CN106187907A - A kind of synthetic method of bendazol - Google Patents
A kind of synthetic method of bendazol Download PDFInfo
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- CN106187907A CN106187907A CN201610593412.XA CN201610593412A CN106187907A CN 106187907 A CN106187907 A CN 106187907A CN 201610593412 A CN201610593412 A CN 201610593412A CN 106187907 A CN106187907 A CN 106187907A
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- Prior art keywords
- bendazol
- synthetic method
- reaction
- phenylenediamine
- toluene
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- C—CHEMISTRY; METALLURGY
- 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
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides the synthetic method of a kind of bendazol, comprise the following steps: o-phenylenediamine and toluene are added to reaction vessel in the lump, and drip phenyllacetyl chloride in this reaction vessel, drip and finish, heating reflux reaction, until reaction is completely；Post processing, prepares bendazol product.Compared with prior art, this synthetic method has following useful technique effect: (1) reduces reaction temperature, so that the reaction of synthesis bendazol can be carried out in a mild condition；(2) due to this synthetic method and be not added with any dehydrant or catalyst, and side reaction is few, therefore, effectively reduces the generation of impurity, thus decreases the number of times of follow-up decolouring crystallization；(3) this synthetic method simplifies post-processing operation, thus has saved production cost, beneficially large-scale industrial production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to the synthetic method of a kind of bendazol.
Background technology
Bendazol, is a kind of depressor, its chemical entitled Bendazol hydrochlorate, molecular formula: C14H12N2·
HCl, molecular weight: 244.72, chemical structural formula is:
Bendazol is white crystalline powder, odorless.Fusing point is 182～186 DEG C, is practically insoluble in chloroform and benzene, is slightly soluble in heat
Water or ethanol.
At present, domestic application most commonly used bendazol production technology is with o-phenylenediamine and phenylacetic acid as raw material, hydrochloric acid
For catalyst, at high temperature it is condensed to yield bendazol (whole nation crude drug technique collects, and medicine management general bureau of country compiles, 1980).
But, this technique needs pyroreaction, and it is more to produce impurity, needs repeatedly to crystallize decolouring and just can obtain qualified products, therefore,
Process energy consumption is higher and complex steps.
In prior art, Chinese patent CN101906074A discloses the preparation method of a kind of dibazol hydrochloride, and it is main
Want step to include: o-phenylenediamine and phenylacetic acid to be dissolved in alcohols solvent, add dehydrant, be warming up to 100～130 DEG C of insulations
Reaction；After reaction terminates, it is cooled to room temperature, then carries out sucking filtration, be spin-dried for filtrate carrying out decolouring crystallization again.Wherein, have employed
Selected from dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylamino-propyl) carbon imidodicarbonic diamide hydrochlorate, N, N-carbonyl diurethane miaow
Azoles, the dehydrant of n-pro-pyl phosphoric anhydride, although causing this method reducing reaction temperature, but the dehydrant used brings additionally
Impurity, subsequent technique is difficult to eliminate completely.And for example, the synthetic method of the bendazol that Chinese patent CN103113305A is provided
Avoiding above-mentioned dehydrant or the use of any catalyst, the method uses temperature-gradient method, the technique of hypothermic response successfully to use neighbour
Phenylenediamine and phenylacetic acid have synthesized bendazol product；But, the method technology controlling and process is complicated, and reaction temperature is higher, hence it is evident that increase
The difficulty of operation also improves energy consumption, thus cost when adding large-scale industrial production.
Therefore, develop the synthetic method of a kind of brand-new bendazol, to reduce energy consumption, to reduce impurity life
Become, be beneficial to the purpose of industrialized production, be one of current research emphasis of field of medicaments research staff.
Summary of the invention
For many disadvantages present in existing bendazol synthesis technique with not enough, inventor have developed a kind of with neighbour
Phenylenediamine and phenyllacetyl chloride are the method for reaction raw materials synthesis bendazol.
Therefore, the synthetic method of a kind of bendazol provided by the present invention, comprise the following steps:
O-phenylenediamine and toluene are added to reaction vessel in the lump, and in this reaction vessel, drips phenyllacetyl chloride, drip and finish, add
Hot reflux is reacted, until reaction is completely；Post processing, prepares bendazol product.
Preferably, in above-mentioned synthetic method, the molar ratio of described o-phenylenediamine and described phenyllacetyl chloride be 1:1～
1:2.
Preferably, in above-mentioned synthetic method, the quality of described o-phenylenediamine and the volume ratio of described toluene are 1g:1mL
～1g:20mL.
Preferably, in above-mentioned synthetic method, the temperature of described heating reflux reaction is 100 ~ 120 DEG C and duration
It it is 3 ~ 5 hours.
