CN101723942B - Method for preparing imide derivatives - Google Patents
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- CN101723942B CN101723942B CN 200810167903 CN200810167903A CN101723942B CN 101723942 B CN101723942 B CN 101723942B CN 200810167903 CN200810167903 CN 200810167903 CN 200810167903 A CN200810167903 A CN 200810167903A CN 101723942 B CN101723942 B CN 101723942B
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- FBVFZWUMDDXLLG-UHFFFAOYSA-N O=C(C1C2CCCC1)N(CCCCN(CC1)CCN1c1n[s]c3ccccc13)C2=O Chemical compound O=C(C1C2CCCC1)N(CCCCN(CC1)CCN1c1n[s]c3ccccc13)C2=O FBVFZWUMDDXLLG-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention provides a method for preparing imide derivatives, in particular a method for preparing the imide derivatives shown in a formula (I) and used as antipsychotic medicaments or pharmaceutically acceptable salts thereof or hydrates of the pharmaceutically acceptable salts. Compared with the conventional methods, the preparation method does not need chromatographic equipment such as a silica gel chromatographic column for purification to prepare the products with qualified purification, and has the advantages of simple and convenient operation, short time, improvement of yield by over 30 percent, great reduction of impurities, suitability for industrial production, reduction of production cost, great reduction of consumption of organic solvent and contribution to environmental protection.
Description
Technical field
The present invention relates to a kind of preparation method of imide derivatives, be specifically related to a kind of preparation method who is used as the imide derivatives of antipsychotics.
Background technology
Atypical antipsychotic agents hydrochloric acid Perospirone (Perospirone Hydrochloride) belongs to imide derivatives; Its chemical name is that [[[4-(1 for 4-for N-; 2-benzisothiazole-3-yl)-and the 1-piperazinyl] butyl]-1; 2-is suitable-hexanaphthene dicarboximide hydrochloride dihydrate, and structure is following:
The hydrochloric acid Perospirone is succeeded in developing by SUMITOMO CHEMICAL Co., Ltd. (sumitomo), and goes on the market in Japan first February 9 calendar year 2001, and commodity are called Lullan, carry out commercial cooperative marketing by Sumitomo and Ji Fu company.The formulation of list marketing at present has tablet and granule, and the tablet specification is 4mg/ sheet, 8mg/ sheet.
Perospirone is a kind of novel atypical antipsychotic, and its main pharmacological mechanism is 5-HT2 and d2 dopamine receptor antagonistic action.Compare with traditional psychotroptic drug, its tolerance and security are good, and spinoff is lighter, particularly extrapyramidal system untoward reaction and to cause lactotropin rising effect slight; Comprehensively the improvement rate is high, to the effect that also has clear improvement of negative symptoms and cognitive function aspect; Oral dosage is little; The treatment cost is low.These article succeed in developing the demand that will satisfy clinical application, change the present situation of the main dependence on import of home market atypical antipsychotics, create good economic benefit and social benefit.
Price is the main factor that the restriction atypical antipsychotic is popularized.At present the novel atypical antischizophrinic owner in home market wants courteous olanzapine (commodity are called Zyprexa), the risperidone (commodity are called Wei Sitong) of Yang Sen company and the Quetiapine (commodity are called Seroquel) of Astrazeneca AB that comes company; They compare security with leoponex good; But cost an arm and a leg; The retail price of risperidone is about 3.5 yuan/1mg, and the olanzapine retail price is about 28 yuan/5mg.Perospirone 4mg tablet approximates 2 yuans at 27 yen/sheet of Japanese price, has ideal curative effect/price ratio, in antipsychotics, the very strong market competitiveness will be arranged.
Continuous 3 years of National Drug Administration south medical pointing information portion shows the tracking investigation result of family's typical hospital surplus the whole nation 14 metropolitan 200; The sale total charge in China psychotropic substances market in 2000 increased by 49.6% than 1999, and calendar year 2001 rate of growth reach 15.1%.Wherein import kind has accounted for most shares.At present, Wei Sitong occupies the share more than 60% on the treatment of schizophrenia pharmaceutical market at home, annual over the past two years about 40% the high growth rate that all kept of its consumption sum.This investigation shows that the sales volume of Wei Sitong in 2000 is 0.32 hundred million yuan, and calendar year 2001, its consumption sum reached 0.37 hundred million yuan.Therefore developing the home-made antipsychotic agent has positive social effect and economic implications.
