CN104447723A - Method for preparing 7-(4-(4-(benzo[b]thienyl)-1-piperazinyl) butoxy)-2(1H)-quinolinone - Google Patents
Method for preparing 7-(4-(4-(benzo[b]thienyl)-1-piperazinyl) butoxy)-2(1H)-quinolinone Download PDFInfo
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- CN104447723A CN104447723A CN201410714069.0A CN201410714069A CN104447723A CN 104447723 A CN104447723 A CN 104447723A CN 201410714069 A CN201410714069 A CN 201410714069A CN 104447723 A CN104447723 A CN 104447723A
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- piperazinyl
- benzo
- butoxy
- thienyl
- quinolinones
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- C—CHEMISTRY; METALLURGY
- 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 relates to a method for preparing 7-(4-(4-(benzo[b]thienyl)-1-piperazinyl) butoxy)-2(1H)-quinolinone, and belongs to the technical field of preparation of quinolinone derivatives. The method comprises the following steps: reacting 7-hydroxy-3,4-dihydro-2(1H)-quinolinone serving as an initial raw material with 1,4-dibromobutane to generate a compound III; reacting the compound III with 4-(1-piperazinyl) benzo[b]thienyl or hydrochloride thereof in an alkaline environment to generate a compound V; reacting the compound V with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in a solvent, extracting and drying the reacting product to prepare a crude product of a target product, and recrystallizing the crude product to obtain a competitive product 7-(4-(4-(benzo[b]thienyl)-1-piperazinyl) butoxy)-2(1H)-quinolinone. The method has the advantages of easily available raw materials, simple process, economy and environment friendliness, and is suitable for industrial production.
Description
Technical field
The present invention relates to the preparation method of a kind of 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones, belong to the preparing technical field of qualone derivative.
Background technology
7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones are first Dopamine HCL, the part 5-HT of the research and development of Ben Otsuka Pharmaceutical Co., Ltd
1Areceptor stimulant and 5-HT
2Areceptor agonist compounds, it has active widely at multiple monoamine systems, to dopamine D
2the partial agonist activity of acceptor declines, and to specific 5-HT acceptor (as 5-HT
1A, 5-HT
2A, 5-HT
7) avidity improve, there is better curative effect and tolerance, the untoward reactions such as patient cathisophobias, uneasy and/or insomnia can be reduced.Current this product is in for schizoid treatment in the clinical study of III phase, and the assisting therapy of major depressive disorder.In addition, this compound also for attention deficit hyperactivity disorder (ADHD) in expansion II phase clinical study.This product is a kind of Mutiple Targets resisting mental disease medicine having very much clinical meaning, has good DEVELOPMENT PROSPECT, is considered to well selling medicine---the another heavy pound kind after Aripiprazole continue the said firm's research and development.The structural formula of 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones is as follows:
About the preparation method of 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones has bibliographical information, patent WO2013162046, CN101258147B reports the synthetic method of 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones and analogue thereof, its method is summarized as follows: with 7-hydroxyl-1H quinolinone for starting raw material, react with the bromo-4-chlorobutane of 1-, generate 7-(4-chlorine butoxy)-2 (1H)-quinolinones, react with 4-(1-piperazinyl) benzo [b] thiophene or its hydrochloride again and generate 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones.Its reaction equation is as follows:
The shortcoming of this route is that starting raw material 7-hydroxyl-2 (1H) quinolinone price is higher and not easily buy, and causes production cost high, limits its suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones, its raw material be easy to get, technique is simple, economic environmental protection and be applicable to suitability for industrialized production.
The preparation method of 7-of the present invention (4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones (I), comprises the following steps:
(1) with 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone (II) for starting raw material, with Isosorbide-5-Nitrae-dibromobutane reacting generating compound III;
(2) under alkaline environment, compound III and 4-(1-piperazinyl) benzo [b] thiophene (IV) or its hydrochloride reacting generating compound V;
(3) compound V and 2,3-bis-chloro-5,6-dicyan para benzoquinone (DPQ) reacts in a solvent, reaction product is extracted, dry, the crude product of obtained target product, then recrystallization is carried out to crude product, obtained fine work 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones (I).
For 4-(1-piperazinyl) benzo [b] thiophene raw material, reaction equation is as follows:
The mol ratio of described 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone and Isosorbide-5-Nitrae-dibromobutane is 1:6-12, be preferably 1:9, this reaction can in salt of wormwood and acetone reacting generating compound III.
