CN102199122A - Homopiperazine derivative and preparation method thereof - Google Patents
Homopiperazine derivative and preparation method thereof Download PDFInfo
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- CN102199122A CN102199122A CN2010101297322A CN201010129732A CN102199122A CN 102199122 A CN102199122 A CN 102199122A CN 2010101297322 A CN2010101297322 A CN 2010101297322A CN 201010129732 A CN201010129732 A CN 201010129732A CN 102199122 A CN102199122 A CN 102199122A
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- compound
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- fasudil hydrochloride
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- salt
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- WHIDHHUCCTYJKA-UHFFFAOYSA-N O=S(c1cccc2cnccc12)(Cl)=O Chemical compound O=S(c1cccc2cnccc12)(Cl)=O WHIDHHUCCTYJKA-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a homopiperazine derivative, in particular to N,N-di(5-isoquinolinesulfonyl)homopiperazine, and a preparation method and application thereof. The invention provides a structural identification and synthesis method for an impurity in fasudil hydrochloride or injection thereof, and application of the prepared impurity contrast in quality control of the fasudil hydrochloride or the injection thereof. The invention also provides a new hepatitis B virus (HBV) resistant compound.
Description
Technical field
The invention relates to high bridged piperazine derivatives, more particularly, the invention relates to N, the high piperazine of N-two isoquinolinesulfonylcompounds, and preparation method thereof and uses thereof.
Background technology
N, the high piperazine structure of N-two (5-isoquinolinesulfonylcompounds) is as follows:
This compound is not seen bibliographical information, and we find that through screening it has the effect of resisting HBV virus.
Summary of the invention
We find to contain an impurity in the commercially available injection liquid in carrying out commercially available fasudil hydrochloride injection quality examination process, and are definite through scrutinizing, and being surprised to find this impurity is compound shown in the formula (I).
We have carried out pharmacological research to formula (I) compound, find that this product has the effect of resisting HBV virus, and experiment in vitro shows that this product can significantly be killed HBV virus.
The synthetic of this product can adopt 5-isoquinoline 99.9 SULPHURYL CHLORIDE and the reaction of high piperazine to get final product.Reaction can be carried out in solvent or under the condition of no solvent.If without solvent, only need directly the isoquinoline 99.9 SULPHURYL CHLORIDE to be mixed with high piperazine, can react, carry out separation and purification after the reaction and get final product.If carry out in solvent, solvent can be haloalkane such as methylene dichloride, trichloromethane, 1,1-ethylene dichloride, 1,2-ethylene dichloride etc.; Also can be protic solvent such as alcohols, methyl alcohol, ethanol, Virahol, propyl carbinol, n-propyl alcohol etc.; Also can be non-protic polar solvent such as DMF or DMSO or acetone etc.
After finishing with Liquid Detection reaction, extract, be spin-dried for, promptly get the product crude product, promptly get highly purified product through making with extra care again.
Process for purification is determined according to crude product purity and impurity situation, can use simple recrystallization, also can column chromatography, or adopt the preparation of preparation liquid phase separation.Generally just passable with recrystallization, recrystallization solvent can be used methyl alcohol, ethanol, Virahol etc.With cross pillar or liquid phase separation product also can, moving phase is methanol-water or degree or gradient elutions such as acetonitrile water or methanol acetonitrile water, accepts product flow part, evaporate to dryness or lyophilize promptly get product then.Product can purity as required be determined process for purification, generally will be as standard substance or reference substance, purity generally needs liquid phase peak area normalizing to draw method more than at least 90%, preferred reaching more than 98%, most preferably reach more than 99%, such purity just can be used for quality approach.We studies show that, adopt method of the present invention, can accomplish the purity more than 99%, can be used for fully using as the standard substance or the reference substance of impurity in the quality control.
We studies show that, impurity HPLC peak position in the fasudil hydrochloride injection is in full accord with our synthetic compound (I) liquid phase retention time, liquid matter molecular weight is also identical, therefore illustrate that our synthetic compound promptly is the impurity in the fasudil hydrochloride injection, determine that through LC-MS both molecular weight are in full accord.
Embodiment
The invention will be further described below by embodiment.It should be understood that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, under design prerequisite of the present invention, simple modifications of the present invention is all belonged to the scope of protection of present invention.
