CN1557803A - Sibutramine aliphatic salt of organic acid, its preparation process and use - Google Patents
Sibutramine aliphatic salt of organic acid, its preparation process and use Download PDFInfo
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- CN1557803A CN1557803A CNA2004100138963A CN200410013896A CN1557803A CN 1557803 A CN1557803 A CN 1557803A CN A2004100138963 A CNA2004100138963 A CN A2004100138963A CN 200410013896 A CN200410013896 A CN 200410013896A CN 1557803 A CN1557803 A CN 1557803A
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Abstract
The present invention relates to aromatic organic salt of Sibutramine and its preparation process. The hydrochloride of Sibutramine as initial material is added into water solution of caustic alkali and reacted for some time before ethyl ether extraction and drying to concentrate to obtain white solid free Sibutramine alkali. Organic solution of free Sibutramine alkali and organic solution of ketoacetic acid or similar organic fatty acid are then mixed at room temperature via stirring to react and separate white crystal, which is filtered and dried to obtain the aromatic organic salt of Sibutramine. The salt has excellent diabetes and obesity preventing and treating effect.
Description
Technical field
The salt that the present invention relates to sibutramine (Sibutramine) and organic acid effect formed salt, especially sibutramine and a class aliphatics organic acid effect and form, and the preparation method of this salt and application.
Background technology
The compound of structure shown in the formula I has the medical science effect to organism, according to R
1, R
2The difference of two groups can form a series of compounds.Work as R
1, R
2When all being methyl, just become " N, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methylbutylamine ", the English name of this compound is " Sibutramine ", and the application is translated into " sibutramine ", and its structure is suc as formula shown in the II.
British patent specification 2098602 has illustrated preparation and the application in treating depression of formula I compound and salt thereof; European patent number 282206 has illustrated formula I compound and the application of salt in the treatment Parkinson's disease thereof; Chinese patent application (application number 97199787.X, publication number CN1237905A) has illustrated formula I compound and the application of salt in prevent diabetes thereof; United States Patent (USP) 4939175 has illustrated formula II compound and the application of salt in the treatment cerebral disorder thereof.Those skilled in the art are appreciated that, no matter be the compounds shown in the formula I, or a kind of concrete compound shown in the formula II, they can both exist with the form of the salt of formation with pharmaceutically acceptable acid effect, and, mostly occur during practical application with the form of these salt.To this, forefathers have done a large amount of work in this respect, " salt " that sibutramine and various acid effect form mainly contains: hydrochloride, hydrobromate, vitriol, mesylate, nitrate, maleate, acetate, Citrate trianion, fumarate, tartrate, succinate, benzoate, fumarate, benzaldehyde hydrochlorate, and the salt that forms with amino acid (as L-glutamic acid).Different salt can produce different drug effects, and drug effect is close sometimes, and drug effect is totally different sometimes.We can say that people never stopped for containing the formula I or the compound of formula II structure and the research of salt thereof.
In the middle of various " salt " studied, N, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-the easiest preparation of 3-3-methyl butylamine hydrochloride (that is: sibutramine hydrochloride), use also extensively.Describe according to GB2098602, the sibutramine hydrochloride for preparing has water absorbability.Because " amount of contained active constituent should be identical in each formulation " is a basic demand of pharmaceutical preparation, the active constituent that can absorb water from environment is difficult to reach this requirement, so people are reluctant to use hygroscopic ingredients when useful in preparing drug formulations.When being directly used in useful in preparing drug formulations as this hygroscopic ingredients of sibutramine hydrochloride, intractable on the technology.PCT application case WO88106444 thinks, best of breed form when single hydrochloride hydrate of sibutramine is the treatment Parkinson's disease, CN86108547A also is described to the preparation method of Sibutramine hydrochloride monohydrate, and the preparation medicine of listing all is as medicine material with this form at present.Although people have obtained certain achievement in these areas,, form the better salt of effect about sibutramine and the effect of aliphatics organic acid, people's research degree is still very limited.
