CN105367486B - A kind of new impurity of cinbitrate tartrate and its preparation method and application - Google Patents
A kind of new impurity of cinbitrate tartrate and its preparation method and application Download PDFInfo
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- CN105367486B CN105367486B CN201510939816.5A CN201510939816A CN105367486B CN 105367486 B CN105367486 B CN 105367486B CN 201510939816 A CN201510939816 A CN 201510939816A CN 105367486 B CN105367486 B CN 105367486B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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Abstract
The present invention provides new impurity of a kind of cinbitrate tartrate and its preparation method and application, belong to technical field of medicine synthesis.The new impurity is the salt of type I compound or type I compound or the solvate of type I compound.It can be applied to detection cinbitrate tartrate bulk pharmaceutical chemicals or the quality of its formulation samples, and the impurity in analyzing tartaric acid cinitapride improves cinbitrate tartrate bulk pharmaceutical chemicals or the quality standard of its preparation；Meanwhile preparation method has many advantages, such as stable reaction, easy to operate, high income, realizes the preparation of new impurity type I compound；The structure of new impurity type I compound is as follows:
Description
Technical field
The present invention relates to technical field of medicine synthesis, a kind of new impurity in particular to cinbitrate tartrate and
Preparation method and application.
Background technique
Cinbitrate tartrate is researched and developed by Almirall Prodesfarma company, Spain, and in nineteen ninety in western class
Tooth listing, for treating mild to moderate motility dysfunction-type indigestion, it is also possible to be not enough to treat as proton pump inhibitor
The adjuvant treatment of gastroesophageal reflux disease patient can effectively improve gastroesophageal reflux disease symptom, and structure is as follows:
Although some cinbitrate tartrate related impurities of existing literature and document announcement, paratartaric acid cinitapride
The miscellaneous Quality Research of the novel structure generated in synthesis process is an active development and the process that constantly promotes, can be applied
In the impurity analysis of cinbitrate tartrate, cinbitrate tartrate bulk pharmaceutical chemicals or the quality standard of its preparation are further improved.
Summary of the invention
The purpose of the present invention is to provide new impurity of a kind of cinbitrate tartrate and its preparation method and application, so that
New impurity is applied to detection cinbitrate tartrate bulk pharmaceutical chemicals or the quality of its formulation samples, in analyzing tartaric acid cinitapride
Impurity improves cinbitrate tartrate bulk pharmaceutical chemicals or the quality standard of its preparation；Meanwhile so that preparation method has reaction steady
The advantages that fixed, easy to operate, high income.
The present invention provides a kind of new impurity of cinbitrate tartrate, the new impurity is that type I compound or formula I are changed
Close the salt of object or the solvate of type I compound:
Wherein, R=H or C atomicity is the alkyl of 1-18.
The salt of above-mentioned type I compound includes the hydrochloride of type I compound or the sulfate of type I compound.
Preferably, R H, methyl, ethyl or isopropyl.
Inventor passes through careful the probing into of paratartaric acid cinitapride synthesis technology, finds and confirms depositing for above-mentioned impurity
?.The impurity is by starting material when nitration reaction prepares intermediate 1, and the hydrogen of No. 3 positions of phenyl ring is also replaced by nitro, and with
What intermediate 1 was finally generated through subsequent reactions, structure novel.The nitration reaction of starting material is as follows:
In the process that medicament research and development and quality control, the discovery and preparation of new impurity are often for the types of drugs
Quality research, which has, cannot be neglected important function, and the impurity that can be applied in cinbitrate tartrate production technology is fixed
Property and quantitative analysis, so as to improve and improve the quality standard of cinbitrate tartrate, be cinbitrate tartrate peace
Full medication provides great importance.
The present invention provides a kind of preparation methods of above-mentioned new impurity, under condensing agent or activating reagent, by II chemical combination of formula
Object and III compound of formula carry out condensation reaction in organic solvent, the type I compound are prepared, reaction equation is as follows:
Under the action of condensing agent, the amino for being conducive to the carboxyl and III compound of formula of above-mentioned II compound of formula is condensed
Reaction, so that type I compound be prepared.
Alternatively, the carboxyl of above-mentioned II compound of formula acts on activating reagent and generates and mix under the action of activating reagent
Acid anhydrides sends out II compound of formula and III compound of formula so that the amino for being conducive to it with III compound of formula reacts
It gives birth to condensation reaction and type I compound is prepared.
Further, the organic solvent is selected from halogenated hydrocarbon solvent, esters solvent, aromatic hydrocarbon solvent, ketones solvent, ethers
At least one of solvent, nitrile solvents and amide solvent.
