CN1420117A - Method for preparing olanzapine - Google Patents
Method for preparing olanzapine Download PDFInfo
- Publication number
- CN1420117A CN1420117A CN 01134868 CN01134868A CN1420117A CN 1420117 A CN1420117 A CN 1420117A CN 01134868 CN01134868 CN 01134868 CN 01134868 A CN01134868 A CN 01134868A CN 1420117 A CN1420117 A CN 1420117A
- Authority
- CN
- China
- Prior art keywords
- olanzapine
- compound
- formula
- methyl
- present
- 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
- 238000000034 method Methods 0.000 title claims abstract description 16
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 229960005017 olanzapine Drugs 0.000 title claims abstract description 14
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 238000007069 methylation reaction Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 3
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 description 3
- 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 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- YEHIIKLKSBNZDR-UHFFFAOYSA-N Cl.N1N=CC=CC=C1.C1=CC=CC=C1 Chemical compound Cl.N1N=CC=CC=C1.C1=CC=CC=C1 YEHIIKLKSBNZDR-UHFFFAOYSA-N 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention provides a method for preparing 2-methyl-10- (4-methyl-1-piperazinyl) -4H-thieno [2, 3-b ] [1, 5] benzodiazepine (olanzapine) or an acid addition salt thereof. The method takes low-cost piperazine as a raw material, and then olanzapine is prepared in a high yield through methylation reaction.
Description
The present invention relates to organic chemistry and pharmaceutical chemistry field, particularly, the invention provides a kind of method for preparing olanzapine.
Many antipsychotic drugs are arranged at present, and the thieno-benzodiazepine is a class wherein, and this compounds is open in English Patent GB1533235, and this compounds has following general formula:
In this compounds, it is found that one of them compound, promptly 2-methyl isophthalic acid 0-(4-methyl-piperazinyl)-4H-thieno-[2,3-b] [1,5] benzazepine (formula I compound) or its acid salt have more obvious curative effect.
For this reason, people have studied this compound and preparation method thereof individually and have applied for U.S. Pat 5229382, and the popular name of this compound is decided to be olanzapine (Olanzapine).In U.S. Pat 5229382, disclose two kinds of methods that prepare olanzapine, having comprised:
(a) with N methyl piperazine with or (II) compound reaction:
Or
(b) make formula (III) compound generation ring-closure reaction:
Need to use more expensive methylpiperazine raw material in the above-mentioned method (a), the operation process of method (b) is complicated, need to use the high-pressure hydrogenation device, and the productive rate of two kinds of methods is not high, is unfavorable for suitability for industrialized production.
The industrialized method for preparing olanzapine that helps that the purpose of this invention is to provide a kind of cheapness.
Particularly, the present invention uses cheap piperazine to replace N methyl piperazine and the reaction of formula V compound, the direct then methylation reaction through post-mature and high yield prepares olanzapine, and is necessary, with ordinary method olanzapine and corresponding acid-respons changed into its acid salt.Method of the present invention can and prepare olanzapine with high yield with cheapness, is very beneficial for suitability for industrialized production, and its reaction scheme is:
Further specify method of the present invention below by embodiment.The preparation method who it should be understood that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, and the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.Embodiment: preparation 2-methyl isophthalic acid 0-(4-methyl-piperazinyl)-4H-thieno-[2,3-b] [1,5] benzazepine
With 2-methyl-4-amino-10H-thieno-[2,3-b] [1,5] benzene diazepine hydrochloride (50g, 0.19mol), Piperazine anhydrous (200g, 2.3mol), DMSO (250ml), toluene (250ml) drop in the reaction flask, back flow reaction 12 hours is put and is chilled to 40～50 ℃.In 1 liter of frozen water of impouring, place.Filter, wash with water, drying gets yellow solid.This solid is dropped in 1 liter of reaction flask, add DMSO (500ml), 37% formaldehyde (14.6g, 0.18mol), 98% formic acid (8.5g, 0.18mol), in 80 ℃ of stirrings 2 hours, in the impouring frozen water, filter, wash with water, drying obtains 2-methyl isophthalic acid 0-(4-methyl-piperazinyl)-4H-thieno-[2,3-b] [1,5] benzazepine (olanzapine) crude product (50g), get its highly finished product (40g) with the 500ml ethyl alcohol recrystallization, yield 68%, fusing point: 193～195 ℃.
Claims (1)
1, the olanzapine of a kind of preparation formula (I) or the method for its acid salt:
This method comprises:
A) with piperazine and following formula V compound reaction, obtain formula (IV) compound,
B) formula (IV) compound is prepared formula (I) compound through methylation reaction, if necessary, formula (I) compound and corresponding acid-respons are obtained the acid salt of formula (I) compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01134868 CN1420117A (en) | 2001-11-16 | 2001-11-16 | Method for preparing olanzapine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01134868 CN1420117A (en) | 2001-11-16 | 2001-11-16 | Method for preparing olanzapine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1420117A true CN1420117A (en) | 2003-05-28 |
Family
ID=4672809
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 01134868 Pending CN1420117A (en) | 2001-11-16 | 2001-11-16 | Method for preparing olanzapine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1420117A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101061124B (en) * | 2004-11-22 | 2010-07-28 | 阿达梅德公司 | A process for the preparation of n-demethylolanzapine |
| CN102234285A (en) * | 2010-04-19 | 2011-11-09 | 江苏豪森药业股份有限公司 | Preparation method of olanzapine |
| CN102268010A (en) * | 2011-06-17 | 2011-12-07 | 大连美罗大药厂 | Preparation method and refining method of olanzapine |
| CN102838619A (en) * | 2012-08-16 | 2012-12-26 | 四川省百草生物药业有限公司 | Olanzapine intermediate and method for preparing olanzapine using same |
| CN102924470A (en) * | 2011-08-31 | 2013-02-13 | 江苏豪森药业股份有限公司 | Olanzapine preparation method |
| CN102942573A (en) * | 2011-10-09 | 2013-02-27 | 江苏豪森药业股份有限公司 | Preparation method of olanzapine |
-
2001
- 2001-11-16 CN CN 01134868 patent/CN1420117A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101061124B (en) * | 2004-11-22 | 2010-07-28 | 阿达梅德公司 | A process for the preparation of n-demethylolanzapine |
| CN102234285A (en) * | 2010-04-19 | 2011-11-09 | 江苏豪森药业股份有限公司 | Preparation method of olanzapine |
| CN102268010A (en) * | 2011-06-17 | 2011-12-07 | 大连美罗大药厂 | Preparation method and refining method of olanzapine |
| CN102924470A (en) * | 2011-08-31 | 2013-02-13 | 江苏豪森药业股份有限公司 | Olanzapine preparation method |
| CN102924470B (en) * | 2011-08-31 | 2014-12-03 | 江苏豪森药业股份有限公司 | Novel olanzapine preparation method |
| CN102942573A (en) * | 2011-10-09 | 2013-02-27 | 江苏豪森药业股份有限公司 | Preparation method of olanzapine |
| CN102942573B (en) * | 2011-10-09 | 2015-03-25 | 连云港恒运医药科技有限公司 | Preparation method of olanzapine |
| CN102838619A (en) * | 2012-08-16 | 2012-12-26 | 四川省百草生物药业有限公司 | Olanzapine intermediate and method for preparing olanzapine using same |
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| C06 | Publication | ||
| PB01 | Publication | ||
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| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |