CN105061414B - One kettle way prepares Brexpiprazole - Google Patents
One kettle way prepares Brexpiprazole Download PDFInfo
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- CN105061414B CN105061414B CN201510427992.0A CN201510427992A CN105061414B CN 105061414 B CN105061414 B CN 105061414B CN 201510427992 A CN201510427992 A CN 201510427992A CN 105061414 B CN105061414 B CN 105061414B
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- C07—ORGANIC CHEMISTRY
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- 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
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Abstract
The present invention relates to a kind of methods that Brexpiprazole is prepared with one kettle way.7- hydroxyl -2- quinolone reacts in the presence of pure and mild alkali with the bromo- 4- chlorobutane of the 1- of addition, and 1- (benzo [B] thiophene -4- base) piperazine hydrochloride then is added and water further reacts, is finally separated by filtration drying, obtains Brexpiprazole.Compared with prior art, the invention has the following advantages: 1, solve the problem of reacting insufficient in the prior art, purification difficult；2, operating process is simplified, production efficiency is substantially increased；3, solvent for use safety, environmental pollution are smaller.
Description
Technical field
The present invention relates to the preparation methods of Brexpiprazole a kind of, especially a kind of to be prepared with one kettle way
The method of Brexpiprazole.
Technical background
Brexpiprazole, structural formula are, the entitled 7- (4- of chemistry
(4- (benzo [b] thiophene -4- base)-piperazine -1- base) butoxy) -1H- quinoline-2-one.
On July 14th, 2014, Denmark's Lundbeck pharmacy is announced and the big tomb pharmacy of Japan is to U.S. Food and Drug Administration
(FDA) New Drug Application (NDA) of brexpiprazole is had submitted, obtains FDA approval listing on July 10th, 2015.The drug is available
In the adjuvant treatment and schizophrenia of major depressive disorder.
Brexpiprazole is a serotonin-dopamine active regulator (SDAM), may act on dopamine D 2 and 5-
HT2A receptor has extensive activity in multiple monoamine systems, declines to the partial agonist activity of d2 dopamine receptor,
And the affinity of specific 5-HT receptor (such as 5-HT1A, 5-HT2A, 5-HT7) is improved, there is better curative effect and tolerance, it can
Reduce patient cathisophobia, the adverse reactions such as uneasy and/or insomnia.It is a kind of multiple target point resisting mental disease for having very much clinical meaning
Drug has a good application prospect.It is considered as the well selling medicine after the research and development of great Zhong drugmaker --- after Aripiprazole
Another heavy pound kind.
WO2006112464(CN101155804B the method for two of them synthesis Brexpiprazole) is provided.
Route one:
This route using 1- (benzo [b] thiophene -4- base) piperazine or its salt as starting material, by with compound (II) 1-
Substitution reaction occurs for bromo- 4- chlorobutane, and column chromatography for separation obtains 1- benzo [b] thiophene -4- base -4- (4- chlorobutyl) piperazine, institute
1- benzo [b] thiophene -4- base -4- (4- chlorobutyl) piperazine obtained is reacted with compound (I) 7- hydroxyl -2- quinolone again, and is led to
Column chromatography for separation is crossed, target product Brexpiprazole is tentatively obtained.In the route, step 1 and step 2 need to pass through column layer
Isolated mode is analysed to extract to obtain target product, it is cumbersome, be not suitable for industry amplification.
Route two:
The route in single solvent methanol, compound (I) 7- hydroxyl -2- quinolone in the presence of alkali with compound
(II) the bromo- 4- chlorobutane reaction of 1-, column chromatography for separation obtain compound (III) 7- (4- neoprene oxygroup) -1H- quinoline-2-one；Change
It closes object (III) to react with compound (IV) 1- (benzo [B] thiophene -4- base) piperazine, tentatively be obtained by column chromatography
0170-0172 sections, 0355-0357 sections in Brexpiprazole(referenced patent CN101155804B).Two in the route
Step all needs target product needed for extracting by column chromatography for separation, cumbersome, is not suitable for industry amplification.And compound (III)
Synthesis in, raw material 7- hydroxyl -2- quinolone can not react completely.
