CN107936005A - One kind is according to piperazine azoles novel crystal forms II and preparation method thereof - Google Patents
One kind is according to piperazine azoles novel crystal forms II and preparation method thereof Download PDFInfo
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- CN107936005A CN107936005A CN201610891725.3A CN201610891725A CN107936005A CN 107936005 A CN107936005 A CN 107936005A CN 201610891725 A CN201610891725 A CN 201610891725A CN 107936005 A CN107936005 A CN 107936005A
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- piperazine azoles
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The present invention relates to one kind according to piperazine azoles novel crystal forms and preparation method thereof.Described is named as crystal form II according to a piperazine azoles novel crystal forms, in the X-ray powder diffraction pattern detected using Cu K α radiations, at about 5.2 °, 7.4 °, 9.8 °, 10.5 °, 14.3 °, 14.8 °, 18.6 °, 19.7 °, there is characteristic peak at 23.6 ° of (2 θ) places.Prepared the present invention also provides a kind of according to a method for piperazine azoles novel crystal forms II, easy, favorable reproducibility, gained is good according to II purity of a piperazine azoles novel crystal forms height, stability, suitable for industrialized production.
Description
Technical field
The present invention relates to according to novel crystal forms of piperazine azoles (Brexpiprazole) and preparation method thereof.
Technical background
According to entitled (7- (4- (4- benzothiophene -4- bases) piperazine -1- bases) the butoxy) -1H- quinoline -2- of a piperazine azoles chemistry
Ketone), structural formula is as shown in following formula I：
In dopamine D 2 receptoroid, D2 acceptor portion agonist centering limbic brain paths can produce functional antagonism work
With can effectively improve schizophrenia positive symptom caused by D2 over-activities；Centering cortex path can produce function
Property agonism, can improve negative symptoms, the cognitive impairment caused by D2 hypofunctions.Lundbeck pharmacy (license) and big tomb pharmacy
The Brexpiprazole of (original is ground) joint development is a experimental serotonin-dopamine activity adjustment agent (SDAM), is a kind of
The medicine for mental disorder of new multiple target effect mechanism, except mainly possessing d2 dopamine receptor partial agonist
Outside effect, D3 acceptor portions agonism, 5-HT1A partial receptors agonism and 5-HT2A partial receptor antagonisms are also equipped with
Effect, the new drug with anti-schizophrenia and antidepressant effect while being for the exploitation of monoamine neurotransmitter Mutiple Targets.
In recent years, the polymorphism of drug molecule increasingly causes the extensive concern of people.In CN 104254530A and
The preparation method according to two crystal type of a piperazine azoles and anhydrous crystal forms, CN201510180947 are reported in WO2013/162046 patents
Report unformed and preparation method thereof；The present inventor has obtained the novel crystal forms II according to a piperazine azoles through research screening, different from nothing
Water and two crystal types, in terms of stability and solubility preferably, have extensive prospect.
The content of the invention
The invention discloses a kind of stability is good, purity is high, favorable reproducibility according to piperazine azoles novel crystal forms II and its a preparation side
Method.
It is of the present invention according to a piperazine azoles novel crystal forms II, use X-ray powder diffraction pattern Fig. 1 of Cu-K α radiation detections
In, there is following characteristics peak, its 2 θ angle value and relative intensity are as shown in the table：
| 2θ | Relative intensity |
| 5.2 | 100.0 |
| 7.4 | 54.4 |
| 9.8 | 58.7 |
| 10.5 | 53.2 |
| 14.3 | 34.6 |
| 14.8 | 74.6 |
| 18.6 | 45.5 |
| 19.7 | 45.6 |
| 23.6 | 32.3 |
It is of the present invention according to a piperazine azoles novel crystal forms II, it is characterised in that the II differential scanning calorimetry analytical spectra of crystal form
About 80~91 DEG C are shown in Fig. 2 crystallization water endothermic peak, has solvent endothermic peak at 130~150 DEG C, has knot at 176~186 DEG C
Brilliant exothermic peak, has melting endothermic peak at 212~223 DEG C.
It is of the present invention according to a piperazine azoles novel crystal forms II to there is differential scanning calorimetry as shown in Figure 2 to analyze collection of illustrative plates.
Present invention simultaneously provides a kind of prepare to include according to a method of piperazine azoles novel crystal forms II, this method：
(a) it will be mixed at room temperature according to a piperazine azoles with ethanol water mixed solvent, and be configured to suspension；
(b) acetic acid is added to the suspension described in step (a), is heated to being completely dissolved；
(c) clarified solution of step (b) is cooled down.
(d) by step (c) with 25% sodium hydroxide solution tune PH to 10-11；
(e) the solid insulation separated out step (d) continue stirring 1 it is small when, filtering, washing filter cake to filtrate PH is 7, dry
Obtain according to a piperazine azoles novel crystal forms II.
Preparation method of the present invention, ethanol that step (a) uses, aqueous systems ratio are：3/10.
Preparation method of the present invention, the clarified solution cooling temperature described in step (c) are：- 10~5 DEG C.
Preparation method of the present invention, the PH scopes described in step (d) are：10~11.
Preparation method of the present invention, the temperature described in step (e) are：0~5 DEG C.
According to a method of piperazine azoles novel crystal forms II, easy to operate, favorable reproducibility, obtains product purity for preparation provided by the present invention
Height, stability are good, can meet large-scale industrial production.
Brief description of the drawings
X-ray powder diffraction (XRPD) collection of illustrative plates according to a piperazine azoles novel crystal forms II that Fig. 1 according to embodiments of the present invention 1 is obtained.
The differential scanning calorimetry according to a piperazine azoles novel crystal forms II that Fig. 2 according to embodiments of the present invention 1 is obtained analyzes collection of illustrative plates
(DSC)。
Embodiment
Following embodiment is that the present invention will be described in detail, rather than is only restricted in the present invention.
The analysis testing conditions of the present invention are as follows：
1st, X-ray powder diffraction data are measured using the BRUKER D8 Advance of German Brooker company, electricity
Current voltage：40kV,40mA；Angular instrument：Vertical angular instrument, radius 280mm；Slit：DS=2 °, SS=1/2 °, mask=15mm,
RS=5.0mm；Detector：LYNXEYE detectors；Scan pattern：Continuous scanning；Scanning range：3°-40°2θ；When often step counts
Between：0.2s；Scan total time：390s.
2nd, DSC is measured by the NETZSCH DSC 200F3Maia of German Nai Chi companies, test condition 120ml/min
N2,10 DEG C/min of programming rate.
Embodiment 1
At room temperature, weigh 0.5g to be added in 30% ethanolic aqueous system of 50ml according to a piperazine azoles, add the acetic acid of 0.25g,
70~75 DEG C are warming up to be allowed to be completely dissolved；Clarified solution is cooled to -10~5 DEG C, 25% sodium hydrate aqueous solution is added dropwise to it
Adjust PH to 10~11, separate out solid, when 0~5 DEG C of insulated and stirred 1 is small after filter, be washed with water filter cake to filtrate PH be 7, it is dry
Filter cake, obtain off-white color according to an II (KF of piperazine azoles novel crystal forms:0.89%, EtOH<500ppm、HAc<400ppm,MS:433)
1H-NMR(DMSO-d6,400M):1.57~1.64 (m, 2H)；1.73~1.82 (m, 2H)；2.39~2.43 (t,
2H)；2.58(m,4H)；3.03(m,4H)；4.01~4.04 (t, 2H)；6.25~6.28 (d, 1H)；6.76~6.78 (m, 2H)；
6.84~6.86 (d, 1H)；7.22~7.26 (t, 1H)；7.36~7.37 (d, 1H)；7.51~7.53 (d, 1H)；7.57~
7.59(d,1H)；7.65~7.67 (d, 1H)；7.76~7.78 (d, 1H)；11.55(s,1H)).
Embodiment 2
At room temperature, weigh 5g to be added in 30% ethanolic aqueous system of 500ml according to a piperazine azoles, add the acetic acid of 2.5g, rise
Warm to 70~75 DEG C are allowed to be completely dissolved；Clarified solution is cooled to -10~5 DEG C, 25% sodium hydrate aqueous solution tune is added dropwise to it
PH to 10~11, separates out solid, when 0~5 DEG C of insulated and stirred 1 is small after filter, be washed with water filter cake to filtrate PH be 7, dry filter
Cake, obtain off-white color according to a piperazine azoles novel crystal forms II.
Claims (10)
1. one kind is according to a crystal form II for piperazine azole compounds (Formulas I), it is characterised in that the X-ray powder diffraction pattern of the crystal form II
Include the characteristic peak (± 0.2 °) shown in following 2 θ angles：
5.2 °, 7.4 °, 9.8 °, 10.5 °, 14.3 °, 14.8 °, 18.6 °, 19.7 °, 23.6 °.
2. as claimed in claim 1 according to a piperazine azoles novel crystal forms II, it is characterised in that the crystal form II differential scanning calorimetries point
Analysis collection of illustrative plates, which is shown in about 80~91 DEG C, crystallization water endothermic peak, has solvent endothermic peak at 130~150 DEG C, has at 176~186 DEG C
Crystalline exotherm peak, has melting endothermic peak at 212~223 DEG C.
3. a kind of method for preparing compound of formula I novel crystal forms II described in claim 1, comprises the following steps：
(a) it will be mixed at room temperature according to a piperazine azoles with ethanol water mixed solvent, and be configured to suspension；
(b) acetic acid is added to the suspension described in step (a), is heated to being completely dissolved；
(c) clarified solution of step (b) is cooled down.
