CN114989163A

CN114989163A - Praziquantel synthesis process

Info

Publication number: CN114989163A
Application number: CN201910395269.7A
Authority: CN
Inventors: 陈保才; 钱肖波; 王建磊
Original assignee: Nanjing Pharmaceutical Factory Co ltd
Current assignee: Nanjing Pharmaceutical Factory Co ltd
Priority date: 2019-05-13
Filing date: 2019-05-13
Publication date: 2022-09-02

Abstract

The invention provides a praziquantel synthesis process, which adopts a compound I as an initial reaction material, firstly carries out hydrolysis reaction on the compound I and a low-concentration inorganic acid aqueous solution, then uses dichloromethane or trichloromethane to extract and separate an aqueous layer and an organic phase, carries out reduced pressure distillation on the organic phase, then adds a solvent such as toluene and the like, heats up and dissolves the organic phase, then cools down, crystallizes and filters to obtain a compound II, and adds triethylamine and cyclohexanecarbonyl chloride to carry out reaction to obtain the praziquantel. The invention adopts low-concentration acid, separates and purifies intermediate product compounds, eliminates impurities, further optimizes the process flow and greatly improves the purity of the final product.

Description

Praziquantel synthesis process

Technical Field

The invention relates to a synthesis technology of a medicine.

Background

Praziquantel (Praziquantel) is a broad-spectrum antiparasitic drug, has killing effects on flukes, schistosomes, clonorchis sinensis, echinococcus, cysticercosis, fascioliasis, tapeworms, schizocysticercosis mansoni and the like, has small toxic and side effects, is not easy to generate drug resistance, and is the first choice drug for treating various parasitic diseases. Praziquantel has the advantages of high curative effect, short course of treatment, small dosage, quick metabolism, low toxicity and convenient oral administration.

German patents DE2441261 and DE2362539 disclose a process for preparing praziquantel by reacting isoquinoline, cyanide salt, benzoyl chloride and an alkaline compound in a mixture, then carrying out hydrogenation reaction and cyclization reaction, and finally carrying out hydrolysis reaction and amidation reaction to obtain a crude praziquantel product. The praziquantel synthesized by the process has high impurity content and cannot meet the quality requirement of the existing medicine.

Chinese patent CN1683346 discloses a preparation method of praziquantel, which comprises taking phenethylamine, aminoacetyl halide hydrochloride, halogenated acetaldehyde acetal and cyclohexanecarbonyl chloride as raw materials, and synthesizing the praziquantel through condensation reaction, cyclization reaction and acylation reaction. Then carrying out reduction, cyclization reaction and other steps. The method has mild reaction conditions, but the aminoacetyl halide hydrochloride and the halogenated acetaldehyde acetal have high price and are not easy to obtain raw materials, so that the cost is high; and the method has many byproducts, difficult separation and limited application prospect.

International patent PCT2009/115333 discloses a method for preparing praziquantel, which comprises the steps of taking phenethyl isocyanide, aminoethyl diglycol and formaldehyde as raw materials, performing amidation reaction, acid-catalyzed cyclization reaction and the like. The method has the advantages of short route, mild reaction conditions and high yield. However, the method uses highly toxic phenethyl isocyanide, which does not meet the requirements of safety and environmental protection, and has expensive raw materials and limited market competitiveness.

The synthetic process for preparing praziquantel disclosed in the US patent 4523013 is characterized in that diacetonitrile amine, cyclohexane formyl chloride, sodium nitrite, sodium borohydride, beta-bromoethylbenzene and hydroxylamine hydrochloride are used as main raw materials, and the praziquantel is prepared through acylation, hydroxylamination, diazotization, alkylation, reduction, cyclization and other reactions. The process has low toxicity of the material, mild operation condition and high total yield up to 35%. However, the use of a large amount of sodium borohydride is still dangerous, the raw material of the diacetonitrile amine is not easy to purchase, the cost is high due to the large use amount of the diacetonitrile amine and the sodium borohydride, the product quality is not obviously improved, and the industrial application of the process is limited.

The technical problems of the synthesis process are as follows: the content of impurities in the finished product of the synthetic praziquantel is higher, and the finished product cannot simultaneously meet the quality standard requirements of United states pharmacopoeia, European pharmacopoeia and Chinese pharmacopoeia.

Disclosure of Invention

The invention aims to: provides a praziquantel synthesis process with low impurity content in a finished product.

The technical scheme is as follows: the synthetic process of praziquantel of the invention comprises the following steps: the compound 2-benzoyl-1, 2,3,6,7,11 b-hexahydro-4H-pyrazino [2, 1-alpha ] isoquinoline-4-ketone (compound I for short) shown in the following structural formula is adopted as a starting reaction material, and the structural formula is as follows:

。

preferably, the compound I is racemic, which is favorable for forming a compound II with better stability.

