CN108863960A - A kind of synthetic method for the key intermediate being used to prepare Clozapine - Google Patents
A kind of synthetic method for the key intermediate being used to prepare Clozapine Download PDFInfo
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- CN108863960A CN108863960A CN201810811545.9A CN201810811545A CN108863960A CN 108863960 A CN108863960 A CN 108863960A CN 201810811545 A CN201810811545 A CN 201810811545A CN 108863960 A CN108863960 A CN 108863960A
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- C07—ORGANIC CHEMISTRY
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- 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
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Abstract
The invention discloses a kind of synthetic methods of key intermediate for being used to prepare Clozapine, belong to pharmaceutical synthesis field.Using 2- ((2- amino -4- chlorphenyl) amino) benzoic acid, as raw material, the cyclization under the reflux of aqueous sulfuric acid obtains chloro- 5,10- dihydro -11H- dibenzo [b, e] [the 1,4]-phenodiazine of 8- to this method
Description
Technical field
The invention belongs to pharmaceutical synthesis field more particularly to a kind of synthesis sides for the key intermediate for being used to prepare Clozapine
Method.
Background technique
Clozapine is light yellow crystalline powder, odorless, tasteless, effective to psychosis positive symptom, to negative symptoms
There is certain effect.It is good to hallucinatory paranoid form, hebephrenictype effect suitable for acute and chronic schizophrenia each hypotype.?
It can reduce affective symptom related with schizophrenia (such as：Depression, sense of guilt, anxiety).Traditional antipsychotics are used to some
Invalid or bad curative effect patient is treated, using this product instead may be effectively.It is also used for treatment mania or other psychotic disorders
Excitement restless and illusion vain hope etc..
Currently, Clozapine synthetic method (synthesis of Wang Fuxiang, Peng Zhen cloud Clozapine, Chinese Journal of Pharmaceuticals,
2013,44 (10)) it is to carry out condensation reaction under Anhydrous potassium carbonate effect with 2,5- dichloronitrobenzene and ortho-aminobenzoic acid to obtain
To 2- (4- chloro-2-nitroaniline base) benzoic acid, chloro- 5, the 10- dihydro -11H- hexichol of 8- then is obtained through reduction, cyclization reaction
And [b, e] [1,4]-phenodiazine- 11- ketone, chloro- 5,10- dihydro -11H- dibenzo [b, e] [the Isosorbide-5-Nitrae]-phenodiazine of 8-- 11- ketone exists
Titanium tetrachloride effect is lower and N methyl piperazine is condensed to obtain Clozapine.It can be found through observation, chloro- 5, the 10- dihydro -11H- two of 8-
Benzo [b, e] [1,4]-phenodiazine- 11- ketone is the key intermediate for synthesizing Clozapine, in conventional synthesis route, cyclization step
Reflux water-dividing cyclization is carried out using dimethylbenzene and polyphosphoric acids system, but, energy consumption height long there are the high temperature reflux time, product black
The problems such as.Applied Radiation and Isotopes 55 (2001) 789-791, Modified synthesis simultaneously
It is referred in of 11- [14C]-clozapine, is directly restored, closed from the first step using stannous chloride, ethyl alcohol, acetic acid
Ring, but it is long there are the reaction time, be not easy the problems such as industrialized production.Therefore how to improve tradition reaction the middle reaction time compared with
The problems such as length, temperature are higher, processing is complicated, so as to efficiently obtain chloro- 5, the 10- dihydro -11H- dibenzo [b, e] [Isosorbide-5-Nitrae]-of 8-
Phenodiazine- 11- ketone is crucial.
Chinese Journal of Pharmaceuticals, 2013,44 (10) Clozapine synthetic methods are shown in reaction equation 1：
Reaction equation 1
The synthetic method of Modified synthesis of 11- [14C]-clozapine is shown in reaction equation 2：
Reaction equation 2
Summary of the invention
In order to solve the above technical problems, the present invention provides a kind of key intermediates for being used to prepare Clozapine (i.e.：8-
Chloro- 5,10- dihydro -11H- dibenzo [b, e] [1,4]-phenodiazine- 11- ketone) synthetic method, this method is simple and quick, reaction
Temperature is lower, and obtained product purity is high.
The present invention provides a kind of chloro- 5,10- dihydro -11H- dibenzo [b, e] [the 1,4]-phenodiazines of 8-The conjunction of -11- ketone
At method, 2- ((2- amino -4- chlorphenyl) amino) benzoic acid is mixed with acid solution, flows back, cool down after fully reacting, mistake
Filter, washing, dry chloro- 5,10- dihydro -11H- dibenzo [b, e] [the Isosorbide-5-Nitrae]-phenodiazine of 8-- 11- ketone.
Chemical equation is as follows：
Further, reflux temperature is 70-105 DEG C.
Further, return time is 3-5 hours.
Further, the mass ratio of 2- ((2- amino -4- chlorphenyl) amino) benzoic acid and acid solution is 1：(3-50), acid
The mass concentration of solution is 5%-60%.
Further, acid solution includes one of sulfuric acid solution, hydrochloric acid solution or phosphoric acid solution or a variety of.
Further, 55 ± 5 DEG C are cooled to after fully reacting.
Further, washing process is：It is washed with aqueous slkali to alkalinity, is then washed till neutrality with hot water.
Further, aqueous slkali include sodium hydroxide solution, potassium hydroxide solution, lithium hydroxide solution, solution of potassium carbonate,
One of sodium carbonate liquor, Lithium carbonate solution or ammonia spirit are a variety of.
Further, the mass concentration of aqueous slkali is 0.5%-10%.
Further, the temperature of hot water is 55 ± 5 DEG C.
Be prepared it is a further object of the present invention to provide the above method the chloro- 5,10- dihydro -11H- dibenzo of 8- [b,
E] [1,4]-phenodiazine- 11- ketone.
It is a further object of the present invention to provide chloro- 5,10- dihydro -11H- dibenzo [b, e] [the 1,4]-phenodiazines of above-mentioned 8--
11- ketone is preparing the application in Clozapine.
According to the above aspect of the present invention, the present invention has at least the following advantages：The present invention has carried out cyclization using aqueous sulfuric acid, gram
Many insufficient (reaction time length, high temperature reflux, processing are cumbersome) for having taken the prior art, react simple and efficient.In cyclization process
In, raw material can introduce the impurity such as the intermediate of previous step reaction incorporation, and 2- ((2- amino -4- chlorphenyl) amino) benzoic acid is
Inner salt, through aqueous sulfuric acid cyclization, non-inner salt compound can not react cyclization, and the impurity introduced in raw material is by aqueous sulfuric acid height
Warm dissolution filter removes, and obtains the higher product of purity and waste liquid is easy to handle, while avoiding and being increased using solvent bring cost
Environmental pollution is summed it up, there is good industrial prospect.
Specific embodiment
Embodiment 1
2- ((2- amino -4- chlorphenyl) amino) benzoic acid 15g is added in three mouthfuls of reaction flasks, 100g sulfuric acid water is added
Solution (85g purified water and 15g sulfuric acid mix), is warming up to reflux temperature (100-104 DEG C), stirs 4 hours.TLC tracking reaction,
58 DEG C are cooled to after fully reacting, filtering is that 3% sodium hydroxide solution is washed to alkalinity with mass percentage；58 DEG C of hot water
It is washed till weakly acidic pH, is drained；Dry chloro- 5,10- dihydro -11H- dibenzo [b, e] [the 1,4]-phenodiazine of 8-- 11- ketone 12.5g,
Yield 89.5%, purity 99.111%.
Embodiment 2
2- ((2- amino -4- chlorphenyl) amino) benzoic acid 15g is added in three mouthfuls of reaction flasks, 100g hydrochloric acid acid is added
Aqueous solution (70g purified water and 30g concentrated hydrochloric acid mix), is warming up to reflux temperature (100-104 DEG C), stirs 4 hours.TLC tracking
Reaction, is cooled to 58 DEG C after fully reacting, filtering is that 3% sodium hydroxide solution is washed to alkalinity with mass percentage；58℃
Hot water is washed till weakly acidic pH, drains；Dry chloro- 5,10- dihydro -11H- dibenzo [b, e] [the 1,4]-phenodiazine of 8-- 11- ketone
11.8g, yield 84.5%, purity 96.0%.
Comparative example 1
According to the synthetic method of embodiment 1, other parameters are constant, adjust the concentration of sulfuric acid solution, and the influence to product is shown in
Table 1.
Table 1
Although the present invention has been described by way of example and in terms of the preferred embodiments, it is not intended to limit the invention, any to be familiar with this skill
The people of art can do various change and modification, therefore protection model of the invention without departing from the spirit and scope of the present invention
Enclosing subject to the definition of the claims.
