CN106632592A - Preparation method of pidotimod - Google Patents
Preparation method of pidotimod Download PDFInfo
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- CN106632592A CN106632592A CN201611042310.5A CN201611042310A CN106632592A CN 106632592 A CN106632592 A CN 106632592A CN 201611042310 A CN201611042310 A CN 201611042310A CN 106632592 A CN106632592 A CN 106632592A
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- pidotimod
- acid
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- reaction
- alcohol
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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 37
- 229960001163 pidotimod Drugs 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 6
- 239000011230 binding agent Substances 0.000 claims abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 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 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical group CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- POZRVZJJTULAOH-LHZXLZLDSA-N danazol Chemical compound C1[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=CC2=C1C=NO2 POZRVZJJTULAOH-LHZXLZLDSA-N 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 8
- 229940043131 pyroglutamate Drugs 0.000 abstract 2
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 230000020477 pH reduction Effects 0.000 abstract 1
- 238000001953 recrystallisation Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 238000011084 recovery Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- VLSOAXRVHARBEQ-UHFFFAOYSA-N [4-fluoro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=C(F)C=C1CO VLSOAXRVHARBEQ-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 125000001984 thiazolidinyl group Chemical group 0.000 description 2
- 0 CC[C@@](CCCC(N1C(*)CSC1)O)N=C Chemical compound CC[C@@](CCCC(N1C(*)CSC1)O)N=C 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 208000031320 Teratogenesis Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Chemical group 0.000 description 1
- 229910052801 chlorine Chemical group 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- IWZKICVEHNUQTL-UHFFFAOYSA-M potassium hydrogen phthalate Chemical compound [K+].OC(=O)C1=CC=CC=C1C([O-])=O IWZKICVEHNUQTL-UHFFFAOYSA-M 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of pidotimod. L-pyroglutamic acid is acylated by an acylatign reagent, then, L-acyl chloride pyroglutamate is obtained; next, the obtained L-acyl chloride pyroglutamate and L-thiazolidinyl-4-carboxylic acid are esterified under the participating condition of an acid-binding agent to obtain pidotimod salts; pure products of pidotimod are obtained through filtering, water dissolution, acidification and recrystallization. The method has the advantages that the raw materials can be easily obtained; the reaction conditions are mild; the yield is high; the method is suitable for industrial production; meanwhile, the reaction raw materials are recovered and utilized, so that the influence on environment is reduced.
Description
Technical field
The present invention relates to a kind of medical synthesis field, and in particular to a kind of preparation side of Immunopromoter Pidotimod
Method.
Background technology
Pidotimod (pidotimod), entitled (R) -3- [(S)-(5- oxygen -2- pyrrolidinyls) the carbonyl]-thiazolidine of chemistry
Base -4- formic acid, trade name Puli not, be by Italian Poli chemical industrial companies research and develop immunomodulator, 1993
Italy's approval is listed and enters clinical, and the structural formula of Pidotimod is as follows：
Pidotimod is mainly used in preventing and treating children's recurrent respiratory infection, urinary system infection contamination, allergia nose
Scorching and asthma, treats and prevents acute attack, the infection of the upper respiratory tract slowly, it may also be used for various virus infection, malignant tumour and
Other chronic diseases cause body's immunity low.
With regard to the synthesis path of Pidotimod, mainly there is following several：
A kind of synthetic method is disclosed in patent CN102952172 as follows：
With L-cysteine hydrochloride and L-Glutimic acid as raw material, it is refining to obtain Jing cyclization, esterification, condensation and after hydrolyzing
Pidotimod, the method step is relatively complicated, and yield is relatively low, and only 38.8%.
The synthetic method reported in patent CN 103897025 is as follows：
The method is to adopt mixed anhydride method, and raw material is more expensive, and reaction temperature requires low temperature, relatively costly.
The synthetic method of Dan Shiming etc. (Chinese Medicine magazine, 2000,9 (11), 764-765) reports is as follows：
It is relatively low as the yield of Material synthesis target product with L-cysteine hydrochloride and L-Glutimic acid, only
26.9%, and using the reagent-pentachlorophenol with carcinogenicity and teratogenesis, toxicity is big.
