CN106916098A - A kind of mono- tartaric acid salt hemihydrates of piperazine Ma Selin and preparation method - Google Patents
A kind of mono- tartaric acid salt hemihydrates of piperazine Ma Selin and preparation method Download PDFInfo
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- CN106916098A CN106916098A CN201710131893.7A CN201710131893A CN106916098A CN 106916098 A CN106916098 A CN 106916098A CN 201710131893 A CN201710131893 A CN 201710131893A CN 106916098 A CN106916098 A CN 106916098A
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- China
- Prior art keywords
- piperazine
- selin
- tartaric acid
- mono
- acid salt
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- 0 C*(CC1)CCC1*(Cc(cc1)ccc1N)C(C)=O Chemical compound C*(CC1)CCC1*(Cc(cc1)ccc1N)C(C)=O 0.000 description 1
- KPLQALBFSIFFPV-UHFFFAOYSA-N CC(C)COc1ccc(CC(C)=C)cc1 Chemical compound CC(C)COc1ccc(CC(C)=C)cc1 KPLQALBFSIFFPV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a kind of novel crystal forms of piperazine Ma Selin, it is single tartaric acid salt hemihydrate, its powder X-ray x ray diffration pattern x of the polymorphic forms has diffraction maximum at 7.1 °, 15.6 °, 18.6 °, 20.6 ° and 22.9 ° of about (2 θ ± 0.2 °).The crystal formation is easily prepared, simple to operate, can preferably be applied to and prepare pharmaceutical preparation and large-scale production, has a extensive future.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of piperazine Ma Selin tartrates and preparation method thereof.
Background technology
Piperazine Ma Selin (Pimaverserin), chemistry is entitled：1- (4- luorobenzyls) -3- (4- isobutoxies benzyl) -1- (1-
Methyl piperidine -4- bases) urea, its chemical abstracts accession number is：706779-91-1, structure such as formula 2；
The chemical abstracts accession number of the tartrates of piperazine Ma Selin half is：706782-28-7, structure such as formula 3:
Piperazine Ma Selin is the selectively targeting 5-HT of drugmaker of Acadia exploitation2AAcceptor medicine, in September in 2014 3 days
Obtain food and medicine Surveillance Authority of the U.S. (FDA) and authorize breakthrough sex therapy certification, breaking through sex therapy certification is created by FDA
, it is intended to accelerate exploitation and examine the new drug of serious or life-threatening the disease for the treatment of.On April 29th, 2016 obtains FDA batches
It is mutatis mutandis to experience the mental symptom such as illusion and vain hope in treatment Parkinsonian.
Found through literature survey and patent retrieval, it is special that drugmaker of Acadia has applied for that a series of piperazine horse color forest forms are closed
Profit：Compound, compound salt, preparation method and crystal formation patent etc..CN1443167 is general formula compound patent,
ZL200480004479.0 and ZL200910225582.2 disclose half tartrate of piperazine Ma Selin and preparation method thereof, the party
What method was that piperazine Ma Selin and tartaric acid obtain in ethanol is half tartrate.Piperazine is protected in ZL200580032649.0
Ma Selin citrates and other various acylates；Protected in patent ZL200580032650.3 and ZL201110039289.4
Crystal formation of half tartrate of piperazine Ma Selin and preparation method thereof.
The content of the invention
The invention belongs to field of medicaments, and in particular to a kind of piperazine Ma Selin tartrates and preparation method thereof, method operation
Simply, the advantages of favorable reproducibility, purification effect are good.
Concrete operations of the present invention are as follows:
Piperazine Ma Selin is added in solvent and heats molten clear, addition is dissolved in the tartaric acid of solvent, be heated to reflux waiting separating out solid
Body, continues to stir 2h, then continues to stir 2 hours at room temperature, and suction filtration obtains solid, forced air drying.
The theoretical content 25.58% of the mono- tartaric acid salt hemihydrate mesotartaric acid of piperazine Ma Selin of the invention, the theory of water
Content 1.53%,
Testing result：Tartaric acid content is 26.05%, and water content is 1.58%, and as piperazine Ma Selin is mono- for the solid for obtaining
Tartaric acid salt hemihydrate.
The X-ray powder diffraction characteristic spectrum of gained solid is as follows：
| 2 θ angles | D values | Intensity % |
| 5.244 | 16.839 | 29.4 |
| 7.090 | 12.458 | 77.8 |
| 11.493 | 7.693 | 22.0 |
| 13.933 | 6.351 | 19.2 |
| 15.573 | 5.686 | 41.7 |
| 18.639 | 4.757 | 74.4 |
| 20.590 | 4.310 | 79.5 |
| 22.896 | 3.881 | 100.0 |
| 25.642 | 3.471 | 29.2 |
| 32.113 | 2.785 | 12.5 |
| 32.357 | 2.765 | 13.0 |
| 34.905 | 2.568 | 14.0 |
| 36.228 | 2.478 | 14.5 |
| 36.930 | 2.432 | 34.2 |
| 39.201 | 2.296 | 23.6 |
Summary of drawings
Fig. 1：The X-ray powder diffraction figure of the mono- tartaric acid salt hemihydrates of piperazine Ma Selin of the present invention.