U.S. Pat 4745117A discloses a kind of having contained, and [[[4-(1 for 4-for N-; 2-benzisothiazole-3-yl)-and the 1-piperazinyl] butyl]-1; 2-is suitable-preparation method as the imide derivatives of antipsychotics of hexanaphthene dicarboximide, and its synthetic imide derivatives all need pass through the purification step of silica gel chromatographic column, causes preparation technology's complicated operation; Length consuming time, production cost improves and easily environment is polluted.
Summary of the invention
Therefore, the object of the present invention is to provide a kind of easy and simple to handlely, production cost reduces, and not only has been suitable for the preparation method of suitability for industrialized production but also environmentally friendly imide derivatives as antipsychotics.
Be used to realize that technical scheme of the present invention is following:
The preparation method of the hydrate of the imide derivatives shown in a kind of formula (I) or its pharmacologically acceptable salt, pharmacologically acceptable salt,
Wherein
A is carbonyl or alkylsulfonyl;
When A is carbonyl, B have formula (a) or (b) shown in structure:
(1)
In formula (a), E is methylene radical, ethylidene or Sauerstoffatom, the optional two keys of dotted line representative;
(2)
In formula (b), R
1, R
2, R
3, R
4, R
5And R
6Be hydrogen or methyl independently;
Perhaps when A was alkylsulfonyl, B was a phenylene;
D is for randomly by the substituted ethylidene of hydroxyl, vinylidene or ethynylene; And
N is 0,1 or 2 integer,
This preparation method may further comprise the steps: compound shown in compound shown in the formula (II) and the formula (III) reacted in aprotic solvent,
In formula (II) and formula (III), when G be-during O-, J does
G is-during NH-, J does
G is-N (CH
2-D-CH
2-X)-time, J does
Perhaps G does
The time, J is X '; Wherein, X, X ' are identical or different leavings group, and A, B, D and n are with the above.
Above-mentioned preparation method can also may further comprise the steps: in the presence of acid binding agent and/or alkaline metal iodide, compound shown in compound shown in the formula (II) and the formula (III) is reacted in aprotic solvent.
In above-mentioned preparing method's a specific embodiments, A is that carbonyl and B have the structure shown in the formula (a):
In formula (a), E is methylene radical, ethylidene or Sauerstoffatom, the optional two keys of dotted line representative.
In another specific embodiments of above-mentioned preparation method, A is that carbonyl and B have the structure shown in the formula (b):
In formula (b), R
1, R
2, R
3, R
4, R
5And R
6Be hydrogen or methyl independently.
In another specific embodiments of above-mentioned preparation method, A is that alkylsulfonyl and B are phenylene.
In above-mentioned preparation method, X, X ' are independently selected from halogen, for example chlorine, bromine or iodine; Alkylsulfonyloxy, for example methanesulfonyloxy group; Perhaps aryl-sulfonyl oxygen, for example tolysulfonyl oxygen base.
In above-mentioned preparation method, the hydrate of the imide derivatives shown in the formula (I) or its pharmacologically acceptable salt, pharmacologically acceptable salt is specially the structure shown in the formula (IV):
Be preferably the structure shown in the formula V:
The structure shown in the formula (VI) more preferably:
In above-mentioned preparation method, acid binding agent can be organic bases or mineral alkali, specifically is selected from tertiary amine, for example triethylamine; Pyridine; The carbonate of basic metal or earth alkali metal, for example yellow soda ash, salt of wormwood; The supercarbonate of basic metal or earth alkali metal, for example sodium hydrogencarbonate, saleratus; The hydrogenate of basic metal or earth alkali metal, for example one or more in sodium hydride, the potassium hydride KH.
Above-mentioned non-protonic solvent can be aprotic polar solvent, and for example one or more are selected from acetonitrile, N, the aprotic polar solvent of dinethylformamide, acetone and pyridine.Above-mentioned non-protonic solvent can also be inert solvent, and for example one or more are selected from the inert solvent of benzene,toluene,xylene, ether and tetracol phenixin.
Above-mentioned preparation method can also may further comprise the steps: in said reaction product, add nonpolar or weakly polar organic solvent and stirring, and solids removed by filtration, randomly will filtrate transforms salify, carries out recrystallization again.Wherein, said nonpolar or weakly polar organic solvent is selected from: alkane, for example hexane, octane; Aromatic hydrocarbon, for example benzene; Halohydrocarbon, for example trichloromethane; Alcohols, the for example trimethyl carbinol, octanol; Ethers, for example ether; Ketone, for example acetone; Ester class, for example one or more in the ETHYLE ACETATE.