The content of the invention
Present invention aims to problem present in existing technology, there is provided one kind is easy to get with raw material, technique
Simply, the synthetic method of low production cost and suitable industrialized Pidotimod.Reaction raw materials are recycled simultaneously from
And reduce the impact to environment.
In order to realize above-mentioned goal of the invention, technical scheme below is present invention employs：
A kind of preparation method of Pidotimod, it is comprised the following steps that：
A, chloride reagent is added drop-wise in L-Glutimic acid, heating response obtains L- pyroglutamyl chlorine；
B, the L- pyroglutamyl chlorine solvent dissolving for obtaining the synthesis of step a, then sequentially add acid binding agent, L- thiazolidines
Base -4- carboxylic acids, at a certain temperature reaction obtains the mixed solution containing Pidotimod salt；
C, the mixed solution Jing of step b is filtered into obtain Pidotimod salt, is used water dissolves, then add hydrochloric acid acidifying,
Then through being filtrated to get Pidotimod crude product again；
The mixed solvent of d, the Pidotimod crude product water that step c is obtained and alcohol is recrystallized under uniform temperature, is passed through
Filter, is dried, and fine work Pidotimod is obtained.
Chloride reagent used is phosphorus trichloride, oxalyl chloride or thionyl chloride in preferred steps a.In preferred steps a
L-Glutimic acid is 1 with chloride reagent mol ratio：(2～3.5)；It is preferred that the temperature of heating response is 50～80 DEG C；During reaction
Between 3～5h.
Acid binding agent is sodium acid carbonate, saleratus, pyridine or triethylamine in preferred steps b；It is preferred that L-Glutimic acid with tie up
Sour agent mol ratio is 1:(1.5～3).
The addition of L- thiazolidinyls -4- carboxylic acids is the L-Glutimic acid and L- in step b in step a in preferred steps b
The mol ratio of thiazolidinyl -4- carboxylic acids is 1:(1.5～2.5).
Reaction dissolvent in preferred steps b is dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, dichloroethanes or chlorine
It is imitative；Preferred solvent is using front through removing water process；Reaction temperature in preferred steps b is 40～60 DEG C；4～6h of reaction time.
The addition of hydrochloric acid is 1 for the L-Glutimic acid in step a and hydrochloric acid mol ratio in preferred steps c:(1.5～
2.5)。
Alcohol used is methyl alcohol, ethanol, isopropanol or n-butanol in preferred steps d；In the mixed solvent of water and alcohol water with
The volume ratio of alcohol is preferably 1：(4～7).
Temperature when recrystallizing in preferred steps d is 80～90 DEG C.
The route of reaction is as follows：
Beneficial effect：
The raw material that the inventive method is used is cheap and easy to get, and can recycle excessive chloride reagent, keeps away
The waste of raw material is exempted from, has reduced its pollution to environment, while the L- pyroglutamyl chlorine for preparing reduces cost；The method
Reaction condition is gentle, and easy to operate, the yield of product is higher, and industrial cost is low.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but therefore by this invention is not limited in described reality
Among applying a scope.
Embodiment one：
In the three neck round bottom flask of dry 250ml, L-Glutimic acid 20.0g (0.156mol) is added, then in room
Temperature is lower to instill phosphorus trichloride 27.2ml (0.312mol), and 30min completion of dropping stirs lower 60 DEG C of reactions 3h, after reaction terminates, will
Reactant liquor is transferred in eggplant-shape bottle 40 DEG C of revolvings lower in -0.095MPa pressure, and (rate of recovery is for recyclable unnecessary phosphorus trichloride
65.7%), while obtaining white solid；White solid is transferred completely into the three neck round bottom flask of 500ml, carbon is subsequently adding
Sour hydrogen sodium 19.7g (0.234mol), then 150ml dichloromethane thereto, stirring makes solids all dissolve, and then stirs lower adding
Then plus 200ml water L- thiazolidinyls -4- carboxylic acid 31.2g (0.234mol) will be entered, 40 DEG C of reaction 4h after reaction terminates, are filtered,
Its dissolving, then concentrated hydrochloric acid 19.6ml (0.234mol) that mass fraction is 37% is added thereto to, it is stirred overnight under room temperature, mistake
Filter, drying obtains Pidotimod crude product；Then with mixed solvent, (water is 1 with the volume ratio of methyl alcohol:4) Pidotimod crude product is existed
Recrystallize at 80 DEG C, obtain fine work Pidotimod 30.5g, total recovery is 80.0%, fusing point is 192～194 DEG C.