Summary of the invention
The object of the present invention is to provide a kind of new sibutramine aliphatics organic acid salt, and the preparation method of this salt.This sibutramine aliphatics organic acid salt is a kind of non-hygroscopic active substance, can be used to prepare new medicinal compositions, can play better effect to the control of some diseases.
Purpose of the present invention is achieved through the following technical solutions:
A kind of sibutramine aliphatics organic acid salt is the ketone carbonyl with group that carboxyl directly links to each other in the described aliphatics organic acid molecular structure, and the structure of described organic acid salt is shown in formula III.
The preparation method of aforesaid sibutramine aliphatics organic acid salt prepares according to following steps:
The first step, preparation sibutramine free alkali
In the reaction flask of thermometer is housed, add sodium hydroxide NaOH and distilled water, after treating that NaOH dissolves fully, under 15～35 ℃ of conditions, add the sibutramine hydrochloride, the mol ratio of sibutramine hydrochloride and NaOH is 1: 1～1: 8, maintain the temperature at 20～28 ℃, stirring reaction 0.5～4hr uses twice of ether extraction then, the each ether that uses and the mol ratio of sibutramine hydrochloride are 80: 1～250: 1, merge the resulting ether layer of extracted twice, in this diethyl ether solution, add distilled water again, stirring and washing, standing separation, repeat this cleaning process, be weakly alkaline until washing lotion, last, use anhydrous magnesium sulfate MgSO
4Dry ether layer 0.5～4hr, filtering and concentrating promptly gets white solid sibutramine free alkali;
Second step, preparation sibutramine aliphatics organic acid salt
According to adding 0.01～0.5 gram sibutramine free alkali, the aforesaid aliphatics organic acid ratio of 0.01～1 gram in every milliliter of organic solvent, prepare sibutramine free alkali and aliphatics organic acid organic solution respectively, be 10: 1～1: 10 consumption again by the mol ratio of aliphatics organic acid and sibutramine free alkali, to join aliphatics organic acid organic solution join in the organic solution of sibutramine free alkali, stirring at room 0.5～2hr, there are a large amount of white crystals to separate out, filtration, drying promptly get aforesaid sibutramine aliphatics organic acid salt.
The application of above-mentioned sibutramine aliphatics organic acid salt aspect the preparation medicinal compositions, this medicinal compositions is used for prevention or treatment diabetes or obesity, described organic acid salt is the main property of medicine composition of this medicinal compositions, and the medicinal forms of composition is tablet, capsule, granule, syrup or suspension.
Purpose of the present invention can also further realize by following optimal technical scheme:
Aforesaid sibutramine aliphatics organic acid salt, wherein said organic acid salt are left-handed structure of optics and/or dextrorotation structure.
Aforesaid sibutramine aliphatics organic acid salt, wherein R in the formula III
1Group is the alkyl that contains 1～6 carbon atom.
Aforesaid sibutramine aliphatics organic acid salt, wherein R in the formula III
1Group preferable methyl, ethyl, propyl group or sec.-propyl.
Aforesaid sibutramine aliphatics organic acid salt, wherein R in the formula III
1The group most preferable, that is: described aliphatics organic acid is a pyruvic acid, the structure of described organic acid salt is suc as formula shown in the IV.
The preparation method of aforesaid sibutramine aliphatics organic acid salt, wherein said aliphatics organic acid is a pyruvic acid, described sibutramine aliphatics organic acid salt is the sibutramine pyruvate salt.
The preparation method of aforesaid sibutramine aliphatics organic acid salt, wherein in preparation sibutramine free alkali process, temperature of reaction is 22～25 ℃.
The preparation method of aforesaid sibutramine aliphatics organic acid salt, wherein in preparation sibutramine aliphatics organic acid salt process, organic solvent is the volatile alcohols of lower boiling, ketone or ether organic solvent, particular methanol, ethanol, acetone, butanone, ether or isopropyl ether, most preferably ether.
Aforesaid sibutramine aliphatics organic acid salt is in the application of preparation aspect the medicinal compositions, wherein sibutramine aliphatics organic acid salt sibutramine pyruvate salt most preferably.
