CN109456336A - The refining methd of Olanzapine - Google Patents
The refining methd of Olanzapine Download PDFInfo
- Publication number
- CN109456336A CN109456336A CN201710795036.7A CN201710795036A CN109456336A CN 109456336 A CN109456336 A CN 109456336A CN 201710795036 A CN201710795036 A CN 201710795036A CN 109456336 A CN109456336 A CN 109456336A
- Authority
- CN
- China
- Prior art keywords
- olanzapine
- refining methd
- crystallization
- refining
- methd according
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Olanzapine is also known as Zyprexa, olanzapine, is a kind of common antipsychotic drug.When declaring Olanzapine bulk pharmaceutical chemicals, need to be defined the related content of material of Olanzapine.The application is intended to provide a kind of refining methd of Olanzapine, so that impurity 2- methyl-1 0H- thiophene-[2 in finished product, 3-B] benzo [1,5] diazepine -4 [5H] -one content be lower than bound requirements, and this method be suitable for the other Olanzapine of pharmaceutical grade industrialized production.
Description
Technical field
The application belongs to field of medicinal chemistry.
Background technique
Olanzapine is also known as Zyprexa, olanzapine, is a kind of common antipsychotic drug, clinically for controlling spirit
Split disease, bipolar mania and the agitation of Dementia patients, can significantly improve it is schizoid it is negative (such as: feelings
Feel indifferent, emotion and social withdrawal, poverty of speech), positive symptom (such as: vain hope, illusion, the disturbance of thought, hostility and suspect),
Also schizophrenia and the common secondary affective symptom of related disease be can be relieved.Its oral absorption is good, reaches within 5 to 8 hours
Plasma peak concentration, and do not influenced by feed, by combining with oxidation reaction in liver metabolism；Main loop metabolite is
10-N- glucosiduronate.Animal experiment shows Olanzapine to a variety of receptors such as 5-HT, dopamine D, α-adrenaline, histamine Hs
There is affinity, in vitro and in vivo 5-HT2 receptor affinity is greater than the affinity of itself and d2 dopamine receptor.Animal behavior research table
Bright, Olanzapine has 5-HT, dopamine and cholinergic antagonism, and situation is consistent in conjunction with its receptor.
Summary of the invention
According to the study found that existing most of Olanzapine purifying process can make finished product reach industrial rank, even if
Medicinal rank can be reached, but the content in relation to substance is often also close to the medicinal limit of national regulation, a possibility that having more than, in order to
Guarantee the safety of many patients medication, the application is to the research of the purifying crystal form of Olanzapine, this research is suitable on the market may be used
The further purification for the other Olanzapine of non-pharmaceutical grade bought, the present processes make related substance lower than bound requirements, for
Medicine safety provides guarantee.
The purpose of the application is to provide a kind of high-purity, and in high yield, reaction step is succinct, environmentally friendly, is suitable for work
The Olanzapine refining methd of industry.
To achieve the above objectives, the process for refining of the Olanzapine of the application are as follows: Olanzapine crude product is dissolved in the organic molten of heat
Active carbon decoloring is added in agent, and cooling, crystallization filters, dry, obtains high-purity Olanzapine, wherein impurity 2- methyl-1 0H- thiophene
Pheno-[2,3-B] benzo [1,5] [5H] -one content of diazepine -4 is not high by 0.05%, and product purity is not less than 99.90%.
The optional methanol of refining methd recrystallization solvent, ethyl alcohol, the acetonitrile, ethyl acetate of the application, dosage are the 7-8 of crude product
Times；Recrystallization solvent selects acetonitrile.
Active carbon decoloring is added in the refining methd of the application, and decoloration return time is 0.5-1h, preferential selection decoloration reflux
1h。
Drying has In Shade drying, forced air drying and vacuum drying in the refining methd of the application, and drying temperature is
20-80 DEG C, drying time 8-14h；Drying means is forced air drying, and drying temperature is 40-80 DEG C, drying time 10-
13h。
The refining methd products obtained therefrom purity of the application is finally not less than 99.90%.