It is further preferred that in above-mentioned synthetic method, described post processing includes: filter to obtain filter cake, wash with toluene, very
Empty be dried, then with water dissolution, be heated to reflux molten clearly；Add activated carbon decolorizing, filter, take filtrate crystallisation by cooling；Sucking filtration, uses
Washing filter cake, is finally vacuum dried.
Compared with prior art, the synthetic method of bendazol provided by the present invention has a following useful technique effect:
(1) reaction temperature is reduced, so that the reaction of synthesis bendazol can be carried out in a mild condition；(2) due to this synthesis
Method is also not added with any dehydrant or catalyst, and side reaction is few, therefore, effectively reduces the generation of impurity, thus subtracts
Lack the number of times of follow-up decolouring crystallization；(3) this synthetic method simplifies post-processing operation, thus has saved production cost, favorably
In large-scale industrial production.
Detailed description of the invention
Below in conjunction with detailed description of the invention, the present invention is further elaborated, but the present invention is not limited to following embodiment party
Formula.
The invention provides the synthetic method of a kind of bendazol, comprise the following steps:
O-phenylenediamine and toluene are added to reaction vessel in the lump, and in this reaction vessel, drips phenyllacetyl chloride, drip and finish, add
Hot reflux is reacted, until reaction is completely；Post processing, prepares bendazol product.
In a preferred embodiment, the molar ratio of described o-phenylenediamine and described phenyllacetyl chloride is 1:1～1:2.
In a preferred embodiment, the quality of described o-phenylenediamine and the volume ratio of described toluene are 1g:1mL～1g:
20mL。
In a preferred embodiment, the temperature of described heating reflux reaction is 100 ~ 120 DEG C and duration is 3 ~ 5
Hour.
In a further preferred embodiment, described post processing includes: filter to obtain filter cake, washs with toluene, vacuum
Be dried, then with water dissolution, be heated to reflux molten clearly；Add activated carbon decolorizing, filter, take filtrate crystallisation by cooling；Sucking filtration, uses water
Filter wash cake, is finally vacuum dried.
The following synthetic method further describing bendazol of the present invention with specific embodiment, wherein, is made
Raw material or reagent the most all can be either commercially available from open, described step is the most then often
Rule process operation.
Embodiment 1
50g(0.46mol is added in reaction bulb) o-phenylenediamine, and add 500mL toluene in order to dissolve；Then, by 70.8g
(0.46mol) during phenyllacetyl chloride is slowly dropped into described reaction bulb, dripping and finish, heated and stirred, in 100 ~ 120 DEG C of back flow reaction 4 hours
(thin layer chromatography monitoring reaction)；After reaction completely, stop heating, be cooled to room temperature, filter to obtain filter cake, wash with toluene, vacuum
After drying, then use 400g water dissolution, be heated to reflux molten being subsequently adding 20g activated carbon decolorizing clearly, filter, take filtrate crystallisation by cooling；
Sucking filtration, washes filter cake with water, vacuum drying, final prepared bendazol product 90g, yield 80.0%.
The proton nmr spectra of obtained bendazol is as follows:1H NMR(400MHz, DMSO-d6) δ 4.13(s, 2H),
7.05-7.10(m, 2H), 7.18-7.20(m, 1H), 7.25-7.30(m, 4H) and, 7.44(br s, 2H), 12.34(br s, 1H).
The elementary analysis of obtained bendazol is as follows: theoretical value: C 68.71%, H 5.35%, N 11.45%；Measured value:
C 68.70%、H 5.36%、N 11.44%。
As can be seen here, the proton nmr spectra of above bendazol product and the proton nmr spectra one of bendazol reference substance
Causing, its elementary analysis measured value is consistent with theoretical value, shows that product obtained by embodiment 1 is bendazol.
Embodiment 2
50g(0.46mol is added in reaction bulb) o-phenylenediamine, and add 500mL toluene in order to dissolve；Then, by 106.2g
(0.69mol) during phenyllacetyl chloride is slowly dropped into described reaction bulb, dripping and finish, heated and stirred, in 100 ~ 120 DEG C of back flow reaction 4 hours
(thin layer chromatography monitoring reaction)；After reaction completely, stop heating, be cooled to room temperature, filter to obtain filter cake, wash with toluene, vacuum
After drying, then use 400g water dissolution, be heated to reflux molten being subsequently adding 20g activated carbon decolorizing clearly, filter, take filtrate crystallisation by cooling；
Sucking filtration, washes filter cake with water, vacuum drying, final prepared bendazol product 94g, yield 83.5%.
The proton nmr spectra of obtained bendazol is as follows:1H NMR(400MHz, DMSO-d6) δ 4.12(s, 2H),
7.05-7.10(m, 2H), 7.18-7.20(m, 1H), 7.25-7.30(m, 4H) and, 7.43(br s, 2H), 12.34(br s, 1H).
