CN108892643B - Novel preparation method of albendazole - Google Patents
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Abstract
A novel preparation method of albendazole. The invention provides a brand-new synthesis route of albendazole, which takes 2-nitro-5-chloroaniline as an initial raw material to obtain the albendazole with high purity through substitution, condensation, reduction and cyclization reactions. The method is characterized in that 2-nitro-5-chloroaniline is subjected to substitution reaction and then is subjected to condensation reaction with halogenated n-propane to obtain the 2-nitro-5-propylthioaniline, so that the use of propanethiol which is high in price and has pungent odor is avoided. The method avoids the use of a high-risk hydrogenation reduction process, adopts an alkali sulfide reduction process with cheap and easily-obtained raw materials, provides a set of nontoxic treatment scheme for reducing the layered wastewater, and can obtain a byproduct sodium thiosulfate at the same time, thereby changing waste into valuable. The new process has high yield, low safety risk and easy industrial production, and the prepared albendazole has high content and small content of single impurity, and meets the latest standards of United states pharmacopoeia, European pharmacopoeia and the like.
Description
Technical Field
The invention belongs to the field of chemistry or pharmaceutical chemistry, and particularly relates to a preparation method of albendazole.
Background
Albendazole (Albendazole), also called Albendazole, chemical name 5-propylthio-1H-benzimidazole-2-methyl carbamate, is a broad-spectrum, high-efficiency and low-toxicity anthelmintic which is firstly marketed in 1977 by SmithKline, USA, and is widely used for clinically treating various helminth infectious diseases at present, has strong expelling and killing effects on nematodes, trematodes and tapeworms parasitic to human bodies and animals, has the effective rate of 100 percent on human cysticercosis and nematode intestinal diseases, can obviously inhibit the development of worm eggs, and has no accumulation effect in vivo.
Since the middle of the 7O's, there have been many reports on the synthetic routes of albendazole at home and abroad, and the existing synthetic routes can be mainly summarized as the following four routes:
1) route using o-nitroaniline as raw material
In 1979, Thomas J Walter et al (US4152522) reported that 2-nitro-4-thiocyano-aniline was produced by adding bromine or chlorine to o-nitroaniline and thiocyanate in lower alcohol, then in aqueous sodium cyanide solution with bromo-n-propane and n-propanol, 2-nitro-4-propylthioaniline was produced by using methyltributylammonium chloride or tetrabutylammonium bromide as phase transfer catalyst, the nitro group was reduced with sodium sulfide to produce 4-propylthio-o-phenylenediamine, and finally methyl cyanocarbamate was cyclized to produce propylthioimidazole. The method has more steps, the used main raw materials of bromine, bromopropane and sodium cyanide have higher toxicity, the reduction by using sodium sulfide can generate a large amount of sulfur-containing wastewater to pollute the environment, and the intermediate 2-nitro-4-propylsulfanylaniline has low melting point, is a red oil-like liquid and is difficult to separate and purify, so that the quality of the prepared propylthioimidazole is not high.
2) Route using pesticide carbendazim as raw material
Japanese patent JP74-117460 reports that carbendazim reacts with chlorine and potassium thiocyanate to produce methyl 5-thiocyanobenzoimidazole-2-carbamate, which is then subjected to conventional hydrolysis and thioetherification to obtain propylthioimidazole, but the yield is low, and the amount of acetic acid used in the thiocyanization step is too large, so improvement is needed.
In addition, similar methods are disclosed in patents EP31473, EP191940, US4675413 and CN1147507A, wherein carbendazim is chlorosulfonated to obtain 4-chlorosulfonyl benzimidazole-2-methyl carbamate, reduced to obtain 4-mercaptobenzimidazole-2-methyl carbamate or its thiophenoxide, and then thioetherified to obtain propylthioimidazole. This process also has a low yield and severer reaction conditions than the former, and has no industrial value so far.
3) Route using o-phenylenediamine as raw material
Zhang Changli (J.Med.Med.Industrie., L988,9:379) reported that o-phenylenediamine was used to prepare 4-thiocyano-o-phenylenediamine under the action of thiocyanate and bromine, and then the 4-thiocyano-o-phenylenediamine was subjected to reduction and cyclization to produce albendazole. The reaction in step 1 is not easy to proceed because o-phenylenediamine is easily oxidized. The overall yield of this route is only 45.8%.