Adopt technical solution of the present invention can play following technique effect:
(1) obtained non-hygroscopic active substance---N, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-3-methylbutylamine aliphatics organic acid salt, especially sibutramine pyruvate salt.
(2) provide the method for preparing an above-mentioned compounds, this method raw material is easy to get, and preparation condition is not harsh, and product yield and purity are all higher.
(3) adopt pyruvic acid or aliphatics organic acid similar,, and then be applied to prepare medicinal compositions, can play collaborative prevention and effects such as treatment diabetes, obesity with sibutramine parent salify with it.
(4) not only security is very high for employed pyruvic acid, and processes such as tricarboxylic acid cycle, amino acid and the carbohydrate thereof of human body be synthetic are played a part important intermediate, it can make the body fat metabolic rate reach 48%, and can cause that the phenomenons such as metabolic acidosis of general play antagonistic action to a certain degree to diabetic coma, hunger and serious vomiting etc.
Description of drawings
Fig. 1 is the infrared analysis collection of illustrative plates of the resulting sibutramine free alkali of preparation method's the first step of the present invention.Fig. 2 is the infrared analysis collection of illustrative plates of The compounds of this invention sibutramine pyruvate salt.X-coordinate is a wave number among two figure, and unit is cm
-1Ordinate zou is a transmittance, and unit is %.
Embodiment
The present invention is based on the achievement in research of forefathers to sibutramine and salt thereof, and development research goes out the new sibutramine aliphatics organic acid salt of a class, and the control of diseases such as these salt pair diabetes, obesity can be played better effect.
Invention uses the sibutramine hydrochloride as starting raw material, it is joined in the caustic-alkali aqueous solution, and molar ratio is: hydrochloride: NaOH=1: 1～1: 8, use ether extraction after reaction for some time, dry again concentrating obtains the sibutramine free alkali of white solid.Then, with sibutramine free alkali and pyruvic acid or with the similar aliphatics organic acid of pyruvic acid, be dissolved in the organic solvent wiring solution-forming respectively, again these two kinds of organic solutions are at room temperature mixed, stirred, separate out white crystals behind reaction 0.5～2hr, filter, be drying to obtain sibutramine aliphatics organic acid salt.
In the preparation process of free alkali, temperature of reaction is a room temperature, is preferably 22 ℃～25 ℃; When the preparation pyruvate salt, organic solvent is selected the volatile alcohols of lower boiling, ketone, ether solvent, is specially methyl alcohol, ethanol, acetone, butanone, ether or isopropyl ether etc., is good with ether especially.For intermediate product " sibutramine free alkali " and final product " sibutramine aliphatics organic acid salt ", can use analysis means such as fusing point test, infrared or mass spectrum, determine the exactness of its structure.
Be example below with the pyruvic acid, the present invention done more specifically to describe in conjunction with Figure of description:
The preparation of " 1 " sibutramine free alkali
In the 500ml reaction flask of thermometer is housed, add 8 gram NaOH and 300ml distilled water, treat that NaOH dissolves fully, temperature is reduced to 22 ℃, add 16 gram sibutramine hydrochlorides, stirring reaction 1hr under 22～28 ℃ of conditions.Reaction product merges resulting ether layer twice with 150ml ether extraction twice, cleans this diethyl ether solution with distilled water again, is weakly alkaline until washing lotion.The anhydrous MgSO of final diethyl ether solution that obtains after cleaning
4Dry 2hr refilters the concentrated 12 gram white solid materials that obtain, and yield 85%, fusing point are 51～54 ℃.According to report (J.Chem.Soc.Perkin Trans.1; EN; 21; 1996; 2583-2590), the fusing point of sibutramine free alkali (base) is 51～55 ℃, illustrates that the resulting material of preparation is the sibutramine free alkali really, and its infrared analysis collection of illustrative plates is seen Fig. 1.
