CN106916148B - Method for synthesizing brexpiprazole - Google Patents
Method for synthesizing brexpiprazole Download PDFInfo
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- CN106916148B CN106916148B CN201510993612.XA CN201510993612A CN106916148B CN 106916148 B CN106916148 B CN 106916148B CN 201510993612 A CN201510993612 A CN 201510993612A CN 106916148 B CN106916148 B CN 106916148B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention aims to provide a novel synthesis method of Brexpiprazole (Brexpiprazole): (a) taking a compound of formula I or a salt thereof as a raw material and a compound A under alkaline conditionsThen carrying out halogenation reaction in an aprotic solvent to obtain an intermediate II; (b) reacting the intermediate II with a compound III to obtain the ipiprazole, namely a compound IV, wherein the reaction formula is as follows:
Description
Technical Field
The present invention relates to a process for the synthesis of Brexpiprazole (Brexpiprazole) which is a useful antidepressant drug.
Background
The brexpiprazole is an experimental serotonin-dopamine activity regulator (SDAM) jointly developed by Lingbei pharmacy (license) and Tsukamur pharmacy (original research), is a novel multi-target action mechanism therapeutic drug for mental disorder diseases, mainly has partial excitation of a dopamine D2 receptor, partial excitation of a D3 receptor, partial excitation of a 5-HT1A receptor and partial antagonism of a 5-HT2A receptor, and is a novel drug which is developed aiming at multiple targets of a monoamine neurotransmitter and has the effects of resisting schizophrenia and depression: the chemical name of the compound is 7- (4- (4- (benzothiophen-4 yl) piperazine-1-yl) butoxy) quinoline-2 (1H) -ketone, and the chemical structure is as follows:
the methods for preparing ipiprazole reported at present all have the problems of more impurities and low yield, for example, a synthetic route of the ipiprazole is disclosed in CN101155804B, and the reaction route is as follows:
the route is that 7-hydroxyquinoline-2-ketone (compound III) reacts with halobutane to form a compound V, and then the compound V reacts with a compound I for substitution reaction, so that the final product of the ipiprazole is obtained. The reaction of the halobutane and the 7-hydroxyquinoline-2 ketone has more impurities, which is not beneficial to improving the product quality and the yield.
Disclosure of Invention
The invention aims to provide a novel synthesis method of brexpiprazole, which comprises the following steps: (a) taking a compound of formula I or a salt thereof as a raw material, and carrying out halogenation reaction on the compound A in an aprotic solvent under an alkaline condition to obtain an intermediate II; (b) reacting the intermediate II with a compound III to obtain the ipiprazole, namely a compound IV, wherein the reaction formula is as follows:
wherein:
the compound A is halobutane, X1 and X2 are halogens and are selected from chlorine or bromine; x1 and X2 may be the same or different halogens.
The compound I and the compound A are reacted in a non-aqueous solvent under the alkaline condition to obtain a compound II. Wherein the base is selected from inorganic bases such as sodium hydroxide and potassium carbonate, and the organic base is selected from triethylamine, N, N-diisopropylethylamine and DBU, preferably potassium carbonate. The using amount of the alkali is 4-7 times of the molar ratio of the compound I.
The solvent in step a may be selected from acetonitrile, N-dimethylformamide, dichloromethane, toluene, tetrahydrofuran, etc., preferably acetonitrile. The weight ratio of the selected solvent volume to the compound I is 5-20 times.
The method provided by the invention has the advantages of effectively improving the product yield, along with simple operation, low cost and high environmental friendliness, and is suitable for industrial production.
Detailed Description
Example 1:
preparation of compound IV:
4-piperazinyl benzothiopheneHydrochloride (29.2g, 0.1mol), 1, 4-dibromobutane (25.9g, 0.12mol), potassium carbonate (55.2g, 0.4mol) were added to acetonitrile (150ml), stirred, and heated to 60 degrees. After 4 hours of reaction, adding 7-hydroxyquinoline-2-one (16g, 0.1mol) into the reaction solution, heating to reflux and stirring for 16 hours, cooling to room temperature, filtering, pulping with water to obtain 38.6g of crude Ipiprazole (IV) as a white solid with the yield of 89.1%; MS (Mass Spectrometry)+＝434。
1H NMR(DMSO-d6,400M):11.55(s,1H),7.76～7.78(d,1H),7.65～7.67(d,1H),7.57～7.59(d,1H),7.51～7.53(d,1H),7.36～7.37(d,1H),7.22～7.26(t,1H),6.84～6.86(d,1H),6.76～6.78(m,2H),6.25～6.28(d,1H),4.01～4.04(t,2H),3.03(m,4H),2.58(m,4H),2.39～2.43(t,2H),1.57～1.64(m,2H)
