CN103172571B - New preparation method of insect repellent albendazole - Google Patents
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Abstract
The invention discloses a new preparation method of an insect repellent albendazole and provides a brand-new synthesis route of albendazole. The new preparation method adopting m-dichlorobenzene as the starting material is used for obtaining high-purity albendazole through nitration, amination, condensation, reduction and cyclization reaction; the new preparation method is characterized in that an unstable intermediate condensation compound 2-nitryl-4-propyl sulfenyl aniline in the existing industrial route is changed into 2-nitryl-5-propyl sulfenyl aniline with stable quality. The reducing process is changed into a clean and efficient reducing process by virtue of sodium sulfide. The synthesis process is simple and efficient, less in pollution, high in quality and suitable for industrial production.
Description
Technical field
The invention belongs to chemistry or medicinal chemistry art, be specifically related to the preparation method of albendazole.
Background technology
Albendazole (Albendazole) has another name called Zental, chemical name Albenzadole, it is the anthelmintic of a broad-spectrum high-efficiency and low-toxicity, by the Initial Public Offering in 1977 of SmithKline company of the U.S., this medicine is widely used in the various helminth infection disease of clinical treatment at present, all have human body and zoobiotic nematode, fluke, tapeworm and powerful kill effect, efficient up to 100% to human cysticercosis, Intestinal Nematode Infections, and significantly can suppress ovulation development, in vivo without depot action.
Since 7O mid-nineties 90, both at home and abroad about the existing many reports of synthetic route of albendazole, its existing synthetic route mainly can be summarized as following three:
1) take o-Nitraniline as the route of raw material
1979, Thomas J Walter etc. (US4152522) report, in lower alcohol, bromine is added or chlorine generates 2-nitro-4-sulfur cyano-aniline with o-Nitraniline and thiocyanate-, then by itself and n-propyl bromide and n-propyl alcohol in sodium cyanide solution, with methyltributylammonichloride chloride or Tetrabutyl amonium bromide for phase-transfer catalyst, generate 2-nitryl-4-propylthioaniline, nitro makes 4-rosickyite base O-Phenylene Diamine through sodium sulphite reduction, finally obtains albendazole with Methyl cyanocarbamate cyclization.This route steps is more, main raw material bromine used, n-propyl bromide, sodium cyanide have larger toxicity, sodium sulphite is used to reduce, a large amount of sulfur-containing waste water can be produced, contaminate environment, and intermediate 2-nitryl-4-propylthioaniline fusing point is low, is red oily liquids, difficult separation and purification, causes the albendazole of preparation of low quality.
2) take pesticide carbendazim as the route of raw material
Japanese Patent JP74-117460 report derosal and chlorine and potassium sulfocyanate react and generate 5-thiocyanogen benzimidazolyl-2 radicals-Urethylane, again through routine hydrolysis, thioetherification obtains albendazole, but yield is low, and acetic acid consumption is excessive in thiocyanation one step, improvement of still needing.
Separately there is similar approach; patent EP31473, EP191940, US4675413 and CN1147507A report obtain 4-chlorosulfonyl benzimidazolyl-2 radicals-Urethylane by derosal through chlorosulphonation; reduce to obtain 4-mercaptobenzimidazole-2-Urethylane or its thiophenol salt, then obtain albendazole through thioetherification.The same yield of this method is on the low side, and reaction conditions is harsher than the former, there is no industrial value so far.
3) take O-Phenylene Diamine as the route of raw material
Zhang Changli (Chinese Journal of Pharmaceuticals, l988,9:379) report O-Phenylene Diamine is obtained 4-thiocyanogen O-Phenylene Diamine under thiocyanate-and bromine effect, then generates albendazole through reduction and cyclization.Because O-Phenylene Diamine is easily oxidized, the 1st step reaction is not easily carried out.The total recovery of this route is only 45.8%.