The synthesis steps have the following sequence:

(1) the compound I and 10-85% inorganic acid aqueous solution are hydrolyzed (preferably 10-35%, low concentration can separate out the compound II in the subsequent step; high concentration is disclosed by the reference literature and is not beneficial to forming an intermediate product II. simultaneously, the pollution problem of high-concentration waste water is avoided, and the purity of the final product is improved), and the inorganic acid is phosphoric acid, sulfuric acid, nitric acid, hydrochloric acid, acid sulfate or acid phosphate. The hydrolysis reaction temperature is 70-180 ℃, and the reaction time is 2-48 hours. The reaction formula is as follows:

。

(2) and (2) adding the reaction liquid obtained in the step (1) into water for dilution while the reaction liquid is hot, and cooling to obtain a mixture of the salt of the intermediate 1,2,3,6,7,11 b-hexahydro-4H-pyrazino [2, 1-alpha ] isoquinoline-4-one and the by-product benzoic acid.

(3) Cooling the mixture obtained in step (2) to below 45 ℃, extracting with dichloromethane or chloroform, and separating the aqueous layer and the organic layer.

(4) And (4) slowly adding an alkaline solution (a sodium hydroxide or potassium hydroxide solution or a soluble carbonate solution) into the water layer material obtained in the step (3) at a reduced temperature, and adjusting the pH value of the material to 8-12. The resulting solution is further extracted with dichloromethane or chloroform, and the aqueous and organic phases are separated and combined with the organic phase after extraction in step (3) in order to increase the amount of organic phase and the yield of the final product.

After the hydrolysis reaction, the reaction product exists in the form of salt, the pH value of the material is adjusted to make the material alkaline, and the intermediate product II can be well dissociated due to the alkaline nature of the compound II (as shown in the following formula), so that the intermediate product can be conveniently separated and obtained.

(5) And (4) carrying out reduced pressure distillation on the organic phase obtained in the step (4), controlling the distillation temperature to be 50 → 100 ℃, and evaporating the organic solvent. And slowly adding toluene (or benzene, xylene and a mixed solvent thereof, wherein the mass ratio of the toluene to the compound I is preferably 0.5-10: 1) into the obtained residual materials, heating to 40-140 ℃ to completely dissolve the solid, slowly cooling to 0-5 ℃ for heat preservation and crystallization for 2 hours to precipitate a white-like solid, and filtering to obtain a filter cake. The filter cake can be washed with a small amount of toluene and the filtrate drained off. And (3) carrying out vacuum drying on the obtained filter cake, wherein the drying temperature is as follows: at 40-80 ℃ and the vacuum degree is not lower than 0.05MPa, so as to obtain a compound II, wherein the structural formula is as follows:

。

(6) dissolving the compound II obtained in the previous step by using trichloromethane or dichloromethane, adding an alkaline compound triethylamine, cooling to-5-15 ℃, slowly dropwise adding cyclohexanecarbonyl chloride, controlling the temperature to-5-15 ℃, after dropwise adding, heating to 20-35 ℃, preserving heat at 20-35 ℃, stirring for 3.5 hours, and reacting. (the intermediate compound II can be recrystallized by using an organic solvent to remove impurities, and then the cyclohexyl formylation reaction is carried out, so that the product quality is obviously improved). The reaction formula is as follows:

。

1,2,3,6,7,11 b-hexahydro-4H-pyrazino [2, 1-alpha ] isoquinolin-4-one cyclohexanecarbonyl chloride triethylamine praziquantel triethylamine hydrochloride.

The reaction process releases heat, the reaction is violent, the temperature reduction aims at controlling the reaction speed, the reaction is not violent, otherwise, the temperature of the reaction liquid can also rise quickly along with the reaction, the temperature is not easy to control, impurities are increased, and the product quality and the yield are reduced. Meanwhile, the reaction is too violent and unsafe.

And when the reaction is in the later stage, the concentration of the raw materials participating in the reaction is reduced, the reaction power is reduced, the reaction speed is slowed, and in order to ensure the complete reaction, the temperature is increased, the reaction speed is accelerated, and the reaction is carried out more thoroughly.

The reaction solution after the reaction is washed by water (until the water layer is basically neutral, the pollution of discharged water is reduced), a water layer and an organic matter layer are separated, and the water layer is discharged.

(7) And carrying out reduced pressure distillation on the obtained organic matter layer, wherein the vacuum degree is not lower than 0.05MPa, and the distillation temperature is as follows: room temperature → 140 ℃ and the solvent is evaporated off.