Example 2:
4-Piperazinylbenzothiophene hydrochloride (29.2g, 0.1mol), 1, 4-dichlorobutane (15.2g, 0.12mol), potassium carbonate (55.2g, 0.4mol) were added to acetonitrile (150ml), stirred and heated to 60 ℃. After 4 hours of reaction, adding 7-hydroxyquinoline-2-one (16g, 0.1mol) into the reaction solution, heating to reflux and stirring for 16 hours, cooling to room temperature, filtering, pulping with water to obtain 34.7g of crude epipiprazole (IV) as a white solid, wherein the yield is 80.2%; MS (Mass Spectrometry)+＝434。
Example 3:
4-Piperazinylbenzothiophene hydrochloride (29.2g, 0.1mol), 1 chloro-4 bromobutane (20.5g, 0.12mol), potassium carbonate (55.2g, 0.4mol) were added to acetonitrile (150ml), stirred and heated to 60 degrees. After 4 hours of reaction, adding 7-hydroxyquinoline-2-one (16g, 0.1mol) into the reaction solution, heating to reflux and stirring for 16 hours, cooling to room temperature, filtering, pulping with water to obtain a white solid, namely 35.6g of crude epipiprazole (IV), and the yield is 82.3%; MS (Mass Spectrometry)+＝434。
Example 4:
4-Piperazinylbenzothiophene hydrochloride (29.2g, 0.1mol), 1, 4-dibromobutane (25.9g, 0.12mol), triethylamine (40.4g, 0.4mol) were added to acetonitrile (150ml), stirred, and heated to 60 ℃. After 4 hours of reaction, 7-hydroxyquinolin-2-one (16g, 0.1mol) was added to the reaction mixture, the mixture was heated to reflux and stirred for 16 hours, and then cooled to room temperatureFiltering, pulping with water to obtain a white solid, namely, 32.5g of crude brexpiprazole (IV), with the yield of 75.3%; MS (Mass Spectrometry)+＝434。
Example 5:
4-Piperazinylbenzothiophene hydrochloride (29.2g, 0.1mol), 1, 4-dibromobutane (25.9g, 0.12mol), N, N-diisopropylethylamine (51.6g, 0.4mol) were added to acetonitrile (150ml), stirred and heated to 60 degrees. After 4 hours of reaction, adding 7-hydroxyquinoline-2-one (16g, 0.1mol) into the reaction solution, heating to reflux and stirring for 16 hours, cooling to room temperature, filtering, pulping with water to obtain 33.0g of crude epipiprazole (IV) as a white solid, wherein the yield is 76.5%; MS (Mass Spectrometry)+＝434。
Example 6:
4-Piperazinylbenzothiophene hydrochloride (2.92g, 0.01mol), 1, 4-dibromobutane (2.59g, 0.012mol), DBU (6.08g, 0.04mol) were added to acetonitrile (15ml), stirred, and heated to 60 degrees. After 4 hours of reaction, adding 7-hydroxyquinoline-2-one (1.6g, 0.01mol) into the reaction solution, heating to reflux and stirring for 16 hours, cooling to room temperature, filtering, pulping with water to obtain a white solid, namely 3.1g of crude epipiprazole (IV), with the yield of 71.8%; MS (Mass Spectrometry)+＝434。
Example 7:
4-Piperazinylbenzothiophene hydrochloride (2.92g, 0.01mol), 1, 4-dibromobutane (2.59g, 0.012mol), sodium hydroxide (1.6g, 0.04mol) were added to acetonitrile (15ml), stirred, and heated to 60 degrees. After 4 hours of reaction, adding 7-hydroxyquinoline-2-one (1.6g, 0.01mol) into the reaction solution, heating to reflux and stirring for 16 hours, cooling to room temperature, filtering, pulping with water to obtain a white solid, namely 3.3g of crude epipiprazole (IV), with the yield of 76.8%; MS (Mass Spectrometry)+＝434。
Example 8:
4-Piperazinylbenzothiophene hydrochloride (2.92g, 0.01mol), 1, 4-dibromobutane (2.59g, 0.012mol), potassium carbonate (9.7g, 0.07mol) were added to acetonitrile (15ml), stirred, and heated to 60 degrees. After 4 hours of reaction, adding 7-hydroxyquinoline-2-one (1.6g, 0.01mol) into the reaction solution, heating to reflux and stirring for 16 hours, cooling to room temperature, filtering, pulping with water to obtain a white solid, namely crude product of ipiprazole(IV)3.8g, yield 87.7%; MS (Mass Spectrometry)+＝434。
Example 9:
4-Piperazinylbenzothiophene hydrochloride (2.92g, 0.01mol), 1, 4-dibromobutane (2.59g, 0.012mol), potassium carbonate (9.7g, 0.07mol) were added to acetonitrile (60ml), stirred, and heated to 60 degrees. After 4 hours of reaction, adding 7-hydroxyquinoline-2-one (1.6g, 0.01mol) into the reaction solution, heating to reflux and stirring for 16 hours, cooling to room temperature, filtering, pulping with water to obtain a white solid, namely 3.67g of crude epipiprazole (IV), with the yield of 84.9%; MS (Mass Spectrometry)+＝434。
Example 10:
4-Piperazinylbenzothiophene hydrochloride (2.92g, 0.01mol), 1, 4-dibromobutane (2.59g, 0.012mol), potassium carbonate (9.7g, 0.07mol) were added to N, N-dimethylformamide (15ml), stirred, and heated to 60 degrees. After 4 hours of reaction, adding 7-hydroxyquinoline-2-one (1.6g, 0.01mol) into the reaction solution, heating to reflux and stirring for 16 hours, cooling to room temperature, adding water for filtration, pulping the filter cake with water, and obtaining a white solid, namely 3.32g of crude product (IV) of ipiprazole with the yield of 76.9%; MS (Mass Spectrometry)+＝434。
Example 11:
4-Piperazinylbenzothiophene hydrochloride (2.92g, 0.01mol), 1, 4-dibromobutane (2.59g, 0.012mol), potassium carbonate (9.7g, 0.07mol) were added to dichloromethane (15ml), stirred, and heated to 40 degrees. After 4 hours of reaction, adding 7-hydroxyquinoline-2-one (1.6g, 0.01mol) into the reaction solution, heating to reflux and stirring for 22 hours, concentrating to dryness, pulping with water for 1 hour, and filtering by suction to obtain a white solid, namely 3.19g of crude product (IV) of ipiprazole, wherein the yield is 73.9%; MS (Mass Spectrometry)+＝434。
Example 12:
4-Piperazinylbenzothiophene hydrochloride (2.92g, 0.01mol), 1, 4-dibromobutane (2.59g, 0.012mol), potassium carbonate (9.7g, 0.07mol) were added to toluene (15ml), stirred, and heated to 80 ℃. After 4 hours of reaction, adding 7-hydroxyquinoline-2-one (1.6g, 0.01mol) into the reaction solution, heating to reflux and stirring for 12 hours, cooling to room temperature, filtering, pulping with water to obtain a white solid, namely 3.25g of crude epipiprazole (IV), with the yield of 75.3%; MS (Mass Spectrometry)+＝434。
Example 13:
4-Piperazinylbenzothiophene hydrochloride (2.92g, 0.01mol), 1, 4-dibromobutane (2.59g, 0.012mol), potassium carbonate (9.7g, 0.07mol) were added to tetrahydrofuran (15ml), stirred, and heated to 60 degrees. After 4 hours of reaction, adding 7-hydroxyquinoline-2-one (1.6g, 0.01mol) into the reaction solution, heating to reflux and stirring for 16 hours, concentrating to dryness, pulping with water and filtering by suction, wherein the obtained white solid is 3.4g of crude product (IV) of ipiprazole, and the yield is 78.7%; MS (Mass Spectrometry)+＝434。
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make several improvements and modifications to the present invention without departing from the principle of the present invention, and these improvements and modifications also fall within the scope of the claims of the present invention.
Claims (4)
1. A method for synthesizing Brexpiprazole (Brexpiprazole), which is characterized by comprising the following steps: (a) taking a compound of a formula I as a raw material, and carrying out halogenation reaction on the compound A in an aprotic solvent in the presence of alkali to obtain an intermediate II; (b) reacting the intermediate II with a compound III to obtain the ipiprazole, namely a compound IV, wherein the reaction formula is as follows:
in the above formulae, X1 and X2 are halogens, and X1 and X2 may be the same or different halogens;
wherein the molar ratio of the dosage of the alkali to the compound I is 4-7 times;
wherein the base is selected from the group consisting of organic bases and inorganic bases; the inorganic base is selected from: potassium carbonate, sodium hydroxide; the organic base is selected from: triethylamine, N-diisopropylethylamine, DBU;
wherein the aprotic solvent is selected from acetonitrile, toluene, dichloromethane, tetrahydrofuran, N-N-dimethylformamide.
2. The method of claim 1, wherein compound a is selected from: 1, 4-dichlorobutane, 1, 4-dibromobutane, 1-bromo-4-chlorobutane.
3. The process of claim 1, wherein the base is potassium carbonate.
4. The method according to claim 1, wherein the volume of the aprotic solvent is 5 to 20 times the weight of the compound I.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101155804A (en) * | 2005-04-14 | 2008-04-02 | 大塚制药株式会社 | Piperazine-substituted benzothiophenes for treatment of mental disorders |
| CN103717587A (en) * | 2011-07-28 | 2014-04-09 | 大塚制药株式会社 | Method for producing benzo[B]thiophene compound |
| CN104829602A (en) * | 2015-04-15 | 2015-08-12 | 重庆医药工业研究院有限责任公司 | Brexpiprazole preparation method |
| CN105061414A (en) * | 2015-07-21 | 2015-11-18 | 杭州新博思生物医药有限公司 | Method for preparing Brexpiprazole with one-pot process |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101155804A (en) * | 2005-04-14 | 2008-04-02 | 大塚制药株式会社 | Piperazine-substituted benzothiophenes for treatment of mental disorders |
| CN103717587A (en) * | 2011-07-28 | 2014-04-09 | 大塚制药株式会社 | Method for producing benzo[B]thiophene compound |
| CN104829602A (en) * | 2015-04-15 | 2015-08-12 | 重庆医药工业研究院有限责任公司 | Brexpiprazole preparation method |
| CN105061414A (en) * | 2015-07-21 | 2015-11-18 | 杭州新博思生物医药有限公司 | Method for preparing Brexpiprazole with one-pot process |
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