CN111718302A - Clozapine intermediate and synthetic method and application thereof - Google Patents
Clozapine intermediate and synthetic method and application thereof Download PDFInfo
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- CN111718302A CN111718302A CN202010543884.0A CN202010543884A CN111718302A CN 111718302 A CN111718302 A CN 111718302A CN 202010543884 A CN202010543884 A CN 202010543884A CN 111718302 A CN111718302 A CN 111718302A
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- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 229960004170 clozapine Drugs 0.000 title claims abstract description 40
- 238000010189 synthetic method Methods 0.000 title claims description 5
- 239000012065 filter cake Substances 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 19
- HMVPMZFEYCGSTC-UHFFFAOYSA-N 2-(2-amino-4-chloroanilino)benzoic acid Chemical compound NC1=CC(Cl)=CC=C1NC1=CC=CC=C1C(O)=O HMVPMZFEYCGSTC-UHFFFAOYSA-N 0.000 claims abstract description 17
- YVWNDABPZGGQFE-UHFFFAOYSA-N 3-chloro-5,11-dihydrobenzo[b][1,4]benzodiazepin-6-one Chemical compound O=C1NC2=CC(Cl)=CC=C2NC2=CC=CC=C21 YVWNDABPZGGQFE-UHFFFAOYSA-N 0.000 claims abstract description 17
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 17
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 17
- 238000001308 synthesis method Methods 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 238000001035 drying Methods 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 17
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 16
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 13
- 238000007670 refining Methods 0.000 claims description 13
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 12
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 9
- 239000003651 drinking water Substances 0.000 claims description 8
- 235000020188 drinking water Nutrition 0.000 claims description 8
- -1 2- (4-chloro-2-nitrophenyl) aminobenzoic acid Chemical compound 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000002386 leaching Methods 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 230000001276 controlling effect Effects 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 239000000047 product Substances 0.000 abstract description 8
- 239000002932 luster Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract 1
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 12
- 229960003638 dopamine Drugs 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 206010043118 Tardive Dyskinesia Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 102000004305 alpha Adrenergic Receptors Human genes 0.000 description 1
- 108090000861 alpha Adrenergic Receptors Proteins 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
Abstract
The invention discloses a clozapine intermediate, a synthesis method and application thereof, and belongs to the technical field of drug synthesis. The synthesis method comprises the following steps: 1) synthesis of 2- [ (2-amino-4-chlorophenyl) amino ] benzoic acid, 2) synthesis of 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one; the filter cake of each step is refined in the synthesis process, so that the product yield and purity are increased. The synthesis method of the clozapine intermediate has the advantages of simple preparation process, recoverable solvent, easy operation and control, good color and luster of the obtained product, good quality, high purity and high yield, can be directly used for production and use, and has good practicability.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a clozapine intermediate, and a synthesis method and application thereof.
Background
Clozapine (Clozapine), alternative name: 8-chloro-11 (4-methyl-1-piperazinyl) -5H-dibenzo [ B, E][1,4]Diaza derivatives
8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo [ b, e][1,4]Diaza derivatives
Chlorazapine, molecular formula: c18H19ClN4. Clozapine is a benzodiazepine. Has strong blocking effect on 5-hydroxytryptamine (5-HT2A) receptors and dopamine (DA1) receptors in brain, also has blocking effect on dopamine (DA4) receptors, has weak blocking effect on dopamine (DA2) receptors, and also has the effects of resisting choline (M1), histamine (H1) and alpha-adrenergic receptors, has light extrapyramidal reaction and tardive dyskinesia, and generally does not cause increase of prolactin in blood. Can directly inhibit the brain stem network structure ascending activation system, has strong sedative and hypnotic effects, and is used for treating various types of schizophrenia. The existing clozapine preparation process is a traditional process, is complex in method and multiple in steps, and cannot meet the use requirement.
Disclosure of Invention
The invention aims to solve the technical problem of providing a synthetic method of a clozapine intermediate, which has the advantages of simple method and easy operation and control. The invention also aims to solve the technical problem of providing a clozapine intermediate, and the obtained product has good color and luster, good quality, high purity and high yield. The invention also provides an application of the clozapine intermediate in the preparation of clozapine, and the prepared intermediate can be directly used for production and use and has good practicability.
In order to solve the problems, the technical scheme adopted by the invention is as follows:
a method for synthesizing a clozapine intermediate, comprising the steps of:
(1) synthesis of 2- [ (2-amino-4-chlorophenyl) amino ] benzoic acid:
adding dilute ammonia water, 2- (4-chloro-2-nitrophenyl) aminobenzoic acid and sodium hydrosulfite into a reduction reactor, heating to dissolve, and controlling the temperature to react for 0.5-2 hours; after the reaction is finished, cooling to room temperature, regulating the pH value of the system to 4-5 with hydrochloric acid, centrifuging, washing a filter cake with water, spin-drying, and refining the filter cake to obtain 2- [ (2-amino-4-chlorophenyl) amino ] benzoic acid;
(2) synthesis of 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one:
adding dimethylbenzene into a cyclization reactor, starting stirring, adding 2- [ (2-amino-4-chlorphenyl) amino ] benzoic acid obtained in the step (1), heating until reflux and water separation reaction are carried out, cooling to 15-20 ℃ after the reaction is finished, stirring for crystallization for 2.5-3.5 h, centrifuging, leaching a filter cake with dimethylbenzene, and drying; then refining the filter cake to obtain 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one.
According to the synthesis method of the clozapine intermediate, the mass fraction of the dilute ammonia water is 6% -10%.
The synthesis method of the clozapine intermediate comprises the following steps that in the step (1), the mass ratio of 2- (4-chloro-2-nitrophenyl) aminobenzoic acid to dilute ammonia water to sodium hydrosulfite is 1: 6-8: 1-3; in the step (2), the mass ratio of the 2- [ (2-amino-4-chlorphenyl) amino ] benzoic acid to the xylene is 7: 1-8: 1.
In the step (1), the sodium hydrosulfite is fed at a low temperature of 30-40 ℃, the temperature is kept for 0.5-1 h, the temperature is raised to 80 ℃ at a speed of 5 ℃/min, and then the temperature is controlled to react for 1-2 h.
The synthesis method of the clozapine intermediate comprises the following steps of (1), filter cake refining: adding a filter cake and drinking water into the reduction treatment kettle, stirring, heating to 65-70 ℃, stirring and washing for 0.5-1.5 h, cooling to room temperature after washing, centrifuging, spin-drying, and drying the filter cake at 70 ℃ to obtain the 2- [ (2-amino-4-chlorophenyl) amino ] benzoic acid.
According to the synthesis method of the clozapine intermediate, in the step (1), the drinking water consumption in the filter cake refining process is 1-3 times of the mass of the filter cake, and after 1-3 times of the drinking water in the filter cake is added for stirring, washing and refining, large-polarity impurities generated by side reactions can be removed, and the chromatographic purity of the obtained product is more than or equal to 97%.
The synthesis method of the clozapine intermediate comprises the following steps (2) of filter cake refining: adding n-butyl alcohol into a cyclization treatment kettle, starting stirring, adding a filter cake into the kettle, heating to reflux, stirring to dissolve until the mixture is clear, cooling to 0-5 ℃, stirring to crystallize for 2.5-3.5H, centrifuging, and drying the filter cake at the temperature of 70-75 ℃ under reduced pressure for 3.5-4.5H to obtain 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one.
According to the synthesis method of the clozapine intermediate, the amount of n-butanol in the refining process of the filter cake in the step (2) is 2-10 times of the mass of the filter cake.
The clozapine intermediate 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one prepared by the synthetic method of the clozapine intermediate.
The application of the clozapine intermediate 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one in preparing clozapine.
Has the advantages that: compared with the prior art, the invention has the advantages that:
the production process of the clozapine intermediate has the advantages of simple preparation method, few steps, easy operation and control, good color and luster of the obtained product, good quality, high purity and high yield, wherein the yield of 2- [ (2-amino-4-chlorphenyl) amino ] benzoic acid reaches 68-80%, the chromatographic purity is more than or equal to 97%, the yield of 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one reaches 65-75%, and the chromatographic purity is more than or equal to 98%; and the prepared product can be directly used for production and use and has good practicability.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with examples are described in detail below.
Example 1
A production method of clozapine intermediate comprises the following process route:
the method comprises the following steps:
1) synthesis of 2- [ (2-amino-4-chlorophenyl) amino ] benzoic acid
700kg of dilute ammonia water with the concentration of 6 percent is added into a dry and clean reduction reaction kettle, stirring is started, and 100kg of 2- (4-chloro-2-nitrophenyl) aminobenzoic acid is added into the reaction kettle. After the addition, the temperature is raised to 80 ℃, 200kg of sodium hydrosulfite is slowly added into the kettle, the temperature is kept for reaction for 2 hours after the addition, and the feeding speed needs to be paid attention to in the adding process of the sodium hydrosulfite to prevent the flushing. And (5) finishing heat preservation. And after the reaction is finished, cooling the reaction liquid to room temperature, adjusting the pH of the system to 4-5 by using industrial hydrochloric acid, centrifuging, washing a filter cake by using 30kg of water, and spin-drying.
