CN106916148A - A kind of synthesis is according to a method for piperazine azoles - Google Patents
A kind of synthesis is according to a method for piperazine azoles Download PDFInfo
- Publication number
- CN106916148A CN106916148A CN201510993612.XA CN201510993612A CN106916148A CN 106916148 A CN106916148 A CN 106916148A CN 201510993612 A CN201510993612 A CN 201510993612A CN 106916148 A CN106916148 A CN 106916148A
- Authority
- CN
- China
- Prior art keywords
- compound
- piperazine azoles
- nitrae
- isosorbide
- added
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
It is an object of the invention to provide one kind according to a new synthetic method of piperazine azoles (Brexpiprazole)：A () is that raw material and compound A obtain intermediate II in aprotic solvent through halogenating reaction in the basic conditions with compound of formula I or its salt；B () reacts intermediate II and compound III, that is, obtain according to a piperazine azoles i.e. compound IV, reaction equation is as follows：
Description
Technical field
The present invention relates to synthesize suitable for preparing antidepressant according to a method for piperazine azoles (Brexpiprazole).
Background technology
It is that Lundbeck pharmacy (license) and big tomb pharmacy (original is ground) joint development are a experimental thrombocytin-many according to a piperazine azoles
Bar amine activity adjustment agent (SDAM), is a kind of medicine for mental disorder of new multiple target effect mechanism, except master
Possess outside the effect of d2 dopamine receptor partial agonist, be also equipped with D3 acceptor portions agonism, 5-HT1A partial receptors
Agonism and 5-HT2A partial receptor antagonisms, being directed to while monoamine neurotransmitter Mutiple Targets are developed has anti-essence
God's division and the new drug of antidepressant effect：Chemical name is 7- (4- (4- (base of benzothiophene -4) piperazine -1- bases) butoxy) quinoline
- 2 (1H) -one, its chemical constitution is as follows：
The preparation of report at present has that impurity is more according to a method for piperazine azoles, the low problem of yield, in such as CN101155804B
Disclose according to a piperazine azoles synthetic route, reaction scheme is as follows：
Above route is to be reacted to form compound V by the ketone (compound III) of 7- oxyquinolines -2 and butyl halide, then by itself and chemical combination
Thing I carries out substitution reaction, so as to obtain end-product according to a piperazine azoles.Because butyl halide has with the reactive ketone of 7- oxyquinolines -2
More impurity, is unfavorable for that product quality and yield are improved, and is prepared according to a variation route for piperazine azoles the invention provides a kind of, uses
The route prepare according to a piperazine azoles high income.
The content of the invention
It is an object of the invention to provide a kind of according to a new synthetic method of piperazine azoles：A () is raw material with compound of formula I or its salt and changes
Compound A obtains intermediate II in aprotic solvent through halogenating reaction in the basic conditions；B () makes intermediate II and compound III
Reaction, that is, obtain according to a piperazine azoles i.e. compound IV, reaction equation is as follows：
Wherein：
Compound A is butyl halide, and X1, X2 are halogen, selected from chlorine or bromine；X1, X2 can be identical or different
Halogen.
Compound I and compound A in the basic conditions, is obtained and compound II in nonaqueous solvents.Wherein alkali is selected from inorganic
Alkali such as NaOH, potassium carbonate, organic base may be selected from triethylamine, DIPEA, preferably DBU, potassium carbonate.
The usage amount scope of the alkali is 4~7 times of the mol ratio of compound I.
Solvent described in step a can be selected from acetonitrile, DMF, dichloromethane, toluene, tetrahydrofuran etc.,
It is preferred that acetonitrile.Selected solvent volume is 5~20 times with compound I weight ratio.
The method provided using the present invention, effectively improves product yield, and simple to operate, and with low cost, environment friendly is high,
It is adapted to industrialized production.
Specific embodiment
Embodiment 1：
Prepare compound IV：
By 4- piperazinyl phenyl bithiophenes hydrochloride (29.2g, 0.1mol), Isosorbide-5-Nitrae-dibromobutane (25.9g, 0.12mol), carbon
Sour potassium (55.2g, 0.4mol) is added into acetonitrile (150ml), stirring, is heated to 60 degree.After reaction 4 hours, to
The ketone (16g, 0.1mol) of 7- oxyquinolines -2 is added in reaction solution, is warming up to and is refluxed 16h, be cooled to room temperature filtering, used
Water is beaten, and gained white solid is according to piperazine azoles crude product (IV) 38.6g, yield 89.1%；MS+=434.
1H NMR(DMSO-d6,400M):11.55 (s, 1H), 7.76~7.78 (d, 1H), 7.65~7.67 (d, 1H), 7.57~7.59
(d, 1H), 7.51~7.53 (d, 1H), 7.36~7.37 (d, 1H), 7.22~7.26 (t, 1H), 6.84~6.86 (d, 1H),
6.76~6.78 (m, 2H), 6.25~6.28 (d, 1H), 4.01~4.04 (t, 2H), 3.03 (m, 4H), 2.58 (m, 4H),
2.39~2.43 (t, 2H), 1.57~1.64 (m, 2H)
Embodiment 2：
By 4- piperazinyl phenyl bithiophenes hydrochloride (29.2g, 0.1mol), Isosorbide-5-Nitrae-dichloroetane (15.2g, 0.12mol), carbon
Sour potassium (55.2g, 0.4mol) is added into acetonitrile (150ml), stirring, is heated to 60 degree.After reaction 4 hours, to
The ketone (16g, 0.1mol) of 7- oxyquinolines -2 is added in reaction solution, is warming up to and is refluxed 16h, be cooled to room temperature filtering, used
Water is beaten, and gained white solid is according to piperazine azoles crude product (IV) 34.7g, yield 80.2%；MS+=434.
Embodiment 3：
By 4- piperazinyl phenyl bithiophenes hydrochloride (29.2g, 0.1mol), 1 chloro- 4 NBB (20.5g, 0.12mol), carbonic acid
Potassium (55.2g, 0.4mol) is added into acetonitrile (150ml), stirring, is heated to 60 degree.After reaction 4 hours, to anti-
The ketone (16g, 0.1mol) of addition 7- oxyquinolines -2 in liquid is answered, is warming up to and is refluxed 16h, be cooled to room temperature filtering, use water
Mashing, gained white solid is according to piperazine azoles crude product (IV) 35.6g, yield 82.3%；MS+=434.
Embodiment 4：
By 4- piperazinyl phenyl bithiophenes hydrochloride (29.2g, 0.1mol), Isosorbide-5-Nitrae-dibromobutane (25.9g, 0.12mol), three
Ethamine (40.4g, 0.4mol) is added into acetonitrile (150ml), stirring, is heated to 60 degree.After reaction 4 hours, to
The ketone (16g, 0.1mol) of 7- oxyquinolines -2 is added in reaction solution, is warming up to and is refluxed 16h, be cooled to room temperature filtering, used
Water is beaten, and gained white solid is according to piperazine azoles crude product (IV) 32.5g, yield 75.3%；MS+=434.
Embodiment 5：
By 4- piperazinyl phenyl bithiophenes hydrochloride (29.2g, 0.1mol), Isosorbide-5-Nitrae-dibromobutane (25.9g, 0.12mol), N,
N- diisopropylethylamine (51.6g, 0.4mol) is added into acetonitrile (150ml), stirring, is heated to 60 degree.Reaction 4
After hour, to the ketone (16g, 0.1mol) of 7- oxyquinolines -2 is added in reaction solution, it is warming up to and is refluxed 16h, is cooled to room
Temperature filtering, is beaten with water, and gained white solid is according to piperazine azoles crude product (IV) 33.0g, yield 76.5%；MS+=434.
Embodiment 6：
By 4- piperazinyl phenyl bithiophenes hydrochloride (2.92g, 0.01mol), Isosorbide-5-Nitrae-dibromobutane (2.59g, 0.012mol),
DBU (6.08g, 0.04mol) is added into acetonitrile (15ml), stirring, is heated to 60 degree.After reaction 4 hours, to
The ketone (1.6g, 0.01mol) of 7- oxyquinolines -2 is added in reaction solution, is warming up to and is refluxed 16h, be cooled to room temperature filtering,
It is beaten with water, gained white solid is according to piperazine azoles crude product (IV) 3.1g, yield 71.8%；MS+=434.
Embodiment 7：
By 4- piperazinyl phenyl bithiophenes hydrochloride (2.92g, 0.01mol), Isosorbide-5-Nitrae-dibromobutane (2.59g, 0.012mol),
NaOH (1.6g, 0.04mol) is added into acetonitrile (15ml), stirring, is heated to 60 degree.After reaction 4 hours,
To the ketone (1.6g, 0.01mol) of 7- oxyquinolines -2 is added in reaction solution, it is warming up to and is refluxed 16h, is cooled to room temperature filtering,
It is beaten with water, gained white solid is according to piperazine azoles crude product (IV) 3.3g, yield 76.8%；MS+=434.