Claims (10)
1. a kind of chloro- 5,10- dihydro -11H- dibenzo [b, e] [1,4]-phenodiazine of 8-The synthetic method of -11- ketone, feature exist
In：2- ((2- amino -4- chlorphenyl) amino) benzoic acid is mixed with acid solution, flows back, cools down after fully reacting, filters, washes
It washs, dry chloro- 5,10- dihydro -11H- dibenzo [b, e] [the Isosorbide-5-Nitrae]-phenodiazine of 8-- 11- ketone,
Chemical equation is as follows：
2. synthetic method according to claim 1, it is characterised in that：The acid solution includes sulfuric acid solution, hydrochloric acid solution
Or one of phosphoric acid solution or a variety of.
3. synthetic method according to claim 2, it is characterised in that：2- ((2- amino -4- chlorphenyl) amino) benzoic acid
Mass ratio with acid solution is 1：(3-50), the mass concentration of acid solution are 5%-60%.
4. synthetic method according to claim 1, it is characterised in that：Reflux temperature is 70-105 DEG C.
5. synthetic method according to claim 1, it is characterised in that：Return time is 3-5 hours.
6. synthetic method according to claim 1, it is characterised in that：55 ± 5 DEG C are cooled to after fully reacting.
7. synthetic method according to claim 1, it is characterised in that：Washing process is：It is washed with aqueous slkali to alkalinity, so
Neutrality is washed till with hot water afterwards.
8. synthetic method according to claim 7, it is characterised in that：Aqueous slkali includes sodium hydroxide solution, potassium hydroxide
One of solution, lithium hydroxide solution, solution of potassium carbonate, sodium carbonate liquor, Lithium carbonate solution or ammonia spirit are a variety of.
9. the chloro- 5,10- dihydro -11H- dibenzo [b, e] [1,4]-two of the 8- that any the method for claim 1-8 is prepared
Nitrogen- 11- ketone.
10. chloro- 5,10- dihydro -11H- dibenzo [b, e] [the 1,4]-phenodiazine of 8- as claimed in claim 9- 11- ketone is preparing chlorine
Application during nitrogen is flat.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109678805A (en) * | 2019-03-06 | 2019-04-26 | 方志刚 | A kind of preparation method of Clozapine intermediate |
| CN113387897A (en) * | 2021-06-11 | 2021-09-14 | 江苏农牧科技职业学院 | Method for synthesizing clozapine by photocatalysis |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3962248A (en) * | 1972-04-04 | 1976-06-08 | Sandoz, Inc. | Process for making 11-piperazino-diazepines, oxazepines, thiazepines and azepines |
| CN106220576A (en) * | 2016-07-28 | 2016-12-14 | 常州大学 | A kind of synthetic method of clozapine key intermediate |
| CN106279048A (en) * | 2016-07-28 | 2017-01-04 | 常州大学 | A kind of method preparing clozapine key intermediate |
-
2018
- 2018-07-23 CN CN201810811545.9A patent/CN108863960A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3962248A (en) * | 1972-04-04 | 1976-06-08 | Sandoz, Inc. | Process for making 11-piperazino-diazepines, oxazepines, thiazepines and azepines |
| CN106220576A (en) * | 2016-07-28 | 2016-12-14 | 常州大学 | A kind of synthetic method of clozapine key intermediate |
| CN106279048A (en) * | 2016-07-28 | 2017-01-04 | 常州大学 | A kind of method preparing clozapine key intermediate |
Non-Patent Citations (6)
| Title |
|---|
| ALUMMOOTTIL V. JOSHUA等: "Synthesis and biodistribution of 8-iodo-11-(4-methyl-piperazino)-5H-dibenzo[b,e][1,4]-diazepine: Iozapine", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| HOJATOLLAH MATLOUBI等: "Modified synthesis of 11-[14C]-clozapine", 《APPLIED RADIATION AND ISOTOPES》 * |
| USTUN B. SUNAY等: "Synthesis of carbon‐14 and tritium labelled analogs of the noval antischizophrenic agent clozapine", 《JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS》 * |
| 奚若明等: "《中国化工医药产品大全 第2卷》", 31 December 1990, 科学出版社 * |
| 徐开坤等: "《有机药物合成手册 补编》", 31 December 1983, 上海医药工业研究院 * |
| 王福祥等: "氯氮平的合成", 《中国医药工业杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109678805A (en) * | 2019-03-06 | 2019-04-26 | 方志刚 | A kind of preparation method of Clozapine intermediate |
| CN113387897A (en) * | 2021-06-11 | 2021-09-14 | 江苏农牧科技职业学院 | Method for synthesizing clozapine by photocatalysis |
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