The elementary analysis of obtained bendazol is as follows: theoretical value: C 68.71%, H 5.35%, N 11.45%；Measured value:
C 68.72%、H 5.35%、N 11.46%。
As can be seen here, the proton nmr spectra of above bendazol product and the proton nmr spectra one of bendazol reference substance
Causing, its elementary analysis measured value is consistent with theoretical value, shows that product obtained by embodiment 2 is bendazol.
Embodiment 3
50g(0.46mol is added in reaction bulb) o-phenylenediamine, and add 500mL toluene in order to dissolve；Then, by 141.6g
(0.92mol) during phenyllacetyl chloride is slowly dropped into described reaction bulb, dripping and finish, heated and stirred, in 100 ~ 120 DEG C of back flow reaction 4 hours
(thin layer chromatography monitoring reaction)；After reaction completely, stop heating, be cooled to room temperature, filter to obtain filter cake, wash with toluene, vacuum
After drying, then use 400g water dissolution, be heated to reflux molten being subsequently adding 20g activated carbon decolorizing clearly, filter, take filtrate crystallisation by cooling；
Sucking filtration, washes filter cake with water, vacuum drying, final prepared bendazol product 92g, yield 81.7%.
The proton nmr spectra of obtained bendazol is as follows:1H NMR(400MHz, DMSO-d6) δ 4.13(s, 2H),
7.06-7.11(m, 2H), 7.19-7.21(m, 1H), 7.25-7.30(m, 4H) and, 7.43(br s, 2H), 12.33(br s, 1H).
The elementary analysis of obtained bendazol is as follows: theoretical value: C 68.71%, H 5.35%, N 11.45%；Measured value:
C 68.71%、H 5.34%、N 11.45%。
As can be seen here, the proton nmr spectra of above bendazol product and the proton nmr spectra one of bendazol reference substance
Causing, its elementary analysis measured value is consistent with theoretical value, shows that product obtained by embodiment 3 is bendazol.
Being described in detail the specific embodiment of the present invention above, but it is intended only as example, the present invention does not limit
It is formed on particular embodiments described above.To those skilled in the art, any equivalent modifications that the present invention is carried out and
Substitute the most all among scope of the invention.Therefore, the impartial conversion made without departing from the spirit and scope of the invention and
Amendment, all should contain within the scope of the invention.
Claims (5)
1. the synthetic method of a bendazol, it is characterised in that comprise the following steps:
O-phenylenediamine and toluene are added to reaction vessel in the lump, and in this reaction vessel, drips phenyllacetyl chloride, drip and finish, add
Hot reflux is reacted, until reaction is completely；Post processing, prepares bendazol product.
The synthetic method of bendazol the most according to claim 1, it is characterised in that described o-phenylenediamine and described phenylacetyl
The molar ratio of chlorine is 1:1～1:2.
The synthetic method of bendazol the most according to claim 1, it is characterised in that the quality of described o-phenylenediamine and described
The volume ratio of toluene is 1g:1mL～1g:20mL.
The synthetic method of bendazol the most according to claim 1, it is characterised in that the temperature of described heating reflux reaction is
100 ~ 120 DEG C and duration are 3 ~ 5 hours.
5. according to the synthetic method of the bendazol according to any one of claim 1-4, it is characterised in that described post processing bag
Include: filter to obtain filter cake, wash with toluene, vacuum drying, then with water dissolution, be heated to reflux molten clearly；Add activated carbon decolorizing,
Filter, take filtrate crystallisation by cooling；Sucking filtration, washes filter cake with water, is finally vacuum dried.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610593412.XA CN106187907A (en) | 2016-07-26 | 2016-07-26 | A kind of synthetic method of bendazol |
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|---|---|---|---|
| CN201610593412.XA CN106187907A (en) | 2016-07-26 | 2016-07-26 | A kind of synthetic method of bendazol |
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| CN106187907A true CN106187907A (en) | 2016-12-07 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101397275A (en) * | 2008-09-28 | 2009-04-01 | 浙江鼎龙化工有限公司 | Method for preparing 2-( p-aminophenyl) benzimidazole-5-amine |
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- 2016-07-26 CN CN201610593412.XA patent/CN106187907A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101397275A (en) * | 2008-09-28 | 2009-04-01 | 浙江鼎龙化工有限公司 | Method for preparing 2-( p-aminophenyl) benzimidazole-5-amine |
Non-Patent Citations (2)
| Title |
|---|
| K. RAVI KUMAR ET AL.: "NaHSO4-SiO2-Promoted Solvent-Free Synthesis of Benzoxazoles,Benzimidazoles, and Benzothiazole Derivatives", 《JOURNAL OF CHEMISTRY》 * |
| SEUNG WOOK MOON ET AL.: "Synthesis of 2-substituted Benzimidazoles as anti-inflammatory agents", 《YAKHAK HOEJI》 * |
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Application publication date: 20161207 |