Wherein it is preferred to which halogenated hydrocarbon solvent is chloroform, methylene chloride and carbon tetrachloride；Esters solvent is butyl acetate
And ethyl acetate；Aromatic hydrocarbons solvent is toluene and ortho-xylene；Ketones solvent is acetone and butanone；Ether solvent is ether and four
Hydrogen furans；Nitrile solvents are acetonitrile and propionitrile；Amide solvent is N,N-dimethylformamide and DMAC N,N' dimethyl acetamide.
Further, it is sub- to be selected from 1,1'- carbonyl dimidazoles, dicyclohexylcarbodiimide, diisopropyl carbon two for the condensing agent
At least one of amine and 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate.
It is the activity that the amino at its ortho position is reduced due to electron-withdrawing group because of nitro, so that II compound of formula and formula III are changed
Condensation reaction can successfully be carried out by closing object.
Further, the activating reagent is selected from chloro-formate, pivaloyl chloride, di-tert-butyl dicarbonate or N- benzyl succinyl
Imido-carbonic ester.
Preferably, above-mentioned condensation reaction carries out under alkaline condition.Wherein, alkali used in alkaline condition can be selected from hydrogen-oxygen
Change inorganic bases and triethylamine, diisopropylethylamine, the pyrroles such as potassium, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate
One of organic bases such as pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, can also be two or more of in
Meaning combination.
Further, condensing agent described in the condensation reaction or the activating reagent are added before III compound of formula,
III compound of formula is added after II compound of formula is reacted with the condensing agent or the activating reagent to be reacted,
The type I compound is prepared.
Above-mentioned condensation reaction can use a variety of feed way, wherein preferably, be contracted by being added before III compound of formula
Mixture or activating reagent, so that II compound of formula can sufficiently react with condensing agent or activating reagent generation first and form activity
Intermediate, consequently facilitating III compound of the formula reaction being added thereafter, to be more conducive to the progress of condensation reaction.
Further, also added with catalyst in the condensation reaction, the catalyst is selected from N, N- lutidines, 1- hydroxyl
In benzotriazole, 1- hydroxyl -7- azo benzotriazole, n-hydroxysuccinimide and n-Hydroxyphthalimide extremely
Few one kind.
In order to improve the activity of reaction, accelerate reaction rate, it is preferable that it also added catalyst in above-mentioned condensation reaction,
In this way, reducing the activation energy of reaction by the effect of catalyst, this improves reactivities, accelerate reaction rate.
Wherein, catalyst be selected from N, N- lutidines, I-hydroxybenzotriazole, 1- hydroxyl -7- azo benzotriazole,
It is one of n-hydroxysuccinimide and n-Hydroxyphthalimide, two kinds or more of.
The present invention also provides the preparation method of another above-mentioned new impurity, by VI compound of formula and V compound of formula in
Nucleophilic substitution is carried out in organic solvent, type I compound is prepared, and reaction equation is as follows:
Wherein, X=mesyl, p-toluenesulfonyl, trifyl or halogen.
X group in above-mentioned V compound of formula is leaving group, has electrophilicity, and on the piperidine ring in VI compound of formula
Amino rich in electronics has strong nucleophilicity, and S occurs for the twoN2 substitution reactions, are prepared type I compound.
Further, the nucleophilic substitution carries out under alkaline condition, and alkali used is inorganic base or organic base.
Preferably, above-mentioned nucleophilic substitution in alkaline condition carry out, in this way, make nucleophilic substitution be more easier into
Row, is conducive to the preparation of type I compound.
Further, the inorganic base is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate and cesium carbonate
At least one of；The organic base be selected from triethylamine, diisopropylethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide and
At least one of sodium tert-butoxide.
The stable reaction of above-mentioned preparation method, mild condition, yield easy to operate and product are higher, realize new miscellaneous
The preparation of matter type I compound.
Wherein, II compound of formula and VI compound of formula can refer to document " Bioorganic&Medicinal Chemistry,
Volume 16, Issue 7,2008, Pages 3839-3847 " are prepared；III compound of formula can refer to Patent No.
The patent of DE2706038 is prepared；V compound of formula can refer to document " Tetrahedron, Volume 48, Issue 22,
1992, Pages 4659-4676 " are prepared；Commercially available acquisition can also be passed through.
The present invention provides a kind of purposes of above-mentioned new impurity, and the new impurity is in detection cinbitrate tartrate raw material
Application in the quality of medicine or its formulation samples.
