CN106167468B - A method of replace N-Propyl Bromide to prepare albendazole with chloropropane - Google Patents
A method of replace N-Propyl Bromide to prepare albendazole with chloropropane Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
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Abstract
The present invention discloses a kind of method for replacing N-Propyl Bromide to prepare albendazole with chloropropane, belongs to glyoxaline compound synthesis technical field.This method sequentially adds carbendazim, sodium sulfocyanate and glacial acetic acid in the reactor first, is warming up to 35 DEG C after mixing evenly, and hydrogen peroxide is slowly added dropwise under stirring, reacts and solid 5- thiocyanogen benzimidazolyl-2 radicals-methyl carbamate is made；Chlorobenzene Grignard Reagent is prepared as initiator with glycol dibromide Grignard Reagent；Then phase transfer catalyst benzyltriethylammoinium chloride is added into solid 5- thiocyanogen benzimidazolyl-2 radicals-methyl carbamate, the tetrahydrofuran solution of sodium hydride is slowly added dropwise under stirring, after reaction 30 minutes, start that chlorobenzene Grignard Reagent is slowly added dropwise under agitation, reacts and albendazole product is made.The present invention chloropropane N-Propyl Bromide relatively expensive instead of price, not only reduces the input cost of reaction raw materials, and ensure that the yield of albendazole and purity all increase.
Description
Technical field:
The invention belongs to glyoxaline compound synthesis technical fields, and in particular to a kind of albendazole synthetic method, the party
Method is to replace N-Propyl Bromide to synthesize albendazole with chloro-propane.
Background technique:
Albendazole (Albendazole, ABZ) also known as albendazole, the entitled 5- rosickyite base -1H- benzimidazole 2- of chemistry
Methyl carbamate is the anthelmintic of a broad-spectrum high-efficiency and low-toxicity.The medicine by Smith Kline company of the U.S. 1977 for the first time on
City is clinically widely used in the various invermination diseases for the treatment of.About albendazole synthesis path there are many, existing market
There are two types of upper main production process: first is that paper " synthesis of albendazole " (Zhu Shuigeng, " Chinese Journal of Pharmaceuticals " (1990,
21 (5)) in report using carbendazim as raw material, acetysalicylic acid phenobarbital is made through four steps such as thiocyanation, thioetherification, reduction and cyclization and reaches
Azoles, but participate in reacting the method use toxic gas chlorine, and unfavorable with the generation of a large amount of chlorine byproducts, while also
In the yield and purity that improve albendazole；Second is that paper " improvement of broad-spectrum de-worming medicine albendazole synthesis technology " (Yao Jianwen,
It reports in " Journal of Yantai University (natural science and engineering version) " (2006,19 (1)) using pesticide carbendazim as raw material, through chlorine sulphur
Three steps such as change, reduction, thioetherification and albendazole is made, but this method also use poisonous drugs chlorosulfonic acid participate in it is anti-
It answers, is still difficult to realize industrialized production in the present circumstance with a large amount of waste liquid and useless solid generation in production process.It is existing
The specific reaction equation of two methods is as follows:
The reaction equation of method one:
The reaction equation of method two:
At present the country when produce albendazole, thioetherification process be all using the higher N-Propyl Bromide of price, when selection its
Reaction is difficult to obtain the ideal recovery of final products when its raw material, therefore the N-Propyl Bromide used in the reaction is difficult by other phases
The raw material of pass is replaced.However, N-Propyl Bromide is a kind of more expensive industrial chemicals for chloropropane, in order to have reaction
There is higher economic benefit, under the premise of guaranteeing reaction yield, other cheap raw materials need to be selected, this is also exactly current
The place of technological difficulties.In order to solve series of technical present in current domestic production albendazole, and further
Production cost is reduced, the invention proposes a kind of highly-safe and added value novel albendazole synthesis technologies that benefit is evident.
