CN108892643A - A kind of novel preparation method of albendazole - Google Patents
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Abstract
A kind of novel preparation method of albendazole.The present invention provides the synthetic routes of a completely new albendazole, using 2- nitro -5- chloroaniline as starting material, obtain the albendazole of high-purity by substitution, condensation, reduction, cyclization reaction.It is characterized in that 2- nitro -5- chloroaniline, is substituted reaction, then obtain 2- nitro -5- propylthioaniline with halogenated n-propane condensation reaction, avoid using price height, and the propanethiol of irritating stink.It avoids using high-risk hydro-reduction technique, using the sodium sulfide reducing technique that raw material is cheap and easy to get, and provides a set of reduction layering waste water Non-toxic processing scheme, while by-product sodium thiosulfate can be obtained, turn waste into wealth.New process high income, security risk are low, easy to industrialized production, and the albendazole content prepared is high, single impurity content is small, meets the newest standards such as United States Pharmacopeia and European Pharmacopoeia.
Description
Technical field
The invention belongs to chemistry or field of medicinal chemistry, and in particular to the preparation method of albendazole.
Background technique
Albendazole (Albendazole) also known as albendazole, chemical name 5- rosickyite base -1H- benzimidazolyl-2 radicals-amino
Methyl formate is the antihelmintic of a broad-spectrum high-efficiency and low-toxicity, by the Initial Public Offering in 1977 of SmithKline company of the U.S., at present
The medicine is widely used in the various invermination diseases of clinical treatment, has to human body and zoobiotic nematode, fluke, tapeworm
Powerful kills effect, is up to 100% to human cysticercosis, Intestinal Nematode Infections effective percentage, and can significantly inhibit ovulation development,
In vivo without depot action.
Since 7O mid-nineties 90, the domestic and international existing many reports of the synthetic route in relation to albendazole, existing conjunction
Following four can be mainly summarized as at route：
1) using ortho-nitraniline as the route of raw material
1979, Thomas J Walter etc. (US4152522) report, with ortho-nitraniline and rhodanate rudimentary
Bromine or chlorine is added to generate 2- nitro -4- sulfur cyano-aniline in alcohol, it is then that it is water-soluble in Cymag with n-propyl bromide and normal propyl alcohol
In liquid, using methyltributylammonichloride chloride or tetrabutylammonium bromide as phase transfer catalyst, 2- nitryl-4-propylthioaniline is generated,
4- rosickyite base o-phenylenediamine is made through vulcanizing sodium reduction in nitro, finally obtains albendazole with Methyl cyanocarbamate cyclization.This
One route steps are more, and primary raw material bromine used, n-propyl bromide, Cymag have larger toxicity, gone back using vulcanized sodium
Original can generate a large amount of sulfur-containing waste waters, pollute environment, and intermediate 2- nitryl-4-propylthioaniline fusing point is low, be red oily liquid
Body, difficulty isolate and purify, and cause the albendazole of preparation of low quality.
2) using pesticide carbendazim as the route of raw material
Japan Patent JP74-117460 report carbendazim is reacted with chlorine and potassium rhodanide generates 5- thiocyanogen benzo
Imidazoles -2- methyl carbamate, then through routine hydrolysis, thioetherification obtains albendazole, but yield is low, and second in one step of thiocyanation
Sour dosage is excessive, and it is still necessary to improve.
Separately there is similar approach, patent EP31473, EP191940, US4675413 and CN1147507A are reported by carbendazim
4- chlorosulfonyl benzimidazolyl-2 radicals-methyl carbamate is obtained through chlorosulfonation, restores to obtain 4- mercaptobenzimidazole -2- carbamic acid
Methyl esters or its thiophenol salt, then albendazole is obtained through thioetherification.The same yield of this method is relatively low, and reaction condition is than the former
Harshness there is no industrial value so far.
3) using o-phenylenediamine as the route of raw material
Zhang Changli (Chinese Journal of Pharmaceuticals, l988,9:379) report o-phenylenediamine is acted in rhodanate and bromine
4- thiocyanogen o-phenylenediamine is made down, then generates albendazole through reduction and cyclization.Since o-phenylenediamine is easily oxidized, the 1st
Step reaction is not easy to carry out.The total recovery of this route is only 45.8%.
4) using m-dichlorobenzene as the route of raw material
Chinese patent CN103172571B report using m-dichlorobenzene as starting material, by nitrification, amination, condensation, also
Former, cyclization reaction prepares albendazole, and process is condensed in the route will use propanethiol, since propanethiol price is high, and has
Pungent odor is extremely difficult to environmental requirement, can not industrialized production.In addition, the hydro-reduction technique that the route uses belongs to height
Danger technique requires height to equipment, automation control, and equipment investment cost is big.