4) Route using m-dichlorobenzene as raw material
The albendazole is prepared by taking m-dichlorobenzene as a starting raw material and carrying out nitration, amination, condensation, reduction and cyclization reactions, wherein propyl mercaptan is used in a condensation process in the route, and is high in price and has pungent odor, so that the environment-friendly requirement is difficult to meet, and industrial production cannot be realized. In addition, the hydrogenation reduction process adopted by the route belongs to a high-risk process, has high requirements on equipment and automation control, and has high equipment investment cost.
In view of the fact that the unstable intermediate condensate 2-nitro-4-propylsulfanylaniline in the existing industrial route is changed into the stable-quality 2-nitro-5-propylsulfanylaniline in the 4 th synthesis route, the separation and the purification are easy, the propylsulfanilamide prepared by reduction and cyclization has high content and small content of single impurity, and the advanced standards of United states pharmacopoeia, European pharmacopoeia and the like are met. In order to realize industrialization of the 4 th synthetic route, the synthesis process of the condensation procedure needs to be improved, a preparation method for replacing propanethiol is sought, and meanwhile, in order to avoid using a high-risk hydrogenation reduction process, how to treat the layered wastewater after the reduction of the sodium sulfide is still to be researched and researched.
Disclosure of Invention
Aiming at various defects of the above route, the invention aims to provide a novel method for preparing high-purity albendazole, which has the advantages of cheap and easily available raw materials, high yield, low safety risk, effective and nontoxic treatment of wastewater and easy industrial production, and the specific technical scheme is as follows:
a novel process for the preparation of albendazole, characterized by the fact that it is prepared by the following chemical reaction equation:
wherein M is one of Li, Na and K elements; x is one of F, Cl, Br and I elements;
the reaction equation is prepared by the following steps:
(1) substitution and condensation reaction: in a solvent 1, 2-nitro-5-chloroaniline is subjected to alkali sulfide substitution reaction and then is subjected to condensation reaction with halogenated n-propane to obtain 2-nitro-5-propylthioaniline;
(2) reduction reaction: in a solvent 2, 2-nitro-5-propylsulfanylaniline is subjected to reduction reaction to obtain 4-propylsulfanylaniline, and meanwhile, reduction layering water is subjected to vulcanization, catalytic oxidation, concentration and crystallization to obtain a byproduct sodium thiosulfate;
(3) and (3) cyclization reaction: in a solvent 3, 4-propylthio-o-phenylenediamine and a cyclization agent undergo cyclization reaction to obtain propylthioimidazole.
In the reaction step (1), the sodium sulfide is selected from any one of sodium sulfide, potassium sulfide and lithium sulfide, and the using amount of the sodium sulfide is 1-3 times of the molar amount of the 2-nitro-5-chloroaniline; the solvent 1 is at least one selected from ethanol, methanol, propanol, isopropanol, n-butanol and water, and the dosage of the solvent 1 is 2-8 times of the weight ratio of the 2-nitro-5-chloroaniline; the halogenated n-propane is selected from any one of fluoro-n-propane, bromo-n-propane, chloro-n-propane and iodo-n-propane, and the using amount of the halogenated n-propane is 1-2 times of the molar amount of the 2-nitro-5-chloroaniline.
In the reaction step (1), sodium sulfide or potassium sulfide is preferably used as the alkali sulfide, and the use amount of the alkali sulfide is preferably 1.1-2.0 times of the molar weight of 2-nitro-5-chloroaniline; the solvent 1 is preferably ethanol or methanol, and the dosage of the solvent 1 is preferably 2.5-4 times of the weight ratio of the 2-nitro-5-chloroaniline; the halogenated n-propane is preferably bromo-n-propane or chloro-n-propane, and the amount of the halogenated n-propane is preferably 1.1 to 1.5 times the molar amount of the 2-nitro-5-chloroaniline.
In the reaction step (2), the solvent 2 is at least one selected from methanol, ethanol, propanol, isopropanol and n-butanol, the dosage of the solvent 2 is 2-5 times of the weight of the 2-nitro-5-propylsulfanylaniline, the reducing agent is any one selected from sodium sulfide and sodium hydrosulfide, and the dosage of the reducing agent is 1.1-5.0 times of the molar weight of the 2-nitro-5-propylsulfanylaniline.
In the reaction step (2), the solvent 2 is preferably ethanol or isopropanol, the dosage of the solvent 2 is preferably 2-3 times of the weight of 2-nitro-5-propylthioaniline, and the dosage of the reducing agent is preferably 1.5-2.5 times of the molar weight of 2-nitro-5-propylthioaniline.
