CN109879813A - A kind of new process synthetic method of 2- sulfydryl -5- methoxybenzimidazol - Google Patents
A kind of new process synthetic method of 2- sulfydryl -5- methoxybenzimidazol Download PDFInfo
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Abstract
The invention discloses a kind of process synthetic methods of 2- sulfydryl -5- methoxybenzimidazol, N- benzyl -5- methoxyl group -2- nitroaniline is obtained including substitution reaction is occurred for the fluoro- 4- methoxyl group -1- nitrobenzene of 2- and benzylamine, then hydrogenated reduction reaction obtains 4- methoxybenzene -1,2- diamino；Last cyclization obtains target product compound 2- sulfydryl -5- methoxybenzimidazol；The process synthetic method of 2- sulfydryl -5- methoxybenzimidazol of the present invention, Optimal improvements synthesis route method, reduce operational hazards grade and production cost, good operation safety, post-process environmentally protective, each step method is simple and easy to get, and solvent and process conditions are cheap safely, environment-friendly and green industrialized production can be achieved, have broad application prospects.
Description
Technical field
The present invention relates to pharmaceutical intermediate synthesis technical fields, more particularly, are related to a kind of 2- sulfydryl -5- methoxybenzene
And the new process synthetic method of imidazoles.
Background technique
2- sulfydryl -5- methoxybenzimidazol is the key intermediate for synthesizing Omeprazole, and structural formula is shown below:
In the preparation method of existing disclosed 2- sulfydryl -5- methoxybenzimidazol, all by nitration reaction to phenyl ring
It carries out nitrifying nitro, reduction obtains 4- methoxyl group -1,2- diaminobenzene, and then cyclization obtains 2- sulfydryl -5- methoxyl group benzo
Imidazoles.It is existing disclose preparation method using nitration reaction, danger coefficient is high, and operational safety is poor, improves the safety of production
Grade and production cost are unfavorable for industrialized popularization and application；There is harm, energy consumption cost to operator and environment
Height, post-processing generate the sewage largely with pollution environment, are unfavorable for environmentally protective industrialized production.
Therefore, to optimization Omeprazole key intermediate, 2- sulfydryl -5- methoxybenzimidazol preparation process,
Workshop amplification can especially be carried out and realize the process of environment protection requirement there are demands.
Summary of the invention
In order to solve the problems in the existing technology, the object of the present invention is to provide a kind of process safe operation,
Simply, low in cost, the process synthetic method of the 2- sulfydryl -5- methoxybenzimidazol of environmentally protective suitable industrialized production.
An aspect of of the present present invention provides a kind of process synthetic method of 2- sulfydryl -5- methoxybenzimidazol (formula A), institute
Stating process synthetic method includes that substitution reaction is occurred for the fluoro- 4- methoxyl group -1- nitrobenzene of 2- and benzylamine to obtain N- benzyl -5- methoxy
Base -2- nitroaniline, then hydrogenated reduction reaction obtains 4- methoxybenzene -1,2- diamino；Last cyclization obtains mesh
It marks product compound 2- sulfydryl -5- methoxybenzimidazol (formula A).
Further, the substitution reaction includes following preparation route and step:
Compound A-2 is reacted with benzylamine in the presence of a base, post-processing obtains compound A-3；
Further, the reduction reaction includes following preparation route and step:
Compound A-3 is subjected to hydrogenation reduction in the presence of a catalyst, post-processing obtains compound A-4；
Further, the alkali be sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, DIPEA,
It is one or more in potassium tert-butoxide, sodium tert-butoxide；
Further, the substitution reaction carries out in non-protonic solvent；
Further, the non-protonic solvent is DMF, DMA；
Further, the reaction temperature of the substitution reaction is 80~120 DEG C；
Further, the molar ratio of the compound A-2 and alkali is 1:1~1:4；
Further, the molar ratio of the compound A-2 and benzylamine is 1:1~1:2；
Further, the w/v (gram: milliliter) of the compound A-2 and non-protonic solvent is 1:5~1:20；
Further, the process synthetic method includes following preparation route and step:
Step 1 reacts compound A-1 with methylating reagent in the presence of a base, and post-processing obtains compound A-2；
Step 2 reacts compound A-2 in the presence of alkali is with aprotic solvent with benzylamine at 80~120 DEG C, post-processes
To compound A-3；
Compound A-3 is carried out hydrogenation reduction by step 3 in the presence of a catalyst, and post-processing obtains compound A-4；
Compound A-4 is carried out cyclization by step 4 under alkaline condition, obtains product compound 2- sulfydryl -5- methoxy
Base benzimidazole (compound A).
Wherein, in the step 2, the molar ratio of compound A-2 and alkali is 1:1~1:3；Compound A-2 and benzylamine rub
You are than being 1:1~1:2；The w/v (gram: milliliter) of compound A-2 and non-protonic solvent is 1:5~1:10；
Further, in the step 1, the alkali is sodium carbonate, in potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide
It is one or more；
Further, in the step 1, the methylating reagent is one of iodomethane, dimethyl suflfate or a variety of；
Further, in the step 1, the reaction carries out in non-protonic solvent；
Further, the non-protonic solvent is DMF, DMA；
Further, the step 2 specifically: compound A-2 in the presence of a base, using aprotic polar solvent as solvent,
It is reacted with benzylamine 2~8 hours at 80~120 DEG C, post-processing obtains compound A-3；Wherein, mole of compound A-2 and alkali
Than for 1:1~1:3；The molar ratio of compound A-2 and benzylamine is 1:1~1:2；The weight of compound A-2 and aprotic polar solvent
Amount volume ratio (gram: milliliter) it is 1:5~1:10；
Further, in the step 3, the hydrogenation reduction carries out in alcoholic solvent, the compound A-3 and alcohol
The w/v (gram: milliliter) of solvent is 1:30~1:40；
Further, the alcoholic solvent be methanol, in ethyl alcohol it is a kind of；
Further, in the step 3, the weight (gram) of the compound A-3 and catalyst is than being 1:0.1~1:0.3；
Further, the catalyst is 5%~10% palladium carbon catalyst or zinc powder；
Further, in the step 3, the reaction temperature of the hydrogenation reduction is 20~65 DEG C, and the reaction time is
12~48 hours；
Further, the step 3 specifically: compound A-3 5%~10% palladium carbon catalyst or zinc powder catalysis under,
Using alcoholic solvent as solvent, hydrogenation reduction 12~30 hours at 20~65 DEG C, post-processing obtains compound A-4；
Wherein, the weight (gram) of compound A-3 and 5%~10% palladium carbon catalyst or zinc powder is than being 1:0.1~1:0.3；
The w/v (gram: milliliter) of compound A-3 and alcoholic solvent is 1:30~1:40；
Further, in the step 4, the alkali is sodium carbonate, in potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide
It is one or more；
Further, in the step 4, the reaction dissolvent of the cyclization is alcohol:
Further, in the step 4, the reaction temperature of the cyclization is 60~80 DEG C:
Further, in the step 4, the reaction time of the cyclization is 4~14 hours:
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 2, the molar ratio of the compound A-2 and alkali is 1:1；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 2, the molar ratio of the compound A-2 and alkali is 1:2；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 2, the molar ratio of the compound A-2 and alkali is 1:3；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 2, the molar ratio of the compound A-2 and benzylamine is 1:1；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 2, the molar ratio of the compound A-2 and benzylamine is 1:1.5；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 2, the molar ratio of the compound A-2 and benzylamine is 1:2；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 2, and the w/v of the compound A-2 and non-protonic solvent (gram: milliliter) it is 1:5；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 2, and the w/v of the compound A-2 and non-protonic solvent (gram: milliliter) it is 1:8；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 2, and the w/v of the compound A-2 and non-protonic solvent (gram: milliliter) it is 1:10；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 3, and the w/v of the compound A-3 and alcoholic solvent (gram: milliliter) it is 1:30；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 3, and the w/v of the compound A-3 and alcoholic solvent (gram: milliliter) it is 1:33；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 3, and the w/v of the compound A-3 and alcoholic solvent (gram: milliliter) it is 1:40；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 3, the weight (gram) of the compound A-3 and catalyst is than being 1:0.1；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 3, the weight (gram) of the compound A-3 and catalyst is than being 1:0.2；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 3, the weight (gram) of the compound A-3 and catalyst is than being 1:0.3；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 3, the reaction temperature of the hydrogenation reduction is 20 DEG C；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 3, the reaction temperature of the hydrogenation reduction is 25 DEG C；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 3, the reaction temperature of the hydrogenation reduction is 30 DEG C；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 3, the reaction temperature of the hydrogenation reduction is 50 DEG C；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 3, the reaction temperature of the hydrogenation reduction is 65 DEG C；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 3, the reaction time of the hydrogenation reduction is 12 hours；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 3, the reaction time of the hydrogenation reduction is 18 hours；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 3, the reaction time of the hydrogenation reduction is 20 hours；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 3, the reaction time of the hydrogenation reduction is 30 hours；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 3, the reaction time of the hydrogenation reduction is 48 hours；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
Rapid 3 specifically: compound A-3 is under the catalysis of 10% palladium carbon catalyst, and using methanol as solvent, hydrogenating reduction is anti-at 20~30 DEG C
It answers 12~30 hours, post-processing obtains compound A-4；Wherein, compound A-3 and weight (gram) ratio of 10% palladium carbon catalyst are
1:0.2；The w/v (gram: milliliter) of compound A-3 and methanol is 1:33；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 4, the molar ratio of the compound A-4 and alkali is 1:1.5；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 4, the molar ratio of the compound A-4 and alkali is 1:2；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 4, the molar ratio of the compound A-4 and alkali is 1:3；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 4, and the w/v of the compound A-4 and alcohol (gram: milliliter) it is 1:100；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 4, and the w/v of the compound A-4 and alcohol (gram: milliliter) it is 1:200；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
In rapid 4, and the w/v of the compound A-4 and alcohol (gram: milliliter) it is 1:300；
The preferred embodiment of the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol according to the present invention, the step
Rapid 4 specifically: compound A-4 is in the presence of sodium hydroxide, using ethyl alcohol as solvent, reacts 4 at 60~80 DEG C with carbon disulfide
~8 hours, post-processing obtained product compound 2- sulfydryl -5- methoxybenzimidazol；Wherein, compound A-4, sodium hydroxide,
Molar ratio between carbon disulfide is 1:2:1.3；The w/v (gram: milliliter) of compound A-4 and ethyl alcohol is 1:200；
Technical parameter feature in present invention method made above can be in any combination.
In aforesaid operations, post-processing include but is not limited to stirring, extraction, the transfer of liquid or solid, washing, alkali cleaning,
The operations such as pickling, tune pH value, filtering, ultrafiltration, loop ultrafiltration, suction filtration, dilution, concentration, drying, recrystallization, freeze-drying, or stir
Mix, extract, the transfer of liquid or solid, washing, alkali cleaning, pickling, adjust pH value, filtering, ultrafiltration, loop ultrafiltration, suction filtration, dilution,
The combination of one or more of the operation such as concentration, dry, recrystallization, freeze-drying.
In the synthesis field of medicine intermediate organic compound molecule, the purity strong influence of midbody compound most
The quality of whole medical product.Since chemically synthesized reaction has reaction site not single, the reaction of impurity carries out and not simultaneously
Evitable feature.Under normal conditions, reaching by optimum synthesis method and optimization reaction condition, medical product compound
On the basis of certain purity, then improve its purity to the higher stage be very difficult.On the other hand, as treating disease
Disease and be applied to human body or the living individual of other animals, in order to reduce the issuable toxic side effect of impurity in medical product,
Medical product has high requirement in terms of purity and content.So in the demand for being not only able to satisfy industry's enlarging production, but also energy
Medical product purity is improved, and on the basis of not reducing yield, the preparation method of different medical products is carried out
Improvement is not regular to follow, and also not ready-made experience and enlightenment can use for reference.
Specific to the present invention, the purity and quality of 2- sulfydryl -5- methoxybenzimidazol are closed to intermediate is used it as
Be affected at the quality of Omeprazole, influence of the purity to the purity of finished product Omeprazole in subsequent preparation process into
The amplification of one step.Therefore, compound 2- sulfydryl -5- methoxybenzimidazol (formula A) is used as key intermediate, it is necessary to carry out stringenter
Quality control.
Compared with prior art, the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol of the invention has as follows
The utility model has the advantages that
The process synthetic method of 2- sulfydryl -5- methoxybenzimidazol of the invention, Optimal improvements synthesis route side
Method, avoids dangerous nitration reaction, and, good operation safety low to the anticorrosive class requirement of reaction tankage reduces
It to the potential threat grade of production line employee's life harm, post-processes environmentally protective, does not generate with the useless of pollution environment
Water reduces the security level and production cost of production, is conducive to the application of environmentally protective industrialized production；
The process synthetic method of 2- sulfydryl -5- methoxybenzimidazol of the invention, raw material is cheap and easily-available, is substantially reducing
While preparation cost, operating condition is mild, reduces operation difficulty, and low energy consumption, no pollution to the environment, be suitble to environmentally protective
Industrialized production, be conducive to amplification production and industrialization promotion；
2- sulfydryl -5- the methoxybenzene of the process synthetic method preparation of 2- sulfydryl -5- methoxybenzimidazol of the invention
And imidazoles purity is high, the 2- sulfydryl -5- methoxybenzimidazol for using the method to obtain produce Aomei as key intermediate
Azoles is drawn, the purity and quality of Omeprazole is improved, reduces the toxic side effect that Omeprazole is used as drug, improve use
Medicine safety.
In conclusion the process synthetic method of 2- sulfydryl -5- methoxybenzimidazol of the present invention, the synthesis of Optimal improvements technique
Route methods reduce operational hazards grade and production cost；It is low to the anticorrosive class requirement of reaction tankage, operation
Safety is good, environmentally protective, to obtain 2- sulfydryl -5- methoxybenzimidazol purity is high is post-processed, while improving yield
The purity and quality of intermediate product are substantially increased, so as to improve the difficulty of technology controlling and process in subsequent bulk pharmaceutical chemicals process of producing product
Spend and improve subsequent bulk pharmaceutical chemicals product quality and qualification rate；Each step method is simple and easy to get, and solvent and process conditions are cheap safely,
Environment-friendly and green industrialized production can be achieved, have broad application prospects.
Specific embodiment
All features disclosed in this specification or disclosed all methods or in the process the step of, in addition to mutually exclusive
Feature and/or step other than, can combine in any way.
Any feature disclosed in this specification unless specifically stated can be equivalent or with similar purpose by other
Alternative features are replaced.That is, unless specifically stated, each feature is an example in a series of equivalent or similar characteristics
?.
The process synthetic method successively to 2- sulfydryl -5- methoxybenzimidazol of the present invention is carried out below further detailed
Explanation.
