CN102250012B - Process for preparing benzimidazole insectifuge oxibendazole - Google Patents
Process for preparing benzimidazole insectifuge oxibendazole Download PDFInfo
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Abstract
The invention relates to a process for preparing a benzimidazole insectifuge oxibendazole. The oxibendazole product is prepared by condensation, nitration, reduction and cyclization. A phase transfer catalyst is utilized, and the condensation and nitration of the oxibendazole are carried out at one time to improve the process; and in the new synthesis process, a step of discharging a condensation intermediate is eliminated, the yield is improved, the unit consumption of a raw material is reduced, the safety of the nitration operation is improved effectively and the process is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation technology of benzimidazoles insect repellent, be specifically related to a kind of technology that adopts condensation, nitrated, reduction, ring-closure reaction to make the SKF-30310 product.
Background technology
SKF-30310 has another name called oxibendazole, and chemistry 5-propoxy-benzimidazolyl-2 radicals-Urethylane by name is a kind of anti-parasite medicine of broad-spectrum high efficacy for animals.SKF-30310 can stop the synthetic of adenosine triphosphate (ATP) in the polypide, and non-reversibility ground suppresses polypide ingestion of glucose in the enteron aisle, causes polypide dead gradually because of the picked-up energy shortage at last.Be used to treat roundworm, strongylid, nematode, pinworm and the lungworm of horse and other ruminating animals (cattle and sheep etc.).SKF-30310 all has good effect to adult and the larva of large-scale horse quasi-colubriformis adult, naggy quasi-colubriformis adult and large-scale pinworm.Not only to colluding worm and roundworm is effective, the curative effect of driving whipworm also can reach about 70% SKF-30310.
SKF-30310 is succeeded in developing by U.S. SmithKline good fortune drugmaker at first.Shanghai Institute of Pharmaceutical Industry began to copy in 1980, and developed jointly successfully with Jintan, Jiangsu county animal pharmaceutical factory.
The synthetic route of report is following both at home and abroad at present:
This route is the main technique route of at present domestic and international suitability for industrialized production SKF-30310.But mainly there is following deficiency in this synthetic route: this technology condensation step is a homogeneous reaction, and reaction must be taken out material with the solvent evaporate to dryness after finishing, and gets into next step denitrification step again, complex operation and loss material, and yield is on the low side.
Summary of the invention
To above-mentioned shortcoming, the object of the present invention is to provide a new operational path of preparation SKF-30310, be intended to overcome shortcoming in the above synthesis technique, reduce cost, make it operation succinctly safely, be more suitable for suitability for industrialized production.
Technology contents of the present invention is: a kind of new preparation process of SKF-30310; The present invention utilizes phase-transfer catalyst, and to condensation and the nitre process program process modification of cooking all things in one pot, this new synthetic process has saved the step of condensation midbody discharging; Promote yield; Reduce the unit consumption of material, the security of nitration reaction operation has obtained effective improvement, is fit to suitability for industrialized production.With PARACETAMOL BP98 (Paracetamol USP23,BP98) is raw material, gets SKF-30310 through condensation, nitrated, reduction, closed loop.
Details are as follows for concrete synthesis step:
(1) to the preparation of propoxy-Acetanilide: with the PARACETAMOL BP98 is raw material, in organic solvent, adds entry, mineral alkali, must be to the propoxy-Acetanilide with the halogenopropane condensation under the phase-transfer catalyst katalysis.The condensation reaction organic solvent is selected from chlorobenzene, oil of mirbane etc., preferred chlorobenzene; Alkali is selected from mineral alkalis such as sodium hydroxide, Pottasium Hydroxide, salt of wormwood, yellow soda ash, preferred sodium hydroxide; Halogenopropane is selected from chloropropane, N-PROPYLE BROMIDE etc., preferred N-PROPYLE BROMIDE; Phase-transfer catalyst is selected from poly di-alcohol, tetrabutylammonium chloride, Tetrabutyl amonium bromide, tetrabutylammonium hydroxide sodium, α-phosphoryl sulfoxide, benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide, hempa sulfanilamide (SN) etc., preferred benzyltriethylammoinium chloride; The amount of organic solvent is 3～5 times of weight ratio of PARACETAMOL BP98 (Paracetamol USP23,BP98), preferred 4 times; Water is 2～4 times of weight ratio, preferred 2 times; Alkali is 1.1～1.5 times mol ratio, preferred 1.3 times; Halogenopropane is 1.1～1.5 times of mol ratios, preferred 1.3 times; Phase-transfer catalyst is 0.001～0.05 times of weight ratio, preferred 0.02 times; Temperature of reaction be 20 ℃ to reflux temperature, preferred reflux temperature; Reaction times is 1～50 hour, preferred 24 hours.