1H NMR (400MHz, DMSO-d6)δ：13.2 (s, 1H), 8.6 (s, 1H), 5.1～5.9 (m, 4H), 3.7～4.2
(m, 2H), 2.1～2.4 (m, 4H).
Embodiment two：
In the three neck round bottom flask of dry 250ml, L-Glutimic acid 20.0g (0.156mol) is added, then in room
Temperature is lower to instill oxalyl chloride 33.0ml (0.390mol), and 30min completion of dropping stirs lower 70 DEG C of reactions 4h, after reaction terminates, will be anti-
Liquid is answered to be transferred in eggplant-shape bottle 40 DEG C of revolvings lower in -0.095MPa pressure, (rate of recovery is for recyclable unnecessary oxalyl chloride
70.3%), while obtaining white solid；White solid is transferred completely into the three neck round bottom flask of 500ml, pyrrole is subsequently adding
Pyridine 25.1ml (0.312mol), then 150ml ethyl acetate thereto, stirring makes solids all dissolve, and then stirs lower addition
L- thiazolidinyls -4- carboxylic acid 41.5g (0.312mol), 50 DEG C of reaction 5h, after reaction terminates, filters, and then adds 200ml that its is molten
Solution, then concentrated hydrochloric acid 26.1ml (0.312mol) that mass fraction is 37% is added thereto to, it is stirred overnight under room temperature, filter, dry
It is dry to obtain Pidotimod crude product；Then with mixed solvent, (water is 1 with the volume ratio of isopropanol:5) to Pidotimod crude product 85
Recrystallize at DEG C, obtain fine work Pidotimod 31.2g, total recovery is 81.9%, fusing point is 192～194 DEG C.
1H NMR (400MHz, DMSO-d6)δ：13.2 (s, 1H), 8.6 (s, 1H), 5.1～5.9 (m, 4H), 3.7～4.2
(m, 2H), 2.1～2.4 (m, 4H).
Embodiment three：
In the three neck round bottom flask of dry 250ml, L-Glutimic acid 20.0g (0.156mol) is added, then in room
Temperature is lower to instill thionyl chloride 34.0ml (0.468mol), and 30min completion of dropping stirs lower 70 DEG C of reactions 5h, after reaction terminates, will
Reactant liquor is transferred in eggplant-shape bottle 40 DEG C of revolvings lower in -0.095MPa pressure, and (rate of recovery is for recyclable unnecessary thionyl chloride
68.4%), while obtaining white solid；White solid is transferred completely into the three neck round bottom flask of 500ml, three are subsequently adding
Ethamine 43.2ml (0.312mol), then 150ml acetonitriles thereto, stirring makes solids all dissolve, and L- is added under then stirring
Thiazolidinyl -4- carboxylic acid 41.5g (0.312mol), 50 DEG C of reaction 4h, after reaction terminates, filters, and then adds 200ml water that its is molten
Solution, then concentrated hydrochloric acid 26.1ml (0.312mol) that mass fraction is 37% is added thereto to, it is stirred overnight under room temperature, filter, dry
It is dry to obtain Pidotimod crude product；Then with mixed solvent, (water is 1 with the volume ratio of isopropanol:6) to Pidotimod crude product 85
Recrystallize at DEG C, obtain fine work Pidotimod 32.6g, total recovery is 85.5%, fusing point is 192～194 DEG C.
1H NMR (400MHz, DMSO-d6)δ：13.2 (s, 1H), 8.6 (s, 1H), 5.1～5.9 (m, 4H), 3.7～4.2
(m, 2H), 2.1～2.4 (m, 4H).
