CN102532158A - Method for synthesizing olanzapine - Google Patents
Method for synthesizing olanzapine Download PDFInfo
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- CN102532158A CN102532158A CN201010595084XA CN201010595084A CN102532158A CN 102532158 A CN102532158 A CN 102532158A CN 201010595084X A CN201010595084X A CN 201010595084XA CN 201010595084 A CN201010595084 A CN 201010595084A CN 102532158 A CN102532158 A CN 102532158A
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Abstract
The invention relates to a method for synthesizing olanzapine. The method comprises the following steps of: heating a reaction mixture of 4-amino-2-methyl-10H-thiene[2,3-b][1,5]benzodiazepine hydrochloride and N-methyl piperazine to the temperature of between 80 and 100DEG C, and keeping the temperature for 16 to 24 hours to synthesize the olanzapine. The method is simple, easy and convenient to implement, light in pollution, ensures that the product purity is high and the yield is over 90 percent, and is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to chemical pharmacy field; Particularly; Relate to a kind of Synthetic 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno-[2; 3-b] [1,5] benzodiazepine
(olanzapine, method olanzapine).
Background technology
Olanzapine is D-1 and D-2 dopamine-receptor antagonist, and muscarine antagonist and cholinolytic activity are arranged, and import China in 1999 was clinical application medicine for central nervous system widely, was used to treat schizophrenia, acute mania etc. in America and Europe's listing in 1996.When with the low dosage administration, also be used to treat slight anxiety.
European patent document EP0454436 discloses a kind of compound method of olanzapine; Be characterised in that and utilize 2-methyl-4-amino-10H-thieno-[2; 3-b] [1; 5] benzodiazepine
and N methyl piperazine react preferred 80～120 ℃ of temperature of reaction in toluene, methyl-sulphoxide, N and some low boiling point solvents such as acetone, acetonitrile.The yield of this reaction is lower, and impurity is difficult to remove.
American documentation literature US5229382 discloses with benzodiazepine
and piperazine and in organic solvent, has reacted; The production demethylolanzapine is utilized the methylation reaction preparing olanzapine again.This method yield is not high, and impurity is difficult to remove.
PCT patent documentation WO2005/063771 discloses a kind of method of preparing olanzapine; Wherein solvent-free or under the condition that low boiling point solvent exists; Make 2-methyl-4-amino-10H-thieno-[2; 3-b] [1; 5] benzodiazepine
and N methyl piperazine react, and temperature of reaction is 110～145 ℃.This method needs to add two or more mixed solvents such as methyl-sulphoxide, N, acetonitrile etc. after reaction is accomplished, solvent toxicity is bigger, in final product, is difficult to remove to the greatest extent, reclaim difficulty, and environment, operator ' s health are caused very major injury.
PCT patent documentation PCT/US2004/043159 discloses a kind of method of under condition of no solvent, producing olanzapine; But the temperature of reaction of this method preparing olanzapine is high, is prone to produce impurity, and the subsequent recovery purification step need add organic solvent; Complex operation step is unfavorable for suitability for industrialized production.And this method yield is merely 84%.
The method of preparing olanzapine needs exacting terms basically at present, like high temperature, highly basic, uses big organic solvent of toxicity such as methyl-sulphoxide, N, toluene etc., and they are difficult to remove in final product; The method that has also need be used catalyzer, causes undesirable color and impurity to produce thus.
Summary of the invention
In order to solve the problem that exists in the above-mentioned prior art, the invention provides a kind of method of preparing olanzapine, wherein chemical technology is simple, thereby can carry out suitability for industrialized production.
Particularly, the present invention provides:
(1) a kind of method of preparing olanzapine; It comprises: heating 2-methyl-4-amino-10H-thieno-[2 under condition of no solvent; 3-b] [1; 5] reaction mixture of benzodiazepine
hydrochloride and N methyl piperazine to 80-100 ℃ temperature; And under this temperature, keeping 16-24 hour, thereby preparing olanzapine.
(2) according to (1) described method, wherein, said temperature is 90-100 ℃.
(3) according to (2) described method, wherein, under said temperature, kept 20-24 hour.
