CN113683581A - Synthesis method of cariprazine key intermediate 1- (2, 3-dichlorophenyl) piperazine hydrochloride - Google Patents
Synthesis method of cariprazine key intermediate 1- (2, 3-dichlorophenyl) piperazine hydrochloride Download PDFInfo
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- CN113683581A CN113683581A CN202110996756.6A CN202110996756A CN113683581A CN 113683581 A CN113683581 A CN 113683581A CN 202110996756 A CN202110996756 A CN 202110996756A CN 113683581 A CN113683581 A CN 113683581A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
- C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a method for synthesizing a key intermediate 1- (2, 3-dichlorophenyl) piperazine hydrochloride of cariprazine, belonging to the field of medicine synthesis. The method comprises the following steps: (1) taking the compound 1 and the compound a as raw materials, and reacting to obtain a compound 2; (2) carrying out nitro reduction reaction by taking the compound 2 and a reducing agent as raw materials to obtain a compound 3; (3) the compound 3 is used as a raw material to carry out diazotization reaction and deprotection reaction, so as to obtain the 1- (2, 3-dichlorophenyl) piperazine hydrochloride. The synthesis method disclosed by the invention has the advantages of low toxicity of raw materials, low cost, easiness in obtaining, no use of any noble metal catalyst and phosphorus ligand, simple equipment requirement, high product yield and high purity, is suitable for large-scale industrial production, and has a good application prospect.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a method for synthesizing a key intermediate 1- (2, 3-dichlorophenyl) piperazine hydrochloride of cariprazine.
Background
With the increasing pressure of modern society on life and work, the incidence of schizophrenia in various countries of the world is on a rapidly increasing trend. Schizophrenia is a chronic disabling disease, and its symptoms can be divided into three main groups: positive symptoms (hallucinations, delusions, thought disorders, and movement disorders), negative symptoms (such as lack of motivation and social avoidance), and cognitive symptoms (executive ability problems, concerns, and working memory). The disease can cause the patient to be unable to work and live normally, and has high recurrence rate and disability rate, thus causing heavy burden to the patient, family members and society. Second generation antipsychotics are now the first line agents for the treatment of psychosis and include risperidone, ziprasidone, clozapine, olanzapine, amisulpride, aripiprazole, and the like. However, these drugs have many adverse reactions such as acute dystonia, akathisia, parkinson-like reaction, tardive dyskinesia, weight gain, dyslipidemia, hyperglycemia, and worsening cardiovascular disease.
Cariprazine (Cariprazine) is an atypical third-generation antipsychotic drug developed by Forest Laboratories and marketed under the approval of the U.S. Food and Drug Administration (FDA) at 9 months 2015 under the trade designation Vraylar for the treatment of schizophrenia and bipolar i affective disorder. Compared with other similar medicines, the cariprazine has the main advantages of low incidence rate of adverse reactions, reduction of the risk of tardive dyskinesia, lighter negative symptoms and the like, and in addition, the cariprazine only needs to be orally taken once every day, so that a patient can conveniently take the medicine, and the medication compliance is greatly improved. The advent of the medicine brings better treatment options for patients with schizophrenia. Carilazine is chemically known as trans-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -N, N-dimethylformyl-cyclohexylamine and consists of two fragments, one of which is 1- (2, 3-dichlorophenyl) piperazine hydrochloride (shown below). Therefore, 1- (2, 3-dichlorophenyl) piperazine hydrochloride is a key intermediate for the synthesis of cariprazine.
To date, the following two main methods have been reported for synthesizing 1- (2, 3-dichlorophenyl) piperazine hydrochloride.
One method is to use 2, 3-dichloronitrobenzene and bis (2-chloroethyl) amine hydrochloride as starting materials to react at the temperature of 120-135 ℃ in the presence of diethylene glycol ethyl ether, ammonium chloride aqueous solution, iron powder, potassium iodide and tetrabutylammonium bromide (see the Chinese patent application with the application number of 201710259460.X, the synthetic route is as follows). Although the method has short steps, a great problem exists: the key raw material bis (2-chloroethyl) ammonia hydrochloride belongs to a class of compounds which are easy to cause allergy, and the skin can be itchy, red and swollen and inflamed when a small amount of dust of the compounds contacts the skin; if a large amount of the medicament is contacted with the skin or inhaled into the lung, a large area of red swelling and even ulceration of the whole body can be caused. Therefore, the process has great health damage to operators and is not suitable for industrial production.