In the reaction step (3), the solvent 3 is at least one selected from chloroform, dichloromethane, toluene, methanol, ethanol, propanol, isopropanol and n-butanol, the cyclization reagent is any one selected from S-methyl isourea methyl formate, O-methyl isourea methyl formate and cyanamide methyl formate, the dosage of the cyclization agent is 1.0-2.5 times of the molar weight of 4-propylthio-phthalic diamine, the reaction temperature is 60-120 ℃, and the reaction time is 1-24 hours.
When the layered water is reduced to prepare the byproduct sodium thiosulfate in the reaction step (2), the sulfur is 0.5-4% of the volume of the reduced layered water, the vulcanization temperature is 85-100 ℃, and the vulcanization time is 3-8 hours; the oxidation adopts an air bubbling method, the catalyst is any one of nickel chloride, nickel nitrate, manganese chloride, manganese nitrate, manganese sulfate, manganese carbonate and manganese hydroxide, the oxidation temperature is 80-95 ℃, the oxidation end point is judged that the lead acetate test paper does not blacken, and the control requirement of the concentration crystallization specific gravity is more than 1.56 g/ml.
The reaction equation for preparing sodium thiosulfate by reducing demixed water is as follows:
Na2S+S→Na2S2
2Na2S2+3O2→2Na2S2O3
or 2NaHS +2S +2O2→Na2S2O3+H2O+2S
The invention has the beneficial effects that:
1. the invention provides a brand-new synthesis route of albendazole, which takes 2-nitro-5-chloroaniline as a starting raw material, and the raw material is subjected to substitution reaction and then is subjected to condensation reaction with halogenated n-propane to obtain the 2-nitro-5-albendaniline, so that the use of high-price and pungent propanethiol is avoided.
2. The invention avoids using a high-risk hydrogenation reduction process, adopts an alkali sulfide reduction process with cheap and easily-obtained raw materials, provides a set of nontoxic treatment scheme for reducing layered wastewater, and can obtain a byproduct sodium thiosulfate at the same time, thereby changing waste into valuable.
3. The new synthesis process has high yield, low safety risk and easy industrial production, and the prepared albendazole has high content and small content of single impurity, and meets the latest standards of United states pharmacopoeia, European pharmacopoeia and the like.
Drawings
TABLE 1 tabulate albedo impurity
FIG. 1 shows a Mass Spectrum (MS) of an albendazole condensate.
FIG. 2 is an Infrared (IR) spectrum of propylthioimidazole.
FIG. 3 shows the nuclear magnetic hydrogen spectrum (H) of albendazole1-NMR) spectrum.
FIG. 4 shows the nuclear magnetic carbon spectrum (C) of propylthioimidazole13-NMR) spectrum.
FIG. 5 is a Mass Spectrometry (MS) spectrum of albendazole.
Detailed Description
The present invention is described in detail by the following specific examples, which are provided for the purpose of illustration and are not to be construed as limiting the invention.
Example 1
Step preparation of 12-Nitro-5-propylthioaniline
In a 1L four-mouth flask with a thermometer and a stirring device, starting stirring, adding 172.57g of 2-nitro-5-chloroaniline and 3 times of ethanol in weight of the 2-nitro-5-chloroaniline, stirring and heating to 70-78 ℃, dropwise adding 1.2 times of potassium sulfide aqueous solution in molar weight, continuing to react for 4-5 hours after dropwise adding, adding 1.2 times of n-propyl iodide in molar weight of the 2-nitro-5-chloroaniline, refluxing for 2 hours, cooling to 20 ℃ after the reaction is finished, performing suction filtration, washing and drying to obtain 203.14g of dried 2-nitro-5-propylthioaniline, wherein the yield is 95.7%, and the HPLC content is 98.4%. Mass spectrometry data: [ M ] ═ 213.15 (theoretical molecular weight 212.27)
Step 24 preparation of propylthio-o-phenylenediamine
Adding ethanol 4 times the weight of 2-nitro-5-propylthioaniline, 106.14g of 2-nitro-5-propylthioaniline and sodium sulfide 2.0 times the weight of 2-nitro-5-propylthioaniline into a 1L four-neck flask with a thermometer and a stirring device, starting stirring, heating to reflux, carrying out heat preservation reaction for 6 hours, separating out a reddish brown water layer, and directly using an organic layer for the next reaction.