(4) according to each described method in (1) to (3); Wherein, Said 2-methyl-4-amino-10H-thieno-[2; 3-b] mol ratio of [1,5] benzodiazepine
hydrochloride and said N methyl piperazine is 1: 3-1: 12.
(5) according to (4) described method; Wherein, Said 2-methyl-4-amino-10H-thieno-[2; 3-b] mol ratio of [1,5] benzodiazepine
hydrochloride and said N methyl piperazine is 1: 8-1: 12.
(6) according to (5) described method; Wherein, Said 2-methyl-4-amino-10H-thieno-[2; 3-b] mol ratio of [1,5] benzodiazepine
hydrochloride and said N methyl piperazine is 1: 10.
(7) according to (1) described method; Wherein said 2-methyl-4-amino-10H-thieno-[2; 3-b] reaction of [1,5] benzodiazepine
hydrochloride and said N methyl piperazine carries out under protection of inert gas.
(8) according to (7) described method, wherein said rare gas element is a nitrogen.
(9) according to (1) described method, this method also comprises: after preparing olanzapine, remove unreacted N methyl piperazine, then the reaction product of gained is mixed with water, make olanzapine precipitated, with the collection olanzapine.
(10) according to (9) described compound method; The consumption of wherein said water is the 2-methyl-4-amino-10H-thieno-[2 as reactant; 3-b] [1,5] benzodiazepine
hydrochloride quality 10-35 doubly.
The present invention compares with the preparation method of existing olanzapine, has following characteristics:
(1) in reaction process and in the last handling process, do not use any organic solvent, thereby reduce environmental pollution, save production cost;
(2) temperature of reaction is lower, has avoided unnecessary impurity to produce, and the yield of product is high;
(3) after reaction is accomplished, the recyclable utilization of N methyl piperazine, thus economize on resources, reduce environmental pollution;
(4) the present invention has simplified post-processing step, and used various raw material obtains easily, low price, and do not have overt toxicity, have excellent application value;
(5) product purity is high, yield is high, is fit to large-scale industrial production.
Embodiment
Below description through embodiment the present invention is described further; But this is not to be limitation of the present invention; Those skilled in the art are according to basic thought of the present invention; Can make various modifications or improvement, but only otherwise break away from basic thought of the present invention, all within scope of the present invention.
Olanzapine (olanzapine); It is 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno-[2; 3-b] its structural formula of [1,5] benzodiazepine
is as shown in the formula shown in the I:
Formula I
Olanzapine normal temperature is yellow or light yellow crystalline powder down, and its fusing point is 195～201 ℃.It is prone to dissolve in Glacial acetic acid min. 99.5, dissolves in the water part omitted, and slightly soluble in anhydrous methanol, absolute ethyl alcohol, almost insoluble in ether.
2-methyl-4-amino-10H-thieno-[2; 3-b] [1; 5] benzodiazepine
hydrochloride and N methyl piperazine react and can obtain olanzapine, and its reaction formula is:
2-methyl-4-amino-10H-thieno-[2; 3-b] [1; 5] benzodiazepine
hydrochloride normal temperature is yellow or brown solid down, and its fusing point is 283～285 ℃.
N methyl piperazine normal temperature is down colourless liquid, and its boiling point is about 138 ℃, specific density 0.903, water-soluble, ether, ethanol, with water, methyl alcohol etc. arbitrarily than dissolving each other, in the aqueous solution, be weakly alkaline.
The present invention provides a kind of method of preparing olanzapine; It comprises: heating 2-methyl-4-amino-10H-thieno-[2 under condition of no solvent; 3-b] [1; 5] reaction mixture of benzodiazepine
hydrochloride and N methyl piperazine to 80-100 ℃ temperature; And under this temperature, keeping 16-24 hour, thereby preparing olanzapine.
The temperature of control reaction system is 80-100 ℃.If temperature of reaction is too high, will produces reluctant impurity, thereby cause quality product to descend; If reaction temperature is spent low, then reaction is difficult to fully.Preferably, the temperature of control reaction system is 90-100 ℃, for example 90 ℃, 95 ℃, 100 ℃.
Under above-mentioned temperature of reaction, keep reaction 16-24 hour.If the reaction times is long; Then quality product descends; If the reaction times is too short, then reaction is difficult to fully.Preferably, under above-mentioned temperature of reaction, keep reaction 20-24 hour.
