CN111978208A - Preparation method of 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile - Google Patents
Preparation method of 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile Download PDFInfo
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- CN111978208A CN111978208A CN202010900760.3A CN202010900760A CN111978208A CN 111978208 A CN111978208 A CN 111978208A CN 202010900760 A CN202010900760 A CN 202010900760A CN 111978208 A CN111978208 A CN 111978208A
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Abstract
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile. 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile is a main impurity compound in the synthesis process of an olanzapine intermediate 2- (2-nitroanilino) -5-methyl-3-cyanothiophene, and the research significance of the 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile is great, through the preparation and the structural confirmation of the impurity, a reference substance can be provided for the analysis of the related substances of the olanzapine intermediate, is used for quantitative and qualitative analysis of impurities and central control of olanzapine intermediate production, can effectively monitor and timely reduce the impurity content by adopting necessary means, thereby improving the quality standard of olanzapine intermediate and providing help for registration declaration of olanzapine.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile.
Background
Olanzapine, chemical name 2-methyl-4- (4-methyl-1-piperazinyl) -10 hydro-thieno [2,3-b ] [1,5] benzodiazepine, having the following structure:
olanzapine, developed by the company LILLY and marketed in the united states in 1996 under the trade name ZYPREXA, is suitable for the treatment of schizophrenia and other psychoses with severe positive or negative symptoms in the acute and maintenance phases, and also for the relief of secondary affective symptoms of schizophrenia and related diseases, and the mechanism of action of olanzapine is not known, probably by antagonism of dopamine and 5-hydroxytryptamine 2(5-HT 2).
2- (2-nitroanilino) -5-methyl-3-cyanothiophene is an important intermediate in the synthesis of olanzapine and is obtainable by the prior art using the method described in CN 1028429C:
in the synthesis of 2- (2-nitroanilino) -5-methyl-3-cyanothiophene, an olanzapine intermediate, 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile [ compound (1) ] is a major impurity thereof using conventional techniques.
Researchers found that compound (1) and olanzapine intermediate 2- (2-nitroanilino) -5-methyl-3-cyanothiophene have similar properties, and can continuously participate in reaction in the olanzapine synthesis process to generate compound (3) and isomer compound (4) thereof.
The cyano groups of the compound (3) and the compound (4) are further subjected to alcoholysis to form the corresponding esters, and the compound (5) and the compound (6) are obtained.
All of the above impurities may remain in olanzapine, thereby affecting the safety of the drug. Therefore, the research on the compound 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile is significant, a reference substance can be provided for analysis of related substances of an olanzapine intermediate through preparation and structure confirmation of the impurity, the reference substance is used for quantitative and qualitative analysis of the impurity and production control of the olanzapine intermediate, the impurity content can be effectively monitored and timely reduced by adopting necessary means, so that the quality standard of the olanzapine intermediate is improved, and the help is provided for registration and declaration of olanzapine.
For the above reasons, the present invention is intended to provide a process for producing 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile.
Disclosure of Invention
The invention aims to provide a preparation method of 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile, so as to solve the problems in the background technology.
A preparation method of 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile is characterized by comprising the following reaction route:
the specific reaction steps are as follows:
firstly, dissolving propionaldehyde in an organic solvent, adding an organic base, dropwise adding a mixed solution of malononitrile and an aprotic polar solvent, and reacting for 24-48 h at the temperature of 0-30 ℃;
secondly, after the reaction is finished, washing the reaction liquid by using water, and concentrating the organic phase a under reduced pressure to obtain an oily substance a; recrystallizing the oily matter a for 5 to 10 hours by using a mixture of ester and alkane at the temperature of between 10 ℃ below zero and 20 ℃, and drying to obtain a compound (2); dissolving the compound (2) in an aprotic polar solvent, adding inorganic base, dropwise adding a mixed solution of o-fluoronitrobenzene and the aprotic polar solvent, and reacting at the temperature of 10-40 ℃ for 12-24 h;
fourthly, after the reaction is finished, adding water into the reaction solution, extracting by using an organic solvent, and concentrating the organic phase b under reduced pressure to obtain an oily substance b; recrystallizing the oily matter b for 2 to 5 hours by using a mixture of ester and alkane at the temperature of between 10 ℃ below zero and 20 ℃, and drying to obtain the target compound (1).