(d) by step (c) with 25% sodium hydroxide solution tune PH to 10-11；
(e) the solid insulation separated out step (d) continue stirring 1 it is small when, filtering, washing filter cake is to filtrate
PH is 7, is dried to obtain according to a piperazine azoles novel crystal forms II.
4. method as claimed in claim 2, ethanol that step (a) uses, aqueous systems ratio are：30%.
5. method as claimed in claim 3, the organic acid that step (b) uses are：Acetic acid.
6. method as claimed in claim 4, the amount of the acetic acid described in step (b) with being according to a mass ratio for piperazine azoles：1:2.
7. method as claimed in claim 5, the clarified solution cooling temperature described in step (c) are：- 10~5 DEG C.
8. method as claimed in claim 6, the highly basic described in step (d) are：Sodium hydroxide.
9. the method for claim 7, the PH scopes described in step (d) are：10~11.
10. method as claimed in claim 8, the temperature described in step (e) are：0~5 DEG C.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610891725.3A CN107936005A (en) | 2016-10-13 | 2016-10-13 | One kind is according to piperazine azoles novel crystal forms II and preparation method thereof |
| CN202210780490.6A CN114957230A (en) | 2016-10-13 | 2017-10-09 | Novel crystal form of brexpiprazole and preparation method thereof |
| PCT/CN2017/105367 WO2018068690A1 (en) | 2016-10-13 | 2017-10-09 | New crystal form of brexpiprazole and preparation method thereof |
| CN201780047454.6A CN109863149A (en) | 2016-10-13 | 2017-10-09 | One kind is according to piperazine azoles novel crystal forms and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610891725.3A CN107936005A (en) | 2016-10-13 | 2016-10-13 | One kind is according to piperazine azoles novel crystal forms II and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107936005A true CN107936005A (en) | 2018-04-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610891725.3A Pending CN107936005A (en) | 2016-10-13 | 2016-10-13 | One kind is according to piperazine azoles novel crystal forms II and preparation method thereof |
| CN201780047454.6A Pending CN109863149A (en) | 2016-10-13 | 2017-10-09 | One kind is according to piperazine azoles novel crystal forms and preparation method thereof |
| CN202210780490.6A Pending CN114957230A (en) | 2016-10-13 | 2017-10-09 | Novel crystal form of brexpiprazole and preparation method thereof |
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| CN201780047454.6A Pending CN109863149A (en) | 2016-10-13 | 2017-10-09 | One kind is according to piperazine azoles novel crystal forms and preparation method thereof |
| CN202210780490.6A Pending CN114957230A (en) | 2016-10-13 | 2017-10-09 | Novel crystal form of brexpiprazole and preparation method thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (3) | CN107936005A (en) |
| WO (1) | WO2018068690A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111440158A (en) * | 2020-03-24 | 2020-07-24 | 石药集团中奇制药技术（石家庄）有限公司 | Novel crystal form of brexpiprazole hydrochloride and preparation method thereof |
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| 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 |
| CN104254530A (en) * | 2012-04-23 | 2014-12-31 | 大塚制药株式会社 | Dihydrate of benzothiophene compound or of a salt thereof, and process for producing the same |
| 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 |
| CN104844585A (en) * | 2015-04-15 | 2015-08-19 | 重庆医药工业研究院有限责任公司 | Preparation method of brexpiprazole |
| 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 |
| 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 |
| 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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-
2016
- 2016-10-13 CN CN201610891725.3A patent/CN107936005A/en active Pending
-
2017
- 2017-10-09 CN CN201780047454.6A patent/CN109863149A/en active Pending
- 2017-10-09 CN CN202210780490.6A patent/CN114957230A/en active Pending
- 2017-10-09 WO PCT/CN2017/105367 patent/WO2018068690A1/en active Application Filing
Patent Citations (9)
| 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 |
| CN104254530A (en) * | 2012-04-23 | 2014-12-31 | 大塚制药株式会社 | Dihydrate of benzothiophene compound or of a salt thereof, and process for producing the same |
| CN105461703A (en) * | 2014-12-29 | 2016-04-06 | 深圳市泛谷药业股份有限公司 | Preparation method of brexpiprazole |
| 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 |
| CN104844585A (en) * | 2015-04-15 | 2015-08-19 | 重庆医药工业研究院有限责任公司 | Preparation method of brexpiprazole |
| 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 |
| 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 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111440158A (en) * | 2020-03-24 | 2020-07-24 | 石药集团中奇制药技术（石家庄）有限公司 | Novel crystal form of brexpiprazole hydrochloride and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2018068690A1 (en) | 2018-04-19 |
| CN114957230A (en) | 2022-08-30 |
| CN109863149A (en) | 2019-06-07 |
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Application publication date: 20180420 |
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