The mol ratio of described compound III and 4-(1-piperazinyl) benzo [b] thiophene or its hydrochloride is 1:1.1-1.5, be preferably 1:1.3, this reaction can in potassiumiodide and acetonitrile reacting generating compound V.
Step (2) alkali used is sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood or cesium carbonate.
The mol ratio of described compound V and chloro-5, the 6-dicyan para benzoquinone of 2,3-bis-is 1:1.5-2, is preferably 1:1.7.
Step (3) solvent for use is methylene dichloride, acetonitrile, toluene, tetrahydrofuran (THF), DMF or ethyl acetate.
In step (3), temperature of reaction is 15-40 DEG C, is preferably 25 DEG C.
Step (3) extraction agent used is methylene dichloride; To reaction product anhydrous sodium sulfate drying; Recrystallization solvent for use is ethyl acetate.
Compared with prior art, the present invention has following beneficial effect:
The preparation method of 7-of the present invention (4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones, have that raw material is easy to get, technique is simple, the advantage of economic environmental protection, be applicable to suitability for industrialized production.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated, but do not limit enforcement of the present invention.
Raw materials usedly be commercially available prod.
Embodiment 1
(1) acetone (50mL) is added in there-necked flask, open and stir, add Isosorbide-5-Nitrae-dibromobutane (10.8mL, 0.09mol) successively, salt of wormwood (4.2g, 0.03mol), then add 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone (II) (2.5g in batches, 0.015mol), reflux.Reaction terminates rear first steaming and removes acetone, washes twice (25mL × 2), suction filtration, filter cake hexanaphthene drip washing with hexanaphthene.Be the normal hexane of 2:1 and the mixed solution recrystallization of ethyl acetate by gained crude product volume ratio, obtain product 7-(4-bromine butoxy)-3,4-dihydro-2 (1H)-quinolinone (III) 3.8g, productive rate is 85%.
(2) acetonitrile (60mL) is added in there-necked flask, open and stir, add 7-(4-bromine butoxy)-3,4-dihydro-2 (1H)-quinolinone (III) (3.4g, 0.011mol), potassiumiodide (3.3g, 0.022mol), cesium carbonate (7.1g, 0.022mol), reflux 30min, add 4-(1-piperazinyl) benzo [b] thiophene hydrochloride (IV) (3.1g, 0.012mol), back flow reaction 4h.Reaction terminates rear steaming and desolventizes, add the making beating of 100mL water, stir 1h, suction filtration, gets filter cake.Obtain product 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-3,4-dihydro-2 (1H)-quinolinone (V) 4.5g with ethyl alcohol recrystallization, productive rate is 95%.
(3) tetrahydrofuran (THF) (50mL) is added in there-necked flask, open and stir, add 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-3,4-dihydros-2 (1H)-quinolinone (V) (4.4g, 0.01mol), stir 30min, add chloro-5,6-dicyan para benzoquinone (the DDQ) (3.4g of 2,3-bis-, 0.015mol), room temperature reaction 8h.After reaction terminates, aqueous sodium hydroxide solution with 10% will react cancellation, then dichloromethane extraction three times (20mL × 3) is used, crude product is steamed to obtain with revolving after anhydrous sodium sulfate drying, use re-crystallizing in ethyl acetate again, obtain product 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinone (I) 3.9g, productive rate is 91%.
Embodiment 2
(1) acetone (500mL) is added in there-necked flask, open and stir, add Isosorbide-5-Nitrae-dibromobutane (162mL, 1.35mol) successively, salt of wormwood (41.4g, 0.3mol), then add 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone (II) (24.5g in batches, 0.15mol), reflux 30h.Reaction terminates first to steam except acetone afterwards, adds washing, hexanaphthene washes twice (250mL × 2), suction filtration, filter cake hexanaphthene drip washing.Be the sherwood oil of 2:1 and the mixed solution recrystallization of ethyl acetate by gained crude product volume ratio, obtain product 7-(4-bromine butoxy)-3,4-dihydro-2 (1H)-quinolinone (III) 36.2g, productive rate is 81%.