Preferably, the method comprises the following steps: the reaction temperature in the first step is 10-20 ℃, and the reaction time is 35-36 h; the recrystallization temperature in the second step is 0-10 ℃, and the recrystallization time is 7-8 h; in the third step, the reaction temperature is 20-30 ℃, and the reaction time is 17-18 h; in the fourth step, the recrystallization temperature is 0-10 ℃, and the recrystallization time is 3.5-4 h.
Preferably, the method comprises the following steps: malononitrile in step one: organic base: propionaldehyde 1.0: 0.5-1.0: 1-1.5; in the second step, the volume ratio of the ester to the alkane is ester: alkane 1: 5-10; compound (2) in step three: o-fluoronitrobenzene: organic base 1: 1.0-1.5: 2-2.5; the step four middle ester: alkane 1: 2-5.
Further, in step one, malononitrile: organic base: propionaldehyde 1.0:0.6: 1.2; in the second step, the volume ratio of the ester to the alkane is ester: alkane 1: 6; compound (2) in step three: o-fluoronitrobenzene: organic base 1: 1.2: 2.1; the step four middle ester: alkane 1: 3.
Preferably, the method comprises the following steps: the organic base is selected from one of triethylamine, diethylamine, N-diisopropylethylamine, morpholine and piperidine. Further, the organic base is triethylamine.
Preferably, the method comprises the following steps: the aprotic polar solvent is one selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide and dimethylsulfoxide. Further, the aprotic solvent is N, N-dimethylformamide.
Preferably, the method comprises the following steps: the ester is selected from one of ethyl acetate, methyl acetate and propyl acetate; the alkane is selected from one of n-hexane, cyclohexane, petroleum ether and n-heptane. Further, the ester is ethyl acetate, and the alkane is petroleum ether.
Preferably, the method comprises the following steps: the inorganic base is selected from one of sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and potassium hydride. Further, the inorganic base is potassium hydroxide.
Preferably, the method comprises the following steps: the organic solvent is selected from one of dichloromethane, trichloromethane, toluene and xylene. Further, the organic solvent is dichloromethane.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention provides a high-purity impurity reference substance for the olanzapine intermediate;
(2) the method has simple operation steps and high product purity.
Drawings
FIG. 1 is a HPLC chart of 2- (2-nitroanilino) -5-methyl-3-cyanothiophene, an olanzapine intermediate prepared by the prior art;
FIG. 2 is an HPLC chart of Compound (2) prepared in example 1;
FIG. 3 is a mass spectrum of Compound (2) prepared in example 1;
FIG. 4 is an infrared spectrum of the compound (2) prepared in example 1;
FIG. 5 shows the preparation of Compound (2) in example 11H-NMR chart;
FIG. 6 shows the preparation of Compound (2) in example 113C-NMR chart;
FIG. 7 is an HPLC chart of Compound (1) prepared in example 2;
FIG. 8 is a mass spectrum of Compound (1) prepared in example 2;
FIG. 9 is an infrared spectrum of the compound (1) prepared in example 2;
FIG. 10 is a 1H-NMR chart of the compound (1) produced in example 2;
FIG. 11 shows the preparation of Compound (1) in example 213C-NMR chart;
FIG. 12 is a DEPT135 ° plot of compound (1) prepared in example 2;
FIG. 13 is a COSY diagram of compound (1) prepared in example 2;
FIG. 14 is a HMQC plot of compound (1) prepared in example 2;
FIG. 15 is a HMBC diagram of compound (1) prepared in example 2.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Referring to example 1-example XX and FIGS. 1-15, the present invention provides a process for the preparation of 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile:
example 1
Preparation of 2-amino-4-ethyl-5-methylisobenzodinitrile [ compound (2) ]:
adding 180ml of dichloromethane, 17.4g of propionaldehyde and 15.4g of triethylamine into a reaction bottle, cooling to 0-10 ℃, keeping the temperature at 0-10 ℃, dropwise adding a mixed solution of 30ml of N, N-dimethylformamide and 16.5g of malononitrile, keeping the temperature at 10-20 ℃ for reacting for 36h after completing the dropwise addition, washing the reaction solution by using 50ml of drinking water for 3 times, decompressing and concentrating an organic layer to obtain an oily substance, adding 50ml of ethyl acetate into the oily substance, stirring and heating to a clear solution, dropwise adding 300ml of petroleum ether, slowly cooling to 0-10 ℃, stirring and crystallizing for 8h, filtering, and vacuum-drying a filter cake at 40-50 ℃ to obtain 11.8g of the compound (2). (yield: 25.5%, HPLC: 99.658%)
Example 2
Preparation of 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile [ compound (1) ]:
adding 15g of DMF, 11g of the compound (2) obtained in example 1 and 7.1g of potassium hydroxide into a reaction bottle, controlling the reaction temperature to be 20-30 ℃, dropwise adding a mixed solution of 10.2g of o-fluoronitrobenzene and 20g of DMF, controlling the reaction temperature to be 20-30 ℃ after about 1-2h of addition, reacting for 18h, adding 75g of dichloromethane and 50g of water for extraction after the reaction is finished, decompressing and concentrating an organic layer to obtain an oily substance, adding 75ml of ethyl acetate into the oily substance, stirring and heating to a clear solution, dropwise adding 225ml of petroleum ether, slowly cooling to 0-10 ℃, stirring and crystallizing for 4h, filtering, and drying a filter cake in vacuum at 40-50 ℃ to obtain 7.6g of the compound (1). (yield: 41.4%, HPLC: 99.008%)
Example 3
Preparation of 2-amino-4-ethyl-5-methylisobenzodinitrile [ compound (2) ]:
adding 180ml of dichloromethane, 17.4g of propionaldehyde and 19.7g of N, N-diisopropylethylamine into a reaction bottle, cooling to 0-10 ℃, keeping the temperature at 0-10 ℃, dropwise adding a mixed solution of 30ml of N, N-dimethylformamide and 16.5g of malononitrile, keeping the temperature at 0-10 ℃ for 48 hours after dropwise adding, after the reaction is finished, washing the reaction solution by using 50ml of drinking water for 3 times, decompressing and concentrating an organic layer to obtain an oily substance, adding 50ml of ethyl acetate into the oily substance, stirring and heating to a clear solution, dropwise adding 300ml of petroleum ether, slowly cooling to 0-10 ℃, stirring and crystallizing for 8 hours, filtering, and performing vacuum drying on a filter cake at 40-50 ℃ to obtain 11.5g of the compound (2). (yield: 24.8%, HPLC: 99.217%)
Example 4
Preparation of 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile [ compound (1) ]:
15g of DMF, 11g of the compound (2) obtained in example 3 and 8.4g of sodium hydroxide are added into a reaction bottle, the reaction temperature is controlled to be 20-30 ℃, a mixed solution of 10.2g of o-fluoronitrobenzene and 20g of DMF is dropwise added, the reaction temperature is controlled to be 10-20 ℃ after about 1-2h of addition, the reaction is 24h, 75g of dichloromethane and 50g of water are added for extraction after the reaction is finished, an organic layer is decompressed and concentrated into oily matter, 75ml of ethyl acetate is added into the oily matter, the mixture is stirred and heated to be clear, 225ml of petroleum ether is dropwise added, the temperature is slowly reduced to be 0-10 ℃, the mixture is stirred and crystallized for 4h, the mixture is filtered, and a filter cake is dried in vacuum at 40-50 ℃ to obtain 7.5g of the. (yield: 40.8%, HPLC: 99.023%)
