CN104829602A - Brexpiprazole preparation method - Google Patents
Brexpiprazole preparation method Download PDFInfo
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- CN104829602A CN104829602A CN201510177350.XA CN201510177350A CN104829602A CN 104829602 A CN104829602 A CN 104829602A CN 201510177350 A CN201510177350 A CN 201510177350A CN 104829602 A CN104829602 A CN 104829602A
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- 0 *c1cccc(N2CCN(CCCCOc3ccc(C=CC(N4)=O)*4c3)CC2)c1C=C Chemical compound *c1cccc(N2CCN(CCCCOc3ccc(C=CC(N4)=O)*4c3)CC2)c1C=C 0.000 description 1
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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
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Abstract
The present invention relates to a brexpiprazole preparation method, which comprises: (1) carrying out a condensation reaction of a compound represented by a formula III and a compound represented by a formula II in a solvent to prepare a compound represented by a formula IV; and (2) in a solvent, carrying out dehydrogenation on the compound represented by the formula IV with dichloro dicyano benzoquinone to obtain the brexpiprazole. With the method of the present invention, the reaction selectivity can be improved, the impurity generation can be reduced, the low yield problem caused by poor solubility of the key intermediate is avoided, and the total yield of the reaction is higher than 70.0%.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of preparation method according to a piperazine azoles.
Background of invention
Chemical name according to a piperazine azoles (brexpiprazole) is 7-(4-(4-(benzo [b] thiophene-4-base-piperazine-1-base) butoxy)-1
h-quinoline-2-one-, for serotonin-dopamine activity conditioning agent (SDAM), there is the effect of d2 dopamine receptor partial agonist and 5-HT1A partial receptor agonism, also has 5-HT2A receptor antagonism in addition, grind by Japanese Otsuka Pharmaceutical Co., Ltd. is former, the pharmacy of large tomb and Lundbeck joint development.It is severe depression assisting therapy and treatment of schizophrenia that on July 14th, 2014 have submitted U.S. NDA(indication), in September, 2014, FDA accepted NDA, and in November, 2013 have submitted EMA new drug application.Its chemical structural formula is such as formula shown in I:
(I)
Compared with Aripiprazole, the avidity of this medicine and 5-HT acceptor increases, and decreases to the activity of D2 acceptor, and tolerance performance is better, and the common adverse effect of Aripiprazole is cathisophobiaed (25%), is only 7.4% in the incidence of this medicine.According to II phase clinical effectiveness, compared with Aripiprazole, this medicine therapeutic equivalence, the curative effect in schizoid negative symptoms and cognitive function has better trend; During assisting therapy for dysthymia disorders, rapid-action, namely there is significant difference after treating 2 weeks compared with placebo.The III phase clinical effectiveness display of schizophrenia and depressed assisting therapy, this medicine has significant difference compared with placebo on clinical endpoint.Mutiple Targets, the treatment for a series of mental disorder is widely all effective, and following indication is wide
WO2006112464A1 discloses a kind of method prepared according to a piperazine azoles, and the method reaction circuit is as follows:
In the method, formula (2) compound and 1-bromo-4-chlorobutane reaction preference poor, two impurity of easy production a and formula b, cause aftertreatment and purification difficult, and, formula (3) compound and formula (4) compound react, in the presence of base formula (3) compound can with according to a piperazine azoles generation side reaction, produce not segregative impurity.
For these reasons, be necessary to develop a kind of reaction preference high, simply effectively, easy handling, economical prepares the method for high purity according to a piperazine azoles.
Summary of the invention
The object of the present invention is to provide a kind of method prepared according to a piperazine azoles.The method overcome the shortcoming or deficiency that exist in above-mentioned prior art.
A kind of method prepared according to a piperazine azoles of the present invention, its synthetic route is as follows,
The method comprises the following steps:
(1), formula II compound and formula III compound carry out condensation reaction in a solvent and obtain formula IV compound;
(2), formula IV compound in a solvent, obtain according to a piperazine azoles with DDQ dehydrogenation.
The method of the invention described above, in step (1) and step (2), described solvent selected from methanol, ethanol, propyl carbinol, dioxane, tetrahydrofuran (THF), N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, water and their any mixed solvent, preferred N-Methyl pyrrolidone.
The method of the invention described above, in step (1), the mol ratio of formula II compound and formula III compound is 1:0.8 ~ 1.5; In step (2), the mol ratio of formula IV compound and DDQ is 1:0.8 ~ 3, preferred 1:1.2.
The method of the invention described above, in step (1), temperature of reaction 70 ~ 80
oc.