An exemplary embodiment of the present invention, the process synthetic method packet of the 2- sulfydryl -5- methoxybenzimidazol
Include following steps:
Compound A-1 feeds intake with iodomethane, potassium carbonate and DMF and mixes, compound A-1, iodomethane, rubbing between potassium carbonate
You are than being 1:3:2；The w/v (gram: milliliter) of compound A-1 and DMF are 1:30, and reaction solution stirring is warming up to 20~100
It is reacted 10~48 hours at DEG C, reaction solution cooling successively extracts, washes, be concentrated, be dried to obtain compound A-2；
Compound A-2, benzylamine, potassium carbonate and DMF feed intake mixing, and the molar ratio of compound A-2 and potassium carbonate is 1:2；Change
The molar ratio for closing object A-2 and benzylamine is 1:1, and the w/v of compound A-2 and DMF (gram: milliliter) it is 1:10；Reaction solution exists
It is stirred 4 hours at 80 DEG C, filtering, concentration, washing are dried to obtain compound A-3；
Compound A-3 and 10% palladium charcoal feed intake in methanol, and the weight (gram) of compound A-3 and 10% palladium charcoal is than being 1:
0.2；The w/v (gram: milliliter) of compound A-3 and methanol is 1:33, and reaction system replacing hydrogen, reaction solution is at 30 DEG C
Lower stirring 18 hours, filtering, concentration, washing are dried to obtain compound A-4；
Compound A-4, sodium hydroxide, carbon disulfide and ethyl alcohol feed intake mixing, compound A-4, sodium hydroxide, carbon disulfide
Between molar ratio be 1:2:1.3；The w/v (gram: milliliter) of compound A-4 and ethyl alcohol is 1:200；80 DEG C of reaction solution
Under be stirred to react 6 hours, be added active carbon stirring, filtering, adjust pH value, filter, wash, being dried to obtain product compound 2- mercapto
Base -5- methoxybenzimidazol.
Below in conjunction with process synthetic method of the specific embodiment to 2- sulfydryl -5- methoxybenzimidazol of the present invention make into
One step explanation.
Embodiment 1,
1) reaction flask is added in the DMF of 8.8 grams of potassium carbonate and 150mL, 5.0g compound A-1 and 13.5 grams of iodine first is added
Alkane is warming up to 40 DEG C of stirring 18h.Reaction solution cooling filters, washing, dry, is concentrated to get compound A-2 (4.8g, yield
89%)；
2) reaction flask is added in the DMF of 0.5g compound A-2,5.2mL, sequentially adds 0.8 gram of potassium carbonate and 0.3 gram of benzyl
Amine, reaction solution are warming up to 80 DEG C of stirring 4h, filtering, are concentrated under reduced pressure and remove solvent, washing, and (0.73g is received dry compound A-3
Rate 97%)；
3) reaction flask is added in 0.3g compound A-3,10mL methanol, the 10% palladium charcoal of 0.06g, reaction solution displacement hydrogen is added
30 DEG C of stirring 20h of gas, filtering are concentrated under reduced pressure and remove solvent, obtain compound A-4 (0.16g, yield 98%)；
4) reaction flask is added in 0.1 g of compound A-4,0.05 gram of sodium hydroxide, 0.07 gram of carbon disulfide and 20mL ethyl alcohol,
Reaction solution is warming up to 80 DEG C of stirring 6h, and a small amount of active carbon is added, and continues stirring 1 hour, filtering, and filtrate tune pH value is taken out after being 4-5
Filter, solid washing, dry product compound 2- sulfydryl -5- methoxybenzimidazol (0.1 gram, yield 77%).
Embodiment 2,
1) operation similar with 1 step 1 of embodiment obtains compound A-2；
2) reaction flask is added in the DMF of 0.5g compound A-2,3mL, sequentially adds 0.4 gram of cesium carbonate and 0.6 gram of benzylamine,
Reaction solution is warming up to 100 DEG C of stirring 2h, filtering, is concentrated under reduced pressure and removes solvent, washing, dry compound A-3 (0.7g, yield
95%)；
3) reaction flask is added in 0.3g compound A-3,9mL methanol, the 5% palladium charcoal of 0.03g, reaction solution replacing hydrogen is added
60 DEG C of stirring 12h, filtering are concentrated under reduced pressure and remove solvent, obtain compound A-4 (0.14g, yield 96%)；
4) reaction flask is added in 0.1 g of compound A-4,0.04 gram of potassium hydroxide, 0.07 gram of carbon disulfide and 10mL ethyl alcohol,
Reaction solution is warming up to 60 DEG C of stirring 14h, and a small amount of active carbon is added, and continues stirring 1 hour, filtering, and filtrate tune pH value is taken out after being 4-5
Filter, solid washing, dry product compound 2- sulfydryl -5- methoxybenzimidazol (0.12 gram, yield 80%).