The other one is prepared by taking 1,2, 3-trichlorobenzene or 1-bromo-2, 3-dichlorobenzene as a raw material and adding piperazine in Pd2(dba)3And a phosphine ligand (the synthetic route is as follows). However, this method has low yield, and requires the use of expensive palladium catalyst and phosphine ligand, and the high cost makes the process only suitable for laboratory scale synthesis, and mass production has no cost advantage.
Therefore, the method for synthesizing the 1- (2, 3-dichlorophenyl) piperazine hydrochloride with low raw material price, low toxicity and high yield is developed, and has important significance for mass production of the cariprazine.
Disclosure of Invention
In order to solve the problems, the invention provides a novel method for synthesizing 1- (2, 3-dichlorophenyl) piperazine hydrochloride.
The invention specifically provides a preparation method of 1- (2, 3-dichlorophenyl) piperazine hydrochloride suitable for industrial mass production, which comprises the following steps:
(1) taking the compound 1 and the compound a as raw materials, and reacting to obtain a compound 2;
(2) carrying out nitro reduction reaction by taking the compound 2 and a reducing agent as raw materials to obtain a compound 3;
(3) carrying out diazotization reaction and deprotection reaction by using a compound 3 as a raw material to obtain 1- (2, 3-dichlorophenyl) piperazine hydrochloride;
wherein R is an amino protecting group.
Further, in the step (1), the molar ratio of the compound 1 to the compound a is 1: (0.5 to 1.5); the reaction is carried out under the action of alkali, and the alkali is one or two of inorganic alkali and organic alkali; the solvent for the reaction is an organic solvent, and the reaction conditions are as follows: the reaction temperature is 15-60 ℃, and the reaction time is 4-12 hours;
and/or, in the step (2), the molar ratio of the compound 2 to the reducing agent is 1: (3.0-6.0), the reducing agent is dithionite, the reaction solvent is an organic solvent, the reaction temperature is 70-90 ℃, and the reaction time is 3-9 hours;
and/or, the reaction of step (3) is carried out in the presence of nitrite, acid and cuprous chloride.
Further, in the step (1), the molar ratio of the compound 1 to the compound a is 1:1, the base is potassium carbonate and diisopropylethylamine, the solvent for the reaction is dimethyl sulfoxide, and the reaction conditions are as follows: the reaction temperature is 20-55 ℃, and the reaction time is 5-11 hours;
and/or, in the step (2), the molar ratio of the compound 2 to the reducing agent is 1: 4.5, the reducing agent is Na2S2O4The organic solvent is ethanol, the reaction temperature is 75-85 ℃, and the reaction time is 4-8 hours;
and/or, step (3) comprises the following operations: a. adding a nitrite water solution into a mixture of the compound 3 and acid, and reacting to obtain a suspension; b. the suspension was mixed with acid, cuprous chloride, reacted and the solid retained.
Further, in the step (1), the reaction conditions are as follows: firstly reacting for 4-8 hours at 20-25 ℃, and then reacting for 1-3 hours at 50-55 ℃;
and/or in the step (2), the organic solvent is 95% ethanol, the reaction temperature is 80 ℃, and the reaction time is 6 hours;
and/or, in the step (3), the acid is concentrated hydrochloric acid, and the nitrite is sodium nitrite; in the step a, the molar ratio of the compound 3 to the acid to the nitrite is 1: (2-4): (0.8-1.2), wherein the reaction conditions in the step a are as follows: the reaction temperature is-5 to 5 ℃, and the reaction time is 0.3 to 1.0 hour; the molar ratio of the compound 3 to the acid and cuprous chloride in the step b is 1: (8-12): (1.0-1.5), wherein the reaction conditions in the step b are as follows: the reaction temperature is 50-110 ℃, and the reaction time is 4-15 hours.