In addition, [0324] section reference example 9 discloses one kind with compound (I) and compound in patent CN103717587A
(II) it is raw material, makees the method for alkali synthetic intermediate compound (III) in DMF with potassium carbonate.But DMF is that a kind of higher boiling contains
Nitrogen solvent, removal need to be washed with water in general post-processing, to bring the pressure of sewage treatment.
Summary of the invention
The purpose of the present invention is to provide a kind of simple processs, are suitable for the system of the Brexpiprazole of industrialized production
Preparation Method.
In order to achieve the above-mentioned object of the invention, the present invention specifically adopts the following technical scheme that
A kind of one kettle way preparation such as formula (V)
The method of compound represented Brexpiprazole, it is characterised in that: by formula (I)
Compound represented and formula (II)
Compound represented is reacted in the presence of alkali in alcoholic solvent, obtains formula (III)
Compound represented is directly added into water and formula (IV) in the above reaction solution without isolation
Compound represented or its salt further react, are separated by filtration drying, obtain compound Brexpiprazole.With
In upper preparation method, intermediate is not necessarily to through separating-purifying, and direct " one kettle way " prepares Brexpiprazole, is solved and was reacted
In journey the problem of purification difficult, and molar yield is not affected by influence.This invention simplifies technological operations, avoid multiple material and turn
Move, avoid material transfer and separating-purifying during impurity bring into and operating error, substantially increase production efficiency, favorably
In the continuous industrialized production of progress.
During compound (I) is reacted with compound (II), alcoholic solvent used is ethyl alcohol, normal propyl alcohol or isopropanol, and alkali is carbon
Sour potassium or sodium carbonate.Not only it can guarantee faster reaction speed, but also can control the amount of impurity in lower level.The present invention passes through
Suitable solvent and alkali are selected, improves in compound (III) synthesis process and reacts insufficient problem.
In the reaction of compound (III) and compound (IV), in the reaction of compound (III) and compound (IV), added
The volume ratio of the amount of water and the additional amount of above-mentioned alcoholic solvent is 0.5-2.0.
The mol ratio of compound (I) and compound (II) are 1: 1.0 ~ 2.0, preferably 1: 1.1 ~ 1.5.
The molar ratio of compound (I) and alkali compounds is 1: 1.0 ~ 5.0, preferably 1: 1.5 ~ 3.5.
The molar ratio of compound (I) and compound (IV) are 1: 0.6 ~ 2.0, preferably 1: 0.9 ~ 1.5.
Reaction temperature when synthesizing compound (III) is 50 DEG C to reflux temperature, and the reaction time is 1 ~ 4 hour.
Reaction temperature when synthesizing compound (V) is 50 DEG C to reflux temperature, and the reaction time is 6 ~ 12 hours.
Compared with prior art, the invention has the following advantages:
1, it solves and reacts insufficient in the prior art, the problem of purification difficult；
2, operating process is simplified, production efficiency is substantially increased；
3, solvent for use safety, environmental pollution are smaller.
Specific embodiment
Next by the following examples the present invention will be described in more detail, but this is not construed as limiting thereof.
Reference implementation example 1
The determination of alkali and solvent in the synthesis of 7- (4- neoprene oxygroup) -1H- quinoline-2-one
Conjunction of the present inventor to 7- (4- neoprene the oxygroup) -1H- quinoline-2-one (compound (III)) referred in route two
It is studied at condition, single solvent methanol and alkali sodium hydroxide have been used in the synthesis of compound (III) in the patent, but logical
It crosses HPLC and monitors the discovery of reaction progress according to the method in route two, in the case of reflux 14 is small, compound (I) is still remained
22% is remaininged without fully reacting, and produces two other impurities, and other impurities summation is 13%.The present inventor using potassium carbonate and
Ethyl alcohol is respectively as alkali and solvent, and need to only react reacts compound (I) completely, and the total amount of impurity is only 9%.
