CN106496206A - A kind of according to a new preparation method of piperazine azoles - Google Patents
A kind of according to a new preparation method of piperazine azoles Download PDFInfo
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- CN106496206A CN106496206A CN201610794835.8A CN201610794835A CN106496206A CN 106496206 A CN106496206 A CN 106496206A CN 201610794835 A CN201610794835 A CN 201610794835A CN 106496206 A CN106496206 A CN 106496206A
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- piperazine azoles
- quinoline
- ketone
- room temperature
- piperazine
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of according to a new preparation method of piperazine azoles, the present invention relates to 7 hydroxyl 1H quinoline, 2 ketone (2) as initiation material, there is substitution reaction with 1 chlorine, 4 n-butyl bromide, obtain 7 (4 neoprene epoxide) 2 ketone of 1H quinoline (3)；(3) in the presence of potassium hydroxide, and substitution reaction N Boc piperazines occurs and Deprotection obtains 7 (1 piperazine) butoxy 1H quinoline, 2 ketone dihydrochloride (4)；(4) under isopropylmagnesium chloride effect, there is substitution reaction and finally give according to a piperazine azoles.This preparation method has product yield high, and the advantage of products pure, simple and easy to do, high income, quality are good, are easy to industrialized production.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of according to a new preparation method of piperazine azoles.
Background technology
In prior art, reaction generation is relatively great amount of to be difficult to detached by-product, and thus the purity of compound can not keep away
Reduce with exempting from.Even if completely removing by-product by column chromatography purification is also extremely difficult, the method is not suitable for large-scale industry life
Produce.Accordingly, it would be desirable to develop manufacture high-purity according to a new method for piperazine azoles.
Content of the invention
For the deficiencies in the prior art, the invention provides a kind of according to a new preparation method of piperazine azoles, convert with product
Rate is high, the advantage of products pure.
For realizing that object above, the present invention are achieved by the following technical programs：
A kind of according to a new preparation method of piperazine azoles, method is as follows：
With -2 ketone (2) of 7- hydroxyl -1H- quinoline as initiation material, there is substitution reaction in 4- n-butyl bromide chloro- with 1-, obtain 7-
(4- neoprene epoxides) -2 ketone of -1H- quinoline (3)；
In the presence of potassium hydroxide, with acetone as solvent, and substitution reaction N-Boc piperazines occurs and Deprotection is obtained
- 2 ketone dihydrochloride (4) of 7- (1- piperazines) butoxy -1H- quinoline；
Under isopropylmagnesium chloride effect, there is substitution reaction and obtain according to a piperazine azoles.
It is according to claim 1 a kind of according to a new preparation method of piperazine azoles, it is characterised in that：Method is as follows：
(1)：The synthesis of 7- (4- neoprene epoxides) -2 ketone of -1H- quinoline (3) at 30-50 DEG C, successively to N, N- bis- under stirring
- 2 ketone of 7- hydroxyl -1H- quinoline and potassium hydroxide is added in methylformamide, solvent is slowly added to into the mixed solution, room
Temperature stirring, disposable add the chloro- 4- n-butyl bromide of 1-, then stir at 50-70 DEG C.Solvent is added, is stirred under room temperature, filtered；Filter
Cake is beaten stirring in water, filters, and filter cake is refining to obtain 7- (4- neoprene epoxides) -2 ketone of -1H- quinoline (3) in methanol；
(2) synthesis of -2 ketone (4) of 7- (1- piperazines) butoxy -1H- quinoline is sequentially added in DMF
Title compound 3 (200.0g), N-Boc piperazines, potassium hydroxide, potassium iodide；It is heated to 70-90 DEG C of stirring.After reaction completely, delay
Slowly add water, be then down under room temperature and stir, filter, filter cake solvent dissolves, and is slowly introducing hydrogen chloride gas, is stirred at room temperature, and filters, and does
Dry, obtain -2 ketone dihydrochloride (4) of 7- (1- piperazines) butoxy -1H- quinoline；
4- bromo benzothiazoles are added according to a synthesis for piperazine azoles (1) in tetrahydrofuran, be cooled to 0 DEG C, Deca isopropyl chloride
Change magnesium, then insulated and stirred is dissolved in title compound 4 in tetrahydrofuran in being slowly added to above-mentioned reactant liquor and stirring.Reaction
Finish and be slowly added to water, be stirred at room temperature, filter, dry, obtain crude product, ethyl alcohol recrystallization is obtained according to a piperazine azoles (1).
Preferably, the time is stirred at room temperature in described step (1) for 2-3h.
Preferably, the time is stirred at room temperature in described step (2) for 4-6h.
Preferably, described is tablet according to a piperazine azoles dosage form,
Preferably, described according to a piperazine azoles tablet producing technology it is：Take according to a piperazine azoles 10mg, starch 87g, magnesium stearate
2g, crosses 100 mesh sieves, plus starch, magnesium stearate mix homogeneously according to a piperazine azoles, makes granule, dries, and tabletting is obtained final product.
Preferably, in described step (1), the time of uniform stirring is 40-60min.
Preferably, the time is surface-treated by described step (4) is 10-100min.
Beneficial effect of the present invention：
Preparation method of the present invention has product yield high, the advantage of products pure.
Specific embodiment
Purpose, technical scheme and advantage for making the embodiment of the present invention is clearer, below in conjunction with the enforcement of the present invention
Example, to the embodiment of the present invention in technical scheme be clearly and completely described.Embodiment in based on the present invention, this area
The every other embodiment obtained under the premise of creative work is not made by those of ordinary skill, belongs to protection of the present invention
Scope.
Embodiment 1：The synthesis of 7- (4- neoprene epoxides) -2 ketone of -1H- quinoline (3)
At 20～30 DEG C, 7- hydroxyl -1H- quinolines under stirring, are added successively in DMF (1000ml)
- 2 ketone of quinoline (200.0g) and potassium hydroxide (205.3g, 1.2eq), 40 DEG C of temperature control ＜ are slowly added to 240ml pure water to the mixing
In solution, be stirred at room temperature 15 minutes or so, disposable add 1- chloro- 4- n-butyl bromide (422g, 2.0eq), then stir 5 at 40 DEG C
～6h.1000ml water is added, under room temperature, 1h is stirred, is filtered；Filter cake is beaten stirring 1h in 1000ml water, filters, and filter cake is in 10
240g title compounds (3) are refining to obtain in times methanol (yield is 77.0%).
HPLC：95%.
Embodiment 2：The synthesis of -2 ketone (4) of 7- (1- piperazines) butoxy -1H- quinoline
Sequentially add 3 (200.0g) in DMF (2000ml), N-Boc piperazines (163g, 1.1eq),
Potassium hydroxide (328.8g, 3.0eq), potassium iodide (145.5g, 1.1eq)；It is heated to 80 DEG C of 4～6h of stirring.After reaction completely, delay
Slowly add water, be then down to stirring 1h under room temperature, filter, filter cake tetrahydrofuran (2000ml) dissolves, and is slowly introducing hydrogen chloride gas, room
Temperature stirring 2h, filters, dries, obtain 215.0g title compounds (4) (yield is 89.6%).
HPLC：96%.
Embodiment 3：According to a synthesis for piperazine azoles (1)
4- bromo benzothiazoles (78g, 1.1eq) are added in tetrahydrofuran (300ml), -5 DEG C are cooled to, Deca 2M different
Title compound 4 (100g, 1.0eq) is then dissolved in tetrahydrochysene furan by propyl group magnesium chloride (182.5ml, 1.1eq), insulated and stirred 2h
3h is stirred in being slowly added in muttering to above-mentioned reactant liquor.Reaction is finished and is slowly added to 1000ml water, and 1h is stirred at room temperature, and is filtered, and is dried
Dry, crude product is obtained, ethyl alcohol recrystallization obtains 90.0g title compounds (1) (yield is 91.5%).
HPLC：93%.
Above example only in order to technical scheme to be described, rather than a limitation；Although with reference to the foregoing embodiments
The present invention has been described in detail, it will be understood by those within the art that：Which still can be to aforementioned each enforcement
Technical scheme described in example is modified, or carries out equivalent to which part technical characteristic；And these modification or
Replace, do not make the essence of appropriate technical solution depart from the spirit and scope of various embodiments of the present invention technical scheme.
Claims (6)
1. a kind of according to a new preparation method of piperazine azoles, it is characterised in that：Method is as follows：
(1) with -2 ketone (2) of 7- hydroxyl -1H- quinoline as initiation material, there is substitution reaction in 4- n-butyl bromide chloro- with 1-, obtain 7-
(4- neoprene epoxides) -2 ketone of -1H- quinoline (3)；
(2) in the presence of potassium hydroxide, with acetone as solvent, and substitution reaction N-Boc piperazines occurs and Deprotection is obtained
- 2 ketone dihydrochloride (4) of 7- (1- piperazines) butoxy -1H- quinoline；
(3) under isopropylmagnesium chloride effect, there is substitution reaction and obtain according to a piperazine azoles.
2. according to claim 1 a kind of according to a new preparation method of piperazine azoles, it is characterised in that：Method is as follows：
(1) synthesis of 7- (4- neoprene epoxides) -2 ketone of -1H- quinoline (3) is at 30-50 DEG C, successively to N, N- dimethyl under stirring
- 2 ketone of 7- hydroxyl -1H- quinoline and potassium hydroxide being added in Methanamide, solvent being slowly added to into the mixed solution, room temperature is stirred
Mix, disposable add the chloro- 4- n-butyl bromide of 1-, then stir at 50-70 DEG C.Solvent is added, is stirred under room temperature, filtered；Filter cake in
Beating stirring in water, filters, and filter cake is refining to obtain 7- (4- neoprene epoxides) -2 ketone of -1H- quinoline (3) in methanol；
(2) synthesis of -2 ketone (4) of 7- (1- piperazines) butoxy -1H- quinoline sequentially adds title in DMF
Compound 3 (200.0g), N-Boc piperazines, potassium hydroxide, potassium iodide；It is heated to 70-90 DEG C of stirring.After reaction completely, slowly add
Water, is then down under room temperature and stirs, filter, and filter cake solvent dissolves, and is slowly introducing hydrogen chloride gas, is stirred at room temperature, and filters, and dries,
Obtain -2 ketone dihydrochloride (4) of 7- (1- piperazines) butoxy -1H- quinoline；
(3) 4- bromo benzothiazoles are added according to a synthesis for piperazine azoles (1) in tetrahydrofuran, be cooled to 0 DEG C, Deca isopropyl chlorination
Then magnesium, insulated and stirred are dissolved in title compound 4 in tetrahydrofuran in being slowly added to above-mentioned reactant liquor and stirring.React
Finish and be slowly added to water, be stirred at room temperature, filter, dry, obtain crude product, ethyl alcohol recrystallization is obtained according to a piperazine azoles (1).