Beneficial effects of the present invention；
The present invention provides new impurity of a kind of cinbitrate tartrate and its preparation method and application, so as to should
New impurity is applied to detection cinbitrate tartrate bulk pharmaceutical chemicals or the quality of its formulation samples, in analyzing tartaric acid cinitapride
Impurity improves cinbitrate tartrate bulk pharmaceutical chemicals or the quality standard of its preparation；Meanwhile preparation method have stable reaction,
The advantages that easy to operate, high income, realize the preparation of new impurity type I compound.
Detailed description of the invention
Fig. 1 is the MS map of new impurity described in embodiment 1；
Fig. 2 is the H-NMR map of new impurity described in embodiment 1.
Specific embodiment
Embodiment 1
The preparation of type I compound:
Successively by 20mL N,N-dimethylformamide, II compound of 7g formula, 7.5g 1- ethyl-(3- dimethylamino third
Base) phosphinylidyne diimmonium salt hydrochlorate and 0.7g I-hydroxybenzotriazole be added in single-necked flask, it is stirred to react 10 points at room temperature
5g 1- (3- cyclohexene methyl) -4- piperidinamine (III compound of formula) is then added in reaction solution by clock, and stirring is anti-at room temperature
It answers 30 minutes；11mL triethylamine is slowly dropped into reaction solution, 50 DEG C of reactions are warming up to after dripping off.TLC monitors fully reacting.
100mL water is added into reaction system, stirring and crystallizing, filtering, filter cake elutes with acetone, collect solid it is dry I chemical combination of 7g formula
Object, yield: 60%, reaction equation is as follows:
The mass spectrum and nuclear magnetic spectrum of type I compound are as depicted in figs. 1 and 2, and HRMS-ESI (m/z): 448.2216 (M+H+)；
1H-NMR(d6- DMSO, 500MHz): δ=8.88 (s, 1H), 7.91 (s, 1H), 7.65 (s, 2H), 5.62~5.59 (m, 2H),
4.10~4.07 (m, 4H), 3.29 (s, 2H), 2.83~2.49 (m, 4H), 2.11~1.68 (m, 10H), 1.38 (t, 3H),
1.20~1.18 (m, 1H) ppm.
II compound of formula in the present embodiment is also selected from:
OrDeng；
Correspondingly, the type I compound of preparation are as follows:
OrDeng.
Other organic solvents can also be selected to replace n,N-Dimethylformamide, for example, chloroform, dichloro in the present embodiment
Methane, carbon tetrachloride, butyl acetate, ethyl acetate, toluene, ortho-xylene, acetone, butanone, ether, tetrahydrofuran, acetonitrile, third
One of nitrile and n,N-dimethylacetamide, or it is therein two or more.
The present embodiment can also select other alkali replace triethylamine, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide,
Potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide and the tert-butyl alcohol
It is a kind of in sodium, or any combination of two or more of them.Certainly, the present embodiment can also be without using triethylamine etc.
Alkali, but the yield of type I compound can reduce.
The present embodiment can also select other condensing agents to replace 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt
Hydrochlorate, one of for example, 1,1'- carbonyl dimidazoles, dicyclohexylcarbodiimide and diisopropylcarbodiimide can also be with
For two or more of them.
The present embodiment can also select other catalyst replace I-hydroxybenzotriazole, for example, N, N- lutidines,
One of 1- hydroxyl -7- azo benzotriazole, n-hydroxysuccinimide and n-Hydroxyphthalimide, Ke Yiwei
It two of them and a variety of uses simultaneously.
Embodiment 2
By II compound of 5g formula, 5mL triethylamine, 20mLN, dinethylformamide is added in round-bottomed flask, is cooled to 0
DEG C, 2.1mL ethyl chloroformate is slowly dropped into reaction solution under stirring condition, room temperature reaction 1h is slowly increased to after dripping off；With
Afterwards, the n,N-Dimethylformamide solution of III compound of 3.6g formula is instilled in reaction solution.After being added dropwise, it is placed in 50 DEG C of oil baths
Middle heating reaction, TLC monitor fully reacting.Reaction solution is slowly dropped in ice water, solid is precipitated, is filtered, collection solid, third
Ketone elutes twice, dry 5.2g type I compound, yield: 63%, reaction equation is as follows:
The present embodiment can also select other activating reagents replace ethyl chloroformate, such as methylchloroformate, pivaloyl chloride,
Di-tert-butyl dicarbonate and N- benzyl succinimdyl carbonate etc..
