CN105061414A - Method for preparing Brexpiprazole with one-pot process - Google Patents
Method for preparing Brexpiprazole with one-pot process Download PDFInfo
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Abstract
The invention relates to a method for preparing Brexpiprazole with a one-pot process. 7-hydroxyl-2-quinolone reacts with added 1-bromine-4-chlorobutane in the presence of alcohol and alkali, 1-(benzo[B]thiophen-4-yl) piperazine hydrochloride and water are added for a further reaction, finally, filtration, separation and drying are performed, and Brexpiprazole is obtained. Compared with the prior art, the method has the benefits as follows: 1, the problems of insufficient reaction and difficulty in purification in the prior art are solved; 2, the operation process is simplified, and the production efficiency is greatly improved; 3, used solvents are safe, and less environment pollution is caused.
Description
Technical field
The present invention relates to the preparation method of a kind of Brexpiprazole, especially a kind of one kettle way prepares the method for Brexpiprazole.
Technical background
Brexpiprazole, structural formula is
, chemistry 7-(4-(4-(benzo [b] thiophene-4-base)-piperazine-1-base) butoxy)-1H-quinoline-2-one-by name.
On July 14th, 2014, the northern pharmacy of Denmark's spirit announces and Japan's large tomb pharmacy have submitted the new drug application (NDA) of brexpiprazole to U.S. food Drug Administration (FDA), obtains FDA approval listing on July 10th, 2015.This medicine can be used for assisting therapy and the schizophrenia of major depressive disorder.
Brexpiprazole is a serotonin-dopamine active regulator (SDAM), dopamine D 2 and 5-HT2A acceptor can be acted on, it has active widely at multiple monoamine systems, the partial agonist activity of d2 dopamine receptor is declined, and the avidity of specific 5-HT acceptor (as 5-HT1A, 5-HT2A, 5-HT7) is improved, there is better curative effect and tolerance, the untoward reactions such as patient cathisophobias, uneasy and/or insomnia can be reduced.Be a kind of Mutiple Targets resisting mental disease medicine having very much clinical meaning, have a good application prospect.Be considered to well selling medicine---the another heavy pound kind after Aripiprazole of Ji great tomb drugmaker research and development.
WO2006112464(CN101155804B) method of wherein two kinds of synthesis Brexpiprazole is provided.
Route one:
This route with 1-(benzo [b] thiophene-4-base) piperazine or its salt for starting raw material, by with compound (II) 1-bromo-4-chlorobutane generation substitution reaction, column chromatography for separation obtains 1-benzo [b] thiophene-4-base-4-(4-chlorobutyl) piperazine, 1-benzo [b] thiophene-4-base-4-(4-chlorobutyl) piperazine of gained reacts with compound (I) 7-hydroxyl-2-quinolone again, and by column chromatography for separation, tentatively obtain target product Brexpiprazole.In this route, step one and step 2 need be extracted by the mode of column chromatography for separation and obtain target product, complex operation, are not suitable for industry and amplify.
Route two:
This route is in single solvent methyl alcohol, and compound (I) 7-hydroxyl-2-quinolone reacts with the bromo-4-chlorobutane of compound (II) 1-under the effect of alkali, and column chromatography for separation obtains compound (III) 7-(4-chlorine butoxy)-1H-quinoline-2-one-; Compound (III) and compound (IV) 1-(benzo [B] thiophene-4-base) piperazine react, and tentatively obtain 0170-0172 section, 0355-0357 section in Brexpiprazole(referenced patent CN101155804B by column chromatography).Two steps in this route all need to extract required target product, complex operation by column chromatography for separation, are not suitable for industry and amplify.And in the synthesis of compound (III), raw material 7-hydroxyl-2-quinolone cannot complete reaction.
In addition, in patent CN103717587A [0324] section reference example 9 disclose a kind of with compound (I) and compound (II) for raw material, make the method for alkali synthetic intermediate compound (III) in DMF with salt of wormwood.But DMF is a kind of high boiling point nitrogen-containing solvent, and general aftertreatment need wash removal with water, thus brings the pressure of sewage disposal.
Summary of the invention
The object of the present invention is to provide a kind of simple process, be suitable for the preparation method of the Brexpiprazole of suitability for industrialized production.
In order to realize foregoing invention object, the present invention specifically adopts following technical scheme:
A kind of one kettle way preparation is as formula V
The method of shown compd B rexpiprazole, is characterized in that: by formula (I)
Shown compound and formula (II)
Shown compound, in alcoholic solvent, reacts under the effect of alkali, obtains formula (III)
Shown compound, without separation, directly adds water and formula (IV) in above reaction solution
Shown compound or its salt, reacts further, and filtering separation is dry, obtains compd B rexpiprazole.In above preparation method, intermediate is without the need to through separating-purifying, and directly " one kettle way " prepares Brexpiprazole, solve the problem of purification difficult in reaction process, and molar yield is not affected.This invention simplifies technological operation, avoid repeatedly material transfer, avoid the bringing into and operate miss of impurity in material transfer and separating-purifying process, substantially increase production efficiency, be conducive to carrying out continuous print suitability for industrialized production.