Method of the present invention, comprise the preparation of formula III compound further, comprise and a) Piperazine anhydrous obtained N-Boc-piperazine with Boc anhydride reaction in methylene chloride, N-Boc-piperazine b) obtained under the existence of catalyst B INAP and palladium with 4-bromobenzene also [
b] thiophene linked reaction, obtain formula V compound, c) formula V compound and hydrochloric acid, preferred concentrated hydrochloric acid salt-forming reaction obtains formula III compound,
。
Method of the present invention, reaction preference is high, and simply effectively, easy handling, economical, product purity is high.
Embodiment
Further illustrate by the following examples and understand essence of the present invention, but not limiting the scope of the invention with this.
The preparation of embodiment 1 formula IV compound
N-Methyl pyrrolidone 4ml is added, formula II compound 0.5g and formula III compound 0.53g, sodium carbonate 0.28g in 25ml there-necked flask, Sodium Bromide 0.2g, be warming up to 70 ~ 80 degree of reactions 3 ~ 5 hours, after question response, be cooled to room temperature, add water 12ml, separate out white solid, suction filtration, filter cake washing twice, drying under reduced pressure obtains formula IV compound, dry weight 0.84g.Yield: 97.8%, purity 98.3%.
The preparation of embodiment 2 formula IV compound
N-Methyl pyrrolidone 400L is added, formula II compound 50g and formula III compound 50g, sodium carbonate 27.6g in 2L there-necked flask, potassiumiodide 28.6g, be warming up to 70 ~ 80 degree of reactions 3 ~ 5 hours, after question response, be cooled to room temperature, add water 1.2L, separate out white solid, suction filtration, filter cake washing twice, drying under reduced pressure obtains formula IV compound, dry weight 82.3g.Yield: 95.8%, purity 97.6%.
Embodiment 3 is according to the preparation of a piperazine azoles
N-Methyl pyrrolidone 700ml is added, formula IV compound 100g, DDQ 67.7g in 1000ml there-necked flask, with 30 ~ 40 DEG C of stirring reactions 3 ~ 4 hours, after completion of the reaction, reaction solution is poured into and is dissolved with in the 2.5L aqueous solution of 48.9g S-WAT, stir after 0.5 hour, suction filtration, filter cake washes three times with water, and drying under reduced pressure obtains according to a piperazine azoles, off-white powder shape solid, 93.6g, yield 94.0%, purity 98.3%.
The preparation of embodiment 4 formula V compound
Piperazine anhydrous 30g is added in 500ml there-necked flask, methylene dichloride 300ml, add Boc acid anhydrides 72.21g, stirring at room temperature reaction 2h, after no longer producing gas, stopped reaction, add water washing reaction solution twice, organic phase is after anhydrous sodium sulfate drying, be evaporated to dry, distillation residue add toluene 200ml, add 4-bromobenzene also [b] thiophene 63.9g, palladium 0.2g, BINAP0.5g, sodium tert-butoxide 28.8g, oil bath is stirred and is warming up to 80 ~ 90 degree, reaction 2h, after treating raw material reaction, be cooled to room temperature, add water 200ml, stir separatory, toluene layer is with water 200ml × 3 washing 3 times, anhydrous sodium sulfate drying, suction filtration precipitation obtains the off-white color solid 90.7g of formula V compound, yield 95.0%, purity, 98.3%.
The preparation of embodiment 5 formula III compound
Ethanol 1.2L is added, formula V compound 90.0g, concentrated hydrochloric acid 40.0ml in 2000ml there-necked flask, gas is had to produce gradually, white solid is separated out, and TLC monitors reaction, after treating raw material reaction, be cooled to 0 ~ 10 degree, insulated and stirred 1.0h, suction filtration, filter cake absolute ethanol washing twice, filter cake 40 degree of drying under reduced pressure, obtain formula III compound.White powdery solids, 63.4g, yield 88.0%, purity 99.3%.
Claims (9)
1., according to a preparation method for a piperazine azoles, comprise the following steps,
(1), formula II compound and formula III compound carry out condensation reaction in a solvent and obtain formula IV compound;
(2), formula IV compound in a solvent with DDQ dehydrogenation obtain formula (I) according to a piperazine azoles,
。
2. method according to claim 1, in step (1) and (2), described solvent is selected from acetonitrile, ethanol, propyl carbinol, dioxane, DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone and their any mixed solvent.
3. method according to claim 2, described solvent is N-Methyl pyrrolidone.
4. method according to claim 1, in step (1), the mol ratio of formula II compound and formula III compound is 1:0.8 ~ 1:1.5.
5. method according to claim 1, in step (2), the mol ratio of formula IV compound and DDQ is 1:0.8 ~ 1:3.