In view of the 4th article of synthetic route by the unstable intermediate condensate 2- nitro -4- third in existing industrialized route
Sulfenyl aniline is changed to the stable 2- nitro -5- propylthioaniline of quality, is easily isolated purifying, by the third of reduction, cyclization preparation
Sulphur imidazole content is high, single impurity content is small, meets the advanced standard such as United States Pharmacopeia and European Pharmacopoeia.In order to make the 4th article of conjunction
It realizes and industrializes at route, need to improve condensation process synthesis technology, find the preparation method of substitution propanethiol, meanwhile, in order to
The layering waste water using high-risk hydro-reduction technique, after how handling sodium sulfide reducing is avoided to need further to explore
Research.
Summary of the invention
For the various shortcoming of above-mentioned route, cheap and easy to get, high income that the purpose of the present invention is to provide a kind of raw materials,
Security risk is low, the effective Non-toxic processing of waste water, the new method of preparation high-purity albendazole easy to industrialized production, tool
Body technique scheme is as follows：
A kind of new method preparing albendazole, which is characterized in that prepared via following chemical equation：
Wherein, one of M Li, Na, K element；X is F, Cl, Br, one of I element；
Specific preparation process is as follows for above-mentioned reaction equation：
(1) replace, condensation reaction：In solvent 1,2- nitro -5- chloroaniline through akali sulphide substitution reaction, then with it is halogenated
N-propane condensation reaction obtains 2- nitro -5- propylthioaniline；
(2) reduction reaction：In solvent 2,2- nitro -5- propylthioaniline obtains 4- rosickyite base neighbour's benzene through reduction reaction
Diamines, while layering water is restored through over cure, catalysis oxidation, condensing crystallizing obtains by-product sodium thiosulfate；
(3) cyclization reaction：In solvent 3,4- rosickyite base o-phenylenediamine and cyclizing agent occur cyclization reaction and obtain rosickyite miaow
Azoles.
Wherein, in reaction step (1), the akali sulphide is selected from any one of vulcanized sodium, potassium sulfide, lithium sulfide, sulphur
The dosage of choline is 1~3 times of 2- nitro -5- chloroaniline mole；The solvent 1 is selected from ethyl alcohol, methanol, propyl alcohol, isopropyl
At least one of alcohol, n-butanol, water, the dosage of solvent 1 are 2~8 times of 2- nitro -5- chloroaniline weight ratio；The halogen
Any one of fluoro n-propane, n-propyl bromide, chloro n-propane, propyl iodide, halogenated n-propane are selected from for n-propane
Dosage be 1~2 times of 2- nitro -5- chloroaniline mole.
In reaction step (1), the preferred vulcanized sodium of akali sulphide or potassium sulfide, the dosage of akali sulphide are preferably 2- nitro -5- chlorine
1.1~2.0 times of the mole of aniline；1 preferred alcohol of solvent or methanol, the dosage of solvent 1 are preferably 2- nitro -5- chlorobenzene
2.5~4 times of amine weight ratio；The preferred n-propyl bromide of halogenated n-propane or chloro n-propane, the dosage of halogenated n-propane are preferred
It is 1.1-1.5 times of 2- nitro -5- chloroaniline mole.
Solvent 2 is selected from least one of methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, solvent 2 in reaction step (2)
Dosage is 2~5 times of 2- nitro -5- propylthioaniline weight, and reducing agent is selected from any one of vulcanized sodium, NaHS, also
Former agent dosage is 1.1~5.0 times of 2- nitro -5- propylthioaniline mole.
2 preferred alcohol of solvent or isopropanol in reaction step (2), the dosage of solvent 2 are preferably 2- nitro -5- rosickyite base
2~3 times of aniline weight, go back original reagent dosage are preferably 1.5-2.5 times of 2- nitro -5- propylthioaniline mole.
In reaction step (3) solvent 3 be selected from chloroform, methylene chloride, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol,
At least one of n-butanol, cyclization reagent are selected from S- methyl-isourea methyl formate, O- methyl-isourea methyl formate, cyanamide base
Any one of methyl formate, cyclizing agent dosage are 1.0~2.5 times of 4- rosickyite base o-phenylenediamine mole, and reaction temperature is
60 DEG C~120 DEG C, the reaction time 1~24 hour.
When reduction layering water prepares by-product sodium thiosulfate in reaction step (2), sulphur is that reduction stratified water accumulates
0.5-4%, curing temperature are 85-100 DEG C, and vulcanization time is 3-8 hours；Oxidation uses air-blow method, and catalyst selects chlorine
Change any one of nickel, nickel nitrate, manganese chloride, manganese nitrate, manganese sulfate, manganese carbonate, manganous hydroxide, oxidizing temperature 80-95
DEG C, oxidation terminal point determining is no longer to black on Lead acetate paper, and condensing crystallizing specific gravity control requires 1.56g/ml or more.
