrow range of 7.5-8.5, not easy to operate, and because acyl chlorides is easy to hydrolysis in water, cause reaction to be difficult to control, test-results less stable and yield are not high.
Summary of the invention
The object of the present invention is to provide a kind of synthesis technique of pidotimod, it is low to solve existing synthesis technique yield, the problem that production cost is high.The present invention adopts anhydrous organic solvent to react as solvent by the acyl chlorides method is improved, and has reduced the hydrolysis of acyl chlorides, adopts simultaneously mineral alkali as acid binding agent, has obtained pidotimod with high yield at last.
Synthetic method of the present invention is as follows:
Step 1 joins L-thiazolidine-4-carboxylic acid in the anhydrous propanone, adds acid binding agent again;
Step 2 joins L-pyroglutamyl chlorine in the anhydrous propanone, adds the resulting solution reaction of a step;
Step 3, filtering reacting liquid, the solid water dissolution is acidified to PH=0～2.5, and the adularescent crystal generates;
Step 4 is filtered, and oven dry obtains the thick product of pidotimod;
Step 5, thick product water recrystallization filters, and obtains the elaboration pidotimod after the oven dry.
Wherein, L-pyroglutamyl chlorine and L-thiazolidine-4-carboxylic acid mass ratio is 1.1～2: 1; Acid binding agent adopts salt of wormwood or yellow soda ash, and acid binding agent and L-thiazolidine-4-carboxylic acid mass ratio is 0.8～1.5: 1.
Preferred synthetic method of the present invention is as follows:
Step 1, step is suspended in L-thiazolidine-4-carboxylic acid in an amount of anhydrous propanone, adds the acid binding agent of capacity, stirs;
Step 2 is dissolved in L-pyroglutamyl chlorine in the anhydrous propanone, is added dropwise to stirring reaction certain hour in the resulting solution of a step;
Step 3 is filtered, and filter cake is spent with the water dissolution of capacity, ice bath to 0～10, and mentioned solution is acidified to PH=0～2.5 with concentrated hydrochloric acid, and the adularescent crystal generates, and stirs certain hour, makes crystallization complete;
Step 4 is filtered, and oven dry obtains the thick product of pidotimod;
Step 5, thick product water recrystallization filters, and obtains the elaboration pidotimod after the oven dry.
The invention has the advantages that:
1, adopt anhydrous propanone as reaction solvent, the anhydrous propanone low price, toxicity is low, but also provides a water-less environment that L-pyroglutamyl chlorine and L-thiazolidine-4-carboxylic acid are reacted under acid binding agent catalysis, greatly reduces the decomposition of raw material L-pyroglutamyl chlorine,
2, adopt mineral alkali as acid binding agent, cost is low, and toxicity is little.
3, about 90% high yield makes pidotimod, and cost is low, is fit to suitability for industrialized production.
Embodiment
The present invention is described further below by specific embodiment, but embodiment is not used in the scope that the present invention protects that limits.
Embodiment 1, preparation method of the present invention
Step 1 takes by weighing 100gL-thiazolidine-4-carboxylic acid and adds in the 400mL acetone, then adds 114g salt of wormwood and stirs 0.5h.
Step 2 is dissolved in 122gL-pyroglutamyl chlorine in the 300mL acetone, then is added drop-wise to stirring reaction 2h in the resulting solution of a step.
Step 3 is filtered, and filter cake is dissolved in the 500mL water, ice bath to 0～10 degree, and mentioned solution is acidified to PH=2 with concentrated hydrochloric acid, and the adularescent precipitation generates, and continues to stir 1 hour.
Step 4 is filtered, oven dry.Obtain the thick product of pidotimod.
Step 5, the thick product water of pidotimod recrystallization filters, and oven dry is weighed, and obtains 165g elaboration pidotimod, yield 90%
Embodiment 2. preparation methods of the present invention
Step 1 takes by weighing 100gL-thiazolidine-4-carboxylic acid and adds in the 500mL acetone, then adds 96g yellow soda ash and stirs 0.5h.
Step 2 is dissolved in 166gL-pyroglutamyl chlorine in the 400mL acetone, then is added drop-wise to stirring reaction 2h in the resulting solution of a step.
Step 3 is filtered, and filter cake is dissolved in the 500mL water, ice bath to 0～10 degree, and mentioned solution is acidified to PH=2 with concentrated hydrochloric acid, and the adularescent precipitation generates, and continues to stir 1 hour.
Step 4 is filtered, oven dry.Obtain the thick product of pidotimod.
Step 5, the thick product water of pidotimod recrystallization filters, and oven dry is weighed, and obtains 163g elaboration pidotimod, yield 89%.
Claims (3)
1. the synthetic method of a pidotimod is characterized in that, step is as follows:
Step 1 is suspended in L-thiazolidine-4-carboxylic acid in an amount of anhydrous propanone, adds the acid binding agent of capacity, stirs;
Step 2 is dissolved in L-pyroglutamyl chlorine in the anhydrous propanone, is added dropwise to stirring reaction certain hour in the resulting solution of step;
Step 3 is filtered, and filter cake is spent with the water dissolution of capacity, ice bath to 0 ~ 10, and mentioned solution is acidified to PH=0 ~ 2.5 with concentrated hydrochloric acid, and the adularescent crystal generates, and stirs certain hour, makes crystallization complete;
Step 4 is filtered, and oven dry obtains the thick product of pidotimod;
Step 5, thick product water recrystallization filters, and obtains the elaboration pidotimod after the oven dry;
Wherein, L-pyroglutamyl chlorine and L-thiazolidine-4-carboxylic acid mass ratio is 1.1 ~ 2:1; Acid binding agent adopts salt of wormwood or yellow soda ash, and acid binding agent and L-thiazolidine-4-carboxylic acid mass ratio is 0.8 ~ 1.5:1.
2. the synthetic method of a kind of pidotimod as claimed in claim 1 is characterized in that, step is as follows:
Step 1 takes by weighing 100gL-thiazolidine-4-carboxylic acid and adds in the 400mL acetone, then adds 114g salt of wormwood and stirs 0.5h;
Step 2 is dissolved in 122gL-pyroglutamyl chlorine in the 300mL acetone, then is added drop-wise to stirring reaction 2h in the resulting solution of step;
Step 3 is filtered, and filter cake is dissolved in the 500mL water, ice bath to 0 ~ 10 degree, and mentioned solution is acidified to PH=2 with concentrated hydrochloric acid, and the adularescent precipitation generates, and continues to stir 1 hour;
Step 4 is filtered, oven dry.Obtain the thick product of pidotimod;
Step 5, the thick product water of pidotimod recrystallization filters, and oven dry is weighed, and obtains 165g elaboration pidotimod.
3. the synthetic method of a kind of pidotimod as claimed in claim 1 is characterized in that, step is as follows:
Step 1 takes by weighing 100gL-thiazolidine-4-carboxylic acid and adds in the 500mL acetone, then adds 96g yellow soda ash and stirs 0.5h;
Step 2 is dissolved in 166gL-pyroglutamyl chlorine in the 400mL acetone, then is added drop-wise to stirring reaction 2h in the resulting solution of step;
Step 3 is filtered, and filter cake is dissolved in the 500mL water, ice bath to 0 ~ 10 degree, and mentioned solution is acidified to PH=2 with concentrated hydrochloric acid, and the adularescent precipitation generates, and continues to stir 1 hour;
Step 4 is filtered, oven dry.Obtain the thick product of pidotimod;
Step 5, the thick product water of pidotimod recrystallization filters, and oven dry is weighed, and obtains the 163g pidotimod.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110235340 CN102234313B (en) | 2011-08-16 | 2011-08-16 | Method for synthesizing pidotimod |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110235340 CN102234313B (en) | 2011-08-16 | 2011-08-16 | Method for synthesizing pidotimod |
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| Publication Number | Publication Date |
|---|---|
| CN102234313A CN102234313A (en) | 2011-11-09 |
| CN102234313B true CN102234313B (en) | 2013-02-27 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 201110235340 Expired - Fee Related CN102234313B (en) | 2011-08-16 | 2011-08-16 | Method for synthesizing pidotimod |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103059099B (en) * | 2013-01-03 | 2013-11-27 | 福州乾正药业有限公司 | Novel pidotimod crystal form and preparation method thereof |
| CA2901338A1 (en) * | 2013-04-05 | 2014-10-09 | Polichem Sa | Use of pidotimod to treat inflammatory bowel disease |
| 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 |
| CN106749515B (en) * | 2016-11-28 | 2020-02-21 | 无锡福祈制药有限公司 | Method for synthesizing pidotimod |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2005022976A (en) * | 2001-07-18 | 2005-01-27 | Ajinomoto Co Inc | Carboxylic acid derivative |
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