CN102234285B - 奥氮平的制备方法 - Google Patents
奥氮平的制备方法 Download PDFInfo
- Publication number
- CN102234285B CN102234285B CN 201110098521 CN201110098521A CN102234285B CN 102234285 B CN102234285 B CN 102234285B CN 201110098521 CN201110098521 CN 201110098521 CN 201110098521 A CN201110098521 A CN 201110098521A CN 102234285 B CN102234285 B CN 102234285B
- Authority
- CN
- China
- Prior art keywords
- formula
- olanzapine
- compound
- preparation
- impurity
- 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.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 229960005017 olanzapine Drugs 0.000 title abstract description 60
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 title abstract description 54
- 238000006243 chemical reaction Methods 0.000 claims description 45
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 32
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 24
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 13
- 235000019253 formic acid Nutrition 0.000 claims description 13
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 claims description 7
- 239000000292 calcium oxide Substances 0.000 claims description 7
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims description 7
- 239000012535 impurity Substances 0.000 abstract description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 25
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 239000002250 absorbent Substances 0.000 abstract 1
- 230000002745 absorbent Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- 235000019441 ethanol Nutrition 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 8
- PFHNIUBFAGAGBP-UHFFFAOYSA-N Cl.N1C=CC=CC=C1.[N] Chemical compound Cl.N1C=CC=CC=C1.[N] PFHNIUBFAGAGBP-UHFFFAOYSA-N 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- -1 demethyl olanzapine Chemical compound 0.000 description 6
- 238000007670 refining Methods 0.000 description 6
- QENGPZGAWFQWCZ-UHFFFAOYSA-N 3-Methylthiophene Chemical compound CC=1C=CSC=1 QENGPZGAWFQWCZ-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 0 CC(SC1Nc2ccccc2)=CC1C(N1CC*CC1)=O Chemical compound CC(SC1Nc2ccccc2)=CC1C(N1CC*CC1)=O 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229940126601 medicinal product Drugs 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 description 1
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 1
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 101000748141 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 32 Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 102100040050 Ubiquitin carboxyl-terminal hydrolase 32 Human genes 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910000474 mercury oxide Inorganic materials 0.000 description 1
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HUAUNKAZQWMVFY-UHFFFAOYSA-M sodium;oxocalcium;hydroxide Chemical compound [OH-].[Na+].[Ca]=O HUAUNKAZQWMVFY-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Description
Claims (4)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 201110098521 CN102234285B (zh) | 2010-04-19 | 2011-04-14 | 奥氮平的制备方法 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201010153034 | 2010-04-19 | ||
CN201010153034.6 | 2010-04-19 | ||
CN 201110098521 CN102234285B (zh) | 2010-04-19 | 2011-04-14 | 奥氮平的制备方法 |
Publications (2)
Publication Number | Publication Date |
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CN102234285A CN102234285A (zh) | 2011-11-09 |
CN102234285B true CN102234285B (zh) | 2013-06-12 |
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CN 201110098521 Expired - Fee Related CN102234285B (zh) | 2010-04-19 | 2011-04-14 | 奥氮平的制备方法 |
Country Status (1)
Country | Link |
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CN (1) | CN102234285B (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5934004B2 (ja) * | 2012-03-22 | 2016-06-15 | 株式会社トクヤマ | 結晶構造を有する4−アミノ−2−メチル−10H−チエノ〔2,3−b〕〔1,5〕ベンゾジアゼピン塩酸塩水和物及びその製造方法 |
CN102924472B (zh) * | 2012-09-03 | 2013-06-05 | 江苏豪森药业股份有限公司 | 一种奥氮平的制备方法 |
CN117820170A (zh) * | 2024-03-06 | 2024-04-05 | 北京哈三联科技有限责任公司 | 一种奥氮平基因毒性杂质及其制备方法 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1420117A (zh) * | 2001-11-16 | 2003-05-28 | 连云港豪森制药有限公司 | 一种制备奥氮平的方法 |
PL203991B1 (pl) * | 2002-06-20 | 2009-11-30 | Adamed Spo & Lstrok Ka Z Ogran | Sposoby wytwarzania olanzapiny, nowa pochodna N-demetyloolanzapiny i sposób wytwarzania nowej pochodnej N-demetyloolanzapiny |
PL199016B1 (pl) * | 2002-06-20 | 2008-08-29 | Adamed Sp Z Oo | Sposób wytwarzania olanzapiny |
US20060035887A1 (en) * | 2004-07-02 | 2006-02-16 | Dr. Reddy's Laboratories Limited | Process for preparing olanzapine |
-
2011
- 2011-04-14 CN CN 201110098521 patent/CN102234285B/zh not_active Expired - Fee Related
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Publication number | Publication date |
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CN102234285A (zh) | 2011-11-09 |
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Legal Events
Date | Code | Title | Description |
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C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C53 | Correction of patent of invention or patent application | ||
CB03 | Change of inventor or designer information |
Inventor after: Zhong Huijuan Inventor after: Cen Junda Inventor after: Lv Aifeng Inventor after: Chen Gangsheng Inventor after: Wan Zhonghui Inventor before: Zhong Huijuan Inventor before: Lv Aifeng Inventor before: Chen Gangsheng Inventor before: Wan Zhonghui |
|
COR | Change of bibliographic data |
Free format text: CORRECT: INVENTOR; FROM: ZHONG HUIJUAN LV AIFENG CHEN GANGSHENG WAN ZHONGHUI TO: ZHONG HUIJUAN CEN JUNDA LV AIFENG CHEN GANGSHENG WAN ZHONGHUI |
|
C56 | Change in the name or address of the patentee | ||
CP01 | Change in the name or title of a patent holder |
Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee before: Jiangsu best Pharmaceutical Co.,Ltd. Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee after: Jiangsu best Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. |
|
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130612 |
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CF01 | Termination of patent right due to non-payment of annual fee |