(2) to the preparation of propoxy-o-Nitroacetanilide: the propoxy-Acetanilide must be sloughed solvent and got dry product the propoxy-o-Nitroacetanilide through nitration reaction.Nitrating agent is a nitric acid, and the concentration of nitric acid is 40%～98%, preferred 67%; The nitric acid amount is 1.02～1.06 times of molar weights of acetyl aminophenol, and preferred 1.05 times, the nitration reaction temperature is-6 ℃～50 ℃, preferred 20 ℃; 20～60 ℃ of holding temperatures, preferred 35 ℃; Soaking time 0.5～3 hour, preferred 2 hours.
(3) to the preparation of propoxy-O-Phenylene Diamine: must be through reduction reaction to the propoxy-O-Phenylene Diamine to the propoxy-o-Nitroacetanilide.Alkali is selected from sodium hydroxide, Pottasium Hydroxide etc., the preferred sodium hydroxide of alkali; Reductive agent is selected from Sodium Sulphide such as sodium sulphite, potassium sulphide, Sodium sulfhydrate, potassium bisulfide and Hydrazine Hydrate 80 etc., preferred sodium sulphite; Reductive agent is to 1.2～3 times of mol ratios of propoxy-o-Nitroacetanilide, preferred 2 times; Temperature of reaction is 20 a ℃～reflux temperature, preferred reflux temperature, 1～24 hour reaction times, preferred 10 hours.
(4) preparation of SKF-30310: the propoxy-O-Phenylene Diamine is being got SKF-30310 with closed loop agent closed loop under acidic conditions.Acids is selected from organic acids such as oxalic acid, acetate, formic acid, tartrate, preferable formic acid; Reaction solvent is selected from organic solvents such as trichloromethane, methylene dichloride, toluene, preferred toluene; Recrystallization solvent is selected from alcohols such as methyl alcohol, ethanol, Virahol, particular methanol; Cyclization reagent is selected from S-methyl-isourea methyl-formiate, O-methyl-isourea methyl-formiate, cyanamide base methyl-formiate etc., preferred S-methyl-isourea methyl-formiate; Temperature of reaction is 40 ℃～80 ℃, preferred 55 ℃; 1～8 hour reaction times, preferred 5 hours.
The reaction formula of above-mentioned concrete making benzene sulphur imidazoles step is following:
1. condensation:
2. nitrated:
3. reduction:
4. closed loop:
The invention has the advantages that: present method is utilized phase-transfer catalyst; To the condensation of SKF-30310 and the nitre process program process modification of cooking all things in one pot; This new synthetic process has saved the step of condensation midbody discharging, promotes yield, reduces the unit consumption of material; The security of nitration reaction operation has obtained effective improvement, is fit to suitability for industrialized production.
Embodiment
Following type reaction is used for illustrating the present invention, within the technical scheme that those skilled in the art all belong to the present invention to simple replacement that the present invention did or improvement etc. and protected.
Embodiment 1.
Step 1: to the preparation of propoxy-Acetanilide
In 1000 milliliters four-hole boiling flask, add the 60g PARACETAMOL BP98 successively; The chlorobenzene solvent of 4 times of weight ratios of PARACETAMOL BP98; The water of 3 times of weight ratios of PARACETAMOL BP98; The sodium hydroxide of 1.3 times of molar weights of PARACETAMOL BP98, the N-PROPYLE BROMIDE of 1.3 times of mol ratios of PARACETAMOL BP98, the phase-transfer catalyst benzyltriethylammoinium chloride of 0.02 times of weight ratio of PARACETAMOL BP98; Be warming up to backflow, be incubated 24 hours, GC tracks to reaction and finishes, and is cooled to 20 ℃, and water layer is cast out in layering, and organic layer directly gets into next step reaction.