Embodiment 3
Successively by 20mLN, dinethylformamide, V chemical combination of VI compound of 10g formula, 10g Anhydrous potassium carbonate and 6.5g formula
Object is added in round-bottomed flask, is heated to 100 DEG C of reactions.TLC monitors fully reacting.Stop reaction, is cooled to 30~40
DEG C, ice water is added into system, stirring and crystallizing, filtering, filter cake water, acetone are respectively washed twice, obtains 10g type I compound, receive
Rate: 80%, reaction equation is as follows:
V compound of formula in the present embodiment is also selected from:
OrDeng.
Be readily appreciated that ground, the type I compound of any preparation in above-described embodiment 1-3, can also at salt or with solvent shape
Solvate, such as type I compound forms hydrochloride or itself with hydrochloric acid and sulfuric acid forms sulfate.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (8)
1. a kind of preparation method of the new impurity of cinbitrate tartrate, which is characterized in that the new impurity is type I compound,
Type I compound salt or type I compound solvate:
Wherein, R=H or ethyl；The preparation method of the new impurity of the cinbitrate tartrate is in condensing agent or activating reagent
Under, II compound of formula and III compound of formula are subjected to condensation reaction in organic solvent, the type I compound is prepared,
Reaction equation is as follows:
2. preparation method according to claim 1, which is characterized in that the condensing agent is selected from 1,1'- carbonyl dimidazoles, two
In carbodicyclo hexylimide, diisopropylcarbodiimide and 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate
At least one.
3. preparation method according to claim 1, which is characterized in that the activating reagent is selected from chloro-formate, pivaloyl
Chlorine, di-tert-butyl dicarbonate or N- benzyl succinimdyl carbonate.
4. preparation method according to any one of claims 1 to 3, which is characterized in that be condensed described in the condensation reaction
Agent or the activating reagent are added before III compound of formula, to II compound of formula and the condensing agent or the activation
III compound of formula is added after reagent reaction to be reacted, and the type I compound is prepared.
5. preparation method according to any one of claims 1 to 3, which is characterized in that also added with urging in the condensation reaction
Agent, the catalyst are selected from N, N- lutidines, I-hydroxybenzotriazole, 1- hydroxyl -7- azo benzotriazole, N- hydroxyl
At least one of base succinimide and n-Hydroxyphthalimide.
6. a kind of preparation method of new impurity as described in claim 1, which is characterized in that by VI compound of formula and V chemical combination of formula
Object carries out nucleophilic substitution in organic solvent, and type I compound is prepared, and reaction equation is as follows:
Wherein, X=mesyl, p-toluenesulfonyl, trifyl or halogen.
7. preparation method according to claim 6, which is characterized in that the nucleophilic substitution under alkaline condition into
Row, alkali used are inorganic base or organic base.
8. preparation method according to claim 7, which is characterized in that the inorganic base be selected from potassium hydroxide, sodium hydroxide,
At least one of lithium hydroxide, potassium carbonate, sodium carbonate and cesium carbonate；The organic base be selected from triethylamine, diisopropylethylamine,
At least one of pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide.
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| CN106883138B (en) * | 2017-03-01 | 2018-07-10 | 郑州大学第一附属医院 | The preparation method of tiger element |
| CN109053552A (en) * | 2018-06-26 | 2018-12-21 | 成都欣捷高新技术开发股份有限公司 | A kind of process impurity of cinbitrate tartrate and its preparation method and application |
| CN109369512A (en) * | 2018-11-06 | 2019-02-22 | 威海贯标信息科技有限公司 | A kind of preparation method of spherical shape cinbitrate tartrate crystallization |
| CN109394711A (en) * | 2018-11-06 | 2019-03-01 | 威海贯标信息科技有限公司 | A kind of cinbitrate tartrate tablet composition |
| CN111269157B (en) * | 2020-01-02 | 2021-12-03 | 南京海纳医药科技股份有限公司 | Amisulpride impurity and preparation method thereof |
| CN115304540B (en) * | 2022-09-15 | 2023-12-12 | 仁合益康集团有限公司 | Preparation method of cilnidiride tartrate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1574419A (en) * | 1977-11-11 | 1980-09-03 | Anphar Sa | Piperidine compounds |
| ES2001458A6 (en) * | 1986-12-12 | 1988-05-16 | Fordonal Sa | Benzamide derivs. and their salts prodn. |
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2015
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1574419A (en) * | 1977-11-11 | 1980-09-03 | Anphar Sa | Piperidine compounds |
| ES2001458A6 (en) * | 1986-12-12 | 1988-05-16 | Fordonal Sa | Benzamide derivs. and their salts prodn. |
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