Herein described refining methd crystallization temperature is 0-30 DEG C, and the crystallization time is 3-15h；Crystallization temperature is 10-25 DEG C,
The crystallization time is 5-10h；Crystallization temperature is 15-25 DEG C, and the crystallization time is 5-8h；Crystallization temperature is 20-25 DEG C, and the crystallization time is
5-8h。
The application refining methd, impurity 2- methyl-1 0H- thiophene-[2,3-B] benzo [1,5] diaza in products obtained therefrom
The content of tall and erect -4 [5H] -one is not higher than 0.05%.
Herein described impurity is that European Pharmacopoeia records impurity.
Embodiment
The scheme of the application is further described below by embodiment, but the protection scope of the application is without being limited thereto.
Embodiment 1
380g Olanzapine crude product is added under stirring into 10L reaction flask, 2.6kg acetonitrile is added, is heated to flowing back, Quan Rong.It is added
19g active carbon, reflux decoloration 0.5h.It filters while hot, filtrate moves in 10L reaction flask, and Temperature fall is cooled to 25 DEG C or so, protects
Temperature crystallization 5h is held, is filtered, acetonitrile washs filter cake, and filter cake is placed in the dry 13h of 40 DEG C of air dry ovens, it is solid to obtain 310g yellow
Body, yield 81.6%, high performance liquid chromatography monitoring purity 99.99%(is always miscellaneous 0.008%), impurity 2- methyl-1 0H- thiophene-[2,3-
B] benzo [1,5] diazepine -4 [5H] -one content be 0.0019%.
Embodiment 2
380g Olanzapine crude product is added under stirring into 10L reaction flask, 2.8kg acetonitrile is added, is heated to flowing back, Quan Rong.It is added
19g active carbon, reflux decoloration 1h.It filters while hot, filtrate moves in 10L reaction flask, and Temperature fall is cooled to 20 DEG C or so, keeps
Temperature crystallization 5h is filtered, and acetonitrile washs filter cake, and filter cake is placed in the dry 11h of 60 DEG C of air dry ovens, obtains 325g yellow solid,
Yield 85.5%, high performance liquid chromatography monitoring purity 100%(is always miscellaneous 0.002%), impurity 2- methyl-1 0H- thiophene-[2,3-B] benzene
And [1,5] diazepine -4 [5H] -one is not detected.
Embodiment 3
380g Olanzapine crude product is added under stirring into 10L reaction flask, 3kg acetonitrile is added, is heated to flowing back, Quan Rong.19g is added
Active carbon, reflux decoloration 1h.It filters while hot, filtrate moves in 10L reaction flask, and 10 DEG C or so are cooled to after Temperature fall, keeps
Temperature crystallization 8h is filtered, and acetonitrile washs filter cake, and filter cake is placed in the dry 10h of 80 DEG C of air dry ovens, obtains 334g yellow solid,
Yield 87.9%, high performance liquid chromatography monitoring purity 99.96%(is always miscellaneous 0.04%), impurity 2- methyl-1 0H- thiophene-[2,3-B] benzene
And [1,5] diazepine -4 [5H] -one content is 0.0040%.
Comparative example
380g Olanzapine crude product is added under stirring into 10L reaction flask, 3kg acetone is added, is heated to flowing back, Quan Rong.19g is added
Active carbon, reflux decoloration 1h.It filters while hot, filtrate moves in 10L reaction flask, and 10 DEG C or so are cooled to after Temperature fall, keeps
Temperature crystallization 8h is filtered, acetone washing filter cake, and filter cake is placed in the dry 10h of 80 DEG C of air dry ovens, obtains 295g yellow solid,
Yield 77.6%, high performance liquid chromatography monitoring purity 98.96%(is always miscellaneous 1.04%), impurity 2- methyl-1 0H- thiophene-[2,3-B] benzene
And [1,5] diazepine -4 [5H] -one content 0.12%.
Claims (9)
1. the refining methd of Olanzapine, it is characterised in that: Olanzapine crude product is dissolved in organic solvent, and decoloration, heat is taken out, and filtrate is cold
But crystallization for a period of time, filters, and organic solvent elutes filter cake, dry, impurity 2- methyl-1 0H- thiophene-[2,3- in products obtained therefrom
B] benzo [1,5] diazepine -4 [5H] -one content be not higher than 0.05%, product purity be not less than 99.90%.