During compound (I) and compound (II) react, alcoholic solvent used is ethanol, n-propyl alcohol or Virahol, and alkali is salt of wormwood or sodium carbonate.Speed of response faster can be ensured, the amount of impurity can be controlled again in lower level.The present invention, by selecting suitable solvent and alkali, improves in compound (III) building-up process and reacts insufficient problem.
In the reaction of compound (III) and compound (IV), in the reaction of compound (III) and compound (IV), add the amount of water and the add-on of above-mentioned alcoholic solvent volume ratio be 0.5-2.0.
Compound (I) is 1:1.0 ~ 2.0 with the mol ratio of compound (II), is preferably 1:1.1 ~ 1.5.
Compound (I) is 1:1.0 ~ 5.0 with the molar ratio of basic cpd, is preferably 1:1.5 ~ 3.5.
Compound (I) is 1:0.6 ~ 2.0 with the molar ratio of compound (IV), is preferably 1:0.9 ~ 1.5.
Temperature of reaction time synthetic compound (III) be 50 DEG C to reflux temperature, the reaction times is 1 ~ 4 hour.
Temperature of reaction time synthetic compound (V) be 50 DEG C to reflux temperature, the reaction times is 6 ~ 12 hours.
Compared with prior art, the present invention has following beneficial effect:
1, solve in prior art and react insufficient, the problem of purification difficult;
2, simplify operating process, substantially increase production efficiency;
3, solvent for use safety, environmental pollution is less.
Embodiment
Come by the following examples to describe the present invention in more detail, but this should not regard limitation of the present invention as.
Reference example 1
The determination of alkali and solvent in the synthesis of 7-(4-chlorine butoxy)-1H-quinoline-2-one-
The synthesis condition of the present inventor to the 7-mentioned in route two (4-chlorine butoxy)-1H-quinoline-2-one-(compound (III)) is studied, in this patent, single solvent methyl alcohol and alkali sodium hydroxide have been used in the synthesis of compound (III), but find according to the method in route two by HPLC monitoring reaction progress, when backflow 14 hours, compound (I) still remains 22% and does not react completely, and creating two other impurity, other impurity summations are 13%.The present inventor adopts salt of wormwood and ethanol respectively as alkali and solvent, and only need react and within 2 hours, just make compound (I) obtain complete reaction, the total amount of impurity is only 9%.
Concrete outcome is as shown in the table:
In addition, the present invention in reaction 1 when 22h unreacted compound (I) also measure, be 12.6%, the method for visible reaction 1 is difficult to make starting compound (I) obtain complete reaction.The present inventor has also carried out the test salt of wormwood in reaction 2 being replaced with potassium hydroxide, although energy complete reaction, the impurity summation produced is 32%.Therefore, select salt of wormwood as alkali, ethanol as solvent, can fast reaction speed, also can reduce foreign matter content.
Embodiment 1
The preparation of Brexpiprazole
Compound (I) 7-hydroxyl-2-quinolone (10.0g, 62mmol), 120ml ethanol and salt of wormwood (19.0g, 138mmol) is added in 500ml reaction flask.Add the bromo-4-chlorobutane (12.0g, 70mmol) of compound (II) 1-under stirring, be warming up to return stirring 2 hours.Add 100ml water and compound (IV) 1-(benzo [b] thiophene-4-base) piperazine hydrochloride (15.0g, 59mmol), continue return stirring 9 hours.Steam partial solvent, be cooled to 50 DEG C, add after 40ml ethyl acetate stirs 0.5 hour and continue to be cooled to less than 20 DEG C, filtration under diminished pressure, filter cake, with after 20ml washing with alcohol three times, puts into air dry oven 70 DEG C of dryings 3 hours.Obtain Brexpiprazole(compound V) 14.5g, molar yield is 54%, compared with the molar yield 55% of method described in route two, does not substantially have difference.
1HNMR(400MHz,dmso)δ11.58(s,1H),7.79(d,
J=9.5Hz,1H),7.68(d,
J=3.5Hz,1H),7.60(d,
J=7.8Hz,1H),7.54(d,
J=8.3Hz,1H),7.39(s,1H),7.26(t,
J=7.4Hz,1H),6.86(d,
J=7.5Hz,1H),6.80(d,
J=8.5Hz,2H),6.29(d,
J=9.4Hz,1H),4.04(s,2H),3.04(s,4H),2.60(s,4H),2.42(s,2H),1.79(s,2H),1.62(s,2H).。
Claims (7)
1. one kettle way prepares a method of Brexpiprazole, it is characterized in that: by formula I
Shown compound and formula II
Shown compound, in alcoholic solvent, reacts, obtains formula III under the effect of alkali
Shown compound, compound (III), without separation, adds water and formula IV wherein
Shown compound or its salt, reacts further, and filtering separation is dry, obtains formula (V)
Shown compd B rexpiprazole; Wherein compound (I) is with the reaction of compound (II), and alcoholic solvent used is ethanol, n-propyl alcohol or Virahol, and alkali is salt of wormwood or sodium carbonate.