(8) Slowly adding a water-soluble alcohol (methanol, ethanol, isopropanol or any combination of the methanol, the ethanol and the isopropanol or a mixture of the methanol, the ethanol and the isopropanol and water), heating to reflux, slowly cooling to-5-10 ℃ after all solids are dissolved, carrying out heat preservation and crystallization, and carrying out heat preservation, stirring and crystallization at-5-10 ℃ for 3-24 hours. Filtering, eluting the filter cake with water soluble alcohol (methanol, ethanol, isopropanol, etc.) or their combination or their mixture with water, and draining the filtrate to obtain crude praziquantel product.

The crude praziquantel product can be subjected to subsequent refining process to obtain a praziquantel refined product.

Has the advantages that:

the invention adopts high-concentration and low-concentration acid to complete the first-step hydrolysis reaction, the literature is limited to the high-concentration acid, and the compound II is not separated and is difficult to be separated in the synthesis of praziquantel, and only the mixed solution of the praziquantel is directly used for the next reaction. The invention adopts low-concentration acid, can separate and purify the intermediate product compound II, eliminates impurities in the intermediate product, further optimizes the subsequent process, reduces the impurity level, improves the purity of the final product, and can simultaneously meet the quality standards of United states pharmacopoeia, European pharmacopoeia and Chinese pharmacopoeia. Meanwhile, the pollution of high-concentration wastewater and a complex later treatment process are avoided, and the production meets the environmental protection requirement.

Detailed Description

Example 1:

adding 33g of compound I and 99g of 30% phosphoric acid into a 250mL four-neck round bottom flask with a condenser, a thermometer and a stirrer, stirring, heating in an oil bath, raising the temperature to 140-150 ℃, keeping the temperature at 140-150 ℃, and stirring for 3 hours.

Secondly, pouring the reaction materials into a beaker filled with 350mL of ice water, violently stirring while pouring, and controlling the temperature to ensure that the temperature of the materials does not exceed 45 ℃.

③ transferring the material to a 1000mL separating funnel, adding trichloromethane for three times for extraction (the dosage of the trichloromethane is 100g, 50g and 50g respectively), merging separated trichloromethane layers, and reserving a water layer.

Transferring the water layer into a beaker, cooling in an ice-water bath, continuously stirring, and adjusting the pH of the material to be =10 by using a 40% sodium hydroxide solution.

Extracting with chloroform three times (100 g, 50 g), discarding the water layer, and combining the organic layers.

The organic layer was distilled under reduced pressure, the distillation temperature: room temperature → 70 deg.C, temperature controlled in water bath, and solvent evaporated. 22g of toluene was added. Heating to 80 ℃, stirring until the solid is completely dissolved, then slowly cooling to 0-5 ℃, and stirring at 0-5 ℃ for crystallization for 2 hours.

Sixthly, filtering, leaching the filter cake with a small amount of toluene, draining the filtrate, and drying the obtained filter cake in vacuum at the drying temperature: 40-50 ℃ and 0.08MPa of vacuum degree.

Seventhly, pouring the organic layer into a dry and clean four-neck flask with 500mL, adding 11g of triethylamine, stirring, cooling to 5 ℃ in an ice water bath, and slowly dropwise adding 16g of cyclohexanecarbonyl chloride.

Heating the mixture to 20-25 ℃ in a water bath after the dropwise addition is finished, and stirring the mixture for 3.5 hours at the temperature of 20-25 ℃.

Ninthly, transferring the materials into a 1000mL separating funnel.

The chloroform layer at the red spot is washed by water, and is kept still for layering, and the lower organic layer is kept until the water layer is neutral.

⑪ the organic layer after washing is decompressed and steamed to constant weight, the temperature of the water bath is: and (3) taking down the distillation flask, placing the distillation flask in a condensation tube, adding 100g of ethanol, heating until the temperature is back-flowed, after the solid is completely dissolved, transferring to magnetic stirring, cooling in ice-water bath, slowly cooling the material to 0 ℃, and crystallizing for 8 hours at 0 ℃.

⑫ filtering, draining the mother liquor, leaching the filter cake with 25g ethanol, and filtering until the filtrate is drained, wherein the mass of the filter cake is 38g, and the filter cake is the crude praziquantel product.

⑬ adding 38g crude praziquantel and 5 times of ethanol into a 500mL four-neck round-bottom flask with a stirrer and a glass condenser, stirring, heating to reflux, stirring while keeping the temperature until the solid is completely dissolved, adding 1g of activated carbon, and stirring for decolorizing for 30 minutes.

⑭ filtering when the solution is hot, transferring the filtrate into a beaker, cooling in ice water bath, cooling the material to 0-5 ℃, keeping the temperature and crystallizing for 8 hours, filtering, pulping with 25g ethanol, washing the material once, and filtering until the filtrate is discharged completely.