At present, the suitability for industrialized production route of albendazole in the 1st kind of synthetic route, has done part improve: 1) prepare in 2-nitryl-4-propylthioaniline process, uses sodium hydroxide or sodium sulphite to replace highly toxic product sodium cyanide; 2) because intermediate 2-nitryl-4-propylthioaniline difficulty is separated, intermediate 4-rosickyite base O-Phenylene Diamine is easily oxidized, and industrial production all adopts, and " one kettle way " prepares albendazole product.Because centre is not separated, cause synthesizing the albendazole crude product purity obtained low, color and luster is dark, though product purity can reach more than 98% after repeatedly refining, but product color is still partially yellow or partially red off-white color, single foreign matter content is high, and quality is difficult to reach the advanced standard such as American Pharmacopeia and European Pharmacopoeia.For this reason, really can be applied to yield in industrial production high, operate succinct safety, the method preparing high purity albendazole of environmental protection needs further exploratory development.
Summary of the invention
For the various shortcoming of above-mentioned route, the object of the present invention is to provide that a kind of cheaper starting materials is easy to get, yield is high, operate succinct safety, environmental protection, be easy to the novel method of industrialized preparation high purity albendazole, concrete technical scheme is as follows:
A novel preparation method for albendazole, it take Meta Dichlorobenzene as starting raw material, carries out through following chemical equation:
As follows by above-mentioned reaction formula preparation process:
(1) nitration reaction: take Meta Dichlorobenzene as raw material, in the vitriol oil and nitric acid, through nitration reaction, point remove spent acid layer, alkali neutralization &washing organic layer obtains 2,4-dichloronitrobenzene;
(2) amination reaction: in organic solvent or water, 2,4-dichloronitrobenzene and amination reagent amination reaction obtain 2-nitro-5-chloroaniline;
(3) condensation reaction: in organic solvent or water, 2-nitro-5-chloroaniline, under base catalysis, obtains 2-nitro-5-propylthioaniline with propylmercaptan condensation reaction;
(4) reduction reaction: in organic solvent, 2-nitro-5-propylthioaniline obtains 4-rosickyite base O-Phenylene Diamine through reduction reaction in the presence of a catalyst;
(5) ring-closure reaction: in organic solvent, 4-rosickyite base O-Phenylene Diamine and cyclization reagent generation cyclization are obtained by reacting albendazole.
Nitrating agent described in reactions steps (1) is nitric acid, its consumption is 0.8 ~ 1.5 times of the molar weight of Meta Dichlorobenzene, preferable amount is 1.04 ~ 1.2 times, vitriol oil consumption is Meta Dichlorobenzene molar weight 0.5 ~ 5 times, preferable amount is 0.9 ~ 3 times, nitrated temperature is 0 ~ 20 DEG C, preferably 5 ~ 20 DEG C, and the nitration reaction time is 1 ~ 5 hour.Neutralization &washing alkali used is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood, any one in potassium bicarbonate aqueous solution that concentration is 1% ~ 50%.
Amination reagent described in reactions steps (2) is selected from liquefied ammonia, ammoniacal liquor, is preferably liquefied ammonia; Amination solvent selected from methanol, ethanol, propyl alcohol, Virahol, dimethylbenzene, toluene, water or their mixture, be preferably methyl alcohol or ethanol; The molar weight of amination reagent is 2,4 ~ 16 times of 4-dichloronitrobenzene, be preferably 6 ~ 10 times, the consumption of solvent is 2 ~ 5 times of 2,4-dichloronitrobenzene weight ratio, preferably 1.5 ~ 3.0 times, temperature of reaction is 80 ~ 250 DEG C, be preferably 120 ~ 160 DEG C, reaction pressure 0.8 ~ 6.0MPa, preferably 2.0 ~ 4.0MPa.
