CN108088936A - Prepare impurity and its quality determining method obtained by Pidotimod ethyl ester - Google Patents
Prepare impurity and its quality determining method obtained by Pidotimod ethyl ester Download PDFInfo
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- CN108088936A CN108088936A CN201711291284.4A CN201711291284A CN108088936A CN 108088936 A CN108088936 A CN 108088936A CN 201711291284 A CN201711291284 A CN 201711291284A CN 108088936 A CN108088936 A CN 108088936A
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- pidotimod
- ethyl ester
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
Abstract
The present invention relates to a kind of quality determining methods for preparing Pidotimod ethyl ester, a kind of quality determining method for preparing Pidotimod ethyl ester, it is reactant with L Thioprolines carbethoxy hydrochloride and L pyroglutamic acids, the reaction product that the ethyl ester containing Pidotimod is made in free, condensation reaction is passed sequentially through, peak area of the peak area no more than 6.5% and contained compound B that the reaction product measures contained compound A by high performance liquid chromatography is not more than 2.0%；Compound A has the structure as shown in formula V, and compound B has the structure as shown in formula VI.The quality determining method for preparing Pidotimod ethyl ester of the present invention is conducive to control drug quality in production process.
Description
Technical field
Present invention offer is a kind of to be prepared the impurity generated during Pidotimod ethyl ester and is applied to quality using this impurity
The method of analysis, belongs to chemosynthesis technical field.
Background technology
Pidotimod (Pidotimod) is the 1980s by Italian Poli industria chimca S.P.A
Company researches and develops, and was approved listing in 1993 for clinic, is a kind of artificial synthesized immunopotentiating agent, structure is similar to two
Peptide, chemical name are (R) -3- (S)-[(5- oxo -2- pyrrolidinyls) carbonyl]-tetrahydrochysene -4- carboxylic acids.It has quick point
The advantages that cloth, excretion, do not accumulate in vivo, better tolerance can promote nonspecific immune reaction and promote specificity
Immune response.At present, it is mainly used in all multiple country's listings such as Asia, Europe, America by body's immunity
Promote to play significant treatment bacterium (pneumococcus, Escherichia coli, Pseudomonas aeruginosa, proteus etc.) and virus (influenza virus,
Herpes simplex virus, myocarditis virus and mengo virus etc.) infection treatment；With antimicrobial share for cellular immunity concentration by
Inhibit the treatment of respiratory tract infection, Respiratory infections, the urinary system infection contamination of recurrent exerbation etc..Its structural formula is as follows：
The process for synthesizing Pidotimod generally use is with L- Thioprolines carbethoxy hydrochloride and L-Glutimic acid
For starting material, Pidotimod ethyl ester is condensed to yield through DCC, finally hydrolyzes to obtain Pidotimod.This method synthetic route is short, reaction
Rationally, easy to operate, low energy consumption, and reaction dissolvent is easily recycled, and agents useful for same is of low cost, and yield is 60% to 64%, is applicable in
In industrialized production.When synthesizing Pidotimod by above-mentioned process, some impurity are inevitably generated.
Any substance for influencing pharmaceutical purity is referred to as impurity.Miscellaneous Quality Research is an important content of drug research and development,
It includes selecting suitable analysis method, differentiates exactly and the content of measure impurity and comprehensive pharmacy, toxicity and clinical research
Result determine the reasonable limit of impurity.This research is through the whole process of drug research and development, and the impurity of drug is by its physics and chemistry
Property is generally divided into three classes：Organic impurities, inorganic impurity and residual solvent.According to its source, impurity can be divided into process contaminants
(including the complete reactant of unreacted in synthesis and reagent, intermediate, by-product etc.), catabolite, from reactant and reagent
In mixed impurity etc..According to its toxicity category, impurity can be divided into toxic impurities and common impurities etc. again.Impurity can also be according to
Its classification of chemical structure, such as steroidal, alkaloid, geometric isomer, optical isomer and polymer.Organic impurities includes technique
The impurity of middle introducing and degradation impurity etc., it may be possible to known impurities or unknown, volatile or non-volatile.Due to this
The chemical constitution of class impurity is generally similar with active ingredient or has original relationship, therefore related substance can be referred to as by usually having.