⑮ vacuum drying the filter cake to obtain 20g of praziquantel refined product.

Example 2:

adding 33g of compound I and 99g of 20% sulfuric acid into a 250mL four-neck round-bottom flask with a condenser, a thermometer and a stirrer, stirring, heating in an oil bath, raising the temperature to 95-100 ℃, keeping the temperature at 95-100 ℃, and stirring for 24 hours.

Secondly, pouring the reaction materials into a beaker filled with 350mL of ice water, and vigorously stirring while pouring, and controlling the temperature to ensure that the temperature of the materials does not exceed 45 ℃.

Thirdly, transferring the materials to a 1000mL separating funnel, adding trichloromethane for three times of extraction (the dosage of the trichloromethane is 100g, 50g and 50g respectively), combining separated trichloromethane layers, and reserving a water layer.

Extracting with chloroform for three times (100 g, 50 g), discarding the water layer, and mixing the organic layers.

Sixthly, filtering, leaching the filter cake with a small amount of toluene, draining the filtrate, and drying the obtained filter cake in vacuum at the drying temperature: at 40-50 ℃ and the vacuum degree of 0.08MPa, 11.9g of a compound II is obtained. The subsequent process was carried out as in example 1.

Claims

1. A praziquantel synthesis process adopts a compound I as an initial reaction material, and is characterized in that: the synthesis steps have the following sequence:

(1) performing hydrolysis reaction on the compound I and a low-concentration inorganic acid aqueous solution with the concentration of 10-25%, wherein the hydrolysis reaction temperature is 70-180 ℃, and the reaction time is 2-48 hours;

(2) adding the reaction solution obtained in the step (1) into water for dilution while the reaction solution is hot, and cooling to obtain a mixture of intermediate 1,2,3,6,7,11 b-hexahydro-4H-pyrazino [2, 1-alpha ] isoquinoline-4-one salt and a by-product benzoic acid;

(3) cooling the mixture in the step (2) to below 45 ℃, extracting with dichloromethane or trichloromethane, and separating an aqueous layer and an organic phase;

(5) carrying out reduced pressure distillation on the organic phase obtained in the step (3), controlling the distillation temperature to be 50 → 100 ℃, and completely evaporating the organic solvent; slowly adding toluene, benzene or xylene or a mixture solvent of toluene, benzene or xylene into the obtained residual materials, wherein the mass ratio of the solvent to the compound I is 0.5-10: 1, heating to 40-140 ℃ to completely dissolve the solid, slowly cooling to 0-5 ℃ for heat preservation and crystallization for 2 hours, separating out a white-like solid, filtering to obtain a filter cake, and performing vacuum drying on the obtained filter cake at the drying temperature: at 40-80 ℃ and the vacuum degree is not lower than 0.05MPa, and a compound II is obtained;

(6) dissolving the compound II obtained in the previous step by using trichloromethane or dichloromethane, adding an alkaline compound triethylamine, and dropwise adding cyclohexanecarbonyl chloride for reaction;

(7) washing the reaction solution with water, separating a water layer and an organic matter layer, and discharging the water layer;

and carrying out reduced pressure distillation on the obtained organic matter layer, wherein the vacuum degree is not lower than 0.05MPa, and the distillation temperature is as follows: room temperature → 140 ℃, evaporate off the solvent;

(8) slowly adding a water-soluble alcohol solvent, heating to reflux, slowly cooling to-5-10 ℃ after the solid is completely dissolved, carrying out heat preservation and crystallization for 3-24 hours, and filtering to obtain a praziquantel crude product.

2. The process for the synthesis of praziquantel of claim 1, wherein: between the step (3) and the step (5), a step (4): slowly adding the water layer material obtained in the step (3) into an alkaline solution under the condition of cooling, and adjusting the pH value of the material to 8-12; extracting the obtained solution with dichloromethane or chloroform, separating water layer and organic phase, and combining with the organic phase extracted in step (3).

3. The process for the synthesis of praziquantel of claim 1, wherein: and (3) recrystallizing the obtained compound II by using an organic solvent, removing impurities, and then performing the cyclohexyl formylation reaction.

4. The process for the synthesis of praziquantel of claim 1, wherein: in the step (6), the temperature is controlled to be-5-15 ℃ when the cyclohexanecarbonyl chloride is dripped, the temperature is raised to 20-35 ℃ after the dripping is finished, and the mixture is stirred for 3.5 hours at the temperature of 20-35 ℃.

5. The process for the synthesis of praziquantel of claim 1, wherein: in the step (8), after filtration, the filter cake is leached by water-soluble alcohol or the combination of the water-soluble alcohol and the water-soluble alcohol, and the filtrate is drained to obtain the crude praziquantel.