(2) acetonitrile (600mL) is added in there-necked flask, open and stir, add 7-(4-bromine butoxy)-3,4-dihydro-2 (1H)-quinolinone (III) (30g, 0.1mol), sodium iodide (30g, 0.2mol), salt of wormwood (27.6g, 0.2mol), reflux 30min, add 4-(1-piperazinyl) benzo [b] thiophene hydrochloride (IV) (32.9g, 0.13mol), back flow reaction 4h.Reaction terminates rear steaming and desolventizes, and adds the making beating of 100mL water, stir 1h, suction filtration, gets filter cake.Obtain product 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-3,4-dihydro-2 (1H)-quinolinone (V) 40g with ethyl alcohol recrystallization, productive rate is 92%.
(3) methylene dichloride (350mL) is added in there-necked flask, open and stir, add 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-3,4-dihydros-2 (1H)-quinolinone (V) (35g, 0.08mol), stir 30min, add chloro-5,6-dicyan para benzoquinone (the DDQ) (31g of 2,3-bis-, 0.14mol), 15 DEG C of reaction 10h.After reaction terminates, aqueous sodium hydroxide solution with 10% will react cancellation, then dichloromethane extraction three times (200mL × 3) is used, crude product is steamed to obtain with revolving after sodium sulphite anhydrous 99.3 drying, use re-crystallizing in ethyl acetate again, obtain product 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinone (I) 31.2g, productive rate is 90%.
Embodiment 3
(1) acetone (7.5L) is added in 20L reactor, open and stir, add Isosorbide-5-Nitrae-dibromobutane (3.24L, 27mol) successively, salt of wormwood (621g, 4.5mol), then add 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone (II) (367.5g in batches, 2.25mol), 65 DEG C of reaction 30h are heated to.After reaction terminates, reaction terminates first to steam except acetone afterwards, adds washing, hexanaphthene washes twice (3L × 2), filter cake hexanaphthene drip washing.Be the hexanaphthene of 2:1 and the mixed solution recrystallization of ethyl acetate by gained crude product volume ratio, obtain product 7-(4-bromine butoxy)-3,4-dihydro-2 (1H)-quinolinone (III) 556.5g, productive rate is 83%.
(2) acetonitrile (10L) is added in 20L reactor, open and stir, add 7-(4-bromine butoxy)-3,4-dihydro-2 (1H)-quinolinone (III) (536g, 1.8mol), sodium iodide (540g, 3.6mol), sodium carbonate (381.6g, 3.6mol), reflux 30min, add 4-(1-piperazinyl) benzo [b] thiophene hydrochloride (IV) (685g, 2.7mol), back flow reaction 4h.Reaction terminates rear steaming and desolventizes, and adds the making beating of 100mL water, stir 1h, suction filtration, gets filter cake.Obtain product 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-3,4-dihydro-2 (1H)-quinolinone (V) 713g with ethyl alcohol recrystallization, productive rate is 91%.
(3) acetonitrile (7L) is added in 20L reactor, open and stir, add 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-3,4-dihydros-2 (1H)-quinolinone (V) (700g, 1.6mol), stir 30min, add chloro-5,6-dicyan para benzoquinone (the DDQ) (726g of 2,3-bis-, 3.2mol), 40 DEG C of reaction 10h.After reaction terminates, aqueous sodium hydroxide solution with 10% will react cancellation, then dichloromethane extraction three times (2L × 3) is used, crude product is steamed to obtain with revolving after sodium sulphite anhydrous 99.3 drying, use re-crystallizing in ethyl acetate again, obtain product 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinone (I) 610g, productive rate is 88%.
Claims (10)
1. a preparation method for 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones, is characterized in that comprising the following steps:
(1) with 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone for starting raw material, with Isosorbide-5-Nitrae-dibromobutane reacting generating compound III;
(2) under alkaline environment, compound III and 4-(1-piperazinyl) benzo [b] thiophene or its hydrochloride reacting generating compound V;
(3) compound V and 2,3-bis-chloro-5,6-dicyan para benzoquinone reacts in a solvent, reaction product is extracted, dry, the crude product of obtained target product, then recrystallization is carried out to crude product, obtained fine work 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones.
2. the preparation method of 7-according to claim 1 (4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones, it is characterized in that: 7-hydroxyl-3, the mol ratio of 4-dihydro-2 (1H)-quinolinone and Isosorbide-5-Nitrae-dibromobutane is 1:6-12.
3. the preparation method of 7-according to claim 1 and 2 (4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones, it is characterized in that: 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone and Isosorbide-5-Nitrae-dibromobutane reacting generating compound III in salt of wormwood and acetone.