Embodiment 3,
1) operation similar with 1 step 1 of embodiment obtains compound A-2；
2) reaction flask is added in the DMF of 0.5g compound A-2,10mL, sequentially adds 1.6 grams of potassium hydroxide and 0.45 gram of benzyl
Amine, reaction solution are warming up to 120 DEG C of stirring 8h, filtering, are concentrated under reduced pressure and remove solvent, washing, dry compound A-3 (0.75g,
Yield 98%)；
3) reaction flask is added in 0.3g compound A-3,12mL methanol, the zinc powder of 0.09g, reaction solution replacing hydrogen 20 is added
DEG C stirring 48h, filtering, be concentrated under reduced pressure remove solvent, obtain compound A-4 (0.12g, yield 95%)；
4) 0.1 g of compound A-4,0.075 gram of potassium hydroxide, 0.07 gram of carbon disulfide and 30mL ethyl alcohol are added and are reacted
Bottle, reaction solution are warming up to 70 DEG C of stirring 4h, a small amount of active carbon are added, and continue stirring 1 hour, filtering, after filtrate tune pH value is 4-5
It filters, solid washing, dry product compound 2- sulfydryl -5- methoxybenzimidazol (0.11 gram, yield 85%).
Under other similar performances,
In above-mentioned steps, DMF can be replaced with DME；Methanol can be replaced with ethyl alcohol；Ethyl alcohol can be replaced with methanol；Hydrogen
Sodium oxide molybdena can be replaced with potassium hydroxide, potassium carbonate, cesium carbonate.
The invention is not limited to specific embodiments above-mentioned.The present invention, which expands to, any in the present specification to be disclosed
New feature or any new combination, and disclose any new method or process the step of or any new combination.
Claims (10)
1. a kind of process synthetic method of 2- sulfydryl -5- methoxybenzimidazol, which is characterized in that the process synthetic method packet
It includes and the fluoro- 4- methoxyl group -1- nitrobenzene of 2- and benzylamine generation substitution reaction is obtained into N- benzyl -5- methoxyl group -2- nitroaniline, so
4- methoxybenzene -1,2- diamino is obtained by hydrogenation reduction；Last cyclization obtains target product compound 2- mercapto
Base -5- methoxybenzimidazol；
2- sulfydryl -5- the methoxybenzimidazol is as shown in formula A:
。
2. method according to claim 1, which is characterized in that the substitution reaction includes following preparation route and step:
Compound A-2 is reacted with benzylamine in the presence of a base, post-processing obtains compound A-3.
The reduction reaction includes following preparation route and step:
Compound A-3 is subjected to hydrogenation reduction in the presence of a catalyst, post-processing obtains compound A-4.
3. method according to claim 1, which is characterized in that
The substitution reaction carries out in non-protonic solvent；
The non-protonic solvent is DMF, DMA；
The w/v of the compound A-2 and non-protonic solvent is 1:5~1:20.
4. method according to claim 2, which is characterized in that
The alkali is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, DIPEA, potassium tert-butoxide, tertiary fourth
It is one or more in sodium alkoxide；
The molar ratio of the compound A-2 and alkali is 1:1~1:4；
The molar ratio of the compound A-2 and benzylamine is 1:1~1:2.