The consumption of the propylmercaptan described in reactions steps (3) is 1 ~ 3 times of the molar weight of 2-nitro-5-chloroaniline, be preferably 1.05 ~ 1.5 times, the consumption of solvent is 2 ~ 8 times of 2-nitro-5-chloroaniline weight ratio, be preferably 2.5 ~ 4 times, the consumption of alkali is 1.1 ~ 2.5 times of 2-nitro-5-chloroaniline mol ratio, described solvent selected from ethanol, methyl alcohol, propyl alcohol, Virahol, propyl carbinol, water or their mixture, preferred alcohol or methyl alcohol, alkali is selected from any one in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, preferred sodium hydroxide or potassium hydroxide.
Solvent load described in reactions steps (4) is 2 ~ 5 times of 2-nitro-5-propylthioaniline weight ratio, be preferably 2 ~ 3 times, reduction reagent dosage is 1.2 ~ 50 times of 2-nitro-5-propylthioaniline mol ratio, be preferably 5-30 doubly, solvent selected from methanol, ethanol, propyl alcohol, Virahol, propyl carbinol or their mixture, also original reagent is selected from hydrogen, hydrazine hydrate, tin protochloride, any one in sodium borohydride, preferred hydrogen, nano nickel selected by catalyzer, palladium (Pd), platinum (Pt), ruthenium (Ru), Raney's nickel (Raney Ni), any one in iron trichloride, preferred palladium (Pd) or Raney's nickel (Raney Ni).
Reaction solvent described in reactions steps (5) is selected from trichloromethane, methylene dichloride, toluene, methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol or their mixture, cyclization reagent is selected from any one in S-methyl-isourea methyl-formiate, O-methyl-isourea methyl-formiate, cyanamide base methyl-formiate, cyclizing agent consumption is 1.0 ~ 2.5 times of 4-rosickyite base O-Phenylene Diamine mol ratio, temperature of reaction is 60 DEG C ~ 120 DEG C, 1 ~ 24 hour reaction times.
Beneficial effect of the present invention is:
1, the invention provides the synthetic route of a brand-new albendazole, change the intermediate condensate 2-nitryl-4-propylthioaniline of the instability in existing industrialized route into stay-in-grade 2-nitro-5-propylthioaniline, be easy to separation and purification, high, the single foreign matter content of albendazole content prepared through reduction, cyclization is little, meets the advanced standard such as American Pharmacopeia and European Pharmacopoeia.
2, the present invention uses the reducing process replacement sulfur choline reducing process of clean and effective, avoids producing a large amount of sulfur-containing waste water contaminate environment.
3, new synthetic process of the present invention succinct efficient, pollute less, quality is high, is applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is albendazole infrared spectra (IR) spectrogram.
Embodiment
Following by specific embodiment, be described in detail the present invention, following examples are for explaining the present invention, instead of limitation of the present invention.
Embodiment 1
The preparation of step 12,4-dichloronitrobenzene
In the four-hole boiling flask of 500ml with thermometer and whipping appts, open and stir, add 100.0g Meta Dichlorobenzene, 0.9 times of weight ratio vitriol oil, molar weight is Meta Dichlorobenzene 1.1 times of nitric acid, 5 ~ 10 DEG C of insulation reaction 3 hours, HPLC followed the tracks of and reacts completely, point sub-cloud spent acid layer, add the aqueous sodium hydroxide solution 100g agitator treating of 5%, separate lower floor and obtain 2,4-dichloronitrobenzene 125.0g, be directly used in next step reaction.This step yield is 95.7%, and content is 98.7%.
The preparation of step 2 2-nitro-5-chloroaniline
2, the 4-dichloronitrobenzenes of the 100.0g that previous step obtains are added, 3.5 times 2 in the autoclave of 1000ml, the methyl alcohol of 4-dichloronitrobenzene weight ratio, the ammoniacal liquor of 10 times of 2,4-dichloronitrobenzene molar weight, temperature controls at 130 ~ 140 DEG C, reaction pressure is at 2.5 ~ 2.7MPa, react after 12 hours and cool, centrifugal, washing, dry, obtain 2-nitro-5-chloroaniline dry product 76.0g.Yield is 84.6%, and content is 98.6%.