With respect to existing preparation method, the preparation method of the hydrate of imide derivatives of the present invention or its pharmacologically acceptable salt, pharmacologically acceptable salt has following advantage:
1. the preparation method of existing imide derivatives need carry out purifying through for example silica gel chromatographic column isochromatic spectrum device; Preparing method of the present invention does not then need this step just can obtain the qualified product of purity; Easy and simple to handle, be fit to very much industriallization, not only reduced production cost; And significantly reduced the usage quantity of organic solvent, help environmental protection.
2. productive rate increases substantially, and improves more than 30% than the existent method productive rate.Foreign matter content also reduces greatly.
3. the pilot scale of criticizing with 5kg/, column chromatography purification need the eluent of 3-5 ton at least, need to spend 10 working dayss, comprising mixing a plurality of steps such as appearance, wash-out, distillation eluent and collection product, have largely limited production-scale expansion.And preparation method of the present invention weak point consuming time is practiced thrift solvent, suits in the suitability for industrialized production of enlargement of scale.
Embodiment
Embodiment 1
Operational path is following:
N-(4-brombutyl)-1 wherein, 2-is suitable-and the compound method of hexanaphthene dicarboximide can be referring to U.S. Pat 4745117 or US4598078; The compound method of 3-piperazinyl benzo isothiazole can be referring to U.S. Pat 4745117 and Journal of Medicinal Chemistry, 1986, Vol.29, No.3.
Process step:
With N-(4-brombutyl)-1,2-is suitable-hexanaphthene dicarboximide 9.4g, 3-piperazinyl benzo isothiazole 6.4g, and salt of wormwood 12.5g, potassiumiodide 3g and N, dinethylformamide (DMF) 62.5g adds in the reaction kettle together, and 90-100 ℃ of reaction is to fully.Solids removed by filtration after filtrate decompression concentrates, adds 20g ETHYLE ACETATE and stirs; Solids removed by filtration, filtrating changes into hydrochloride according to ordinary method, recrystallization; Obtain that [[[4-(1 for 4-for N-; 2-benzisothiazole-3-yl)-and the 1-piperazinyl] butyl]-1,2-is suitable-hexanaphthene dicarboximide hydrochloride dihydrate 13.5g, i.e. hydrochloric acid Perospirone.Detecting purity is 100.1%, single maximum contaminant≤0.1%, and total recovery is 92.8%.And single maximum contaminant≤0.5% of the product that existing compound method obtains, total recovery is merely 64.4%～82.1%.
Claims (16)
1. the preparation method of the hydrate of the imide derivatives shown in the formula (I) or its pharmacologically acceptable salt, pharmacologically acceptable salt,
Wherein
A is carbonyl or alkylsulfonyl;
When A is carbonyl, B have formula (a) or (b) shown in structure:
(1)
In formula (a), E is methylene radical, ethylidene or Sauerstoffatom, the optional two keys of dotted line representative;
(2)
In formula (b), R
1, R
2, R
3, R
4, R
5And R
6Be hydrogen or methyl independently;
Perhaps when A was alkylsulfonyl, B was a phenylene;
D is for randomly by the substituted ethylidene of hydroxyl, vinylidene or ethynylene; And
N is 0,1 or 2 integer,
This preparation method may further comprise the steps:
1) compound shown in compound shown in the formula (II) and the formula (III) is reacted in aprotic solvent;
In formula (II) and formula (III), when G be-during O-, J does
G is-during NH-, J does
G is-N (CH
2-D-CH
2-X)-time, J does
Perhaps G does
The time, J is X '; Wherein, X, X ' are identical or different leavings group, and A, B, D and n are with the above; With
2) in said reaction product, add nonpolar or weakly polar organic solvent and stirring, solids removed by filtration, the conversion salify of randomly will filtrate carries out recrystallization again, and wherein, said nonpolar or weakly polar organic solvent is an ETHYLE ACETATE;
Wherein, said method does not comprise the purification step through silica gel chromatographic column.
2. preparation method according to claim 1; It is characterized in that said preparation method may further comprise the steps: in the presence of acid binding agent and/or alkaline metal iodide, compound shown in compound shown in the formula (II) and the formula (III) is reacted in aprotic solvent.
3. preparation method according to claim 1 is characterized in that, said A is that carbonyl and B have the structure shown in the formula (a):
In formula (a), E is methylene radical, ethylidene or Sauerstoffatom, the optional two keys of dotted line representative.