5. method according to claim 1, which is characterized in that
The process synthetic method includes following preparation route and step:
Step 1 reacts compound A-1 with methylating reagent in the presence of a base, and post-processing obtains compound A-2；
Step 2 reacts compound A-2, post-processingization in the presence of alkali is with aprotic solvent with benzylamine at 80~120 DEG C
Close object A-3；
Compound A-3 is carried out hydrogenation reduction by step 3 in the presence of a catalyst, and post-processing obtains compound A-4；
Compound A-4 is carried out cyclization by step 4 in the presence of a catalyst, obtains product compound 2- sulfydryl -5- methoxyl group
Benzimidazole；
Wherein, in the step 2, the molar ratio of compound A-2 and alkali is 1:1~1:3；The molar ratio of compound A-2 and benzylamine
For 1:1~1:2；The w/v of compound A-2 and non-protonic solvent is 1:5~1:10.
6. method according to claim 5, which is characterized in that in the step 1,
The alkali is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, one or more in potassium hydroxide；
The methylating reagent is one of iodomethane, dimethyl suflfate or a variety of；
The reaction carries out in non-protonic solvent；
The non-protonic solvent is DMF, DMA.
7. method according to claim 5, which is characterized in that the step 2 specifically: compound A-2 in the presence of a base, with
Aprotic polar solvent is solvent, is reacted with benzylamine 2~8 hours at 80~120 DEG C, and post-processing obtains compound A-3；Its
In, the molar ratio of compound A-2 and alkali is 1:1~1:3；The molar ratio of compound A-2 and benzylamine is 1:1~1:2；Compound A-
2 with the w/v of aprotic polar solvent be 1:5~1:10.
8. method according to claim 5, which is characterized in that in the step 3, the hydrogenation reduction is in alcoholic solvent
It carries out, the w/v of the compound A-3 and alcoholic solvent is 1:30~1:40；
The alcoholic solvent be methanol, in ethyl alcohol it is a kind of；
The weight ratio of the compound A-3 and catalyst is 1:0.1~1:0.3；
The catalyst is 5%~10% palladium carbon catalyst or zinc powder.
9. method according to claim 5, which is characterized in that the technique of the 2- sulfydryl -5- methoxybenzimidazol synthesizes
Method includes the following steps:
Compound A-1 feeds intake with iodomethane, potassium carbonate and DMF and mixes, compound A-1, iodomethane, the molar ratio between potassium carbonate
For 1:2:2；The w/v of compound A-1 and DMF are 1:3, and reaction solution stirring, which is warming up at 20~100 DEG C, reacts 10~48
Hour, reaction solution cooling successively extracts, washes, be concentrated, be dried to obtain compound A-2；
Compound A-2, benzylamine, potassium carbonate and DMF feed intake mixing, and the molar ratio of compound A-2 and potassium carbonate is 1:2；Compound
The molar ratio of A-2 and benzylamine is 1:1, and the w/v of compound A-2 and DMF are 1:10；It is small that reaction solution stirs 4 at 80 DEG C
When, filtering, concentration, washing are dried to obtain compound A-3；
Compound A-3 and 10% palladium charcoal feed intake in methanol, and the weight ratio of compound A-3 and 10% palladium charcoal is 1:0.2；Chemical combination
The w/v of object A-3 and methanol is 1:33, and reaction system replacing hydrogen, reaction solution stir 18 hours at 30 DEG C, filter,
Concentration, washing are dried to obtain compound A-4；
Compound A-4, sodium hydroxide, carbon disulfide and ethyl alcohol feed intake mixing, compound A-4, sodium hydroxide, between carbon disulfide
Molar ratio be 1:2:1.3；Compound A-4 and the w/v of ethyl alcohol are 1:200；It is small that 6 are stirred to react at 80 DEG C of reaction solution
When, active carbon stirring is added, pH value is adjusted in filtering, is filtered, is washed, being dried to obtain product compound 2- sulfydryl -5- methoxyl group benzo
Imidazoles.
10. the 2- sulfydryl -5- methoxybenzimidazol that a kind of any one of claim 1~9 the method is prepared.
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| CN113773261A (en) * | 2021-10-21 | 2021-12-10 | 鹤壁元昊化工有限公司 | Preparation method of 2-mercaptobenzimidazole compound |
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