4. the preparation method of 7-according to claim 1 (4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones, is characterized in that: the mol ratio of compound III and 4-(1-piperazinyl) benzo [b] thiophene or its hydrochloride is 1:1.1-1.5.
5. the preparation method of 7-(4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (the 1H)-quinolinones according to claim 1 or 4, is characterized in that: compound III and 4-(1-piperazinyl) benzo [b] thiophene or its hydrochloride reacting generating compound V in potassiumiodide and acetonitrile.
6. the preparation method of 7-according to claim 1 (4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones, is characterized in that: step (2) alkali used is sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood or cesium carbonate.
7. the preparation method of 7-according to claim 1 (4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones, it is characterized in that: compound V and 2, the mol ratio of chloro-5, the 6-dicyan para benzoquinone of 3-bis-is 1:1.5-2.
8. the preparation method of 7-according to claim 1 (4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones, it is characterized in that: step (3) solvent for use is methylene dichloride, acetonitrile, toluene, tetrahydrofuran (THF), DMF or ethyl acetate.
9. the preparation method of 7-according to claim 1 (4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones, it is characterized in that: in step (3), temperature of reaction is 15-40 DEG C.
10. the preparation method of 7-according to claim 1 (4-(4-(benzo [b] thienyl)-1-piperazinyl) butoxy)-2 (1H)-quinolinones, is characterized in that: step (3) extraction agent used is methylene dichloride; To reaction product anhydrous sodium sulfate drying; Recrystallization solvent for use is ethyl acetate.
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| 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 |
| CN104844585A (en) * | 2015-04-15 | 2015-08-19 | 重庆医药工业研究院有限责任公司 | Preparation method of brexpiprazole |
| CN104844586A (en) * | 2015-04-16 | 2015-08-19 | 重庆医药工业研究院有限责任公司 | Amorphous brexpiprazole and preparation method thereof |
| CN105541819A (en) * | 2016-02-04 | 2016-05-04 | 浙江永宁药业股份有限公司 | Preparation method and intermediate of brexpiprazole and preparation method of intermediate |
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| CN106632291A (en) * | 2016-10-09 | 2017-05-10 | 瑞阳制药有限公司 | Brexpiprazole crystal, its preparation method and application, and pharmaceutical composition comprising brexpiprazole crystal |
| WO2017115287A1 (en) | 2015-12-28 | 2017-07-06 | Honour (R&D) | Process for the preparation of quinoline-2(1h)-one derivatives |
| CN107098855A (en) * | 2017-04-05 | 2017-08-29 | 上海诺星医药科技有限公司 | A kind of method for preparing the quinolinone of 7 hydroxyl 2 |
| WO2018015354A1 (en) | 2016-07-19 | 2018-01-25 | Adamed Sp. Z O.O. | The method for manufacture of brexpiprazole, intermediates used in this method, and the method for manufacture thereof |
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| CN104844585A (en) * | 2015-04-15 | 2015-08-19 | 重庆医药工业研究院有限责任公司 | Preparation method of brexpiprazole |
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| EP3397636A4 (en) * | 2015-12-28 | 2019-10-09 | Honour (R&D) | Process for the preparation of quinoline-2(1h)-one derivatives |
| CN105541819A (en) * | 2016-02-04 | 2016-05-04 | 浙江永宁药业股份有限公司 | Preparation method and intermediate of brexpiprazole and preparation method of intermediate |
| CN105541819B (en) * | 2016-02-04 | 2018-09-14 | 浙江永宁药业股份有限公司 | A kind of preparation method of the Preparation Method And Their Intermediate and intermediate of epirizole group |
| CN106188023A (en) * | 2016-07-04 | 2016-12-07 | 山东川成医药股份有限公司 | A kind of process for purification of epirizole group |
| WO2018015354A1 (en) | 2016-07-19 | 2018-01-25 | Adamed Sp. Z O.O. | The method for manufacture of brexpiprazole, intermediates used in this method, and the method for manufacture thereof |
| CN106632291A (en) * | 2016-10-09 | 2017-05-10 | 瑞阳制药有限公司 | Brexpiprazole crystal, its preparation method and application, and pharmaceutical composition comprising brexpiprazole crystal |
| CN107098855A (en) * | 2017-04-05 | 2017-08-29 | 上海诺星医药科技有限公司 | A kind of method for preparing the quinolinone of 7 hydroxyl 2 |
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