The preparation of " 2 " sibutramine pyruvate salt
Get the 4 sibutramine free alkalis that make previously of gram and in clean beaker, be dissolved in the 50ml ether, in addition 1.24 gram pyruvic acid are dissolved in the 20ml ether, under the magnetic agitation latter is added in the middle of the former, stirring reaction is to there being a large amount of white crystals to separate out under the room temperature, filtration, drying, can get 3.3 gram sibutramine pyruvate salts, yield 63%.The fusing point of this salt is 81～84 ℃, and its infrared analysis the results are shown in Figure 2.According to provable this material of fusing point and base and pyruvic acid (normal temperature is down for liquid) is not same substance, comparative analysis Fig. 2 and Fig. 1, and it is different fully with sibutramine free alkali base to further specify this material.1709cm among Fig. 2
-1And 1624cm
-1The strong absorption peak in two places clear showing exists ketone carbonyl and carboxylic carbonyl in this material, prove that this material is the sibutramine pyruvate salt.
Operational condition among the above embodiment is non-restrictive condition, can take the circumstances into consideration as the case may be during practical application to select.The variation of various material usage quantities, and the similar replacement of certain operations condition all are interpreted as within protection scope of the present invention.
In addition, those skilled in the art will appreciate that the compound of formula I, II, III or the IV that the present invention relates to contains chiral centre, a chiral centre can have two kinds of enantiomorphous optical isomers to exist.The present invention includes the mixture of two kinds of single enantiomorphs or two kinds of enantiomorphs.In case of necessity, described enantiomer can split by the method known in this area, such as the salt or the mixture that form diastereomer, and then adopts method such as crystallization to separate; Perhaps, separate this derivative then again by forming diastereoisomeric derivative.
The sibutramine aliphatics organic acid salt that obtains with the present invention---especially the sibutramine pyruvate salt is as main property of medicine composition, and activity or the inert fraction compatible with other pharmacology combine, and can make medicinal compositions.This medicinal compositions can be used in prevention and diseases such as treatment diabetes, obesity.Oral dosage form is a preferred compositions, and this class instructions of taking has some known medicinal forms, as: tablet, capsule, granule, syrup and water-based or oily suspensions etc.
Claims (13)
1. sibutramine aliphatics organic acid salt is characterized in that: be the ketone carbonyl with group that carboxyl directly links to each other in the described aliphatics organic acid molecular structure, the structure of described organic acid salt is shown in formula III.
2. sibutramine aliphatics organic acid salt according to claim 1 is characterized in that: described organic acid salt is left-handed structure of optics and/or dextrorotation structure.
3. sibutramine aliphatics organic acid salt according to claim 1 and 2 is characterized in that: R in the formula III
1Group is the alkyl that contains 1～6 carbon atom.
4. sibutramine aliphatics organic acid salt according to claim 3 is characterized in that: R in the formula III
1Group is methyl, ethyl, propyl group or sec.-propyl.
5. sibutramine aliphatics organic acid salt according to claim 4 is characterized in that: R in the formula III
1Group is a methyl, and described aliphatics organic acid is a pyruvic acid, and the structure of described organic acid salt is suc as formula shown in the IV.
6. the preparation method of the described sibutramine aliphatics of claim 1 organic acid salt prepares according to following steps:
The first step, preparation sibutramine free alkali
In the reaction flask of thermometer is housed, add sodium hydroxide NaOH and distilled water, after treating that NaOH dissolves fully, under 15～35 ℃ of conditions, add the sibutramine hydrochloride, the mol ratio of sibutramine hydrochloride and NaOH is 1: 1～1: 8, maintain the temperature at 20～28 ℃, stirring reaction 0.5～4hr uses twice of ether extraction then, the each ether that uses and the mol ratio of sibutramine hydrochloride are 80: 1～250: 1, merge the resulting ether layer of extracted twice, in this diethyl ether solution, add distilled water again, stirring and washing, standing separation, repeat this cleaning process, be weakly alkaline until washing lotion, last, use anhydrous magnesium sulfate MgSO
4Dry ether layer 0.5～4hr, filtering and concentrating promptly gets white solid sibutramine free alkali;
Second step, preparation sibutramine aliphatics organic acid salt
According to adding 0.01～0.5 gram sibutramine free alkali in every milliliter of organic solvent, 0.01 the described aliphatics organic acid of～1 gram claim 1 ratio, prepare sibutramine free alkali and aliphatics organic acid organic solution respectively, be 10: 1～1: 10 consumption again by the mol ratio of aliphatics organic acid and sibutramine free alkali, to join aliphatics organic acid organic solution join in the organic solution of sibutramine free alkali, stirring at room 0.5～2hr, there are a large amount of white crystals to separate out, filter, drying promptly gets the described sibutramine aliphatics of claim 1 organic acid salt.