2. preparation method according to claim 1, is characterized in that: in the reaction of compound (III) and compound (IV), add the amount of water and the add-on of above-mentioned alcoholic solvent volume ratio be 0.5-2.0.
3. preparation method according to claim 1, is characterized in that: compound (I) is 1:1.1-1.5 with the mol ratio of compound (II).
4. preparation method according to claim 1, is characterized in that: compound (I) is 1:1.5-3.5 with the molar ratio of basic cpd.
5. preparation method according to claim 1, is characterized in that: compound (I) is 1:0.9-1.5 with the molar ratio of compound (IV) or salt.
6. preparation method according to claim 1, is characterized in that: the temperature of reaction of synthetic compound (III) be 50 DEG C to reflux temperature, the reaction times is 1-4 hour.
7. preparation method according to claim 1, is characterized in that: the temperature of reaction of synthetic compound (V) be 50 DEG C to reflux temperature, the reaction times is 6-12 hour.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106770746A (en) * | 2016-12-09 | 2017-05-31 | 成都百裕制药股份有限公司 | According to the detection method of the chlorobutane of 1 bromine 4 in a piperazine azoles intermediate |
| CN106916148A (en) * | 2015-12-25 | 2017-07-04 | 上海科胜药物研发有限公司 | A kind of synthesis is according to a method for piperazine azoles |
| WO2017194002A1 (en) * | 2016-05-12 | 2017-11-16 | 浙江华海药业股份有限公司 | Crystal form of brexpiprazole and preparation method therefor |
| 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 |
| CN107936005A (en) * | 2016-10-13 | 2018-04-20 | 上海科胜药物研发有限公司 | One kind is according to piperazine azoles novel crystal forms II and preparation method thereof |
| US10358440B2 (en) | 2016-05-03 | 2019-07-23 | Cadila Healthcare Limited | Process for the preparation of brexpiprazole and intermediates thereof |
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| EP0570850B1 (en) * | 1992-05-19 | 1996-12-11 | HOECHST MARION ROUSSEL, Inc. | Benzo(b)thiophen-3-yl-piperazines, a process for their preparation and their use as medicaments |
| 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 |
| CN104557896A (en) * | 2013-10-18 | 2015-04-29 | 沈敬山 | Brexpiprezole, and preparation methods of key intermediate and salt thereof |
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| EP0570850B1 (en) * | 1992-05-19 | 1996-12-11 | HOECHST MARION ROUSSEL, Inc. | Benzo(b)thiophen-3-yl-piperazines, a process for their preparation and their use as medicaments |
| CN101155804A (en) * | 2005-04-14 | 2008-04-02 | 大塚制药株式会社 | Piperazine-substituted benzothiophenes for treatment of mental disorders |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106916148A (en) * | 2015-12-25 | 2017-07-04 | 上海科胜药物研发有限公司 | A kind of synthesis is according to a method for piperazine azoles |
| CN106916148B (en) * | 2015-12-25 | 2021-07-06 | 上海科胜药物研发有限公司 | Method for synthesizing brexpiprazole |
| US10358440B2 (en) | 2016-05-03 | 2019-07-23 | Cadila Healthcare Limited | Process for the preparation of brexpiprazole and intermediates thereof |
| CN107365305A (en) * | 2016-05-12 | 2017-11-21 | 上海奥博生物医药技术有限公司 | One kind is according to piperazine azoles novel crystal forms and preparation method thereof |
| CN109071517A (en) * | 2016-05-12 | 2018-12-21 | 浙江华海药业股份有限公司 | According to the crystal form and preparation method thereof of piperazine azoles |
| US10550109B2 (en) | 2016-05-12 | 2020-02-04 | Zhejiang Huahai Pharmaceutical Co., Ltd | Crystal form of brexpiprazole and preparation method therefor |
| WO2017194002A1 (en) * | 2016-05-12 | 2017-11-16 | 浙江华海药业股份有限公司 | Crystal form of brexpiprazole and preparation method therefor |
| 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 |
| CN107936005A (en) * | 2016-10-13 | 2018-04-20 | 上海科胜药物研发有限公司 | One kind is according to piperazine azoles novel crystal forms II and preparation method thereof |
| CN109863149A (en) * | 2016-10-13 | 2019-06-07 | 浙江华海药业股份有限公司 | One kind is according to piperazine azoles novel crystal forms and preparation method thereof |
| CN114957230A (en) * | 2016-10-13 | 2022-08-30 | 浙江华海药业股份有限公司 | Novel crystal form of brexpiprazole and preparation method thereof |
| CN106770746B (en) * | 2016-12-09 | 2019-06-07 | 成都百裕制药股份有限公司 | According to the detection method of the bromo- 4- chlorobutane of 1- in piperazine azoles intermediate |
| CN106770746A (en) * | 2016-12-09 | 2017-05-31 | 成都百裕制药股份有限公司 | According to the detection method of the chlorobutane of 1 bromine 4 in a piperazine azoles intermediate |
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