Step 3 preparation of Thiazol
Adding the 4-propylthio-O-phenylenediamine obtained in the previous step into a 1L four-neck flask with a thermometer and a stirring device, starting stirring, adding acetic acid 2.1 times the weight of the 4-propylthio-O-phenylenediamine, O-methyl isourea methyl formate 1.1 times the molar weight of the 4-propylthio-O-phenylenediamine, reacting for 17 hours at 40-45 ℃, adding formic acid 1.7 times the weight of the 4-propylthio-O-phenylenediamine, heating and refluxing for 6 hours, cooling, centrifuging, washing, drying to obtain 120.06g, wherein the yield of the two steps of reduction and cyclization is 90.5%.
The detection data are as follows:
1H NMR(DMSO-d6)δ：0.94-0.97(t,3H),1.53-1.57(m,2H),2.84-2.87(t,2H), 3.80(s,3H),7.12-7.14(s,1H)，7.37-7.39(s,1H)，7.47(s,1H)，11.81(s,2H)。
IR(KBr):3334.5cm–1(N-H),2957.3cm–1(aromatic ring heterocycle unsaturated hydrocarbon, ═ C-H),1711.6 cm–1(C＝O),1633.2cm–1(C＝C),1590.1cm–1(C＝N),1442.1cm–1And 1326.4cm–1(hydrocarbon of methylene, methyl, C-H),1268.6cm–1(C-C),694.9-792.6cm–1(trisubstituted characteristic absorption Peak on benzene Ring, C ═ CH),598.6cm–1(C-S)。
Example 2
Step preparation of 12-Nitro-5-propylthioaniline
In a 1L four-mouth flask with a thermometer and a stirring device, starting stirring, adding 172.57g of 2-nitro-5-chloroaniline and methanol with 4 times of the weight of the 2-nitro-5-chloroaniline, stirring and heating to 60-65 ℃, dropwise adding a sodium sulfide aqueous solution with 2.0 times of the molar weight, continuing the reaction for 4-5 hours after the dropwise addition, adding bromo-n-propane with 1.5 times of the molar weight of the 2-nitro-5-chloroaniline, carrying out reflux reaction for 2 hours, cooling to 20 ℃ after the reaction is finished, carrying out suction filtration, washing and drying to obtain 203.78g of a dried 2-nitro-5-propylthioaniline product, wherein the yield is 96.0%, and the HPLC content is 99.2%.
Step 24 preparation of propylthio-o-phenylenediamine
Adding isopropanol 5 times the weight of 2-nitro-5-propylthioaniline, 106.14g of 2-nitro-5-propylthioaniline and sodium hydrosulfide 2.5 times the weight of 2-nitro-5-propylthioaniline into a 1L four-neck flask with a thermometer and a stirring device, starting stirring, heating to reflux, carrying out heat preservation reaction for 5 hours, removing a reddish brown water layer, evaporating isopropanol from an organic layer to obtain 92.70g of 4-propylthio o-phenylenediamine, and directly using the mixture in the next reaction.
Step 3 preparation of Thiazol
Adding 4-propylthio-o-phenylenediamine and 550ml of toluene obtained in the previous step into a 1L four-neck flask with a thermometer and a stirring device, starting stirring, adding 1.5 times of formic acid by weight of 4-propylthio-o-phenylenediamine, adding 1.05 times of S-methyl isourea methyl formate by mole of 4-propylthio-o-phenylenediamine, reacting for 3 hours at 75 ℃, cooling to normal temperature, centrifuging, washing and drying to obtain 120.86g, wherein the yield of the two steps of reduction and cyclization is 91.1%, and the content is 99.7%.
The detection data are as follows:
mass spectrometry data: [ M ] ═ 266.09 (theoretical molecular weight 265.33)
The elemental analysis results were as follows:
| theoretical value | First test value | Second test value | |
| C％ | 54.32 | 54.33 | 53.95 |
| H％ | 5.70 | 5.86 | 5.87 |
| N％ | 15.84 | 15.87 | 15.76 |
Example 3
Adding 3000ml of reduction layering wastewater and 30g of sulfur into a 5L reaction bottle, starting stirring, heating to 90-100 ℃, keeping the temperature and stirring for 5 hours, adding 12g of activated carbon, keeping the temperature and stirring for 1 hour at 80-90 ℃, performing suction filtration, adding 20g of manganese chloride into filtrate, starting compressed air to bubble, controlling the temperature to be 70-85 ℃, performing suction filtration until lead acetate test paper does not blacken, concentrating the filtrate until the specific gravity is 1.58mg/ml, slowly cooling to 25 ℃, performing suction filtration, and performing blast drying on a filter cake at 30-40 ℃ to obtain 385g of white sodium thiosulfate, wherein the titration content is 98.8%.