Term " solvent-free " is meant and except that reactant itself, does not use any solvent, comprises and does not use toluene, methyl-sulphoxide, N and some low boiling point solvents, like acetone, acetonitrile.
Found not use the temperature of oxidisability organic solvent DMSO 99.8MIN. and control reaction system, helped improving the purity of olanzapine, simplified the synthetic of olanzapine, and eliminated the product colour variation.
2-methyl-4-amino-10H-thieno-[2; 3-b] [1; 5] benzodiazepine
hydrochloride and N methyl piperazine can mix by any suitable molar ratio; Preferably N methyl piperazine is excessive; So that 2-methyl-4-amino-10H-thieno-[2; 3-b] [1,5] benzodiazepine
hydrochloride fully reacts.More preferably; 2-methyl-4-amino-10H-thieno-[2; 3-b] mol ratio of [1,5] benzodiazepine
hydrochloride and N methyl piperazine is more than 1: 3; Further preferably; 2-methyl-4-amino-10H-thieno-[2; 3-b] mol ratio of [1,5] benzodiazepine
hydrochloride and N methyl piperazine is 1: 3-1: 12; Further preferably; 2-methyl-4-amino-10H-thieno-[2; 3-b] mol ratio of [1,5] benzodiazepine
hydrochloride and N methyl piperazine is 1: 8-1: 12; Most preferably; 2-methyl-4-amino-10H-thieno-[2; 3-b] mol ratio of [1,5] benzodiazepine
hydrochloride and N methyl piperazine is 1: 10-1: 12.
During reaction, reaction mixture can be used rare gas element such as nitrogen protection, and rare gas element also helps removing the ammonia that dereaction produces, and is favourable to reaction.
Reaction can be reclaimed N methyl piperazine through the underpressure distillation mode after accomplishing, and not only reduces cost, and also greatly reduces environmental pollution.
Through after reclaiming N methyl piperazine and removing unreacted N methyl piperazine, the olanzapine of further from remaining reaction product, purifying.What be fit to is, makes olanzapine precipitated through adding solvent, thus the purification olanzapine.Preferably, solvent for use does not contain any organic solvent, does not particularly contain organic solvents such as acetone, acetonitrile, THF, toluene, DMSO.
The water that can in reaction mixture, add capacity is to form olanzapine precipitated.Do not want to be subject to theory; But preferably; The amount of the water that adds is the 2-methyl-4-amino-10H-thieno-[2 before the reaction beginning; 3-b] [1; 5] 10-50 of the quality of benzodiazepine
hydrochloride doubly more preferably 10-35 times, further is preferably 30 times.After adding entry, reaction mixture can further be cooled to below 10 ℃, makes deposition fully.
From reaction mixture, separate the also olanzapine of collecting precipitation.Can adopt the filtration drying method or get rid of filter desiccating method collection product olanzapine.
The present invention has improved the preparation method under the condition of no solvent of olanzapine, and its reaction and last handling process all need not to add organic solvent, and its product yield can be up to more than 90%, even can be up to more than 94%.
In following embodiment; 2-methyl-4-amino-10H-thieno-[2; 3-b] [1; 5] benzodiazepine
hydrochloride can derive from SouthWest Synthetic Pharmaceutical Corp. Ltd, and N methyl piperazine can derive from Shanghai Tylenol chemical company.
In following embodiment, the detection of HPLC is to be undertaken by the mode of describing in the USP (USP).
Embodiment 1:
With 2-methyl-4-amino-10H-thieno-[2; 3-b] [1; 5] benzodiazepine
hydrochloride 50.0g (0.1882mol), N methyl piperazine 151.0g (1.51mol) adding 500mL are equipped with in churned mechanically three mouthfuls of reaction flasks; Feed nitrogen and reacting by heating mixture; 80 ℃ of reactions, N methyl piperazine is reclaimed in underpressure distillation after 24 hours.After recovery finishes, reaction product is changed among the water 1500ml, the frozen water reaction mixture is until olanzapine precipitated.Filtration drying obtains olanzapine 53.0g.Product yield 90.2%, purity detect through HPLC and meet the requirements.