Adding filter cake drinking water into a dry and clean reduction treatment kettle, starting stirring, heating to 65 ℃, stirring and washing for 1h, starting a reaction kettle cooling system, cooling to room temperature, centrifuging, spin-drying, and drying filter cakes to obtain the 2- [ (2-amino-4-chlorphenyl) amino ] benzoic acid, wherein the yield is 68-80%, and the HPLC (high performance liquid chromatography) is more than or equal to 97%.
2) Synthesis of 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one
250kg of dimethylbenzene is added into a dry and clean cyclization reaction kettle, stirring is started, 35kg of 2- [ (2-amino-4-chlorphenyl) amino ] benzoic acid is added into the kettle, and the temperature is increased in a gradient manner at the speed of 5 ℃/min until reflux water diversion reaction. And after the reaction is finished for 25-30 h, starting a reaction kettle cooling system, cooling the reaction liquid to room temperature, stirring for crystallization for 3h, centrifuging, leaching a filter cake with xylene, drying by spin-drying, and weighing the filter cake.
Adding 2 times of n-butanol into a dry and clean cyclization treatment kettle, starting stirring, adding a filter cake into the kettle, heating to reflux, and stirring to dissolve to be clear. And (3) starting a reaction kettle cooling system, cooling the reaction liquid to 0-5 ℃, stirring and crystallizing for 3H, centrifuging, drying a filter cake at 70-75 ℃ under reduced pressure for 4H to obtain 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one, wherein the content of the obtained product is 65-75%, and the content of HPLC (high performance liquid chromatography) is more than or equal to 97%.
Example 2
The production process of the clozapine intermediate is the same as that in example 1, wherein in the synthesis process of the 2- [ (2-amino-4-chlorophenyl) amino ] benzoic acid in the step 1), the concentration of dilute ammonia water is 8%, the low-concentration ammonia water can cause incomplete reaction of raw materials, the high-concentration ammonia water can cause waste and safety hazard of ammonia water, and the ammonia water with proper concentration can cause more complete reaction, save resources and ensure safer production environment; the feeding mode of sodium hydrosulfite is changed into 40 ℃ low-temperature feeding, the temperature is kept for 1h, then the temperature is increased to 80 ℃ at the speed of 5 ℃/min, the temperature is controlled and the reaction is carried out for 1h, the generation of large-polarity impurities is effectively reduced, a solid product obtained by spin-drying is taken out, 2 times of drinking water is used for 65-70 ℃, the stirring and washing are carried out for 1h, the cooling and the centrifugation are carried out, filter cake drinking water is used for leaching, the drying is carried out, 60kg of 2- [ (2-amino-4-chlorophenyl) amino ] benzoic acid is obtained, HPLC (high performance; and 2) the synthesis process of 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one is unchanged, and the quality and yield of the finally obtained product are more stable.
Example 3
The production process of the clozapine intermediate is the same as that of example 1, in the step 2) of the synthesis process of 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one, the subsequent filter cake treatment process adopts 10 times of n-butanol for recrystallization, cooling and centrifugation, the filter cake is leached by the n-butanol, and the filter cake is dried to obtain 35kg of 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one, HPLC is more than or equal to 98%, and gray black solid powder. The material content is improved.
Claims (10)
1. A synthetic method of a clozapine intermediate is characterized by comprising the following steps:
(1) synthesis of 2- [ (2-amino-4-chlorophenyl) amino ] benzoic acid:
adding dilute ammonia water, 2- (4-chloro-2-nitrophenyl) aminobenzoic acid and sodium hydrosulfite into a reduction reactor, heating to dissolve, and controlling the temperature to react for 0.5-2 hours; after the reaction is finished, cooling to room temperature, regulating the pH value of the system to 4-5 with hydrochloric acid, centrifuging, washing a filter cake with water, spin-drying, and refining the filter cake to obtain 2- [ (2-amino-4-chlorophenyl) amino ] benzoic acid;
(2) synthesis of 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one:
adding dimethylbenzene into a cyclization reactor, starting stirring, adding 2- [ (2-amino-4-chlorphenyl) amino ] benzoic acid obtained in the step (1), heating until reflux and water separation reaction are carried out, cooling to 15-20 ℃ after the reaction is finished, stirring for crystallization for 2.5-3.5 h, centrifuging, leaching a filter cake with dimethylbenzene, and drying; then refining the filter cake to obtain 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one.
2. The synthesis method of the clozapine intermediate as claimed in claim 1, wherein the mass fraction of the dilute ammonia water is 6-10%.
