CN109701030A - The preparation method of Pegylation small-molecule drug - Google Patents
The preparation method of Pegylation small-molecule drug Download PDFInfo
- Publication number
- CN109701030A CN109701030A CN201711016142.7A CN201711016142A CN109701030A CN 109701030 A CN109701030 A CN 109701030A CN 201711016142 A CN201711016142 A CN 201711016142A CN 109701030 A CN109701030 A CN 109701030A
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- China
- Prior art keywords
- lovastatin
- modifier
- polyethylene glycol
- carbowax modifier
- preparation
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Abstract
The invention discloses a kind of preparation methods of Pegylation small-molecule drug, and in particular to the preparation method of the carbowax modifier of Lovastatin.Polyethylene glycol progress oxidation reaction is obtained polyethylene glycol monocarboxylic acid by the first step；Polyethylene glycol monocarboxylic acid and Lovastatin are carried out condensation reaction and obtain target product, i.e., polyethyleneglycol modified Lovastatin compound by second step.Contain degradable ester bond in the carbowax modifier of Lovastatin, can reach slow release effect；With amphipathic, the water solubility of Lovastatin is improved, is conducive to absorption of human body, mitigates the stimulation of Lovastatin.
Description
Technical field
A kind of preparation method of Pegylation small-molecule drug, is related specifically to the preparation of Lovastatin Pegylation
Method belongs to pharmaceutical chemistry synthetic technology.
Technical background
Lovastatin be a kind of novel regulating plasma lipid medicine-HMG-CoA (beta-hydroxy, Beta-methyl-glutaryl coacetylase) also
Reductase inhibitor.It can be substantially reduced the concentration of serum total cholesterol, be hydrolyzed into corresponding beta-hydroxy acid, 3- hydroxyl-after oral
3- methyl glutaryl coenzyme A reductase, and inhibit cholesterol biosynthesis.It is clinically used for heterozygous familial hypercholesterolemia, tight
Weight and light-duty primary hypercholesterolemia, can also make dietetic treatment ancillary drug, reduce excessively high cholesterol and low-density egg
White cholesterol levels.
But since the half-life period of Lovastatin is shorter, to maintain certain blood concentration, palpus frequent drug administration can be led in this way
Cause apparent peak valley effect.In order to overcome this disadvantage, it is a kind of common approach that sustained release agent, which is made, in Lovastatin.
Molecular weight is nontoxic greater than 400 polyethylene glycol (PEG), without teratogenesis, non-immunogenicity, cheap and easy to get, has non-
Its excellent performance when single coupling drug molecule, can be assigned the drug after modification, changed by often good water solubility and biocompatibility
Become its biological distribution behavior and dissolubility in aqueous solution.PEG generates physical barrier around the drug of its modification, reduces medicine
The enzymatic hydrolysis of object avoids eliminating quickly in renal metabolism, extends drug half-life, and drug is enable to be identified by immunocyte, has
Conducive to performance drug effect.This field of macromolecular modified medicaments is the research hotspot come this year.It, can after Lovastatin is modified with PEG
To extend its half-life period, increase dissolubility, be conducive to absorption of human body.
Summary of the invention
The invention discloses a kind of preparation method of the carbowax modifier of Lovastatin, this method simple process, at
This is cheap, and yield is up to 75%~84%.
In order to achieve the above object, the carbowax modifier of the Lovastatin prepared by the present invention having following structure,
Its structural formula is as follows:
N represents 100~1000 integer.
The carbowax modifier of Lovastatin of the invention is soluble easily in water at room temperature.It is dissolved in methylene chloride, chloroform,
Tetrahydrofuran, acetone, ethyl alcohol, the majority organic solvent such as n,N-Dimethylformamide do not dissolve in ether, and petroleum ether is solid for white
Body powder.
The carbowax modifier of Lovastatin of the invention is completed using two steps: being first oxidized to poly- second two with polyethylene glycol
Alcohol monocarboxylic acid；Then polyethylene glycol monocarboxylic acid obtained and Lovastatin are subjected to condensation reaction and target product, i.e., poly- second is made
The Lovastatin compound (compound 1 in such as following formula) of glycol modification.Synthetic route is as follows:
It is found by searching document data, currently without the relevant report with polyethyleneglycol modified Lovastatin, the present invention
With specific novelty.