The content of the invention
The technical problem to be solved by the present invention is to provide and a kind of be conducive to drug quality is controlled in production process
It prepares impurity obtained by Pidotimod ethyl ester and prepares the quality determining method of Pidotimod ethyl ester.
A kind of technical solution for iing is proposed to solve above-mentioned technical problem of the present invention is：A kind of matter for preparing Pidotimod ethyl ester
Quantity measuring method is reactant with L- Thioprolines carbethoxy hydrochloride and L-Glutimic acid, passes sequentially through free, condensation reaction
The reaction product of the ethyl ester containing Pidotimod is made, the reaction product measures contained compound A's by high performance liquid chromatography
Peak area of the peak area no more than 6.5% and contained compound B is not more than 2.0%；
The compound A has the structure as shown in formula V：
The compound B has the structure as shown in formula VI：
L- Thioprolines carbethoxy hydrochloride as shown in formula I and the L-Glutimic acid as shown in formula II, in dichloromethane
In, sodium hydroxide solution is added dropwise and carries out free reaction, adds the amide condensed reaction generation of condensing agent progress and contains as shown in formula III
Pidotimod ethyl ester reaction product, reaction equation is as follows：
Above-mentioned condensing agent is dicyclohexylcarbodiimide, N, N '-diisopropylcarbodiimide or 1- (3- dimethylaminos third
Base) -3- ethyl-carbodiimide hydrochlorides.
For the stationary phase of above-mentioned high performance liquid chromatography using octadecylsilane chemically bonded silica as filler, mobile phase is phosphoric acid
Sodium dihydrogen phosphoric acid solution and methanol, Detection wavelength 210nm, column temperature are 30 DEG C, are calculated by area normalization.
The pH value of above-mentioned sodium dihydrogen phosphate phosphoric acid solution and methanol is 2.5~3.5, and the volume ratio of wherein methanol and phosphoric acid is
98:2~45:55.
The pH value of above-mentioned sodium dihydrogen phosphate phosphoric acid solution and methanol is 3.0, and wherein the volume ratio of methanol and phosphoric acid is 70:
30。
A kind of technical solution for iing is proposed to solve above-mentioned technical problem of the present invention is：It is a kind of to prepare obtained by Pidotimod ethyl ester
Impurity, including compound A and compound B；
The compound A has the structure as shown in formula V：
The compound B has the structure as shown in formula VI：
A kind of technical solution for iing is proposed to solve above-mentioned technical problem of the present invention is：It is a kind of above-mentioned to prepare Pidotimod second
Impurity obtained by ester is used to prepare the application of the quality testing of Pidotimod ethyl ester as impurity reference substance.
The present invention has positive effect：The quality determining method for the preparing Pidotimod ethyl ester selection reaction life of the present invention
Into new compound A and compound B joints as impurity reference substance, be used to prepare the quality analysis of Pidotimod ethyl ester, can
Better reference is provided with the selection for process conditions, is conducive in process of production control drug quality.The present invention
It separated, detected using high performance liquid chromatography, select mobile phase suitable, as a result precise and high efficiency.
Specific embodiment
The present invention is specifically described below by embodiment, it is necessary to which indicated herein is that following embodiment is only used
It is further described in the present invention, it is impossible to be interpreted as limiting the scope of the invention, person skilled in art can
Some nonessential modifications and adaptations are made to the present invention according to the invention described above content.Unless otherwise defined, made in text
All professional and scientific terms have the same meanings as commonly understood by one of ordinary skill in the art.