7. the preparation method of the described sibutramine aliphatics of claim 6 organic acid salt, it is characterized in that: described aliphatics organic acid is a pyruvic acid, described sibutramine aliphatics organic acid salt is the sibutramine pyruvate salt.
8. the preparation method of claim 6 or 7 described sibutramine aliphatics organic acid salts is characterized in that: in preparation sibutramine free alkali process, temperature of reaction is 22～25 ℃.
9. the preparation method of claim 6 or 7 described sibutramine aliphatics organic acid salts is characterized in that: in preparation sibutramine aliphatics organic acid salt process, organic solvent is the volatile alcohols of lower boiling, ketone or ether organic solvent.
10. the preparation method of the described sibutramine aliphatics of claim 9 organic acid salt, it is characterized in that: described organic solvent is methyl alcohol, ethanol, acetone, butanone, ether or isopropyl ether.
11. the preparation method of the described sibutramine aliphatics of claim 10 organic acid salt, it is characterized in that: described organic solvent is an ether.
12. the application of the described sibutramine aliphatics of claim 1 organic acid salt aspect the preparation medicinal compositions, this medicinal compositions is used for prevention or treatment diabetes or obesity, described organic acid salt is the main property of medicine composition of this medicinal compositions, and the medicinal forms of composition is tablet, capsule, granule, syrup or suspension.
13. the application of the described sibutramine aliphatics of claim 12 organic acid salt aspect the preparation medicinal compositions, wherein said sibutramine aliphatics organic acid salt is the sibutramine pyruvate salt.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009124458A1 (en) * | 2008-04-08 | 2009-10-15 | 北京嘉事堂生物医药有限公司 | Phenylcyclobutylamide derivatives and their stereoisomers, the preparing processes and the uses thereof |
| CN101890017A (en) * | 2009-05-22 | 2010-11-24 | 北京奥萨医药研究中心有限公司 | Medicament composition containing sibutramine and stanin fat-reducing medicament and application thereof |
-
2004
- 2004-01-13 CN CNA2004100138963A patent/CN1557803A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009124458A1 (en) * | 2008-04-08 | 2009-10-15 | 北京嘉事堂生物医药有限公司 | Phenylcyclobutylamide derivatives and their stereoisomers, the preparing processes and the uses thereof |
| JP2011516506A (en) * | 2008-04-08 | 2011-05-26 | ベイジン イングー センチュリー ファーマシー カンパニー リミテッド | Phenylcyclobutyramide derivatives and their stereoisomers, methods for their preparation and their use |
| AU2009235887B2 (en) * | 2008-04-08 | 2011-05-26 | Yingu Pharmaceutical Co., Ltd. | Phenylcyclobutylamide derivatives and their stereoisomers, the preparing processes and the uses thereof |
| CN101555214B (en) * | 2008-04-08 | 2012-07-11 | 北京嘉事联博医药科技有限公司 | Phenylcyclobutylacylamide derivative as well as optical isomer, preparation method and application thereof |
| RU2479572C2 (en) * | 2008-04-08 | 2013-04-20 | Бейджинг Йангу Сентури Фармаси Ко., ЛТД | Obtaining and using phenylcyclobutylamide derivatives and stereoisomers thereof |
| CN101890017A (en) * | 2009-05-22 | 2010-11-24 | 北京奥萨医药研究中心有限公司 | Medicament composition containing sibutramine and stanin fat-reducing medicament and application thereof |
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