Concrete outcome is as shown in the table:
In addition, the present invention is in 22h, unreacted compound (I) is also determined in reaction 1, it is 12.6%, it is seen that
The method of reaction 1 is difficult to react raw material compound (I) completely.The present inventor has also carried out the potassium carbonate in reaction 2
The test of potassium hydroxide is replaced with, although can react completely, the impurity summation generated is 32%.Therefore, select potassium carbonate as
Alkali, ethyl alcohol can accelerate reaction speed, can also reduce impurity content as solvent.
Embodiment 1
The preparation of Brexpiprazole
In 500ml reaction flask be added compound (I) 7- hydroxyl -2- quinolone (10.0g, 62mmol), 120ml ethyl alcohol and
Potassium carbonate (19.0g, 138mmol).It is added with stirring the bromo- 4- chlorobutane (12.0g, 70mmol) of compound (II) 1-, is warming up to
Return stirring 2 hours.Be added 100ml water and compound (IV) 1- (benzo [b] thiophene -4- base) piperazine hydrochloride (15.0g,
59mmol), continue return stirring 9 hours.Partial solvent is steamed, is cooled to 50 DEG C, 40ml ethyl acetate is added and stirs 0.5 hour
After continue to be cooled to 20 DEG C hereinafter, be filtered under diminished pressure, filter cake with 20ml ethanol washing three times after, be put into 70 DEG C of dryings of air dry oven
3 hours.Obtain Brexpiprazole(compound V) 14.5g, molar yield 54%, mole receipts with method described in route two
Rate 55% is compared, substantially without difference.
1H NMR (400 MHz, dmso) δ 11.58 (s, 1H), 7.79 (d, J = 9.5 Hz, 1H),
7.68 (d, J = 3.5 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H),
7.39 (s, 1H), 7.26 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 6.80 (d, J
= 8.5 Hz, 2H), 6.29 (d, J = 9.4 Hz, 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. a kind of method that one kettle way prepares Brexpiprazole, it is characterised in that: by formula (I)
Compound represented and formula (II)
Compound represented is reacted in the presence of alkali in alcoholic solvent, obtains formula (III)
Compound represented, compound (III) without isolation, add water and formula (IV) thereto
Compound represented or its salt further react, are separated by filtration drying, obtain formula (V)
Compound represented Brexpiprazole；Wherein in the reacting of compound (I) and compound (II), alcoholic solvent used
For ethyl alcohol, normal propyl alcohol or isopropanol, alkali is potassium carbonate or sodium carbonate.
2. preparation method according to claim 1, it is characterised in that: in the reaction of compound (III) and compound (IV),
The volume ratio of the amount of added water and the additional amount of above-mentioned alcoholic solvent is 0.5-2.0.
3. preparation method according to claim 1, it is characterised in that: the mol ratio of compound (I) and compound (II)
It is 1: 1.1-1.5.
4. preparation method according to claim 1, it is characterised in that: compound (I) and alkali compounds feed intake mole
Than being 1: 1.5-3.5.
5. preparation method according to claim 1, it is characterised in that: compound (I) and compound (IV) or salt feed intake
Molar ratio is 1: 0.9-1.5.
6. preparation method according to claim 1, it is characterised in that: synthesis compound (III) reaction temperature be 50 DEG C extremely
Reflux temperature, reaction time are 1-4 hours.
7. preparation method according to claim 1, it is characterised in that: synthesis compound (V) reaction temperature be 50 DEG C extremely
Reflux temperature, reaction time are 6-12 hours.
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| CN201510427992.0A CN105061414B (en) | 2015-07-21 | 2015-07-21 | One kettle way prepares Brexpiprazole |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106916148B (en) * | 2015-12-25 | 2021-07-06 | 上海科胜药物研发有限公司 | Method for synthesizing brexpiprazole |
| US20170320862A1 (en) | 2016-05-03 | 2017-11-09 | 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 |
| PL233778B1 (en) | 2016-07-19 | 2019-11-29 | Adamed Spolka Z Ograniczona Odpowiedzialnoscia | Method for producing brexpiprazole, intermediate compounds used in this method and method for producing them |
| 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 |
| 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 |
Citations (4)
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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 |
-
2015
- 2015-07-21 CN CN201510427992.0A patent/CN105061414B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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