Embodiment 1
The quality determining method for preparing Pidotimod ethyl ester of the present embodiment, by L- Thioproline carbethoxy hydrochlorides
(500g, 2.53mol) and dichloromethane 1500g are added in 3L reaction bulbs, are cooled to 0~5 DEG C, dropwise addition concentration is 20% hydroxide
Sodium solution (531.16g, 2.66mol), when dropwise addition, remain interior 0~10 DEG C of temperature, are added dropwise, and pH value is 8~9, continues to stir
5min is mixed, split-phase washs organic phase with 500g saturated sodium-chlorides, then into organic phase 500g anhydrous sodium sulfates added to dry 1~2h
Afterwards, filter, wash filter cake with 500g dichloromethane, filtrate is poured into another 5L reaction bulb, add in L-Glutimic acid
(326.56g, 2.53mol) stirs 30min, is cooled to 0~5 DEG C, be added dropwise dicyclohexylcarbodiimide (521.88g,
2.53mol) and the mixed solution of dichloromethane 1000g, 0~10 DEG C of temperature is kept during being added dropwise, risen again after dripping off to 15~
25 DEG C of 0.5~1h of stirring, filtering with 500g eluent methylene chloride filter cakes, obtain the dichloromethane solution of the ethyl ester containing Pidotimod,
This dichloromethane solution is concentrated, for use.Reaction equation is as follows：
It is compound A and compound B containing main two impurity in the Pidotimod ethyl ester solution of concentration.Mass Spectrometer Method
As a result it is：Compound A：[M+H]+241.32 compound B：[M+H]+478.36。
The structure of compound A is as follows：
The structure of compound B is as follows：
Grease is detected using high performance liquid chromatography, testing conditions are bonded for stationary phase with octadecylsilane
Silica gel is filler, the volume ratio that mobile phase is sodium dihydrogen phosphate phosphoric acid solution and methanol pH value is 3.0, wherein methanol and phosphoric acid
For 70:30, Detection wavelength 210nm, column temperature are 30 DEG C, and number of theoretical plate is calculated by Pidotimod should be not less than 2000, compound A
Peak area for 4.3272%, the peak area of compound B is 0.8136%, is met the requirements.
By the dichloromethane solution of the ethyl ester containing Pidotimod, 0~5 DEG C is cooled to, the sodium hydroxide that concentration is 7.5% is added dropwise
Solution (1281.53g, 2.41mol), when dropwise addition, remain interior 0~5 DEG C of temperature, are added dropwise, and pH value is 9~10, temperature in holding
Continue to stir 1h, split-phase, then with dichloromethane aqueous phase extracted, combined dichloromethane phase concentrates this dichloromethane phase, you can be made
Grease containing Pidotimod.
Pidotimod ethyl ester as shown in formula III in methylene chloride, alkali (sodium acid carbonate, sodium carbonate, potassium carbonate, hydrogen is added dropwise
Sodium oxide molybdena or potassium hydroxide) reaction product of the obtained Pidotimod containing as shown in formula IV of reaction is hydrolyzed, reaction equation is as follows：
Embodiment 2
The quality determining method for preparing Pidotimod ethyl ester of the present embodiment, rest part is same as Example 1, difference
Be in：Dicyclohexylcarbodiimide uses the N of equimolar amounts, and N '-diisopropylcarbodiimide replaces, sodium dihydrogen phosphate phosphoric acid
The pH value of solution and methanol is 2.5, and wherein the volume ratio of methanol and phosphoric acid is 60:40.Reaction product uses high performance liquid chromatography
Method is detected, and the peak area of compound A is 5.1123%, and the peak area of compound B is 1.8637%, is met the requirements.
Embodiment 3
The quality determining method for preparing Pidotimod ethyl ester of the present embodiment, rest part is same as Example 1, difference
Be in：Dicyclohexylcarbodiimide uses 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides of equimolar amounts
Instead of the pH value of sodium dihydrogen phosphate phosphoric acid solution and methanol is 3.5, and wherein the volume ratio of methanol and phosphoric acid is 80:20.Reaction production
Object is detected using high performance liquid chromatography, and the peak area of compound A is 5.9822%, and the peak area of compound B is
1.5061%, it meets the requirements.
Agents useful for same is bought-in article unless otherwise specified in the present invention, and concentration is that chemistry is pure.
Obviously, the above embodiment is merely an example for clearly illustrating the present invention, and is not to the present invention
The restriction of embodiment.For those of ordinary skill in the art, it can also be made on the basis of the above description
Its various forms of variation or variation.There is no necessity and possibility to exhaust all the enbodiments.And these belong to this hair
The obvious changes or variations that bright spirit is extended out is still in the protection scope of this invention.