Specific embodiment：
In order that those skilled in the art is better understood from technical scheme, some are disclosed further below non-
The present invention is described in further detail for limitation embodiment.
Piperazine Ma Selin (free alkali) used in the present invention refers to the method system in patent CN200480004479.0
It is standby to obtain.
Embodiment 1：The preparation of piperazine Ma Selin free alkalis
Weigh (4- luorobenzyls)-(1- methyl piperidine -4- bases) amine (5.00g, 22.49mmol) and be dissolved in 20ml tetrahydrofurans,
Isocyanates (5.54g, 26.99mmol) is dissolved in 20ml tetrahydrofurans and is added drop-wise to above-mentioned solution, is stirred at room temperature to reaction completely, subtracts
Pressure is evaporated and obtains 8.70g, yield 90%
Embodiment 2：The preparation of the mono- tartaric acid salt hemihydrates of piperazine Ma Selin
Weigh piperazine Ma Selin (free alkali) (8.70g, 20.34mmol, HPLC purity 99.2%) and be dissolved in 60ml tetrahydrofurans,
The tetrahydrofuran solution that 30ml contains L-TARTARIC ACID (3.05g, 20.34mmol) is dropped into above-mentioned reaction solution, backflow is heated to
Molten clear follow-up continuation of insurance temperature continues to stir 2h to solid is separated out, and is cooled to room temperature, stirs 2h, and suction filtration, forced air drying obtains white
Solid 9.20g, HPLC purity 99.7%, moisture：1.58%.
Claims (8)
1. a kind of mono- tartaric acid salt hemihydrates of piperazine Ma Selin, its chemical formula such as formula 1：
Formula 1.
2. mono- tartaric acid salt hemihydrates of piperazine Ma Selin as claimed in claim 1, it is characterised in that X-ray powder diffraction figure
Spectrum exists（2θ±0.2°）7.1 °, 15.6 °, 18.6 °, 20.6 ° and 22.9 ° have characteristic peak.
3. a kind of method for preparing the mono- tartaric acid salt hemihydrates of piperazine Ma Selin, the method include by piperazine Ma Selin and tartaric acid in
Dissolved in solvent, crystallized and separated.
4. method as claimed in claim 3, wherein the solvent is tetrahydrofuran or tetrahydrofuran/aqueous systems.
5. method as claimed in claim 3, wherein described dissolving step be piperazine Ma Selin and tartaric acid be dissolved in solvent or
Mixed after forming solution respectively.
6. method as claimed in claim 3, wherein the dissolving step is piperazine Ma Selin or tartaric acid is first dissolved in solvent, it
After add another component to carry out mixed dissolution.
7. method as claimed in claim 3, wherein the crystallisation step is induction crystallization or direct crystallization.
8. method as claimed in claim 3, wherein the crystallization temperature of the crystallisation step is -20 ~ 80 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710131893.7A CN106916098A (en) | 2017-03-07 | 2017-03-07 | A kind of mono- tartaric acid salt hemihydrates of piperazine Ma Selin and preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710131893.7A CN106916098A (en) | 2017-03-07 | 2017-03-07 | A kind of mono- tartaric acid salt hemihydrates of piperazine Ma Selin and preparation method |
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| Publication Number | Publication Date |
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| CN106916098A true CN106916098A (en) | 2017-07-04 |
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| CN201710131893.7A Pending CN106916098A (en) | 2017-03-07 | 2017-03-07 | A kind of mono- tartaric acid salt hemihydrates of piperazine Ma Selin and preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019120250A1 (en) * | 2017-12-22 | 2019-06-27 | 广东东阳光药业有限公司 | Novel crystal form of pimavanserin hemi-tartrate and method for preparing crystal form |
| CN111825601A (en) * | 2019-04-22 | 2020-10-27 | 杭州珠联医药科技有限公司 | Method for continuously preparing pimavanserin by using microchannel reactor |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101035759A (en) * | 2004-09-27 | 2007-09-12 | 阿卡蒂亚药品公司 | Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms |
| CN101778821A (en) * | 2007-05-15 | 2010-07-14 | 阿卡蒂亚药品公司 | Synthesizing of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-yl)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea and tartrate and crystal formation |
-
2017
- 2017-03-07 CN CN201710131893.7A patent/CN106916098A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101035759A (en) * | 2004-09-27 | 2007-09-12 | 阿卡蒂亚药品公司 | Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms |
| CN101778821A (en) * | 2007-05-15 | 2010-07-14 | 阿卡蒂亚药品公司 | Synthesizing of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-yl)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea and tartrate and crystal formation |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019120250A1 (en) * | 2017-12-22 | 2019-06-27 | 广东东阳光药业有限公司 | Novel crystal form of pimavanserin hemi-tartrate and method for preparing crystal form |
| CN111201218A (en) * | 2017-12-22 | 2020-05-26 | 广东东阳光药业有限公司 | Novel crystal form of pimavanserin hemitartrate and preparation method thereof |
| CN111825601A (en) * | 2019-04-22 | 2020-10-27 | 杭州珠联医药科技有限公司 | Method for continuously preparing pimavanserin by using microchannel reactor |
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