Embodiment 2:
With 2-methyl-4-amino-10H-thieno-[2; 3-b] [1; 5] benzodiazepine
hydrochloride 50g (0.1882mol), N methyl piperazine 226.2g (2.26mol) adding 500mL are equipped with in churned mechanically three mouthfuls of reaction flasks; Feed nitrogen and reacting by heating mixture; 100 ℃ of reactions, N methyl piperazine is reclaimed in underpressure distillation after 16 hours.After recovery finishes, change reaction product over to water 1500ml, the frozen water reaction mixture is until olanzapine precipitated.Filtration drying obtains olanzapine 54.6g.Product yield 92.9%, purity detect through HPLC and meet the requirements.
Embodiment 3:
With 2-methyl-4-amino-10H-thieno-[2; 3-b] [1; 5] benzodiazepine
hydrochloride 390g (1.47mol), N methyl piperazine 1472g (14.70mol) adding 2000mL are equipped with in churned mechanically three mouthfuls of reaction flasks; Feed nitrogen and reacting by heating mixture; 90 ℃ of reactions, N methyl piperazine is reclaimed in underpressure distillation after 20 hours.After recovery finishes, reaction product is poured in the 12L frozen water, the frozen water reaction mixture is until olanzapine precipitated.Filtration drying obtains olanzapine 430g.Product yield 93.6%, purity detect through HPLC and meet the requirements.
Embodiment 4:
With 2-methyl-4-amino-10H-thieno-[2; 3-b] [1; 5] benzodiazepine
hydrochloride 300g (1.13mol), N methyl piperazine 1132g (11.3mol) adding 2000mL are equipped with in churned mechanically three mouthfuls of reaction flasks; Feed nitrogen and reacting by heating mixture; 100 ℃ of reactions, N methyl piperazine is reclaimed in underpressure distillation after 16 hours.After recovery finishes, reaction product is poured in the 10L frozen water, the frozen water reaction mixture is until olanzapine precipitated.Filtration drying obtains olanzapine 326.2g.Product yield 92.4%, purity detect through HPLC and meet the requirements.
Embodiment 5:
With 2-methyl-4-amino-10H-thieno-[2; 3-b] [1; 5] benzodiazepine
hydrochloride 390g (1.47mol), N methyl piperazine 1365g (13.63mol) adding 2000mL are equipped with in churned mechanically three mouthfuls of reaction flasks; Feed nitrogen and reacting by heating mixture; 100 ℃ of reactions, N methyl piperazine is reclaimed in underpressure distillation after 24 hours.After recovery finishes, reaction product is poured in the 12L frozen water, the frozen water reaction mixture is until olanzapine precipitated.Filtration drying obtains olanzapine 428.0g.Product yield 93.2%, purity detect through HPLC and meet the requirements.
Embodiment 6:
With 2-methyl-4-amino-10H-thieno-[2; 3-b] [1; 5] benzodiazepine
hydrochloride 32kg (120.4mol), N methyl piperazine 124kg (1.24kmol) add in the 200L glass-lined reactor; Feed nitrogen; Heat up, 100 ℃ of control reaction temperature are reacted underpressure distillation recovery N methyl piperazine after 20 hours.After recovery finishes, reaction product is changed in the water of 1000kg precooling, be cooled to 10 ℃, stir to make in 2 hours and precipitate fully.Get rid of the filter drying and obtain olanzapine 35.3kg.Product yield 93.8%, purity detect through HPLC and meet the requirements.
Embodiment 7:
With 2-methyl-4-amino-10H-thieno-[2; 3-b] [1; 5] benzodiazepine
hydrochloride 32kg (120.4mol), recovery N methyl piperazine 120kg (1.2kmol) add in the 200L glass-lined reactor; Feed nitrogen; Heat up, 100 ℃ of control reaction temperature are reacted underpressure distillation recovery N methyl piperazine after 20 hours.After recovery finishes, reaction product is changed in the water of 1000kg precooling, be cooled to 10 ℃, stir to make in 2 hours and precipitate fully.Get rid of the filter drying and obtain olanzapine 35.4kg.Product yield 94.0%, purity detect through HPLC and meet the requirements.