Embodiment 8：
By 4- piperazinyl phenyl bithiophenes hydrochloride (2.92g, 0.01mol), Isosorbide-5-Nitrae-dibromobutane (2.59g, 0.012mol),
Potassium carbonate (9.7g, 0.07mol) is added into acetonitrile (15ml), stirring, is heated to 60 degree.After reaction 4 hours, to
The ketone (1.6g, 0.01mol) of 7- oxyquinolines -2 is added in reaction solution, is warming up to and is refluxed 16h, be cooled to room temperature filtering,
It is beaten with water, gained white solid is according to piperazine azoles crude product (IV) 3.8g, yield 87.7%；MS+=434.
Embodiment 9：
By 4- piperazinyl phenyl bithiophenes hydrochloride (2.92g, 0.01mol), Isosorbide-5-Nitrae-dibromobutane (2.59g, 0.012mol),
Potassium carbonate (9.7g, 0.07mol) is added into acetonitrile (60ml), stirring, is heated to 60 degree.After reaction 4 hours, to
The ketone (1.6g, 0.01mol) of 7- oxyquinolines -2 is added in reaction solution, is warming up to and is refluxed 16h, be cooled to room temperature filtering,
It is beaten with water, gained white solid is according to piperazine azoles crude product (IV) 3.67g, yield 84.9%；MS+=434.
Embodiment 10：
By 4- piperazinyl phenyl bithiophenes hydrochloride (2.92g, 0.01mol), Isosorbide-5-Nitrae-dibromobutane (2.59g, 0.012mol),
Potassium carbonate (9.7g, 0.07mol) is added into DMF (15ml), stirring, is heated to 60 degree.Instead
After answering 4 hours, to the ketone (1.6g, 0.01mol) of 7- oxyquinolines -2 is added in reaction solution, it is warming up to and is refluxed 16h, it is cold
But added water filtering to room temperature, filter cake is beaten with water, gained white solid is according to piperazine azoles crude product (IV) 3.32g, yield 76.9%；
MS+=434.
Embodiment 11：
By 4- piperazinyl phenyl bithiophenes hydrochloride (2.92g, 0.01mol), Isosorbide-5-Nitrae-dibromobutane (2.59g, 0.012mol),
Potassium carbonate (9.7g, 0.07mol) is added into dichloromethane (15ml), stirring, is heated to 40 degree.After reaction 4 hours,
To the ketone (1.6g, 0.01mol) of 7- oxyquinolines -2 is added in reaction solution, it is warming up to and is refluxed 22h, be concentrated to dryness, uses water
Mashing 1h suction filtrations, gained white solid is according to piperazine azoles crude product (IV) 3.19g, yield 73.9%；MS+=434.
Embodiment 12：
By 4- piperazinyl phenyl bithiophenes hydrochloride (2.92g, 0.01mol), Isosorbide-5-Nitrae-dibromobutane (2.59g, 0.012mol),
Potassium carbonate (9.7g, 0.07mol) is added into toluene (15ml), stirring, is heated to 80 degree.After reaction 4 hours, to
The ketone (1.6g, 0.01mol) of 7- oxyquinolines -2 is added in reaction solution, is warming up to and is refluxed 12h, be cooled to room temperature filtering,
It is beaten with water, gained white solid is according to piperazine azoles crude product (IV) 3.25g, yield 75.3%；MS+=434.
Embodiment 13：
By 4- piperazinyl phenyl bithiophenes hydrochloride (2.92g, 0.01mol), Isosorbide-5-Nitrae-dibromobutane (2.59g, 0.012mol),
Potassium carbonate (9.7g, 0.07mol) is added into tetrahydrofuran (15ml), stirring, is heated to 60 degree.After reaction 4 hours,
To the ketone (1.6g, 0.01mol) of 7- oxyquinolines -2 is added in reaction solution, it is warming up to and is refluxed 16h, be concentrated to dryness, uses water
Mashing suction filtration, gained white solid is according to piperazine azoles crude product (IV) 3.4g, yield 78.7%；MS+=434.
The explanation of above example is only intended to help and understands the method for the present invention and its core concept.It should be pointed out that for this
For the those of ordinary skill in field, under the premise without departing from the principles of the invention, some improvement can also be carried out to the present invention
And modification, these are improved and modification also falls into the protection domain of the claims in the present invention.
Claims (7)
1. one kind is according to a synthetic method for piperazine azoles (Brexpiprazole), it is characterised in that the method includes following step
Suddenly：(a) with compound of formula I be raw material and compound A in the presence of a base in aprotic solvent through halogenating reaction
Obtain intermediate II；B () reacts intermediate II and compound III, that is, obtain according to a piperazine azoles i.e. compound
IV, reaction equation is as follows：
It is above-mentioned it is various in, X1And X2It is halogen, selected from chlorine or bromine, X1, X2 can be identical or different halogen
Element.