Claims (8)
1. a kind of quality determining method for preparing Pidotimod ethyl ester, it is characterised in that：With L- Thioproline carbethoxy hydrochlorides
It is reactant with L-Glutimic acid, passes sequentially through the reaction product that the ethyl ester containing Pidotimod is made in free, condensation reaction, feature
It is：The peak area that the reaction product measures contained compound A by high performance liquid chromatography is not more than 6.5% and containedization
The peak area for closing object B is not more than 2.0%；
The compound A has the structure as shown in formula V：
The compound B has the structure as shown in formula VI：
2. the quality determining method according to claim 1 for preparing Pidotimod ethyl ester, it is characterised in that：As shown in formula I
L- Thioprolines carbethoxy hydrochloride and the L-Glutimic acid as shown in formula II, in methylene chloride, be added dropwise sodium hydroxide it is molten
Liquid carries out free reaction, adds condensing agent and carries out amide condensed reaction generation containing the anti-of the Pidotimod ethyl ester as shown in formula III
Product is answered, reaction equation is as follows：
3. the quality determining method according to claim 2 for preparing Pidotimod ethyl ester, it is characterised in that：The condensing agent
It is dicyclohexylcarbodiimide, N, N '-diisopropylcarbodiimide or 1- (3- dimethylamino-propyls) -3- ethyl carbodiimide salt
Hydrochlorate.
4. the quality determining method according to claim 1 for preparing Pidotimod ethyl ester, it is characterised in that：The efficient liquid
For the stationary phase of phase chromatography using octadecylsilane chemically bonded silica as filler, mobile phase is sodium dihydrogen phosphate phosphoric acid solution and first
Alcohol, Detection wavelength 210nm, column temperature are 30 DEG C, are calculated by area normalization.
5. the quality determining method according to claim 4 for preparing Pidotimod ethyl ester, it is characterised in that：The di(2-ethylhexyl)phosphate
The pH value of hydrogen sodium phosphoric acid solution and methanol is 2.5~3.5, and wherein the volume ratio of methanol and phosphoric acid is 98:2~45:55.
6. the quality determining method according to claim 5 for preparing Pidotimod ethyl ester, it is characterised in that：The di(2-ethylhexyl)phosphate
The pH value of hydrogen sodium phosphoric acid solution and methanol is 3.0, and wherein the volume ratio of methanol and phosphoric acid is 70:30.
7. a kind of impurity prepared obtained by Pidotimod ethyl ester, it is characterised in that：Including compound A and compound B；The chemical combination
Object A has the structure as shown in formula V：
The compound B has the structure as shown in formula VI：
8. a kind of impurity prepared obtained by Pidotimod ethyl ester as claimed in claim 7 is used to prepare as impurity reference substance
The mostly not application of the quality testing of moral ethyl ester.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111233854A (en) * | 2019-12-30 | 2020-06-05 | 常州寅盛药业有限公司 | Preparation method of pidotimod impurity |
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| CN1158620A (en) * | 1994-09-27 | 1997-09-03 | 波利工业化学公司 | Process for the quantitative synthesis of 3-(L-pyrolutamyl)-L-tiazolidine-4-carboxylic acid and derivatives thereof |
| CN102167727A (en) * | 2011-01-29 | 2011-08-31 | 浙江金立源药业有限公司 | Synthesis method of pidotimod |
| CN102952172A (en) * | 2011-08-18 | 2013-03-06 | 北京澳林森科技有限公司 | Pidotimod preparation method |
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Patent Citations (3)
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|---|---|---|---|---|
| CN1158620A (en) * | 1994-09-27 | 1997-09-03 | 波利工业化学公司 | Process for the quantitative synthesis of 3-(L-pyrolutamyl)-L-tiazolidine-4-carboxylic acid and derivatives thereof |
| CN102167727A (en) * | 2011-01-29 | 2011-08-31 | 浙江金立源药业有限公司 | Synthesis method of pidotimod |
| CN102952172A (en) * | 2011-08-18 | 2013-03-06 | 北京澳林森科技有限公司 | Pidotimod preparation method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111233854A (en) * | 2019-12-30 | 2020-06-05 | 常州寅盛药业有限公司 | Preparation method of pidotimod impurity |
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