Step 2: to the preparation of propoxy-o-Nitroacetanilide
On in 1000 milliliters four-hole boiling flask, adding one go on foot organic layer, controlled temperature drips the nitric acid (67%) of 1.05 times of molar weights of PARACETAMOL BP98 about 20 ℃; Drip to finish and to be warming up to 35 ℃, be incubated 2 hours, the evaporated under reduced pressure solvent gets dry product 78.2g, and yield is 82.66%.
Step 3: to the preparation of propoxy-O-Phenylene Diamine
In 1000 milliliters of four-hole boiling flasks that have TM and a whipping appts; Open and stir; Add 78.2g successively to the propoxy-o-Nitroacetanilide, 2 times of sodium hydroxide solutions, 2 times of sodium sulphite to propoxy-o-Nitroacetanilide molar weight to the molar weight of propoxy-o-Nitroacetanilide; Heat temperature raising is to refluxing insulation reaction 10 hours.Reaction finishes and is cooled to room temperature, adds the extracted in toluene of 3 times of weight ratios, and branch vibration layer, organic layer directly get into next step reaction.
Step 4: the preparation of SKF-30310
In 1000 milliliters of four-hole boiling flasks that have TM and a whipping appts, add the toluene organic layer that a step obtains, add 1.5 times of S-methyl-isourea methyl-formiates, 1.1 times of formic acid propoxy-o-Nitroacetanilide weight ratio to propoxy-o-Nitroacetanilide molar weight; Be warming up to 55 ℃, insulation reaction 5 hours steams solvent; Add 3 times of methyl alcohol, refluxed cold filtration 1 hour propoxy-o-Nitroacetanilide weight ratio; The washing, dry 60.7g, yield is 79.27%.
Embodiment 2.
Step 1: to the preparation of propoxy-Acetanilide
In 1000 milliliters four-hole boiling flask, add the 60g PARACETAMOL BP98 successively; The oil of mirbane solvent of 4 times of weight ratios of PARACETAMOL BP98; The water of 3 times of weight ratios of PARACETAMOL BP98; The Pottasium Hydroxide of 1.3 times of molar weights of PARACETAMOL BP98, the N-PROPYLE BROMIDE of 1.3 times of mol ratios of PARACETAMOL BP98, the phase-transfer catalyst benzyltriethylammoinium chloride of 0.02 times of weight ratio of PARACETAMOL BP98; Be warming up to backflow, be incubated 24 hours, GC tracks to reaction and finishes, and is cooled to 20 ℃, and water layer is cast out in layering, and organic layer directly gets into next step reaction.
Step 2: to the preparation of propoxy-o-Nitroacetanilide
On in 1000 milliliters four-hole boiling flask, adding one go on foot organic layer, controlled temperature drips the nitric acid (70%) of 1.05 times of molar weights of PARACETAMOL BP98 about 20 ℃; Drip to finish and to be warming up to 35 ℃, be incubated 2 hours, the evaporated under reduced pressure solvent gets dry product 77.8g, and yield is 82.24%.
Step 3: to the preparation of propoxy-O-Phenylene Diamine
In 1000 milliliters of four-hole boiling flasks that have TM and a whipping appts; Open and stir; Add 77.8g successively to the propoxy-o-Nitroacetanilide, 2 times of sodium hydroxide solutions, 2 times of Sodium sulfhydrates to propoxy-o-Nitroacetanilide molar weight to the molar weight of propoxy-o-Nitroacetanilide; Heat temperature raising is to refluxing insulation reaction 10 hours.Reaction finishes and is cooled to room temperature, adds the extracted in toluene of 3 times of weight ratios, and branch vibration layer, organic layer directly get into next step reaction.