The preparation of step 3 2-nitro-5-propylthioaniline
In the four-hole boiling flask of 500ml with thermometer and whipping appts, open and stir, add the 2-nitro-5-chloroaniline of 30.4g, the propylmercaptan that molar weight is 1.5 times, the ethanol of 3 times of 2-nitro-5-chloroaniline weight ratios, add the aqueous sodium hydroxide solution of the content 40% of 1.5 times of 2-nitro-5-chloroaniline mol ratios, back flow reaction 4 hours, reacts complete and is cooled to 20 DEG C, centrifugal, wash, dry to obtain 2-nitro-5-propylthioaniline dry product 35.6g, yield is 95.2%, fusing point 69.7-70.6 DEG C.
The preparation of step 4 4-rosickyite base O-Phenylene Diamine
In the four-hole boiling flask of 500ml with thermometer and whipping appts, add the 2-nitro-5-propylthioaniline of propyl alcohol that weight ratio is 2-nitro-5-propylthioaniline 3 times, 21.2g, weight ratio is the iron trichloride of 2-nitro-5-propylthioaniline 0.01 times, open and stir, drip the hydrazine hydrate that mol ratio is 2-nitro-5-propylthioaniline 2 times, back flow reaction 2 hours, filters catalyzer iron trichloride, boil off propyl alcohol and obtain 4-rosickyite base O-Phenylene Diamine 17.1g, be directly used in next step reaction.
The preparation of step 5 albendazole
In the four-hole boiling flask of 500ml with thermometer and whipping appts, add 4-rosickyite base O-Phenylene Diamine obtained in the previous step and 105ml toluene, open and stir, add the acetic acid that weight ratio is 4-rosickyite base O-Phenylene Diamine 0.8 times, mol ratio is the O-methyl-isourea methyl-formiate of 4-rosickyite base O-Phenylene Diamine 1.05 times, 40-45 DEG C is reacted 17 hours, add the formic acid that weight ratio is 4-rosickyite base O-Phenylene Diamine 1.7 times, temperature rising reflux 6 hours, cooling, centrifugal, washing, dry to obtain 33.2g, reduction and cyclization two step yield are 90.1%, content 99.7%.
IR(KBr):3328.1cm
–1,1712.0cm
–1,1632.0cm
–1,1588.9cm
–1,1524.3cm
– 1,1443.0cm
–1,1326.0cm
–1,1268.8cm
–1,1194.7cm
–1,1095.9cm
–1,792.0cm
–1。
Embodiment 2
Step 12, the preparation of 4-dichloronitrobenzene
In the four-hole boiling flask of 500ml with thermometer and whipping appts, open and stir, add 100.0g Meta Dichlorobenzene, 0.5 times of weight ratio vitriol oil, dripping molar weight is Meta Dichlorobenzene 1.05 times of nitric acid, controls dropping temperature at 10 ~ 15 DEG C, dropwise, 10 ~ 15 DEG C of insulation reaction 3 hours, HPLC followed the tracks of and reacts completely, point sub-cloud spent acid layer, add the aqueous sodium carbonate 100g agitator treating of 15%, separate lower floor and obtain 2,4-dichloronitrobenzene 127.0g, be directly used in next step reaction.This step yield is 97.2%, and content is 98.1%.
The preparation of step 2 2-nitro-5-chloroaniline
2, the 4-dichloronitrobenzenes of the 250.0g that previous step obtains are added, 2.5 times 2 in the autoclave of 1000ml, the toluene of 4-dichloronitrobenzene weight ratio, the liquefied ammonia of 12 times of 2,4-dichloronitrobenzene molar weight, temperature controls at 105 ~ 110 DEG C, reaction pressure is at 3.9 ~ 4.4MPa, react after 9 hours and cool, centrifugal, washing, dry, obtain 2-nitro-5-chloroaniline dry product 198.0g.Yield is 88.1%, and content is 97.8%.