Further, in the step (1), the reaction conditions are as follows: firstly reacting for 6 hours at 22 ℃, and then reacting for 2 hours at 52 ℃;
and/or, in the step a of the step (3), the molar ratio of the compound 3 to the acid to the nitrite is 1: 3: 1, the reaction conditions of the step a are as follows: the reaction temperature is 0 ℃, and the reaction time is 0.5 hour; the molar ratio of the compound 3 to the acid and cuprous chloride in the step b is 1: 10: 1.2, the reaction conditions of the step b are as follows: the reaction is carried out for 3-5 hours at 50-55 ℃ and then for 7-9 hours at 90-110 ℃.
Further, the reaction conditions of the step b are as follows: the reaction was carried out at 52 ℃ for 4 hours and at 100 ℃ for 8 hours.
Further, R is pivaloyl.
Further, the method also comprises the following purification steps: adding an organic solvent and water into the 1- (2, 3-dichlorophenyl) piperazine hydrochloride obtained in the step (3), separating the solution under an alkaline condition, taking the organic phase 1, washing the organic phase with an aqueous solution, taking the organic phase 2, filtering, taking the filtrate, stirring under an acidification condition, and retaining the obtained solid.
Further, in the purification step, the organic solvent is dichloromethane, the pH value under the alkaline condition is 11-13, the aqueous solution is EDTA aqueous solution and/or water, and the acidification condition is as follows: the pH value is 1-3, the temperature is 10-20 ℃, and the time is 1-3 hours.
Further, in the purification step, the pH value of the alkaline condition is 12, the aqueous solution is a 10% EDTA aqueous solution and water in sequence, and the acidification condition is as follows: the pH was 1, the temperature 15 ℃ and the time 2 hours.
In the present invention, Piv is a abbreviation for pivaloyl group.
Compared with the prior art, the invention has the beneficial effects that:
1. the raw materials used by the method have low toxicity, do not have health damage to operators and are suitable for large-scale industrial production;
2. the raw materials used by the method are low in price and easy to obtain, any noble metal catalyst and phosphorus ligand are not used, the equipment requirement is simple, and the total cost is low;
3. the 1- (2, 3-dichlorophenyl) piperazine hydrochloride prepared by the method has high yield, high purity and good application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
Example 1: preparation of 1- (2, 3-dichlorophenyl) piperazine hydrochloride
1- (2, 3-dichlorophenyl) piperazine hydrochloride was prepared according to the following reaction scheme:
step 1: preparation of compound 2:
to a solution of compound 1(100.0g,0.521mol,1.0eq) in dimethyl sulfoxide (400mL) were added potassium carbonate (43.1g,0.313mol,0.6eq) and diisopropylethylamine (40.4g,0.313mol,0.6eq), and stirred at 22 ℃ for 5 min. Pivaloylpiperazine (88.7g,0.521mol,1.0eq) was added, stirred at 22 ℃ for 6h, then warmed to 52 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into water (1200mL), extracted with dichloromethane (500mL × 2), the organic phases were combined, water (300mL) was added, and the pH of the aqueous phase was adjusted to 5.5 to 6.0 with 20% citric acid, and the mixture was separated. The organic phase was concentrated under reduced pressure to give 146.0g of Compound 2 in 86% yield.
Step 2: preparation of compound 3:
add sodium hydrosulfite (i.e., Na) portionwise to a solution of Compound 2(120g,0.368mol,1.0eq) in 95% ethanol (960mL)2S2O4288.3g,1.656mol,4.5 eq). After the addition, the temperature is raised to 80 ℃ for reflux reaction for 6 hours. Concentrating under reduced pressure to remove ethanol, and cooling to room temperature. Dichloromethane (720mL) and water (1200mL) were added, the pH was adjusted to 8-9 with 30% NaOH solution, and the mixture was stirred for 30min and allowed to stand. The layers were separated and the aqueous layer was extracted with dichloromethane (600 mL). The organic phases were combined and concentrated under reduced pressure to give 99.1g of compound 3 in 91% yield.