Example 5
Preparation of 2-amino-4-ethyl-5-methylisobenzodinitrile [ compound (2) ]:
adding 180ml of dichloromethane, 17.4g of propionaldehyde and 25.3g of triethylamine into a reaction bottle, cooling to 0-10 ℃, keeping the temperature at 0-10 ℃, dropwise adding a mixed solution of 30ml of N, N-dimethylformamide and 16.5g of malononitrile, heating to 20-30 ℃, preserving the temperature for reaction for 24h, finishing the reaction, washing the reaction solution by using 50ml of drinking water for 3 times, decompressing and concentrating an organic layer to an oily substance, adding 50ml of ethyl acetate into the oily substance, stirring and heating to a clear solution, dropwise adding 300ml of petroleum ether, slowly cooling to 0-10 ℃, stirring and crystallizing for 8h, filtering, and vacuum-drying a filter cake at 40-50 ℃ to obtain 11.4g of the compound (2). (yield: 24.6%, HPLC: 99.211%)
Example 6
Preparation of 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile [ compound (1) ]:
adding 15g of DMF, 11g of the compound (2) obtained in example 5 and 3.0g of sodium hydride into a reaction bottle, controlling the reaction temperature to be 20-30 ℃, dropwise adding a mixed solution of 10.2g of o-fluoronitrobenzene and 20g of DMF, controlling the reaction temperature to be 30-40 ℃, reacting for 12h, adding 75g of dichloromethane and 50g of water to extract after the reaction is finished, decompressing and concentrating an organic layer to obtain an oily substance, adding 75ml of ethyl acetate into the oily substance, stirring and heating to a clear solution, dropwise adding 225ml of petroleum ether, slowly cooling to 0-10 ℃, stirring and crystallizing for 4h, filtering, and vacuum-drying a filter cake at 40-50 ℃ to obtain 7.2g of the compound (1). (yield: 39.2%, HPLC: 98.883%)
Example 7
Preparation of 2-amino-4-ethyl-5-methylisobenzodinitrile [ compound (2) ]:
adding 180ml of dichloromethane, 17.4g of propionaldehyde and 15.4g of triethylamine into a reaction bottle, cooling to 0-10 ℃, keeping the temperature at 0-10 ℃, dropwise adding a mixed solution of 30ml of N, N-dimethylformamide and 16.5g of malononitrile, keeping the temperature at 10-20 ℃ for reacting for 36h after completing dropwise addition, washing the reaction solution by using 50ml of drinking water for 3 times, decompressing and concentrating an organic layer to obtain an oily substance, adding 50ml of ethyl acetate into the oily substance, stirring and heating to clear, dropwise adding 500ml of petroleum ether, slowly cooling to-10-0 ℃, stirring and crystallizing for 5h, filtering, and vacuum-drying a filter cake at 40-50 ℃ to obtain 12.3g of the compound (2). (yield: 26.6%, HPLC: 98.768%)
Example 8
Preparation of 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile [ compound (1) ]:
adding 15g of DMF, 11g of the compound (2) obtained in example 7 and 7.1g of potassium hydroxide into a reaction bottle, controlling the reaction temperature to be 20-30 ℃, dropwise adding a mixed solution of 10.2g of o-fluoronitrobenzene and 20g of DMF, controlling the reaction temperature to be 20-30 ℃ after about 1-2h of addition, reacting for 18h, adding 75g of dichloromethane and 50g of water for extraction after the reaction is finished, decompressing and concentrating an organic layer to obtain an oily substance, adding 75ml of ethyl acetate into the oily substance, stirring and heating to a clear solution, dropwise adding 375ml of petroleum ether, slowly cooling to-10-0 ℃, stirring and crystallizing for 2h, filtering, and performing vacuum drying on a filter cake at 40-50 ℃ to obtain 7.9g of the compound (1). (yield: 43.0%, HPLC: 98.356%)
Example 9
Preparation of 2-amino-4-ethyl-5-methylisobenzodinitrile [ compound (2) ]:
adding 180ml of dichloromethane, 17.4g of propionaldehyde and 15.4g of triethylamine into a reaction bottle, cooling to 0-10 ℃, keeping the temperature at 0-10 ℃, dropwise adding a mixed solution of 30ml of dimethyl sulfoxide and 16.5g of malononitrile, keeping the temperature at 10-20 ℃ for reacting for 36h after completing the dropwise addition, washing a reaction solution by using 50ml of drinking water for 3 times, decompressing and concentrating an organic layer to an oily substance, adding 50ml of ethyl acetate into the oily substance, stirring and heating to clear, dropwise adding 300ml of petroleum ether, slowly cooling to 10-20 ℃, stirring and crystallizing for 10h, filtering, and vacuum-drying a filter cake at 40-50 ℃ to obtain 10.8g of the compound (2). (yield: 23.3%, HPLC: 99.776%)
Example 10
Preparation of 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile [ compound (1) ]:
adding 15g of dimethyl sulfoxide, 11g of the compound (2) obtained in example 9 and 7.1g of potassium hydroxide into a reaction bottle, controlling the reaction temperature to be 20-30 ℃, dropwise adding a mixed solution of 10.2g of o-fluoronitrobenzene and 20g of dimethyl sulfoxide, controlling the reaction temperature to be 20-30 ℃ after about 1-2h of addition, reacting for 18h, adding 75g of dichloromethane and 50g of water for extraction after the reaction is finished, decompressing and concentrating an organic layer to obtain an oily substance, adding 75ml of ethyl acetate into the oily substance, stirring and heating to a clear solution, dropwise adding 225ml of petroleum ether, slowly cooling to 10-20 ℃, stirring and crystallizing for 5h, filtering, and vacuum-drying a filter cake at 40-50 ℃ to obtain 6.9g of the compound (1). (yield: 37.6%, HPLC: 99.395%)
The instrument and materials used in the detection process of the compound (1) and the olanzapine intermediate substance are as follows:
the instrument comprises the following steps: liquid chromatograph, electronic balance (one hundred thousand);
a chromatographic column: zorbax RX C8250X 4.6mm, 5 μm or equivalent chromatography column;
mobile phase A: weighing 0.77g of ammonium acetate, adding 1000mL of water for dissolving, performing ultrasonic treatment, and filtering;
mobile phase B: and (3) acetonitrile.
Gradient elution procedure:
| time (minutes) | Mobile phase A (% v/v) | Mobile phase B (% v/v) |
| 0-5 | 50 | 50 |
| 5-15 | 50→30 | 50→70 |
| 15-20 | 30 | 70 |
Flow rate: 1.5 ml/min; column temperature: 35 ℃; and (3) detection: UV220 nm; sample introduction: 20 ul.
Instrument set and materials used in the detection of compound (2) substance:
the instrument comprises the following steps: liquid chromatograph, electronic balance (one hundred thousand);
a chromatographic column: zorbax SB-C8150X 4.6mm, 3.5 μm or equivalent chromatography column;
mobile phase A: weighing about 2.3g of ammonium dihydrogen phosphate, adding 1000ml of water for dissolving, filtering and degassing;
mobile phase B: acetonitrile-water (90: 10).