The preparation of step 3 2-nitro-5-propylthioaniline
In the four-hole boiling flask of 500ml with thermometer and whipping appts, open and stir, add the 2-nitro-5-chloroaniline of 30.4g, the propylmercaptan that molar weight is 1.2 times, the ethanol of 3 times of 2-nitro-5-chloroaniline weight ratios, add the potassium hydroxide aqueous solution of the content 40% of 1.5 times of 2-nitro-5-chloroaniline mol ratios, finish back flow reaction 4 hours, react complete and be cooled to 20 DEG C of insulations 1 hour, centrifugal, wash, dry to obtain 2-nitro-5-propylthioaniline dry product 34.5g, yield is 92.3%, and content is 99.1%.
The preparation of step 4 4-rosickyite base O-Phenylene Diamine
In the four-hole boiling flask of 500ml with thermometer and whipping appts, add the 2-nitro-5-propylthioaniline of Virahol that weight ratio is 2-nitro-5-propylthioaniline 5 times, 30g, weight ratio is the palladium charcoal of 2-nitro-5-propylthioaniline 0.06 times, open and stir, be heated to 85-95 DEG C of logical hydrogen to pressure 1.2-2.0MPa, hydrogenation reduction 8 hours, filters palladium catalyst charcoal, boil off Virahol and obtain 4-rosickyite base O-Phenylene Diamine 24.7g, be directly used in next step reaction.
The preparation of step 5 albendazole
In the four-hole boiling flask of 500ml with thermometer and whipping appts, add 4-rosickyite base O-Phenylene Diamine obtained in the previous step and 100ml toluene, open and stir, add the acetic acid that weight ratio is 4-rosickyite base O-Phenylene Diamine 0.8 times, add the S-methyl-isourea methyl-formiate that mol ratio is 4-rosickyite base O-Phenylene Diamine 1.05 times, 75 DEG C are reacted 3 hours, are cooled to normal temperature, centrifugal, washing, dry to obtain 24.0g, reduction and cyclization two step yield are 90.5%, content 99.6%.
The invention is not restricted to above-described embodiment, all any simple, equivalent variations of doing above-described embodiment according to technical spirit of the present invention or modification, all belong within the scope of the technology of the present invention.
Claims (1)
1. prepare a novel method for albendazole, described method is through following chemical equation and carries out:
Preparation process is as follows:
(1) nitration reaction: take Meta Dichlorobenzene as raw material, in the vitriol oil and nitric acid, through nitration reaction, point remove spent acid layer, alkali neutralization &washing organic layer obtains 2,4-dichloronitrobenzene;
(2) amination reaction: in organic solvent and/or water, 2,4-dichloronitrobenzene and amination reagent amination reaction obtain 2-nitro-5-chloroaniline;
(3) condensation reaction: in organic solvent and/or water, 2-nitro-5-chloroaniline, under base catalysis, obtains 2-nitro-5-propylthioaniline with propylmercaptan condensation reaction;
(4) reduction reaction: in organic solvent, 2-nitro-5-propylthioaniline obtains 4-rosickyite base O-Phenylene Diamine through reduction reaction in the presence of a catalyst;
(5) ring-closure reaction: in organic solvent, 4-rosickyite base O-Phenylene Diamine and cyclization reagent generation cyclization are obtained by reacting albendazole;