Summary of the invention
It is poor for safety present in existing albendazole preparation method, yield is low and the technologies such as production cost is high are asked
Topic, the present invention start with from the raw material of reaction condition and participation reaction, replace the higher bromine third of price with the lower chloropropane of price
Alkane participates in reaction, and to provide, one kind is easy to operate, react safety, production cost is low replaces N-Propyl Bromide to prepare acetysalicylic acid phenobarbital with chloropropane
Up to the method for azoles.
The method of the present invention is, through thiocyanation and thioetherification reaction step, acetysalicylic acid phenobarbital can be directly made using carbendazim as raw material and reach
Azoles.Specific reaction equation is as follows:
A kind of method for replacing N-Propyl Bromide to prepare albendazole with chloropropane provided by the present invention, this method specific steps
It is as follows:
(1) carbendazim, sodium sulfocyanate and glacial acetic acid are sequentially added into reactor, are warming up to 35 DEG C after mixing evenly,
The hydrogen peroxide of 28wt% is slowly added dropwise under stirring, after hydrogen peroxide completion of dropwise addition, control reaction temperature is constant, and it is anti-to continue stirring
4~6h is answered, obtain solid through vacuum distillation after reaction: (structure is specific for methyl carbamate for 5- thiocyanogen benzimidazolyl-2 radicals-
See the chemical formula II in reactional equation), distillate glacial acetic acid recoverable, 5- thiocyanogen benzimidazolyl-2 radicals-carbamic acid first
The yield of ester is 81.42%.
(2) under nitrogen protection, magnesium chips is first added into reaction flask, magnesium chips is completely covered with ether or tetrahydrofuran,
Ether or tetrahydrofuran solution that 3~5mL contains chloropropane is added dropwise into reaction flask again, stirring is slowly warming up to 45 DEG C, uses
BrMgCH2CH2MgBr makees initiator, when magnesium chips starts to gradually use up, continue under agitation be added dropwise chloropropane ether or
Tetrahydrofuran solution, rate of addition is controlled in 6~8mL/min, and after being added dropwise, control reaction temperature is constant, is continued stirring, is protected
Temperature reaction to magnesium chips is exhausted, and chloropropane Grignard Reagent, 1, the 2- Bromofume Grignard Reagent is made
(BrMgCH2CH2MgBr dosage) is the 1% of the chloropropane quality.
(3) phase transfer catalysis (PTC) is added into solid 5- thiocyanogen benzimidazolyl-2 radicals-methyl carbamate that step (1) obtains
Agent benzyltriethylammoinium chloride, the tetrahydrofuran that the sodium hydride that mass fraction is 40wt% is slowly added dropwise under stirring are molten
Liquid, is to slowly warm up to 45 DEG C, after being stirred to react 30min, starts the chlorine made from slowly a dropping step (2) under agitation
Propane Grignard Reagent controls the temperature in reaction flask at 55~60 DEG C, and stirring, 4~8h of insulation reaction can be prepared by albendazole
Product；The carbendazim, sodium sulfocyanate, 28wt% hydrogen peroxide, 40wt% sodium hydride and chloropropane Grignard Reagent mass ratio are as follows:
1:(1.1~1.5): (3~5): (3.5~4.5): (1.1~1.4), in reaction the quality of glacial acetic acid used be carbendazim 5~
8 times, the quality of the phase transfer catalyst benzyltriethylammoinium chloride is the 1~3% of carbendazim quality.Used in the present invention
Alkali can be replaced with sodium hydride, sodium ethoxide or other organic bases, the solvent of used solvent and Grignard Reagent must polarity it is close.
The present invention has following technical characterstic:
(1) the technique chloro-propane bromo propane relatively expensive instead of price, using cheap chloro third
Alkane participates in reaction, not only ensure that the yield of albendazole and purity all do not reduce, but also it is former to greatly reduce reaction
The input cost of material, to create a further reduction production cost.
(2) entire production process is safe and environment-friendly, generates without apparent side reaction, is joined using the grignard reagent of chloropropane
With react, the yield of albendazole is not only increased to 85.60% from pervious 80.00%, but also guaranteeing that albendazole receives
While rate improves, the purity of albendazole be can also be improved to 99.53%.
(3) manufacturing condition is mild, at 60 DEG C hereinafter, reacting under normal pressure, brings so as to avoid reaction under high pressure latent
In unsafe factor.
(4) without a large amount of waste liquid, useless solid generation in production process, so that the harm to environment greatly reduces, with
Accomplish really green clean manufacturing.
Specific embodiment:
The present invention will be illustrated with following example, but be not limited to these examples, not depart from experiment ancestor of the invention
In purport, present invention work is illustrated in detail.
Embodiment 1: carbendazim 100.00g (0.52mol), sodium sulfocyanate 46.98g are sequentially added in 1500mL reaction flask
(0.58mol), glacial acetic acid 500.00g, is slowly increased to 35 DEG C for temperature, and mass concentration is slowly added dropwise under stirring and is
28% hydrogen peroxide 253.00g (2.08mol) controls the temperature in reaction flask at 35~37 DEG C.After hydrogen peroxide is added dropwise,
Continue stirring, insulation reaction 6h under the conditions of 35 DEG C, it is 5- thiocyanogen benzimidazole-that heat preservation, which obtains solid after being evaporated under reduced pressure after terminating,
2- methyl carbamate, distillate glacial acetic acid recycle.After glacial acetic acid distills, to solid 5- thiocyanogen benzimidazole-
Benzyltriethylammoinium chloride 1.50g is added in 2- methyl carbamate, it is 40% that mass fraction is slowly added dropwise under stirring
Sodium hydride tetrahydrofuran solution 110.00g (1.82mol), slowly increase temperature to 45 DEG C, after being stirred to react 30min, stirring
Start that chloropropane Grignard Reagent 57.13g (0.58mol) is slowly added dropwise under the conditions of mixing.After chloropropane Grignard reagent dropwise, delay
The slow temperature that increases keeps the temperature 6h to 55~60 DEG C at this temperature, and after heat preservation, reaction solution is cooled to room temperature.After suction filtration
Obtained solid is washed with water to neutrality, drains, and obtains product albendazole crude product.First by albendazole crude product mass concentration
It is dissolved for 5% hydrochloric acid solution, active carbon is added to it and decolourizes, then in the sodium hydroxide solution for being 15% with mass concentration
With to pH=7~8, the solid obtained after filtering operation is washed with distilled water to pH=7~8, and what is sufficiently obtained after washing consolidates
Body is dried in vacuo under the conditions of 60 DEG C, the albendazole product 114.10g after being purified, content: 99.53% (HPLC), is received
Rate 83.52%.
Embodiment 2: carbendazim 100.00g (0.52mol), sodium sulfocyanate 51.03g are sequentially added in 1500mL reaction flask
(0.63mol), glacial acetic acid 600.00g, is slowly increased to 35 DEG C for temperature, and mass concentration is slowly added dropwise under stirring and is
28% hydrogen peroxide 253.00g (2.08mol) controls the temperature in reaction flask at 35~37 DEG C.After hydrogen peroxide is added dropwise,
Continue stirring, insulation reaction 4.5h under the conditions of 35 DEG C, it is 5- thiocyanogen benzo miaow that heat preservation, which obtains solid after being evaporated under reduced pressure after terminating,
Azoles -2- methyl carbamate, distillate glacial acetic acid recycle.After glacial acetic acid distills, to solid 5- thiocyanogen benzo miaow
Benzyltriethylammoinium chloride 2.0g is added in azoles -2- methyl carbamate, mass fraction, which is slowly added dropwise, under stirring is
40% sodium hydride tetrahydrofuran solution 124.80g (2.08mol), slowly raising temperature is to 45 DEG C, after being stirred to react 30min,
Start that chloropropane Grignard Reagent 62.06g (0.63mol) is slowly added dropwise under agitation.Chloropropane Grignard reagent dropwise finishes
Afterwards, temperature is slowly increased to 55~60 DEG C, and keeps the temperature 6h at this temperature, and after heat preservation, reaction solution is cooled to room temperature.It takes out
The solid obtained after filter is washed with water to neutrality, drains, and obtains product albendazole crude product.First by albendazole crude product quality
The hydrochloric acid solution that concentration is 5% dissolves, and active carbon is added to it and decolourizes, then molten with the sodium hydroxide that mass concentration is 15%
Liquid is neutralized to pH=7~8, and the solid obtained after filtering operation is washed with distilled water to pH=7~8, sufficiently obtains after washing
Solid be dried in vacuo under the conditions of 60 DEG C, the albendazole product 115.10g after being purified, content: 99.42%
(HPLC), yield 84.13%.
Embodiment 3: carbendazim 100.00g (0.52mol), sodium sulfocyanate 59.13g are sequentially added in 1500mL reaction flask
(0.73mol), glacial acetic acid 500.00g, is slowly increased to 35 DEG C for temperature, and mass concentration is slowly added dropwise under stirring and is
28% hydrogen peroxide 253.00g (2.08mol) controls the temperature in reaction flask at 35~37 DEG C.After hydrogen peroxide is added dropwise,
Continue stirring, insulation reaction 5h under the conditions of 35 DEG C, it is 5- thiocyanogen benzimidazole-that heat preservation, which obtains solid after being evaporated under reduced pressure after terminating,
2- methyl carbamate, distillate glacial acetic acid recycle.After glacial acetic acid distills, to solid 5- thiocyanogen benzimidazole-
Benzyltriethylammoinium chloride 2.00g is added in 2- methyl carbamate, it is 40% that mass fraction is slowly added dropwise under stirring
Sodium hydride tetrahydrofuran solution 140.40g (2.34mol), slowly increase temperature to 45 DEG C, after being stirred to react 30min, stirring
Start that chloropropane Grignard Reagent 66.98g (0.68mol) is slowly added dropwise under the conditions of mixing.After chloropropane Grignard reagent dropwise, delay
The slow temperature that increases keeps the temperature 6h to 55~60 DEG C at this temperature, and after heat preservation, reaction solution is cooled to room temperature.After suction filtration
Obtained solid is washed with water to neutrality, drains, and obtains product albendazole crude product.First by albendazole crude product mass concentration
It is dissolved for 5% hydrochloric acid solution, active carbon is added to it and decolourizes, then in the sodium hydroxide solution for being 15% with mass concentration
With to pH=7~8, the solid obtained after filtering operation is washed with distilled water to pH=7~8, and what is sufficiently obtained after washing consolidates
Body is dried in vacuo under the conditions of 60 DEG C, the albendazole product 115.80g after being purified, content: 99.36% (HPLC), is received
Rate 84.57%.
Embodiment 4: carbendazim 100.00g (0.52mol), sodium sulfocyanate 63.18g are sequentially added in 1500mL reaction flask
(0.78mol), glacial acetic acid 500.00g, is slowly increased to 35 DEG C for temperature, and mass concentration is slowly added dropwise under stirring and is
28% hydrogen peroxide 316.00g (2.6mol) controls the temperature in reaction flask at 35~37 DEG C.After hydrogen peroxide is added dropwise,
Continue stirring, insulation reaction 5h under the conditions of 35 DEG C, it is 5- thiocyanogen benzimidazole-that heat preservation, which obtains solid after being evaporated under reduced pressure after terminating,
2- methyl carbamate, distillate glacial acetic acid recycle.After glacial acetic acid distills, to solid 5- thiocyanogen benzimidazole-
Benzyltriethylammoinium chloride 2.50g is added in 2- methyl carbamate, it is 40% that mass fraction is slowly added dropwise under stirring
Sodium hydride tetrahydrofuran solution 140.40g (2.34mol), slowly increase temperature to 45 DEG C, after being stirred to react 30min, stirring
Start that chloropropane Grignard Reagent 71.91g (0.73mol) is slowly added dropwise under the conditions of mixing.After chloropropane Grignard reagent dropwise, delay
The slow temperature that increases keeps the temperature 6h to 55~60 DEG C at this temperature, and after heat preservation, reaction solution is cooled to room temperature.After suction filtration
Obtained solid is washed with water to neutrality, drains, and obtains product albendazole crude product.First by albendazole crude product mass concentration
It is dissolved for 5% hydrochloric acid solution, active carbon is added to it and decolourizes, then in the sodium hydroxide solution for being 15% with mass concentration
With to pH=7~8, the solid obtained after filtering operation is washed with distilled water to pH=7~8, and what is sufficiently obtained after washing consolidates
Body is dried in vacuo under the conditions of 60 DEG C, the albendazole product 117.00g after being purified, content: 99.48% (HPLC), is received
Rate 85.60%.