It is as follows that reduction layering water prepares sodium thiosulfate reaction equation：
Na2S+S→Na2S2
2Na2S2+3O2→2Na2S2O3
Or 2NaHS+2S+2O2→Na2S2O3+H2O+2S
The beneficial effects of the present invention are：
1, the present invention provides the synthetic routes of a completely new albendazole, are that starting is former with 2- nitro -5- chloroaniline
Material, is substituted reaction, then obtain 2- nitro -5- propylthioaniline with halogenated n-propane condensation reaction, avoids using price height,
And the propanethiol of irritating stink.
2, the present invention is avoided using high-risk hydro-reduction technique, using the sodium sulfide reducing technique that raw material is cheap and easy to get,
And a set of reduction layering waste water Non-toxic processing scheme is provided, while by-product sodium thiosulfate can be obtained, turn waste into wealth.
3, new technique for synthesizing high income of the invention, security risk are low, easy to industrialized production, and the rosickyite miaow prepared
Azoles content is high, single impurity content is small, meets the newest standards such as United States Pharmacopeia and European Pharmacopoeia.
Detailed description of the invention
Table 1 is the list of albendazole impurity
Fig. 1 is albendazole condensation product mass spectrum (MS) spectrogram.
Fig. 2 is albendazole infrared spectroscopy (IR) spectrogram.
Fig. 3 is albendazole nucleus magnetic hydrogen spectrum (H1- NMR) spectrogram.
Fig. 4 is that albendazole nuclear-magnetism carbon composes (C13- NMR) spectrogram.
Fig. 5 is albendazole mass spectrum (MS) spectrogram.
Specific embodiment
Following to be described in detail by specific embodiment to the present invention, following embodiment is used to explain the present invention,
Rather than limiting the invention.
Embodiment 1
The preparation of step 1 2- nitro -5- propylthioaniline
In four-hole boiling flask of the 1L with thermometer and agitating device, stirring is opened, the 2- nitro -5- of 172.57g is added
Chloroaniline, the ethyl alcohol of 3 times of 2- nitro -5- chloroaniline weight, stirring are warming up to 70-78 DEG C, and 1.2 times of mole of vulcanization is added dropwise
Aqueous solutions of potassium, drips off that the reaction was continued 4-5 hours, and the propyl iodide of 1.2 times of 2- nitro -5- chloroaniline moles is added, and flows back
Reaction 2 hours, end of reaction is cooled to 20 DEG C, filters, washs, drying and to obtain 2- nitro -5- propylthioaniline dry product 203.14g,
Yield is that 95.7%, HPLC content is 98.4%.Mass spectrometric data：[M]=213.15 (theoretical molecular weight 212.27)
The preparation of step 2 4- rosickyite base o-phenylenediamine
In four-hole boiling flask of the 1L with thermometer and agitating device, 4 times of weight of 2- nitro -5- propylthioaniline are added
Ethyl alcohol, 106.14g 2- nitro -5- propylthioaniline, the vulcanized sodium of 2- nitro -5- 2.0 times of weight of propylthioaniline opens
Stirring is opened, is heated to flowing back, insulation reaction 6 hours, divides and removes rufous water layer, organic layer is directly used in react in next step.
The preparation of step 3 albendazole
In four-hole boiling flask of the 1L with thermometer and agitating device, 4- rosickyite base neighbour benzene two obtained in the previous step is added
Amine opens stirring, and the acetic acid of 2.1 times of weight of 4- rosickyite base o-phenylenediamine, 4- rosickyite base 1.1 times of moles of o-phenylenediamine are added
O- methyl-isourea methyl formate, 40-45 DEG C react 17 hours, be added 1.7 times of weight of 4- rosickyite base o-phenylenediamine formic acid,
It is temperature rising reflux 6 hours, cooling, it is centrifuged, washing, dries to obtain 120.06g, reduction and two step yield of cyclization are 90.5%.