Wherein, in reactions steps (1), nitrating agent is nitric acid, and its consumption is 0.8 ~ 1.5 times of the molar weight of Meta Dichlorobenzene, and vitriol oil consumption is Meta Dichlorobenzene molar weight 0.5 ~ 5 times, and nitrated temperature is 0 ~ 20 DEG C, and the nitration reaction time is 1 ~ 5 hour; Neutralization &washing alkali used is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood, any one in potassium bicarbonate aqueous solution that concentration is 1% ~ 50%; In reactions steps (2), amination reagent is selected from liquefied ammonia, ammoniacal liquor; Amination solvent selected from methanol, ethanol, propyl alcohol, Virahol, dimethylbenzene, toluene, water or their mixture; The molar weight of amination reagent is 4 ~ 16 times of 2,4-dichloronitrobenzene, and the consumption of solvent is 2 ~ 5 times of 2,4-dichloronitrobenzene weight ratio, and temperature of reaction is 80 ~ 250 DEG C, reaction pressure 0.8 ~ 10.0MPa;
In reactions steps (3), the consumption of propylmercaptan is 1 ~ 3 times of the molar weight of 2-nitro-5-chloroaniline, the consumption of solvent is 2 ~ 8 times of 2-nitro-5-chloroaniline weight ratio, the consumption of alkali is 1.1 ~ 2.5 times of 2-nitro-5-chloroaniline mol ratio, described solvent selected from ethanol, methyl alcohol, propyl alcohol, Virahol, propyl carbinol, water or their mixture, alkali is selected from any one in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood; In reactions steps (4), solvent load is the weight ratio of 2-nitro-5-propylthioaniline 2 ~ 5 times, reduction reagent dosage is the mol ratio of 1.2 ~ 50 times of 2-nitro-5-propylthioaniline, solvent selected from methanol, ethanol, propyl alcohol, Virahol, propyl carbinol or their mixture, also original reagent is selected from any one in hydrogen, hydrazine hydrate, tin protochloride, sodium borohydride, and any one in nano nickel, palladium (Pd), platinum (Pt), ruthenium (Ru), Raney's nickel (Raney Ni), iron trichloride selected by catalyzer;
In reactions steps (5), reaction solvent is selected from trichloromethane, methylene dichloride, toluene, methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol or their mixture, cyclization reagent is selected from any one in S-methyl-isourea methyl-formiate, O-methyl-isourea methyl-formiate, cyanamide base methyl-formiate, cyclizing agent consumption is 1.0 ~ 2.5 times of 4-rosickyite base O-Phenylene Diamine mol ratio, temperature of reaction is 60 DEG C ~ 120 DEG C, 1 ~ 24 hour reaction times.
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| CN103601685A (en) * | 2013-12-05 | 2014-02-26 | 常州亚邦齐晖医药化工有限公司 | Preparation method of oxibendazole |
| CN104945292B (en) * | 2014-03-24 | 2017-04-19 | 济南大学 | Process for preparing 4-propylthio-o-phenylenediamine |
| CN104945291A (en) * | 2014-03-24 | 2015-09-30 | 济南大学 | Process for preparing albendazole intermediate 4-propylthio-o-phenylenediamine |
| CN105859568B (en) * | 2016-05-10 | 2017-08-25 | 江南大学 | The method that a kind of efficient catalytic also original aromatic nitro compound prepares amino-compound |
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| CN108069919A (en) * | 2016-11-08 | 2018-05-25 | 上海医药工业研究院 | The preparation method of click azoles amine key intermediate |
| CN108892643B (en) * | 2018-08-31 | 2021-01-08 | 常州齐晖药业有限公司 | Novel preparation method of albendazole |
| CN110151692A (en) * | 2019-06-21 | 2019-08-23 | 石家庄九鼎动物药业有限公司 | A kind of antiparasite drugs for animals Albendazole suspension preparation method |
| CN110683966A (en) * | 2019-08-11 | 2020-01-14 | 沈阳百傲化学有限公司 | Process for preparing 2-cyano-4-nitroaniline by using microchannel reaction |
| CN113912549B (en) * | 2020-07-08 | 2022-11-15 | 山东国邦药业有限公司 | Preparation method of albendazole |
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