6. method according to claim 5, the mol ratio of formula IV compound and DDQ is 1:1.2.
7. method according to claim 1, comprise the preparation of formula (III) compound further, comprise and a) Piperazine anhydrous obtained N-Boc-piperazine with Boc anhydride reaction in a solvent, N-Boc-piperazine b) obtained in the presence of a catalyst with 4-bromobenzene also [
b] thiophene linked reaction, obtain formula V compound, c) formula V compound and hydrochloric acid salt-forming reaction obtain formula (III) compound,
。
8. method according to claim 7, described solvent is methylene dichloride.
9. method according to claim 7, described catalyzer is BINAP and palladium.
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| CN201510177350.XA CN104829602A (en) | 2015-04-15 | 2015-04-15 | Brexpiprazole preparation method |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN106496206A (en) * | 2016-08-31 | 2017-03-15 | 安徽省润生医药股份有限公司 | A kind of according to a new preparation method of piperazine azoles |
| WO2017078621A1 (en) * | 2015-11-03 | 2017-05-11 | Scinopharm Taiwan, Ltd. | Processes for preparing brexpiprazole |
| 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 |
| WO2017115287A1 (en) | 2015-12-28 | 2017-07-06 | Honour (R&D) | Process for the preparation of quinoline-2(1h)-one derivatives |
| 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 |
| WO2018068690A1 (en) * | 2016-10-13 | 2018-04-19 | 浙江华海药业股份有限公司 | New crystal form of brexpiprazole and preparation method thereof |
| US10358440B2 (en) | 2016-05-03 | 2019-07-23 | Cadila Healthcare Limited | Process for the preparation of brexpiprazole and intermediates thereof |
| CN115677655A (en) * | 2022-09-26 | 2023-02-03 | 湖南省湘中制药有限公司 | Synthesis method of brexpiprazole intermediate |
| CN115894435A (en) * | 2022-11-14 | 2023-04-04 | 山东厚德精诚药业有限公司 | Synthesis method of 1- (benzo [ b ] thiophene-4-yl) piperazine hydrochloride |
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| CN103717587A (en) * | 2011-07-28 | 2014-04-09 | 大塚制药株式会社 | Method for producing benzo[B]thiophene compound |
| CN104447723A (en) * | 2014-11-28 | 2015-03-25 | 瑞阳制药有限公司 | Method for preparing 7-(4-(4-(benzo[b]thienyl)-1-piperazinyl) butoxy)-2(1H)-quinolinone |
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Patent Citations (2)
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| CN103717587A (en) * | 2011-07-28 | 2014-04-09 | 大塚制药株式会社 | Method for producing benzo[B]thiophene compound |
| CN104447723A (en) * | 2014-11-28 | 2015-03-25 | 瑞阳制药有限公司 | Method for preparing 7-(4-(4-(benzo[b]thienyl)-1-piperazinyl) butoxy)-2(1H)-quinolinone |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2017078621A1 (en) * | 2015-11-03 | 2017-05-11 | Scinopharm Taiwan, Ltd. | Processes for preparing brexpiprazole |
| CN106916148B (en) * | 2015-12-25 | 2021-07-06 | 上海科胜药物研发有限公司 | Method for synthesizing brexpiprazole |
| 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 |
| WO2017115287A1 (en) | 2015-12-28 | 2017-07-06 | Honour (R&D) | Process for the preparation of quinoline-2(1h)-one derivatives |
| US10358440B2 (en) | 2016-05-03 | 2019-07-23 | Cadila Healthcare Limited | Process for the preparation of brexpiprazole and intermediates thereof |
| 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 |
| 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 |
| 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 |
| CN106496206A (en) * | 2016-08-31 | 2017-03-15 | 安徽省润生医药股份有限公司 | A kind of according to a new preparation method of piperazine azoles |
| 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 |
| WO2018068690A1 (en) * | 2016-10-13 | 2018-04-19 | 浙江华海药业股份有限公司 | New crystal form of brexpiprazole 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 |
| CN115677655A (en) * | 2022-09-26 | 2023-02-03 | 湖南省湘中制药有限公司 | Synthesis method of brexpiprazole intermediate |
| CN115677655B (en) * | 2022-09-26 | 2023-12-08 | 湖南省湘中制药有限公司 | Synthesis method of epinastine intermediate |
| CN115894435A (en) * | 2022-11-14 | 2023-04-04 | 山东厚德精诚药业有限公司 | Synthesis method of 1- (benzo [ b ] thiophene-4-yl) piperazine hydrochloride |
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Application publication date: 20150812 |