Step 4: the preparation of SKF-30310
In 1000 milliliters of four-hole boiling flasks that have TM and a whipping appts, add the toluene organic layer that a step obtains, add 1.5 times of O-methyl-isourea methyl-formiates, 1.1 times of acetate propoxy-o-Nitroacetanilide weight ratio to propoxy-o-Nitroacetanilide molar weight; Be warming up to 55 ℃, insulation reaction 5 hours steams solvent; Add 3 times of methyl alcohol, refluxed cold filtration 1 hour propoxy-o-Nitroacetanilide weight ratio; The washing, dry 59.7g, yield is 78.37%.
Embodiment 3.
Step 1: to the preparation of propoxy-Acetanilide
In 2000 milliliters four-hole boiling flask, add the 120g PARACETAMOL BP98 successively; The chlorobenzene solvent of 4 times of weight ratios of PARACETAMOL BP98; The water of 3 times of weight ratios of PARACETAMOL BP98; The sodium hydroxide of 1.3 times of molar weights of PARACETAMOL BP98, the N-PROPYLE BROMIDE of 1.3 times of mol ratios of PARACETAMOL BP98, the phase-transfer catalyst benzyl triethyl ammonium bromide of 0.02 times of weight ratio of PARACETAMOL BP98; Be warming up to backflow, be incubated 24 hours, GC tracks to reaction and finishes, and is cooled to 20 ℃, and water layer is cast out in layering, and organic layer directly gets into next step reaction.
Step 2: to the preparation of propoxy-o-Nitroacetanilide
On in 2000 milliliters four-hole boiling flask, adding one go on foot organic layer, controlled temperature drips the nitric acid (67%) of 1.05 times of molar weights of PARACETAMOL BP98 about 20 ℃; Drip to finish and to be warming up to 35 ℃, be incubated 2 hours, the evaporated under reduced pressure solvent gets dry product 157.1g, and yield is 83.03%.
Step 3: to the preparation of propoxy-O-Phenylene Diamine
In 2000 milliliters of four-hole boiling flasks that have TM and a whipping appts; Open and stir; Add 157.1g successively to the propoxy-o-Nitroacetanilide, 2 times of sodium hydroxide solutions, 2 times of sodium sulphite to propoxy-o-Nitroacetanilide molar weight to the molar weight of propoxy-o-Nitroacetanilide; Heat temperature raising is to refluxing insulation reaction 10 hours.Reaction finishes and is cooled to room temperature, adds the extracted in toluene of 3 times of weight ratios, and branch vibration layer, organic layer directly get into next step reaction.
Step 4: the preparation of SKF-30310
In 2000 milliliters of four-hole boiling flasks that have TM and a whipping appts, add the toluene organic layer that a step obtains, add 1.5 times of O-methyl-isourea methyl-formiates, 1.1 times of formic acid propoxy-o-Nitroacetanilide weight ratio to propoxy-o-Nitroacetanilide molar weight; Be warming up to 55 ℃, insulation reaction 5 hours steams solvent; Add 3 times of ethanol, refluxed cold filtration 1 hour propoxy-o-Nitroacetanilide weight ratio; The washing, dry 122.8g, yield is 79.83%.