Embodiment 5: carbendazim 100.00g (0.52mol), sodium sulfocyanate 63.18g are sequentially added in 1500mL reaction flask
(0.78mol), glacial acetic acid 800.00g, is slowly increased to 35 DEG C for temperature, and mass concentration is slowly added dropwise under stirring and is
28% hydrogen peroxide 195.00g (1.60mol) controls the temperature in reaction flask at 35~37 DEG C.After hydrogen peroxide is added dropwise,
Continue stirring, insulation reaction 4h under the conditions of 35 DEG C, it is 5- thiocyanogen benzimidazole-that heat preservation, which obtains solid after being evaporated under reduced pressure after terminating,
2- methyl carbamate, distillate glacial acetic acid recycle.After glacial acetic acid distills, to solid 5- thiocyanogen benzimidazole-
Benzyltriethylammoinium chloride 2.50g is added in 2- methyl carbamate, it is 40% that mass fraction is slowly added dropwise under stirring
Sodium hydride tetrahydrofuran solution 140.40g (2.34mol), slowly increase temperature to 45 DEG C, after being stirred to react 30min, stirring
Start that chloropropane Grignard Reagent 71.91g (0.73mo) is slowly added dropwise under the conditions of mixing.After chloropropane Grignard reagent dropwise, delay
The slow temperature that increases keeps the temperature 6h to 55~60 DEG C at this temperature, and after heat preservation, reaction solution is cooled to room temperature.After suction filtration
Obtained solid is washed with water to neutrality, drains, and obtains product albendazole crude product.First by albendazole crude product mass concentration
It is dissolved for 5% hydrochloric acid solution, active carbon is added to it and decolourizes, then in the sodium hydroxide solution for being 15% with mass concentration
With to pH=7~8, the solid obtained after filtering operation is washed with distilled water to pH=7~8, and what is sufficiently obtained after washing consolidates
Body is dried in vacuo under the conditions of 60 DEG C, the albendazole product 113.30g after being purified, content: 99.34% (HPLC), is received
Rate 82.74%.
Claims (1)
1. a kind of method for replacing N-Propyl Bromide to prepare albendazole with chloropropane, it is characterised in that specific step is as follows for this method:
(1) carbendazim, sodium sulfocyanate and glacial acetic acid are sequentially added into reactor, is warming up to 35 DEG C after mixing evenly, are being stirred
The hydrogen peroxide of 28wt% is slowly added dropwise under state, after hydrogen peroxide completion of dropwise addition, control reaction temperature is constant, continues to be stirred to react 4
~6h obtains solid through vacuum distillation after reaction: 5- thiocyanogen benzimidazolyl-2 radicals-methyl carbamate；
(2) under nitrogen protection, magnesium chips is first added into reaction flask, magnesium chips is completely covered with ether or tetrahydrofuran, then to
Ether or tetrahydrofuran solution that 3~5mL contains chloropropane are added dropwise in reaction flask, stirring is slowly warming up to 45 DEG C, uses
BrMgCH2CH2MgBr makees initiator, when magnesium chips starts to gradually use up, continue under agitation be added dropwise chloropropane ether or
Tetrahydrofuran solution, rate of addition is controlled in 6~8mL/min, and after being added dropwise, control reaction temperature is constant, is continued stirring, is protected
Temperature reaction to magnesium chips is exhausted, and chloropropane Grignard Reagent is made, the dosage of 1, the 2- Bromofume Grignard Reagent is described