Gradient elution procedure:
| time (minutes) | Mobile phase A (% v/v) | Mobile phase B (% v/v) |
| 0 | 80 | 20 |
| 30 | 10 | 90 |
| 35 | 10 | 90 |
| 35.1 | 80 | 20 |
| 40 | 80 | 20 |
Flow rate: 1.0 ml/min; column temperature: 25 ℃; and (3) detection: UV267 nm; sample introduction: 5 ul.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. A preparation method of 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile is characterized by comprising the following reaction route:
the specific reaction steps are as follows:
firstly, dissolving propionaldehyde in an organic solvent, adding an organic base, dropwise adding a mixed solution of malononitrile and an aprotic polar solvent, and reacting for 24-48 h at the temperature of 0-30 ℃;
secondly, after the reaction is finished, washing the reaction liquid by using water, and concentrating the organic phase a under reduced pressure to obtain an oily substance a; recrystallizing the oily matter a for 5 to 10 hours by using a mixture of ester and alkane at the temperature of between 10 ℃ below zero and 20 ℃, and drying to obtain a compound (2);
dissolving the compound (2) in an aprotic polar solvent, adding inorganic base, dropwise adding a mixed solution of o-fluoronitrobenzene and the aprotic polar solvent, and reacting at the temperature of 10-40 ℃ for 12-24 h;
fourthly, after the reaction is finished, adding water into the reaction solution, extracting by using an organic solvent, and concentrating the organic phase b under reduced pressure to obtain an oily substance b; recrystallizing the oily matter b for 2 to 5 hours by using a mixture of ester and alkane at the temperature of between 10 ℃ below zero and 20 ℃, and drying to obtain the target compound (1).
2. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: the reaction temperature in the first step is 10-20 ℃, and the reaction time is 35-36 h; the recrystallization temperature in the second step is 0-10 ℃, and the recrystallization time is 7-8 h; in the third step, the reaction temperature is 20-30 ℃, and the reaction time is 17-18 h; in the fourth step, the recrystallization temperature is 0-10 ℃, and the recrystallization time is 3.5-4 h.
3. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: malononitrile in step one: organic base: propionaldehyde 1.0: 0.5-1.0: 1-1.5; in the second step, the volume ratio of the ester to the alkane is ester: alkane 1: 5-10; compound (2) in step three: o-fluoronitrobenzene: organic base 1: 1.0-1.5: 2-2.5; the step four middle ester: alkane 1: 2-5.
4. The process according to claim 3, wherein the reaction product is 4-ethyl-5-methyl-2- ((2-nitrophenyl) amino) isophthalonitrile: malononitrile in step one: organic base: propionaldehyde 1.0:0.6: 1.2; in the second step, the volume ratio of the ester to the alkane is ester: alkane 1: 6; compound (2) in step three: o-fluoronitrobenzene: organic base 1: 1.2: 2.1; the step four middle ester: alkane 1: 3.
5. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: the organic base is selected from one of triethylamine, diethylamine, N-diisopropylethylamine, morpholine and piperidine.
6. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: the aprotic polar solvent is one selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide and dimethylsulfoxide.
7. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: the ester is selected from one of ethyl acetate, methyl acetate and propyl acetate.
8. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: the alkane is selected from one of n-hexane, cyclohexane, petroleum ether and n-heptane.
9. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: the inorganic base is selected from one of sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and potassium hydride.
10. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: the organic solvent is selected from one of dichloromethane, trichloromethane, toluene and xylene.
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| CN117820170A (en) * | 2024-03-06 | 2024-04-05 | 北京哈三联科技有限责任公司 | Olanzapine genotoxic impurity and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102225941A (en) * | 2011-06-01 | 2011-10-26 | 宁波人健医药化工有限公司 | Preparation method of antipsychotic drug olanzapine |
| CN102250116A (en) * | 2011-07-12 | 2011-11-23 | 景德镇市富祥药业有限公司 | Preparation method of olanzapine |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102225941A (en) * | 2011-06-01 | 2011-10-26 | 宁波人健医药化工有限公司 | Preparation method of antipsychotic drug olanzapine |
| CN102250116A (en) * | 2011-07-12 | 2011-11-23 | 景德镇市富祥药业有限公司 | Preparation method of olanzapine |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117820170A (en) * | 2024-03-06 | 2024-04-05 | 北京哈三联科技有限责任公司 | Olanzapine genotoxic impurity and preparation method thereof |
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