Claims (10)
1. the method for a preparing olanzapine; It comprises: heating 2-methyl-4-amino-10H-thieno-[2 under condition of no solvent; 3-b] [1; 5] reaction mixture of benzodiazepine
hydrochloride and N methyl piperazine to 80-100 ℃ temperature; And under this temperature, keeping 16-24 hour, thereby preparing olanzapine.
2. method according to claim 1, wherein, said temperature is 90-100 ℃.
3. method according to claim 2 wherein, was kept under said temperature 20-24 hour.
4. according to each described method in the claim 1 to 3; Wherein, Said 2-methyl-4-amino-10H-thieno-[2; 3-b] mol ratio of [1,5] benzodiazepine
hydrochloride and said N methyl piperazine is 1: 3-1: 12.
5. method according to claim 4; Wherein, Said 2-methyl-4-amino-10H-thieno-[2; 3-b] mol ratio of [1,5] benzodiazepine
hydrochloride and said N methyl piperazine is 1: 8-1: 12.
6. method according to claim 5; Wherein, Said 2-methyl-4-amino-10H-thieno-[2; 3-b] mol ratio of [1,5] benzodiazepine
hydrochloride and said N methyl piperazine is 1: 10.
7. method according to claim 1; Wherein said 2-methyl-4-amino-10H-thieno-[2; 3-b] reaction of [1,5] benzodiazepine
hydrochloride and said N methyl piperazine carries out under protection of inert gas.
8. method according to claim 7, wherein said rare gas element are nitrogen.
9. method according to claim 1, this method also comprises: after preparing olanzapine, remove unreacted N methyl piperazine, then the reaction product of gained is mixed with water, make olanzapine precipitated, to collect olanzapine.
10. compound method according to claim 9; The consumption of wherein said water is the 2-methyl-4-amino-10H-thieno-[2 as reactant; 3-b] [1,5] benzodiazepine
hydrochloride quality 10-35 doubly.
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| CN201010595084XA CN102532158A (en) | 2010-12-17 | 2010-12-17 | Method for synthesizing olanzapine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102924472A (en) * | 2012-09-03 | 2013-02-13 | 江苏豪森药业股份有限公司 | Preparation method for olanzapine |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1056693A (en) * | 1990-04-25 | 1991-12-04 | 利利工业公司 | Medical compounds |
| US20050272720A1 (en) * | 2004-01-27 | 2005-12-08 | Rolf Keltjens | Process for making olanzapine Form I |
| CN1906201A (en) * | 2003-12-22 | 2007-01-31 | 特瓦制药工业有限公司 | Methods of preparing olanzapine |
| EP1773841B1 (en) * | 2004-07-27 | 2007-12-05 | Inke, S.A. | Mixed solvate of olanzapine, method for preparing it and method for preparing form i of olanzapine therefrom |
| US20080319189A1 (en) * | 2007-06-22 | 2008-12-25 | Apotex Pharmachem Inc. | Processes for the synthesis of olanzapine |
-
2010
- 2010-12-17 CN CN201010595084XA patent/CN102532158A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1056693A (en) * | 1990-04-25 | 1991-12-04 | 利利工业公司 | Medical compounds |
| CN1906201A (en) * | 2003-12-22 | 2007-01-31 | 特瓦制药工业有限公司 | Methods of preparing olanzapine |
| US20050272720A1 (en) * | 2004-01-27 | 2005-12-08 | Rolf Keltjens | Process for making olanzapine Form I |
| EP1773841B1 (en) * | 2004-07-27 | 2007-12-05 | Inke, S.A. | Mixed solvate of olanzapine, method for preparing it and method for preparing form i of olanzapine therefrom |
| US20080319189A1 (en) * | 2007-06-22 | 2008-12-25 | Apotex Pharmachem Inc. | Processes for the synthesis of olanzapine |
Non-Patent Citations (2)
| Title |
|---|
| 岑均达: "奥氮平的合成", 《中国医药工业杂志》 * |
| 杨先金，等: "奥氮平的合成工艺改进", 《中国新药杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102924472A (en) * | 2012-09-03 | 2013-02-13 | 江苏豪森药业股份有限公司 | Preparation method for olanzapine |
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Application publication date: 20120704 |