Example IV：
In the three neck round bottom flask of dry 250ml, L-Glutimic acid 20.0g (0.156mol) is added, then in room
Temperature is lower to instill thionyl chloride 39.7ml (0.546mol), and 30min completion of dropping stirs lower 80 DEG C of reactions 5h, after reaction terminates, will
Reactant liquor is transferred in eggplant-shape bottle 40 DEG C of revolvings lower in -0.095MPa pressure, and (rate of recovery is for recyclable unnecessary thionyl chloride
71.6%), while obtaining white solid；White solid is transferred completely into the three neck round bottom flask of 500ml, carbon is subsequently adding
Potassium hydrogen phthalate 46.9g (0.468mol), then 150ml tetrahydrofurans thereto, stirring makes solids all dissolve, and then stirs lower adding
Then plus 200ml water L- thiazolidinyls -4- carboxylic acid 51.9g (0.390mol) will be entered, 60 DEG C of reaction 6h after reaction terminates, are filtered,
Its dissolving, then concentrated hydrochloric acid 32.6ml (0.390mol) that mass fraction is 37% is added thereto to, it is stirred overnight under room temperature, mistake
Filter, drying obtains Pidotimod crude product；Then with mixed solvent, (water is 1 with the volume ratio of n-butanol:7) to Pidotimod crude product
Recrystallize at 90 DEG C, obtain fine work Pidotimod 31.7g, total recovery is 83.2%, fusing point is 192～194 DEG C.
1H NMR (400MHz, DMSO-d6)δ：13.2 (s, 1H), 8.6 (s, 1H), 5.1～5.9 (m, 4H), 3.7～4.2
(m, 2H), 2.1～2.4 (m, 4H).
Claims (9)
1. a kind of preparation method of Pidotimod, it is comprised the following steps that：
A, chloride reagent is added drop-wise in L-Glutimic acid, heating response obtains L- pyroglutamyl chlorine；
B, by step a synthesis obtain L- pyroglutamyl chlorine solvent dissolving, then sequentially add acid binding agent, L- thiazolidinyls-
4- carboxylic acids, at a certain temperature reaction obtains the mixed solution containing Pidotimod salt；
C, the mixed solution Jing of step b is filtered into obtain Pidotimod salt, used water dissolves, then add hydrochloric acid acidifying, then
Through being filtrated to get Pidotimod crude product again；
The mixed solvent of d, the Pidotimod crude product water that step c is obtained and alcohol is recrystallized under uniform temperature, and Jing is filtered, and is done
It is dry, fine work Pidotimod is obtained.
2. preparation method according to claim 1, it is characterised in that chloride reagent used is tri-chlorination in step a
Phosphorus, oxalyl chloride or thionyl chloride.
3. preparation method according to claim 1, it is characterised in that L-Glutimic acid and chloride reagent mole in step a
Than for 1：(2～3.5)；Heating response temperature is 50～80 DEG C；3～5h of reaction time.
4. preparation method according to claim 1, it is characterised in that in step b acid binding agent be sodium acid carbonate, saleratus,
Pyridine or triethylamine；L-Glutimic acid is 1 with acid binding agent mol ratio:(1.5～3).
5. preparation method according to claim 1, it is characterised in that the amount of L- thiazolidinyls -4- carboxylic acids is step in step b
L-Glutimic acid in rapid a is 1 with the mol ratio of L- thiazolidinyl -4- carboxylic acids:(1.5～2.5).
6. preparation method according to claim 1, it is characterised in that the reaction dissolvent in step b is dichloromethane, acetic acid
Ethyl ester, acetonitrile, tetrahydrofuran, dichloroethanes or chloroform；Reaction temperature in step b is 40～60 DEG C；4～6h of reaction time.
7. preparation method according to claim 1, it is characterised in that in step c the addition of hydrochloric acid be L-Glutimic acid with
Hydrochloric acid mol ratio is 1:(1.5～2.5).
8. preparation method according to claim 1, it is characterised in that alcohol used is methyl alcohol, ethanol, isopropanol in step d
Or n-butanol；Water is 1 with the volume ratio of alcohol with water in the mixed solvent of alcohol：(4～7).
9. preparation method according to claim 1, it is characterised in that temperature when recrystallizing in step d is 80～90 DEG C.
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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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| CN102234313A (en) * | 2011-08-16 | 2011-11-09 | 青岛康地恩药业股份有限公司 | Method for synthesizing pidotimod |
| CN102952172A (en) * | 2011-08-18 | 2013-03-06 | 北京澳林森科技有限公司 | Pidotimod preparation method |
| CN103897025A (en) * | 2012-12-27 | 2014-07-02 | 山东新时代药业有限公司 | Preparation method of pidotimod |
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