2. refining methd according to claim 1, the optional methanol of recrystallization solvent, ethyl alcohol, acetonitrile, ethyl acetate, dosage are
7-8 times of crude product.
3. refining methd according to claim 2, recrystallization solvent is acetonitrile.
4. refining methd according to claim 1, crystallization temperature is 0-30 DEG C, and the crystallization time is 5-10h.
5. refining methd according to claim 1, decoloration reflux 0.5-1h.
6. refining methd according to claim 5, decoloration reflux 1h.
7. refining methd according to claim 1, dry is forced air drying, and drying temperature is 40-80 DEG C, drying time 8-
14h。
8. refining methd according to claim 1, products obtained therefrom purity is not less than 99.90%.
9. refining methd according to claim 1, impurity 2- methyl-1 0H- thiophene-[2,3-B] benzo in products obtained therefrom [1,
5] content of diazepine -4 [5H] -one is not higher than 0.05%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710795036.7A CN109456336A (en) | 2017-09-06 | 2017-09-06 | The refining methd of Olanzapine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710795036.7A CN109456336A (en) | 2017-09-06 | 2017-09-06 | The refining methd of Olanzapine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109456336A true CN109456336A (en) | 2019-03-12 |
Family
ID=65605946
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710795036.7A Pending CN109456336A (en) | 2017-09-06 | 2017-09-06 | The refining methd of Olanzapine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109456336A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112110935A (en) * | 2019-06-20 | 2020-12-22 | 北京万全德众医药生物技术有限公司 | Preparation method of olanzapine crystal form II |
Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004056833A1 (en) * | 2002-12-20 | 2004-07-08 | Adamed Sp. Z O.O. | A process for the preparation of a pharmaceutically pure polymorphic form i of olanzapine |
| EP1513846A1 (en) * | 2002-05-31 | 2005-03-16 | Sandoz Inc. | Process of preparation of olanzapine form i |
| CN101033232A (en) * | 2007-03-30 | 2007-09-12 | 浙江华海药业股份有限公司 | Method of preparing olanzapine crystal system I |
| WO2008139228A2 (en) * | 2007-05-15 | 2008-11-20 | Generics [Uk] Limited | Process for the purification of olanzapine |
| CN102093386A (en) * | 2011-01-05 | 2011-06-15 | 浙江华海药业股份有限公司 | Method for preparing Zyprexa crystal form II |
| CN102268010A (en) * | 2011-06-17 | 2011-12-07 | 大连美罗大药厂 | Preparation method and refining method of olanzapine |
| CN102276592A (en) * | 2011-06-17 | 2011-12-14 | 大连理工大学 | Related substance of olanzapine and preparation method and analytical method thereof |
| JP2013213004A (en) * | 2012-04-02 | 2013-10-17 | Dainippon Printing Co Ltd | Method for producing olanzapine |
| JP2014122164A (en) * | 2012-12-20 | 2014-07-03 | Tokuyama Corp | Method for producing olanzapine ii type crystal |
| KR20160105557A (en) * | 2015-02-27 | 2016-09-07 | 주식회사 경보제약 | Refine Method for the preparation of high purity Olanzapine |
| CN106265571A (en) * | 2016-08-31 | 2017-01-04 | 安徽省润生医药股份有限公司 | A kind of preparation method of olanzapine tablet |
-
2017
- 2017-09-06 CN CN201710795036.7A patent/CN109456336A/en active Pending
Patent Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1513846A1 (en) * | 2002-05-31 | 2005-03-16 | Sandoz Inc. | Process of preparation of olanzapine form i |
| WO2004056833A1 (en) * | 2002-12-20 | 2004-07-08 | Adamed Sp. Z O.O. | A process for the preparation of a pharmaceutically pure polymorphic form i of olanzapine |
| CN1729195A (en) * | 2002-12-20 | 2006-02-01 | 阿达梅德公司 | Process for the preparation of a pharmaceutically pure polymorphic form I of olanzapine |