Detection data is 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 unsaturation is 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(methylene, methyl
It is hydrocarbon, C-H), 1268.6cm–1(C-C),694.9-792.6cm–1(three replace characteristic absorption peak, C=CH on phenyl ring),
598.6cm–1(C-S)。
Embodiment 2
The preparation of step 1 2- nitro -5- propylthioaniline
In four-hole boiling flask of the 1L with thermometer and agitating device, stirring is opened, the 2- nitro -5- of 172.57g is added
Chloroaniline, the methanol of 2- nitro -5- 4 times of weight of chloroaniline, stirring are warming up to 60-65 DEG C, and 2.0 times of mole of vulcanization is added dropwise
Sodium water solution, drips off that the reaction was continued 4-5 hours, and the n-propyl bromide of 1.5 times of moles of 2- nitro -5- chloroaniline, reflux is added
Reaction 2 hours, end of reaction is cooled to 20 DEG C, filters, washs, drying and to obtain 2- nitro -5- propylthioaniline dry product 203.78g,
Yield is that 96.0%, HPLC content is 99.2%.
The preparation of step 2 4- rosickyite base o-phenylenediamine
In four-hole boiling flask of the 1L with thermometer and agitating device, 5 times of weight of 2- nitro -5- propylthioaniline are added
Isopropanol, 106.14g 2- nitro -5- propylthioaniline, 2- nitro -5- 2.5 times of weight of propylthioaniline sulphur hydrogenation
Sodium opens stirring, is heated to flowing back, and insulation reaction 5 hours, divides and removes rufous water layer, organic layer boils off isopropanol and obtains 4- rosickyite
Base o-phenylenediamine 92.70g is directly used in and reacts in next step.
The preparation of step 3 albendazole
In four-hole boiling flask of the 1L with thermometer and agitating device, 4- rosickyite base neighbour benzene two obtained in the previous step is added
Amine and 550ml toluene open stirring, and the formic acid of 1.5 times of weight of 4- rosickyite base o-phenylenediamine is added, and 4- rosickyite base neighbour's benzene is added
The S- methyl-isourea methyl formate of 1.05 times of moles of diamines, 75 DEG C are reacted 3 hours, are cooled to room temperature, and are centrifuged, and are washed, drying
120.86g is obtained, reduction and two step yield of cyclization are 91.1%, content 99.7%.
Detection data is as follows：
Mass spectrometric data：[M]=266.09 (theoretical molecular weight 265.33)
Elemental analysis result is as follows：
| Theoretical value | First time test value | Second of test value | |
| C% | 54.32 | 54.33 | 53.95 |
| H% | 5.70 | 5.86 | 5.87 |
| N% | 15.84 | 15.87 | 15.76 |
Embodiment 3
Reduction layering waste water 3000ml and 30g sulphur is added into 5L reaction flask, opens stirring, is warming up to 90-100 DEG C,
Insulated and stirred 5 hours, be added 12g active carbon, 80-90 DEG C insulated and stirred 1 hour, filter, filtrate be added 20g manganese chloride, open
Compressed air is bubbled, and controls 70-85 DEG C of temperature, until Lead acetate paper no longer blacks, is filtered, filtrate is concentrated into specific gravity and is
1.58mg/ml, slow cooling are filtered to 25 DEG C, and 30-40 DEG C of forced air drying of filter cake obtains white sodium thiosulfate 385g, drips
Determine content 98.8%.
Embodiment 4
Reduction layering waste water 3000ml and 120g sulphur is added into 5L reaction flask, opens stirring, is warming up to 85-90 DEG C,
Insulated and stirred 8 hours, be added 12g active carbon, 80-90 DEG C insulated and stirred 1 hour, filter, filtrate be added 20g nickel nitrate, open
Compressed air is bubbled, and controls 85-95 DEG C of temperature, until Lead acetate paper no longer blacks, is filtered, filtrate is concentrated into specific gravity and is
1.56mg/ml, slow cooling are filtered to 25 DEG C, and 30-40 DEG C of forced air drying of filter cake obtains white sodium thiosulfate 398g, drips
Determine content 98.6%.
1 albendazole impurity list of table
The present invention is not limited to the above embodiments, all any letters made according to the technical essence of the invention to above-described embodiment
Single, equivalent variations or modification, belong within the scope of the technology of the present invention.
Claims (7)
1. a kind of new method for preparing albendazole, which is characterized in that prepared via following chemical equation：
Wherein, one of M Li, Na, K element；X is F, Cl, Br, one of I element；
Specific preparation process is as follows for above-mentioned reaction equation：
(1) replace, condensation reaction：In solvent 1,2- nitro -5- chloroaniline through akali sulphide substitution reaction, then with halogenated n-propane
Condensation reaction obtains 2- nitro -5- propylthioaniline；
(2) reduction reaction：In solvent 2,2- nitro -5- propylthioaniline obtains 4- rosickyite base o-phenylenediamine through reduction reaction,
Layering water is restored simultaneously through over cure, and catalysis oxidation, condensing crystallizing obtains by-product sodium thiosulfate；
(3) cyclization reaction：In solvent 3,4- rosickyite base o-phenylenediamine and cyclizing agent occur cyclization reaction and obtain albendazole.