3. The synthesis method of the clozapine intermediate as claimed in claim 1, wherein in the step (1), the mass ratio of the 2- (4-chloro-2-nitrophenyl) aminobenzoic acid to the dilute ammonia water to the sodium hydrosulfite is 1: 6-8: 1-3; in the step (2), the mass ratio of the 2- [ (2-amino-4-chlorophenyl) amino ] benzoic acid to the xylene is 7: 1-8: 1.
4. The synthesis method of the clozapine intermediate as claimed in claim 1, wherein in the step (1), the sodium hydrosulfite is fed at a low temperature of 30-40 ℃, the temperature is kept for 0.5-1 h, and then the temperature is raised to 80 ℃ at a rate of 5 ℃/min, and then the reaction is controlled for 1-2 h.
5. The process for the synthesis of clozapine intermediate of claim 1, wherein step (1), cake refining: adding a filter cake and drinking water into the reduction treatment kettle, stirring, heating to 65-70 ℃, stirring and washing for 0.5-1.5 h, cooling to room temperature after washing, centrifuging, spin-drying, and drying the filter cake at 70 ℃ to obtain the 2- [ (2-amino-4-chlorophenyl) amino ] benzoic acid.
6. The synthesis method of the clozapine intermediate as claimed in claim 5, wherein in the step (1), the drinking water consumption in the filter cake refining process is 1-3 times of the mass of the filter cake.
7. The process for the synthesis of clozapine intermediate of claim 1, wherein step (2), cake refining: adding n-butyl alcohol into a cyclization treatment kettle, starting stirring, adding a filter cake into the kettle, heating to reflux, stirring to dissolve until the mixture is clear, cooling to 0-5 ℃, stirring to crystallize for 2.5-3.5H, centrifuging, and drying the filter cake at the temperature of 70-75 ℃ under reduced pressure for 3.5-4.5H to obtain 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one.
8. The synthesis method of the clozapine intermediate as claimed in claim 7, wherein the amount of n-butanol used in the refining process of the filter cake in the step (2) is 2-10 times of the mass of the filter cake.
9. A clozapine intermediate 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one prepared by the method of synthesis of a clozapine intermediate of claim 1.
10. Use of the clozapine intermediate 8-chloro-5, 10-dihydro-11H-dibenzo [ b, e ] [1,4] -diazepin-11-one of claim 9 for the preparation of clozapine.
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|---|---|---|---|---|
| CN114195665A (en) * | 2021-12-14 | 2022-03-18 | 武汉世吉药业有限公司 | Neutralization and acidification process and equipment for high-purity NCAA |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008144982A1 (en) * | 2007-05-29 | 2008-12-04 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Compounds with 7-member cycle and the pharmaceutical use thereof for preventing and treating diabetes and metabolism syndrome |
| CN106573917A (en) * | 2014-07-31 | 2017-04-19 | 瓦伦帝克有限责任公司 | Method for synthesizing fluoroclozapine and derivatives thereof |
| WO2019239202A1 (en) * | 2018-06-11 | 2019-12-19 | Sms Pharmaceuticals Ltd | Novel & improved synthesis of antipsychotic drug |
-
2020
- 2020-06-15 CN CN202010543884.0A patent/CN111718302A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008144982A1 (en) * | 2007-05-29 | 2008-12-04 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Compounds with 7-member cycle and the pharmaceutical use thereof for preventing and treating diabetes and metabolism syndrome |
| CN101687886A (en) * | 2007-05-29 | 2010-03-31 | 中国科学院上海药物研究所 | Compounds with 7-member cycle and the pharmaceutical use thereof for preventing and treating diabetes and metabolism syndrome |
| CN106573917A (en) * | 2014-07-31 | 2017-04-19 | 瓦伦帝克有限责任公司 | Method for synthesizing fluoroclozapine and derivatives thereof |
| WO2019239202A1 (en) * | 2018-06-11 | 2019-12-19 | Sms Pharmaceuticals Ltd | Novel & improved synthesis of antipsychotic drug |
Non-Patent Citations (2)
| Title |
|---|
| ANTONIO LEYVA-PÉREZ，等: "Bifunctional solid catalysts for chemoselective hydrogenation-cyclisation- amination cascade reactions of relevance for the synthesis of pharmaceuticals", 《TETRAHEDRON》 * |
| T.K.SASIKUMAR，等: "Hydrazides of clozapine: A new class of D1 dopamine receptor subtype selective antagonists", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114195665A (en) * | 2021-12-14 | 2022-03-18 | 武汉世吉药业有限公司 | Neutralization and acidification process and equipment for high-purity NCAA |
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