3. according to claim 1 according to a new preparation method of piperazine azoles, it is characterised in that room temperature in described step (1)
Mixing time is 2-3h.
4. according to claim 1 according to a new preparation method of piperazine azoles, it is characterised in that room temperature in described step (2)
Mixing time is 4-6h.
5. according to claim 1 according to a piperazine azoles, it is characterised in that described is tablet according to a piperazine azoles dosage form.
6. according to claim 5 according to a piperazine azoles, it is characterised in that described according to a piperazine azoles tablet producing technology is：Take
According to a piperazine azoles 10mg, starch 87g, magnesium stearate 2g, 100 mesh sieves, plus starch, magnesium stearate mix homogeneously is crossed according to a piperazine azoles, make
Into granule, dry, tabletting is obtained final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610794835.8A CN106496206A (en) | 2016-08-31 | 2016-08-31 | A kind of according to a new preparation method of piperazine azoles |
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| CN201610794835.8A CN106496206A (en) | 2016-08-31 | 2016-08-31 | A kind of according to a new preparation method of piperazine azoles |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018172463A1 (en) * | 2017-03-22 | 2018-09-27 | Amneal Pharmaceuticals Company Gmbh | Process for the preparation of brexpiprazole |
| CN109988162A (en) * | 2017-12-29 | 2019-07-09 | 武汉兴华智慧医药科技有限公司 | One kind is according to piperazine Zole derivatives and preparation method thereof |
| CN114044772A (en) * | 2021-11-29 | 2022-02-15 | 浙江国邦药业有限公司 | Epipiprazole synthesis method and intermediate thereof |
| CN114181202A (en) * | 2021-12-17 | 2022-03-15 | 湖南省湘中制药有限公司 | Preparation method of brexpiprazole |
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| CN103889425A (en) * | 2011-10-14 | 2014-06-25 | 大塚制药株式会社 | TABLET INCLUDING 7-[4-(4-BENZO[b]THIOPHEN-4-YL-PIPERAZIN-1-YL) BUTOXY]-1H-QUINOLIN-2-ONE OR SALT THEREOF |
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| CN105175401A (en) * | 2015-10-16 | 2015-12-23 | 北京康立生医药技术开发有限公司 | Preparation method of brexpiprazole |
| CN105440026A (en) * | 2015-12-04 | 2016-03-30 | 上海勋和医药科技有限公司 | Elopiprazole preparation method |
| CN105461704A (en) * | 2015-12-15 | 2016-04-06 | 南京艾德凯腾生物医药有限责任公司 | Preparing method for brexpiprazole |
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Patent Citations (6)
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| CN103889425A (en) * | 2011-10-14 | 2014-06-25 | 大塚制药株式会社 | TABLET INCLUDING 7-[4-(4-BENZO[b]THIOPHEN-4-YL-PIPERAZIN-1-YL) BUTOXY]-1H-QUINOLIN-2-ONE OR SALT THEREOF |
| 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 |
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| CN105175401A (en) * | 2015-10-16 | 2015-12-23 | 北京康立生医药技术开发有限公司 | Preparation method of brexpiprazole |
| CN105440026A (en) * | 2015-12-04 | 2016-03-30 | 上海勋和医药科技有限公司 | Elopiprazole preparation method |
| CN105461704A (en) * | 2015-12-15 | 2016-04-06 | 南京艾德凯腾生物医药有限责任公司 | Preparing method for brexpiprazole |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018172463A1 (en) * | 2017-03-22 | 2018-09-27 | Amneal Pharmaceuticals Company Gmbh | Process for the preparation of brexpiprazole |
| CN109988162A (en) * | 2017-12-29 | 2019-07-09 | 武汉兴华智慧医药科技有限公司 | One kind is according to piperazine Zole derivatives and preparation method thereof |
| CN114044772A (en) * | 2021-11-29 | 2022-02-15 | 浙江国邦药业有限公司 | Epipiprazole synthesis method and intermediate thereof |
| CN114181202A (en) * | 2021-12-17 | 2022-03-15 | 湖南省湘中制药有限公司 | Preparation method of brexpiprazole |
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