2. the preparation method of albendazole according to claim 1, it is characterised in that：In reaction step (1), the sulphur
Choline is selected from any one of vulcanized sodium, potassium sulfide, lithium sulfide, and the dosage of akali sulphide is the 1 of 2- nitro -5- chloroaniline mole
~3 times；The solvent 1 is selected from least one of ethyl alcohol, methanol, propyl alcohol, isopropanol, n-butanol, water, the dosage of solvent 1
It is 2~8 times of 2- nitro -5- chloroaniline weight ratio；The halogenated n-propane is selected from fluoro n-propane, n-propyl bromide, chlorine
For any one of n-propane, propyl iodide, the dosage of halogenated n-propane is the 1~2 of 2- nitro -5- chloroaniline mole
Times.
3. the preparation method of albendazole according to claim 2, it is characterised in that：In reaction step (1), akali sulphide is excellent
Vulcanized sodium or potassium sulfide are selected, the dosage of akali sulphide is preferably 1.1~2.0 times of the mole of 2- nitro -5- chloroaniline；Solvent 1
Preferred alcohol or methanol, the dosage of solvent 1 are preferably 2.5~4 times of 2- nitro -5- chloroaniline weight ratio；Halogenated n-propane is excellent
N-propyl bromide or chloro n-propane are selected, the dosage of halogenated n-propane is preferably the 1.1-1.5 of 2- nitro -5- chloroaniline mole
Times.
4. the preparation method of albendazole according to claim 1, it is characterised in that：Solvent 2 is selected from reaction step (2)
At least one of methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, 2 dosage of solvent are 2- nitro -5- propylthioaniline weight
2~5 times, reducing agent is selected from any one of vulcanized sodium, NaHS, and reducing agent dosage is that 2- nitro -5- propylthioaniline rubs
1.1~5.0 times of that amount.
5. the preparation method of albendazole according to claim 4, it is characterised in that：Solvent 2 is preferred in reaction step (2)
Ethyl alcohol or isopropanol, the dosage of solvent 2 are preferably 2~3 times of 2- nitro -5- propylthioaniline weight, and go back original reagent dosage is excellent
It is selected as 1.5-2.5 times of 2- nitro -5- propylthioaniline mole.
6. the preparation method of albendazole according to claim 1, it is characterised in that：Solvent 3 is selected from reaction step (3)
At least one of chloroform, methylene chloride, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, cyclization reagent is selected from
Any one of S- methyl-isourea methyl formate, O- methyl-isourea methyl formate, cyanamide base methyl formate, cyclizing agent dosage are 4-
1.0~2.5 times of rosickyite base o-phenylenediamine mole, reaction temperature are 60 DEG C~120 DEG C, the reaction time 1~24 hour.
7. the preparation method of albendazole according to claim 1, it is characterised in that：Reduction layering in reaction step (2)
When water prepares by-product sodium thiosulfate, sulphur is the 0.5-4% for restoring stratified water product, and curing temperature is 85-100 DEG C, vulcanization
Time is 3-8 hours；Oxidation uses air-blow method, and catalyst selects nickel chloride, nickel nitrate, manganese chloride, manganese nitrate, sulfuric acid
Any one of manganese, manganese carbonate, manganous hydroxide, oxidizing temperature be 80-95 DEG C, oxidation terminal point determining be Lead acetate paper on no longer
Black, condensing crystallizing specific gravity control requires 1.56g/ml or more.
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| CN109400537A (en) * | 2019-01-03 | 2019-03-01 | 山东国邦药业股份有限公司 | A kind of synthetic method of albendazole |
| CN109884014A (en) * | 2019-03-07 | 2019-06-14 | 济南大学 | A kind of organosilicon imidazoles polymer detecting iron ion |
| 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 |
| CN110498752A (en) * | 2019-09-27 | 2019-11-26 | 山东国邦药业有限公司 | A kind of preparation method of 4- rosickyite base -2- nitroaniline |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109400537A (en) * | 2019-01-03 | 2019-03-01 | 山东国邦药业股份有限公司 | A kind of synthetic method of albendazole |
| CN109884014A (en) * | 2019-03-07 | 2019-06-14 | 济南大学 | A kind of organosilicon imidazoles polymer detecting iron ion |
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