Claims (3)
1. the preparation technology of a benzimidazoles insect repellent SKF-30310 mainly makes with the synthetic method, and it is characterized in that: step is following:
(1) be raw material with the PARACETAMOL BP98, in organic solvent, scale, under the effect of phase-transfer catalyst, with halogenopropane through condensation reaction, must be to the propoxy-Acetanilide;
(2) the propoxy-Acetanilide is obtained the propoxy-o-Nitroacetanilide through nitration reaction;
(3), obtain the propoxy-O-Phenylene Diamine through reduction reaction to the propoxy-o-Nitroacetanilide;
(4) the propoxy-O-Phenylene Diamine is obtained SKF-30310 through ring-closure reaction;
The proportioning of said each composition of step (1) is following: with the PARACETAMOL BP98 is radix; The amount of organic solvent is 3～5 times of weight ratio of PARACETAMOL BP98, and water is 2～4 times of weight ratio, and alkali is 1.1～1.5 times mol ratio; Halogenopropane is 1.1～1.5 times of mol ratios; Phase-transfer catalyst is 0.001～0.05 times of weight ratio, temperature of reaction be 20 ℃ to reflux temperature, the reaction times is 1～50 hour;
In the reactions step (1), the condensation reaction organic solvent is selected from chlorobenzene or oil of mirbane; Alkali is selected from sodium hydroxide or Pottasium Hydroxide, and halogenopropane is selected from N-PROPYLE BROMIDE, and phase-transfer catalyst is selected from benzyltriethylammoinium chloride or benzyl triethyl ammonium bromide;
In the reactions step (2), the nitration reaction organic solvent is selected from chlorobenzene or oil of mirbane; Nitrating agent is a nitric acid, and the concentration of nitric acid is 40%～98%; The nitric acid amount is 1.02～1.06 times of molar weights, and the nitration reaction temperature is-6 ℃～50 ℃, 20～60 ℃ of holding temperatures, soaking time 0.5～3 hour;
In the reactions step (3), the alkali that reacts used is sodium hydroxide or Pottasium Hydroxide, and reductive agent is selected from sodium sulphite or Sodium sulfhydrate, and reductive agent is 1.2～3 times of mol ratios, and temperature of reaction is 20 a ℃～reflux temperature, 1～24 hour reaction times;
In the reactions step (4), reaction solvent is selected from toluene, and recrystallization solvent is selected from methyl alcohol or ethanol; The acid of reacting used is formic acid or acetate; Cyclization reagent is selected from S-methyl-isourea methyl-formiate or O-methyl-isourea methyl-formiate, and temperature of reaction is 40 ℃～80 ℃, 1～8 hour reaction times.
2. the preparation technology of benzimidazoles insect repellent SKF-30310 according to claim 1 is characterized in that, in the reactions step (1); The amount of solvent is selected 4 times of weight ratios, the weight ratio that wet concentration is 2 times, and alkali selects 1.3 times mol ratio; Halogenopropane selects 1.3 times of mol ratios; Phase-transfer catalyst selects 0.02 times of weight ratio, and temperature of reaction is a reflux temperature, and the reaction times is selected 24 hours.
3. the preparation technology of benzimidazoles insect repellent SKF-30310 according to claim 1 is characterized in that: in the reactions step (2), concentration of nitric acid selects 67%; The nitric acid amount is elected 1.05 times of molar weights as; Nitrated temperature is selected 25 ℃, and holding temperature is selected 45 ℃, and soaking time is selected 1 hour.
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| CN102633669B (en) * | 2012-04-23 | 2014-04-30 | 盐城市瓯华化学工业有限公司 | Method for producing 2-amino-4-acetamido benzene alkyl ether by reduction with sodium bisulfide |
| 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 |
| CN104003896A (en) * | 2014-05-22 | 2014-08-27 | 江苏宝众宝达药业有限公司 | Method for recycling intermediate product p-propoxy paranitroacetanilide of oxibendazole |
| CN112094237B (en) * | 2020-11-06 | 2023-01-20 | 江苏宝众宝达药业股份有限公司 | Synthesis method of fluorobenzene imidazole |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1083478A (en) * | 1992-09-01 | 1994-03-09 | 湖北制药厂 | The method for preparing benzimidazole compound |
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| WO2008151437A1 (en) * | 2007-06-14 | 2008-12-18 | Osta Biotechnologies | Heme-oxygenase inhibitors and use of the same in the treatment of cancer and diseases of the central nervous system |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1083478A (en) * | 1992-09-01 | 1994-03-09 | 湖北制药厂 | The method for preparing benzimidazole compound |
Non-Patent Citations (2)
| Title |
|---|
| 李焱 等.苯并咪唑及其衍生物合成与应用研究进展.《有机化学》.2008,第28卷(第2期),210-217. |
| 苯并咪唑及其衍生物合成与应用研究进展;李焱 等;《有机化学》;20081231;第28卷(第2期);210-217 * |
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Address after: 226500 No.10, Yuejiang Road, Changjiang Town, Rugao City, Nantong City, Jiangsu Province Patentee after: Jiangsu Baozhong Baoda Pharmaceutical Co.,Ltd. Address before: 226500 No.10, Yuejiang Road, Changjiang Town, Rugao City, Nantong City, Jiangsu Province Patentee before: JIANGSU BAOZONG & BAODA PHARMACHEM Co.,Ltd. |