| CN101033232A (en) * | 2007-03-30 | 2007-09-12 | 浙江华海药业股份有限公司 | Method of preparing olanzapine crystal system I |
| WO2008139228A2 (en) * | 2007-05-15 | 2008-11-20 | Generics [Uk] Limited | Process for the purification of olanzapine |
| US20100234590A1 (en) * | 2007-05-15 | 2010-09-16 | Abhay Gaitonde | Process for the purification ne of olanzapine |
| CN102093386A (en) * | 2011-01-05 | 2011-06-15 | 浙江华海药业股份有限公司 | Method for preparing Zyprexa crystal form II |
| CN102268010A (en) * | 2011-06-17 | 2011-12-07 | 大连美罗大药厂 | Preparation method and refining method of olanzapine |
| CN102276592A (en) * | 2011-06-17 | 2011-12-14 | 大连理工大学 | Related substance of olanzapine and preparation method and analytical method thereof |
| JP2013213004A (en) * | 2012-04-02 | 2013-10-17 | Dainippon Printing Co Ltd | Method for producing olanzapine |
| JP2014122164A (en) * | 2012-12-20 | 2014-07-03 | Tokuyama Corp | Method for producing olanzapine ii type crystal |
| KR20160105557A (en) * | 2015-02-27 | 2016-09-07 | 주식회사 경보제약 | Refine Method for the preparation of high purity Olanzapine |
| CN106265571A (en) * | 2016-08-31 | 2017-01-04 | 安徽省润生医药股份有限公司 | A kind of preparation method of olanzapine tablet |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112110935A (en) * | 2019-06-20 | 2020-12-22 | 北京万全德众医药生物技术有限公司 | Preparation method of olanzapine crystal form II |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103842332B (en) | Cyclopropylamine compound | |
| EP3153167B1 (en) | Substituted 2-(4-heterocyclylbenzyl)isoindolin-1-one analogs as positive allosteric modulators of the muscarinic acetylcholine receptor m1 | |
| JP5789259B2 (en) | Nitrogen-containing aromatic heterocyclic derivatives | |
| US20190337941A1 (en) | Tyk2 inhibitors, uses, and methods for production thereof | |
| WO2015164374A1 (en) | Irak inhibitors and uses thereof | |
| CN101808666A (en) | Anti-mitotic agent and aurora kinase inhibitor combination as anti-cancer treatment | |
| CN105307655A (en) | Pyridazinone compounds and methods for the treatment of cystic fibrosis | |
| WO2014194201A2 (en) | Cdk8 inhibitors and uses thereof | |
| CN104326984A (en) | Synthesis method of high-purity pharmaceutical injection-grade edaravone raw material | |
| CN109456336A (en) | The refining methd of Olanzapine | |
| CN101885680B (en) | Method for refining ibuprofen for injection | |
| EP0885196A1 (en) | Chinoline-2-(1h)-ones | |
| CN104744357A (en) | Recrystallization purification method of milrinone | |
| JP2020535127A (en) | Heteroaryl allosteric modulator of nicotinic acetylcholine receptor | |
| CN109456337A (en) | The refining methd of Olanzapine | |
| CN105985330A (en) | Heterocyclic compound, preparation method therefor and use of heterocyclic compound | |
| CN103130791B (en) | A kind of new benzamides compounds | |
| IL294786A (en) | Novel cell metabolism modulating compounds and uses thereof | |
| CN104496937A (en) | Synthetic method of 2-mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) isopropoxyiminoacetate | |
| CN103787924A (en) | New purification method of antitumor drug Belinostat | |
| JP2019536759A (en) | Substituted bicyclic heteroaryl nicotinic acetylcholine receptor allosteric modulators | |
| CN106265571A (en) | A kind of preparation method of olanzapine tablet | |
| CN108368106B (en) | Fused heterocyclic compound derivative and application thereof | |
| CN101870696A (en) | N-aryl piperazine derivative having double activity of dopamine D2 and 5-HT2a | |
| CN106187864A (en) | A kind of method being prepared high-purity bupivacaine alkali by bupivacaine hydrochloride |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190312 |
|
| WD01 | Invention patent application deemed withdrawn after publication |