4. preparation method according to claim 1 is characterized in that, said A is that carbonyl and B have the structure shown in the formula (b):
In formula (b), R
1, R
2, R
3, R
4, R
5And R
6Be hydrogen or methyl independently.
5. preparation method according to claim 1 is characterized in that, said A is that alkylsulfonyl and B are phenylene.
6. preparation method according to claim 1 is characterized in that said X, X ' are independently selected from one or more of chlorine, bromine, iodine, methanesulfonyloxy group and tosyloxy.
7. preparation method according to claim 1 is characterized in that, the hydrate of the imide derivatives shown in the said formula (I) or its pharmacologically acceptable salt, pharmacologically acceptable salt is the structure shown in the formula (IV):
8. preparation method according to claim 1 is characterized in that, the hydrate of the imide derivatives shown in the said formula (I) or its pharmacologically acceptable salt, pharmacologically acceptable salt is the structure shown in the formula V:
9. preparation method according to claim 1 is characterized in that, the hydrate of the imide derivatives shown in the said formula (I) or its pharmacologically acceptable salt, pharmacologically acceptable salt is the structure shown in the formula (VI):
10. preparation method according to claim 2 is characterized in that, said acid binding agent is organic bases or mineral alkali.
11. preparation method according to claim 10 is characterized in that, said acid binding agent is selected from tertiary amine; Pyridine; The carbonate of basic metal or earth alkali metal; The supercarbonate of basic metal or earth alkali metal; With in the hydrogenate of basic metal or earth alkali metal one or more.
12. preparation method according to claim 11 is characterized in that, said tertiary amine is a triethylamine; Said alkali-metal carbonate is yellow soda ash or salt of wormwood; Said alkali-metal supercarbonate is sodium hydrogencarbonate or saleratus, and said alkali-metal hydrogenate is sodium hydride or potassium hydride KH.
13. preparation method according to claim 1 is characterized in that, said non-protonic solvent is an aprotic polar solvent.
14. preparation method according to claim 13 is characterized in that, said aprotic polar solvent is selected from acetonitrile, N, one or more in the aprotic polar solvent of dinethylformamide, acetone and pyridine.
15. preparation method according to claim 1 is characterized in that, said non-protonic solvent is an inert solvent.
16. preparation method according to claim 15 is characterized in that, said inert solvent is selected from one or more in benzene,toluene,xylene, ether and the tetracol phenixin.
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| CN 200810167903 CN101723942B (en) | 2008-10-16 | 2008-10-16 | Method for preparing imide derivatives |
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|---|---|---|---|
| CN 200810167903 CN101723942B (en) | 2008-10-16 | 2008-10-16 | Method for preparing imide derivatives |
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| CN101723942B true CN101723942B (en) | 2012-07-18 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105669665A (en) * | 2016-03-15 | 2016-06-15 | 烟台贝森医药科技有限公司 | Preparation method of perospirone |
| CN112225732B (en) * | 2019-07-15 | 2024-01-09 | 四川科瑞德制药股份有限公司 | Crystal form of pirone hydrochloride hydrate and preparation method thereof |
| CN114031574A (en) * | 2021-11-08 | 2022-02-11 | 复旦大学附属肿瘤医院 | Application of perospirone and derivatives thereof in preparation of antitumor drugs |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4745117A (en) * | 1985-03-27 | 1988-05-17 | Sumitomo Pharmaceuticals Company, Limited | Imide derivatives and compositions for use as antipsychotic agents |
-
2008
- 2008-10-16 CN CN 200810167903 patent/CN101723942B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4745117A (en) * | 1985-03-27 | 1988-05-17 | Sumitomo Pharmaceuticals Company, Limited | Imide derivatives and compositions for use as antipsychotic agents |
Non-Patent Citations (1)
| Title |
|---|
| 曾果.非典型抗精神病药SM-9018的合成及其工艺的研究.《中国优秀博硕士学位论文全文数据库（硕士），医药卫生科技辑》.2006,第36页. * |
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Effective date of registration: 20140415 Address after: 519030 Zhuhai Special Economic Zone, Guangdong, Zhuhai Free Trade Zone, Wan Chai Patentee after: Zhuzhou Bonded Zone Lizhu Synthetic Pharmaceutical Co., Ltd. Address before: 519020, Zhuhai Special Economic Zone, Guangdong, Gongbei Osmanthus Road No. 132 Patentee before: Lizhu Medicine Group Co., Ltd. |