Embodiment 1: the preparation of compound (I)
Get the high piperazine of 100 grams, put into the 250ml there-necked flask, drip 20 gram 5-isoquinoline 99.9 SULPHURYL CHLORIDE under the stirring at room and be dissolved in 100ml methylene dichloride wiring solution-forming, add, stirring at room reaction to reaction is finished, and adds 5% sodium hydroxide solution 200ml, revolves methylene dichloride, filter, washing gets white solid, the Virahol recrystallization, promptly get compound (I) 12g, HPLC peak area normalization method content is greater than 99%.
Embodiment 2: the toxicological experiment of compound (I)
With each 100 of mouse, carry out the anxious poison research of compound (I) and Fasudil Hydrochloride with the SD rat, the result is as follows:
Illustrate that compound (I) is more a lot of greatly than Fasudil Hydrochloride toxicity, therefore, the quantitative control of compound in the Fasudil Hydrochloride (I) is very crucial for the quality that ensures fasudil hydrochloride injection.
Embodiment 3: easypro good your related substance of salt acid system is controlled
(I) makes external standard with compound, and (I) content is lower than 0.3% in control Fasudil Hydrochloride and the injection liquid thereof, is preferably lower than 0.01%.
Claims (6)
1. compound and salt and solvate shown in the formula (I):
2. the preparation method of the described compound of claim 1 is characterized by:
1) serve as the reaction starting raw material with compound or its salt shown in the formula (II):
2) react promptly with high piperazine.
3. compound shown in the claim 1 is characterized by HPLC peak area normalizing and draws method content 90%～100%.
Compound shown in the claim 1 as standard substance or reference substance the purposes in fasudil and salt quality control thereof.
Compound shown in the claim 1 as standard substance or reference substance the purposes in the Fasudil Hydrochloride quality control.
6. the purposes of compound shown in the claim 1 in preparation anti HIV-1 virus medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101297322A CN102199122A (en) | 2010-03-23 | 2010-03-23 | Homopiperazine derivative and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101297322A CN102199122A (en) | 2010-03-23 | 2010-03-23 | Homopiperazine derivative and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102199122A true CN102199122A (en) | 2011-09-28 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010101297322A Pending CN102199122A (en) | 2010-03-23 | 2010-03-23 | Homopiperazine derivative and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102199122A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102706997A (en) * | 2012-06-28 | 2012-10-03 | 武汉武药科技有限公司 | Detection method of fasudil hydrochloride-related substance |
| CN103113352A (en) * | 2013-03-09 | 2013-05-22 | 山东方明药业集团股份有限公司 | Method for preparing fasudil impurity-homopiperazine disulfone |
| CN105866263A (en) * | 2016-03-24 | 2016-08-17 | 四川升和药业股份有限公司 | Quality control method for fasudil hydrochloride |
| CN110596293A (en) * | 2019-10-18 | 2019-12-20 | 山东威高药业股份有限公司 | High performance liquid detection method for homopiperazine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993013072A1 (en) * | 1991-12-20 | 1993-07-08 | Italfarmaco S.P.A. | 5-isoquinolinesulfonamide derivatives as protein kinase inhibiting agents |
| CN1183767A (en) * | 1995-03-10 | 1998-06-03 | G·D·瑟尔公司 | Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors |
| CN1310709A (en) * | 1998-07-21 | 2001-08-29 | 卫材株式会社 | N.N-substituted cyclic amine derivatives |
-
2010
- 2010-03-23 CN CN2010101297322A patent/CN102199122A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993013072A1 (en) * | 1991-12-20 | 1993-07-08 | Italfarmaco S.P.A. | 5-isoquinolinesulfonamide derivatives as protein kinase inhibiting agents |
| CN1183767A (en) * | 1995-03-10 | 1998-06-03 | G·D·瑟尔公司 | Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors |
| CN1310709A (en) * | 1998-07-21 | 2001-08-29 | 卫材株式会社 | N.N-substituted cyclic amine derivatives |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102706997A (en) * | 2012-06-28 | 2012-10-03 | 武汉武药科技有限公司 | Detection method of fasudil hydrochloride-related substance |
| CN102706997B (en) * | 2012-06-28 | 2014-07-16 | 武汉武药科技有限公司 | Detection method of fasudil hydrochloride-related substance |
| CN103113352A (en) * | 2013-03-09 | 2013-05-22 | 山东方明药业集团股份有限公司 | Method for preparing fasudil impurity-homopiperazine disulfone |
| CN105866263A (en) * | 2016-03-24 | 2016-08-17 | 四川升和药业股份有限公司 | Quality control method for fasudil hydrochloride |
| CN110596293A (en) * | 2019-10-18 | 2019-12-20 | 山东威高药业股份有限公司 | High performance liquid detection method for homopiperazine |
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| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20110928 |