The 1% of chloropropane quality；
(3) phase transfer catalyst benzyl is added into solid 5- thiocyanogen benzimidazolyl-2 radicals-methyl carbamate that step (1) obtains
The tetrahydrofuran solution for the sodium hydride that mass fraction is 40wt% is slowly added dropwise under stirring, delays for triethylammonium chloride
Slowly 45 DEG C, after being stirred to react 30min are warming up to, start the chloropropane made from slowly a dropping step (2) under agitation
Grignard Reagent controls the temperature in reaction flask at 55~60 DEG C, and stirring, 4~8h of insulation reaction can be prepared by albendazole production
Product；The carbendazim, sodium sulfocyanate, 28wt% hydrogen peroxide, 40wt% sodium hydride and chloropropane Grignard Reagent mass ratio are as follows: 1:
(1.1~1.5): (3~5): (3.5~4.5): (1.1~1.4), the quality of glacial acetic acid used is the 5~8 of carbendazim in reaction
Times, the dosage of the phase transfer catalyst benzyltriethylammoinium chloride is the 1~3% of carbendazim quality.
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Citations (4)
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| US4076825A (en) * | 1977-06-22 | 1978-02-28 | E. R. Squibb & Sons, Inc. | Method of treating helminthiasis by parenteral or topical administration of sulfoxide derivatives of benzimidazoles |
| US4152522A (en) * | 1978-01-03 | 1979-05-01 | Ethyl Corporation | Process for the preparation of 2-benzimidazole carbamates |
| CN101333193A (en) * | 2008-08-06 | 2008-12-31 | 徐州诺特化工有限公司 | Method for synthesizing albendazole |
| CN103304484A (en) * | 2013-05-24 | 2013-09-18 | 苏州诚和医药化学有限公司 | Method for synthesizing albendazole |
-
2016
- 2016-07-25 CN CN201610590414.3A patent/CN106167468B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4076825A (en) * | 1977-06-22 | 1978-02-28 | E. R. Squibb & Sons, Inc. | Method of treating helminthiasis by parenteral or topical administration of sulfoxide derivatives of benzimidazoles |
| US4152522A (en) * | 1978-01-03 | 1979-05-01 | Ethyl Corporation | Process for the preparation of 2-benzimidazole carbamates |
| CN101333193A (en) * | 2008-08-06 | 2008-12-31 | 徐州诺特化工有限公司 | Method for synthesizing albendazole |
| CN103304484A (en) * | 2013-05-24 | 2013-09-18 | 苏州诚和医药化学有限公司 | Method for synthesizing albendazole |
Non-Patent Citations (2)
| Title |
|---|
| 广谱驱虫药阿苯达唑合成工艺的改进;姚建文;《烟台大学学报（自然科学与工程版）》;20060131;第19卷(第1期);74-78 * |
| 格氏试剂的相关性质及其应用概述;慈天元;《宜春学院学报》;20090430;第31卷(第2期);6-10 * |
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Effective date of registration: 20201228 Address after: Room 602, unit 1, building 9, Hexi community, Hexi District, Tanzhong West Road, Liunan District, Liuzhou City, Guangxi Zhuang Autonomous Region Patentee after: Ye Xiulan Address before: 211111 No. 12, Mazhou East Road, Mau Ling Street, Jiangning District, Nanjing, Jiangsu Patentee before: JIANGSU ZHIJU INTELLECTUAL PROPERTY SERVICE Co.,Ltd. |
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Effective date of registration: 20221116 Address after: No. 99, Gangcheng Road, Dongying Port Economic Development Zone, Dongying City, Shandong Province 257237 Patentee after: Dongying Ruigang Investment Service Co.,Ltd. Address before: Room 602, unit 1, building 9, Hexi community, Hexi District, Tanzhong West Road, Liunan District, Liuzhou City, Guangxi Zhuang Autonomous Region Patentee before: Ye Xiulan |
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