And step 3: preparation of crude compound 4 (i.e. 1- (2, 3-dichlorophenyl) piperazine hydrochloride):
concentrated hydrochloric acid (103.0g,1.014mol,3.0eq) and compound 3(100.0g,0.338mol,1.0eq) were added to water (200mL) and the temperature was reduced to 0 ℃. Sodium nitrite (24.0g,0.348mol,1.03eq) is dissolved in water (48mL), slowly dropped into the reaction system, the temperature is controlled at 0 ℃, and stirring is continued for 30min after dropping. The obtained suspension is slowly dropped into a mixed solution of concentrated hydrochloric acid (342.0g,3.38mol,10.0eq) and cuprous chloride (40.2g,0.406mol,1.2eq), the temperature is controlled at 52 ℃, stirring is carried out for 4 hours after dropping, and then the temperature is raised to 100 ℃ and stirring is carried out for 8 hours. Cool to 5-10 deg.C, filter, and wash the filter cake with water (300mL) to give crude compound 4, 74.2g, 82% yield.
And 4, step 4: refining of the crude product
The obtained crude compound 4 was added to a mixed solution of dichloromethane (400mL) and water (100mL), the pH was adjusted to 12 with 30% NaOH, the mixture was separated, and the organic phase was washed with a 10% EDTA (i.e., ethylenediaminetetraacetic acid) aqueous solution (100mL) and water (100mL), respectively. The organic phase was filtered through celite, concentrated hydrochloric acid (51.4g) was added dropwise to the filtrate to pH 1, stirred at 15 ℃ for 2h, filtered and the resulting solid dried to give 69.6g of compound 4 in 77% yield and 99% purity.
1H NMR(400MHz,DMSO-d6):3.20(s,8H),7.18(dd,J＝6.84,2.76Hz,1H),7.32-7.36(m,2H),9.50(s,2H).
In conclusion, the invention provides a synthesis method of a key intermediate 1- (2, 3-dichlorophenyl) piperazine hydrochloride of cariprazine, which is suitable for industrial mass production. The synthesis method disclosed by the invention has the advantages of low toxicity of raw materials, low cost, easiness in obtaining, no use of any noble metal catalyst and phosphorus ligand, simple equipment requirement, high product yield and high purity, is suitable for large-scale industrial production, and has a good application prospect.
Claims (10)
1. A preparation method of 1- (2, 3-dichlorophenyl) piperazine hydrochloride is characterized by comprising the following steps: it comprises the following steps:
(1) taking the compound 1 and the compound a as raw materials, and reacting to obtain a compound 2;
(2) carrying out nitro reduction reaction by taking the compound 2 and a reducing agent as raw materials to obtain a compound 3;
(3) carrying out diazotization reaction and deprotection reaction by using a compound 3 as a raw material to obtain 1- (2, 3-dichlorophenyl) piperazine hydrochloride;
wherein R is an amino protecting group.
2. The method of claim 1, wherein: in the step (1), the molar ratio of the compound 1 to the compound a is 1: (0.5 to 1.5); the reaction is carried out under the action of alkali, and the alkali is one or two of inorganic alkali and organic alkali; the solvent for the reaction is an organic solvent, and the reaction conditions are as follows: the reaction temperature is 15-60 ℃, and the reaction time is 4-12 hours;
and/or, in the step (2), the molar ratio of the compound 2 to the reducing agent is 1: (3.0-6.0), the reducing agent is dithionite, the reaction solvent is an organic solvent, the reaction temperature is 70-90 ℃, and the reaction time is 3-9 hours;
and/or, the reaction of step (3) is carried out in the presence of nitrite, acid and cuprous chloride.