The present invention is further described by the following embodiment, these descriptions are not to make to the content of present invention into one
The restriction of step.It should be understood by those skilled in the art that changing to equivalent replacement made by technical characteristic of the invention, or accordingly
Into still falling within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
The preparation of first step polyethylene glycol monocarboxylic acid
It using 20g polyethylene glycol as raw material, is added in 200ml methylene chloride, ice-water bath is cooled to 3~5 DEG C, and Jones is added dropwise
Reagent is added dropwise, and continues stirring 2 hours, and then plus water, stirring 5min, stratification discard water layer, and organic layer is concentrated,
Condensate residue is poured into ether, and white solid, filtering, dry 16.2g polyethylene glycol monocarboxylic acid is precipitated.Polyethyleneglycol
The structural formula of carboxylic acid is
In formula, n=100.
The preparation of the carbowax modifier of second step Lovastatin
16.2g polyethylene glycol monocarboxylic acid and 4.3g Lovastatin are added in methanol, 0.1g p-methyl benzenesulfonic acid is added,
12h is stirred at room temperature, concentration removes methanol, adds water and methylene chloride, stirs 10min, stands, discards water layer, organic phase is dense
Contracting, residue is poured into petroleum ether, and white solid is precipitated, and is filtered, and vacuum drying obtains the poly- second of 11.8g Lovastatin
Glycol modifier.The structural formula of the compound is
Claims (5)
1. a kind of carbowax modifier of Lovastatin, which is characterized in that the modifier has following structure,
N represents 100~1000 integer.
2. the carbowax modifier of Lovastatin according to claim 1, synthetic method are characterized in that, suitable
Organic solvent in, in the presence of a catalyst, carries out condensation reaction with polyethylene glycol monocarboxylic acid and Lovastatin, obtains target and produce
Object, i.e., polyethyleneglycol modified Lovastatin compound.
3. the synthetic method of the carbowax modifier of Lovastatin according to claim 2, which is characterized in that solvent choosing
From the mixture of one or more of tetrahydrofuran, dioxane, toluene, methanol, ethyl alcohol, isopropanol；Catalyst is selected from chlorine
Change the mixture of one or more of hydrogen, sulfuric acid, p-methyl benzenesulfonic acid, trifluoroacetic acid, 4-dimethylaminopyridine.
4. the synthetic method of the carbowax modifier of Lovastatin according to claim 2, which is characterized in that condensation is anti-
The time answered is 2~16 hours；Reaction temperature is room temperature~solvent reflux temperature.
5. the synthetic method of the carbowax modifier of Lovastatin according to claim 2, which is characterized in that poly- second two
The ratio between mole of alcohol monocarboxylic acid and Lovastatin is 1.1:1~1.5:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711016142.7A CN109701030A (en) | 2017-10-26 | 2017-10-26 | The preparation method of Pegylation small-molecule drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711016142.7A CN109701030A (en) | 2017-10-26 | 2017-10-26 | The preparation method of Pegylation small-molecule drug |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109701030A true CN109701030A (en) | 2019-05-03 |
Family
ID=66252240
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711016142.7A Pending CN109701030A (en) | 2017-10-26 | 2017-10-26 | The preparation method of Pegylation small-molecule drug |
Country Status (1)
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| CN (1) | CN109701030A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1618837A (en) * | 2003-11-17 | 2005-05-25 | 中国科学院过程工程研究所 | Preparation method of polyethylene carboxylic acid and its use |
| CN1676525A (en) * | 2004-03-29 | 2005-10-05 | 北京键凯科技有限公司 | Hydrophilic polymer-thunder good vine extract binding substance and its medicinal composition |
| CN105051057A (en) * | 2012-11-15 | 2015-11-11 | 阿佩利斯制药公司 | Cell-reactive, long-acting, or targeted compstatin analogs and related compositions and methods |
-
2017
- 2017-10-26 CN CN201711016142.7A patent/CN109701030A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1618837A (en) * | 2003-11-17 | 2005-05-25 | 中国科学院过程工程研究所 | Preparation method of polyethylene carboxylic acid and its use |
| CN1676525A (en) * | 2004-03-29 | 2005-10-05 | 北京键凯科技有限公司 | Hydrophilic polymer-thunder good vine extract binding substance and its medicinal composition |
| CN105051057A (en) * | 2012-11-15 | 2015-11-11 | 阿佩利斯制药公司 | Cell-reactive, long-acting, or targeted compstatin analogs and related compositions and methods |
Non-Patent Citations (1)
| Title |
|---|
| 路娟 等: "药物的聚乙二醇修饰研究进展", 《有机化学》 * |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
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| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190503 |