Example 4
Adding 3000ml of reduction layering wastewater and 120g of sulfur into a 5L reaction bottle, starting stirring, heating to 85-90 ℃, keeping the temperature and stirring for 8 hours, adding 12g of activated carbon, keeping the temperature and stirring for 1 hour at 80-90 ℃, performing suction filtration, adding 20g of nickel nitrate into filtrate, starting compressed air to bubble, controlling the temperature to 85-95 ℃ until lead acetate test paper does not blacken, performing suction filtration, concentrating the filtrate until the specific gravity is 1.56mg/ml, slowly cooling to 25 ℃, performing suction filtration, and performing blast drying on a filter cake at 30-40 ℃ to obtain 398g of white sodium thiosulfate with the titration content of 98.6%.
TABLE 1 List of Thiazolidines impurities
The present invention is not limited to the above-described embodiments, and any simple, equivalent changes or modifications made to the above-described embodiments according to the technical spirit of the present invention are within the technical scope of the present invention.
Claims (1)
1. A novel method for preparing albendazole is prepared by the following chemical reaction equation:
wherein M is Na element; x is Cl element;
the reaction equation is prepared by the following steps:
(1) substitution and condensation reaction: in a solvent 1, 2-nitro-5-chloroaniline is subjected to alkali sulfide substitution reaction and then is subjected to condensation reaction with halogenated n-propane to obtain 2-nitro-5-propylthioaniline;
(2) reduction reaction: in a solvent 2, 2-nitro-5-propylthioaniline is subjected to reduction reaction to obtain 4-propylthio o-phenylenediamine, and meanwhile, reduction layering water is subjected to vulcanization, catalytic oxidation, concentration and crystallization to obtain a byproduct sodium thiosulfate;
(3) and (3) cyclization reaction: in a solvent 3, 4-propylthio-o-phenylenediamine and a cyclization agent undergo cyclization reaction to obtain propylthioimidazole;
in the reaction step (1), the sodium sulfide is sodium sulfide, and the using amount of the sodium sulfide is 1.1-2.0 times of the molar weight of the 2-nitro-5-chloroaniline; the solvent 1 is ethanol or methanol, and the dosage of the solvent 1 is 2.5-4 times of the weight ratio of the 2-nitro-5-chloroaniline; the halogenated n-propane is chloro-n-propane, and the dosage of the halogenated n-propane is 1.1 to 1.5 times of the molar weight of the 2-nitro-5-chloroaniline;
in the reaction step (2), the solvent 2 is ethanol or isopropanol, the dosage of the solvent 2 is 2-3 times of the weight of 2-nitro-5-propylthioaniline, and the dosage of the reducing agent is 1.5-2.5 times of the molar weight of 2-nitro-5-propylthioaniline;
the method is characterized in that: in the reaction step (3), the solvent 3 is at least one selected from chloroform, dichloromethane, toluene, methanol, ethanol, propanol, isopropanol and n-butanol, the cyclization reagent is any one selected from S-methyl isourea methyl formate, O-methyl isourea methyl formate and cyanamide methyl formate, the dosage of the cyclization agent is 1.0-2.5 times of the molar amount of 4-propylthio-O-phenylenediamine, the reaction temperature is 60-120 ℃, and the reaction time is 1-24 hours;
when the layered water is reduced in the reaction step (2) to prepare the byproduct sodium thiosulfate, the sulfur is 0.5-4% of the volume of the reduced layered water, the vulcanization temperature is 85-100 ℃, and the vulcanization time is 3-8 hours; the oxidation adopts an air bubbling method, the catalyst is any one of nickel chloride, nickel nitrate, manganese chloride, manganese nitrate, manganese sulfate, manganese carbonate and manganese hydroxide, the oxidation temperature is 80-95 ℃, the oxidation end point is judged that the lead acetate test paper does not blacken, and the control requirement of the concentration crystallization specific gravity is more than 1.56 g/ml.
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| CN102491955A (en) * | 2011-12-08 | 2012-06-13 | 上海易摩生物科技有限公司 | Process method for synthesizing 1, 2-benzisothiazdin-3-ketone |
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| US4152522A (en) * | 1978-01-03 | 1979-05-01 | Ethyl Corporation | Process for the preparation of 2-benzimidazole carbamates |
| CN102491955A (en) * | 2011-12-08 | 2012-06-13 | 上海易摩生物科技有限公司 | Process method for synthesizing 1, 2-benzisothiazdin-3-ketone |
| CN103172571A (en) * | 2013-04-12 | 2013-06-26 | 常州亚邦齐晖医药化工有限公司 | New preparation method of insect repellent albendazole |
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