3. The method of claim 2, wherein: in the step (1), the molar ratio of the compound 1 to the compound a is 1:1, the base is potassium carbonate and diisopropylethylamine, the solvent for the reaction is dimethyl sulfoxide, and the reaction conditions are as follows: the reaction temperature is 20-55 ℃, and the reaction time is 5-11 hours;
and/or, in the step (2), the molar ratio of the compound 2 to the reducing agent is 1: 4.5, the reducing agent is Na2S2O4The organic solvent is ethanol, the reaction temperature is 75-85 ℃, and the reaction time is 4-8 hours;
and/or, step (3) comprises the following operations: a. adding a nitrite water solution into a mixture of the compound 3 and acid, and reacting to obtain a suspension; b. the suspension was mixed with acid, cuprous chloride, reacted and the solid retained.
4. The production method according to claim 3, characterized in that: in the step (1), the reaction conditions are as follows: firstly reacting for 4-8 hours at 20-25 ℃, and then reacting for 1-3 hours at 50-55 ℃;
and/or in the step (2), the organic solvent is 95% ethanol, the reaction temperature is 80 ℃, and the reaction time is 6 hours;
and/or, in the step (3), the acid is concentrated hydrochloric acid, and the nitrite is sodium nitrite; in the step a, the molar ratio of the compound 3 to the acid to the nitrite is 1: (2-4): (0.8-1.2), wherein the reaction conditions in the step a are as follows: the reaction temperature is-5 to 5 ℃, and the reaction time is 0.3 to 1.0 hour; the molar ratio of the compound 3 to the acid and cuprous chloride in the step b is 1: (8-12): (1.0-1.5), wherein the reaction conditions in the step b are as follows: the reaction temperature is 50-110 ℃, and the reaction time is 4-15 hours.
5. The method of claim 4, wherein: in the step (1), the reaction conditions are as follows: firstly reacting for 6 hours at 22 ℃, and then reacting for 2 hours at 52 ℃;
and/or, in the step a of the step (3), the molar ratio of the compound 3 to the acid to the nitrite is 1: 3: 1, the reaction conditions of the step a are as follows: the reaction temperature is 0 ℃, and the reaction time is 0.5 hour; the molar ratio of the compound 3 to the acid and cuprous chloride in the step b is 1: 10: 1.2, the reaction conditions of the step b are as follows: the reaction is carried out for 3-5 hours at 50-55 ℃ and then for 7-9 hours at 90-110 ℃.
6. The method of claim 5, wherein: the reaction conditions of the step b are as follows: the reaction was carried out at 52 ℃ for 4 hours and at 100 ℃ for 8 hours.
7. The production method according to any one of claims 1 to 6, characterized in that: r is pivaloyl.
8. The production method according to any one of claims 1 to 6, characterized in that: the method further comprises the following purification steps: adding an organic solvent and water into the 1- (2, 3-dichlorophenyl) piperazine hydrochloride obtained in the step (3), separating the solution under an alkaline condition, taking the organic phase 1, washing the organic phase with an aqueous solution, taking the organic phase 2, filtering, taking the filtrate, stirring under an acidification condition, and retaining the obtained solid.
9. The method of claim 8, wherein: in the purification step, the organic solvent is dichloromethane, the pH value under the alkaline condition is 11-13, the aqueous solution is EDTA aqueous solution and/or water, and the acidification condition is as follows: the pH value is 1-3, the temperature is 10-20 ℃, and the time is 1-3 hours.
10. The method of claim 9, wherein: in the purification step, the alkaline condition has a pH value of 12, the aqueous solution sequentially comprises a 10% EDTA aqueous solution and water, and the acidification condition is as follows: the pH was 1, the temperature 15 ℃ and the time 2 hours.
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| CN103734137A (en) * | 2004-05-28 | 2014-04-23 | 辛根塔参与股份公司 | Piperazin derivatives and their use in controlling pests |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103734137A (en) * | 2004-05-28 | 2014-04-23 | 辛根塔参与股份公司 | Piperazin derivatives and their use in controlling pests |
| CN107011288A (en) * | 2017-04-20 | 2017-08-04 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of aripiprazole intermediate 1 (2,3 dichlorophenyl) piperazine hydrochloride |
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