2. method according to claim 1, wherein compound A is selected from：Isosorbide-5-Nitrae-dichloroetane, Isosorbide-5-Nitrae-two
NBB, the preferably bromo- 4- chlorobutanes of 1-, Isosorbide-5-Nitrae-dibromobutane.
3. method according to claim 1, wherein the alkali is selected from organic base and inorganic base.Inorganic base is selected from：
Potassium carbonate, NaOH；Organic base is selected from：Triethylamine, DIPEA, DBU.
4. method according to claim 3, wherein alkali is preferably potassium carbonate.
5. method according to claim 3, the wherein consumption of alkali are 4~7 times with the mol ratio of compound I.
6. method according to claim 1, wherein aprotic solvent are selected from acetonitrile, toluene, dichloromethane,
Tetrahydrofuran, N-N- dimethylformamides.The preferred acetonitrile of solvent.
7., according to claim 6, the wherein volume of aprotic solvent and compound I weight ratio is 5~20 times.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510993612.XA CN106916148B (en) | 2015-12-25 | 2015-12-25 | Method for synthesizing brexpiprazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510993612.XA CN106916148B (en) | 2015-12-25 | 2015-12-25 | Method for synthesizing brexpiprazole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106916148A true CN106916148A (en) | 2017-07-04 |
| CN106916148B CN106916148B (en) | 2021-07-06 |
Family
ID=59454629
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510993612.XA Active CN106916148B (en) | 2015-12-25 | 2015-12-25 | Method for synthesizing brexpiprazole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106916148B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN105061414A (en) * | 2015-07-21 | 2015-11-18 | 杭州新博思生物医药有限公司 | Method for preparing Brexpiprazole with one-pot process |
-
2015
- 2015-12-25 CN CN201510993612.XA patent/CN106916148B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN105061414A (en) * | 2015-07-21 | 2015-11-18 | 杭州新博思生物医药有限公司 | Method for preparing Brexpiprazole with one-pot process |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106916148B (en) | 2021-07-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101679283B (en) | Process for preparing 2-amino-5-cyanobenzoic acid derivatives | |
| CN103936694A (en) | Preparation method of antidepressant vortioxetine | |
| CN102020633A (en) | Method for preparing 1-(3,5- dichloropyridine-2-yl)-pyrazolecarboxamide compounds | |
| CN104876899A (en) | Dimethylamino sphaelactone fumarate and use thereof | |
| CN107074738A (en) | For the method for 1,4 phenylenediamines and its salt that prepare 2 substitutions | |
| US20180093950A1 (en) | Ribociclib intermediate and preparation method therefor | |
| CN106916148A (en) | A kind of synthesis is according to a method for piperazine azoles | |
| CN103601645A (en) | Preparation method of 1-(phenethylamino) propane-2-alcoholic compounds or salts thereof | |
| CN105732490A (en) | Preparation method of betrixaban | |
| CN109836382A (en) | The rich preparation method for replacing Buddhist nun and its intermediate of malic acid card | |
| CN105461640A (en) | Preparation method of tyrosine kinase inhibitor | |
| CN105111163B (en) | A kind of synthetic method of 4 (4 aminophenyl) 3 morpholones | |
| CN103980152B (en) | Benzamide compounds with anti-tumor activity and its preparation method and application | |
| CN104262338B (en) | A kind of Eliquis and the synthetic method of intermediate thereof | |
| CN104829571B (en) | Escitalopram oxalate related substances and preparation method thereof | |
| CN106045931B (en) | A kind of 5- phenyl -1-（4- methoxyphenyls）The preparation method of -1H- tetrazoles | |
| CN103980153B (en) | Dibenzoyl amine compound with anti-tumor activity and its preparation method and application | |
| CN106588684B (en) | A kind of synthetic method of N- allyl propine amide | |
| CN100584829C (en) | 6-methoxyl group-1,2,3, the preparation method of 9-tetrahydrochysene-4H-carbazole-4-ketone | |
| CN1235880C (en) | Quinolinenone kind derivative and its accetable salt, its preparation method, application in preparation of alipyrazole and preparation of alipyrazole | |
| CN103073520A (en) | Method for synthesizing 2-phenyl benzothiazole and derivative thereof | |
| CN115974729B (en) | Preparation method of 2- (2, 2-difluoroethoxy) -6-trifluoromethyl benzenesulfonyl chloride | |
| CN108570014A (en) | A kind of preparation method of chirality morpholinium compound | |
| CN107365305A (en) | One kind is according to piperazine azoles novel crystal forms and preparation method thereof | |
| CN107337632A (en) | A kind of preparation method of CV-4093 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |