CN106220625B - A kind of synthetic method of pirenzepine hydrochloride key intermediate - Google Patents
A kind of synthetic method of pirenzepine hydrochloride key intermediate Download PDFInfo
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- CN106220625B CN106220625B CN201610609497.6A CN201610609497A CN106220625B CN 106220625 B CN106220625 B CN 106220625B CN 201610609497 A CN201610609497 A CN 201610609497A CN 106220625 B CN106220625 B CN 106220625B
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a kind of synthetic method of pirenzepine hydrochloride key intermediate.This method, for initiation material, under acidic catalyst effect, occurs rearrangement reaction and obtains the ketone of 5,11 dihydro 6H pyridos [2,3 B] [Isosorbide-5-Nitrae] benzodiazepine 6 with the ketone of 1,3 dihydro 3 phenyl 2H imidazos [4,5 B] pyridine 2.The positive effect of the present invention is to propose relatively new synthesis 5,11 dihydro 6H pyridos [2,3 B] [1,4] method of the ketone of benzodiazepine 6, the method overcome that reactions steps in the prior art are cumbersome, and supplementary material species is various, pollution many deficiencies such as again, step is simple, only needs a step rearrangement reaction, and high income is up to more than 99%；The acid of addition is both reaction dissolvent, is also catalyst, and it can be reclaimed after post processing and is used；Ethyl acetate solvent is recyclable to be reused, and is greatlyd save cost and is protected environment, with good industrial prospect.
Description
Technical field
The present invention relates to a kind of antiulcer drug pirenzepine hydrochloride key intermediate 5,11- dihydro -6H- pyridos
The synthetic method of [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone, more particularly to one kind is with 1,3- dihydro -3- phenyl -2H- imidazos
[4,5-B] pyridin-2-ones are initiation material, under acidic catalyst effect, synthesize 5,11- dihydro -6H- pyridos [2,3-B]
The method of [Isosorbide-5-Nitrae] benzodiazepine -6- ketone, belongs to pharmaceutical synthesis field.
Background technology
Hydrochloric acid piperazine human relations Xiping is a kind of selective anticholinergic agent, has height to the M-ChR of parietal cell
Affinity, and to smooth muscle, the affinity of the M-ChR of cardiac muscle and salivary gland etc. is low.It is primarily adapted for use in treatment stomach and 12
Duodenalulcer, also available for stress ulcer.Recent experimental finds that pirenzepine can suppress the occurrence and development of myopia, therefore,
Once succeeding in developing, the demand of pirenzepine bulk drug will be greatly increased.By substantial amounts of literature survey and carefully analyzing research
It was found that, the key of synthesis pirenzepine seek to first to obtain 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -
6- ketone.Therefore, if a synthesis 5 in high yield, high-quality, inexpensive can be developed, 11- dihydro -6H- pyridos [2,3-
B] synthetic method of [1,4] benzodiazepine -6- ketone will have preferable social and economic benefit.But, at present, 5,11- bis-
It is cumbersome to there are reactions steps in the synthesis technique of hydrogen -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone, supplementary material species
It is various, pollution weight, the low defect of yield.Reaction such as following formula：
The prior synthesizing method of reaction equation 1 5,11- dihydro -6H- pyridos [2,3-B] [1,4] benzodiazepine -6- ketone
The content of the invention
To solve the above problems, i.e. reactions steps are cumbersome, supplementary material species is various, pollution weight, the low problem of yield, this hair
It is bright to provide a kind of side of synthesis 5,11- dihydro -6H- pyridos [2,3-B] [1,4] benzodiazepine -6- ketone simple to operate
Method.
This method provides a kind of safe efficient, in high yield synthesis 5,11- dihydro -6H- pyridos [2,3-B] [1,4] benzene
And the method for diaza -6- ketone.See reaction equation 2.
The reaction equation that the present invention is synthesized is as follows：
The synthesis of reaction equation 2 5,11- dihydro -6H- pyridos [2,3-B] [1,4] benzodiazepine -6- ketone
The synthetic method of the present invention 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone, under
State step progress：
Argon gas is protected, and appropriate amount of acid is added into four-hole boiling flask, is stirred, and is heated to 90-100 DEG C and is maintained 10 minutes；Then divide
Criticize and add 1,3- dihydros -3- phenyl -2H- imidazos [4,5-B] pyridin-2-ones, raise thermotonus.TLC tracking reactions, reaction
It is complete, it is slightly cold, pour into appropriate frozen water, be extracted with ethyl acetate while stirring, merge organic layer and use water and saturated aqueous common salt successively
Solution is washed, and is dried with anhydrous magnesium sulfate, is filtered, and vacuum rotary steam recycling design obtains 5,11- dihydro -6H- pyridos [2,3-
B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone crude products, recrystallized with the mixed solvent of absolute ethyl alcohol and petroleum ether, obtain 5,11- dihydros -
6H- pyridos [2,3-B] [1,4] benzodiazepine -6- ketone finished products.
Sulfuric acid (mass concentration), polyphosphoric acids of the described acid for 95%.
Described 1,3- dihydro -3- phenyl -2H- imidazos [4,5-B] pyridin-2-ones and the w/v of sour addition
1g/12-15mL.1,3- dihydros -3- phenyl -2H- imidazos [4,5-B] pyridin-2-ones can be by urea and 2- chlorine-3-aminopyridines
Reaction is made.
Described reaction temperature is 160-180 DEG C, and the reaction time is 9-11 hours.
Described absolute ethyl alcohol is 5 with petroleum ether addition volume ratio:1.
It is on sale on described reagent and raw materials market.
The positive effect of the present invention is to propose relatively new synthesis 5,11- dihydro -6H- pyridos [2,3-
B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone method, overcome that reactions steps in the prior art are cumbersome, supplementary material species is various, pollution
Many deficiencies such as again, step is simple, only needs a step rearrangement reaction, and high income is up to more than 99%；The acid of addition is both reaction dissolvent,
It is also catalyst, it can be reclaimed after post processing and is used；Ethyl acetate solvent is recyclable to be reused, and greatlys save cost and guarantor
Environment is protected, with good industrial prospect.
Embodiment
With specific embodiment, the present invention will be described in detail.Protection scope of the present invention not using embodiment as
Limit, but be defined in the claims.
Comparison example 1：A kind of method of synthetic hydrochloric acid pirenzepine:China, CN201210388731.9 [P] .2013-4-
17.
(1) 300 milliliters of toluene are added in reaction vessel, 257 grams of 2- chlorine-3-aminopyridines are dissolved in toluene,
Stirred with mechanical agitator.Being added thereto 292 grams of potassium tert-butoxide slowly, addition speed is 5% consumption/minute,
Stir.Then 393 grams of methyl anthranilate is added in reaction dissolvent in the way of being added dropwise, rate of addition is
3% consumption/minute.Reacted 1 hour under conditions of 50 DEG C, after reaction terminates, add 400 milliliters of toluene, 4.49 grams of acetic acid
Palladium and 12.5 grams of dinaphthalene hexichol phosphorus, rise reaction temperature are reacted 24 hours to 110 DEG C.After reaction terminates, decompression boils off solvent, takes out
Filter and obtain white solid, then 600 milliliters of acetone and the mixed solvent of water with 50% are recrystallized, suction filtration is simultaneously washed with petroleum ether
Wash, be dried to obtain 401 grams of cyclisation intermediate benzodiazepine ketone, product yield is 95%, and purity is 99%.
Comparison example 2：A kind of new method of synthetic hydrochloric acid piperazine human relations Xiping intermediate:China, CN201510075537.9
[P].2015-9-9.
(1) in 1000 milliliters of reaction bulb, 600 milliliters of butanol is added, 100 grams of 2- amino-N- (2- chloropyridines base-
3-) benzamide, 2 milliliters of concentrated sulfuric acids, back flow reaction 3 hours, reaction temperature is 80 DEG C, is cooled to room temperature, filters, is washed with acetone
Wash, 50-60 DEG C is dried in vacuo to obtain 98 grams of faint yellow solid product, yield 98%, purity 99%.
Example 1
Argon gas is protected, and polyphosphoric acids 253.2mL is added into 500mL four-hole boiling flasks, and stirring is heated to 90-100 DEG C, guarantor
Hold 10 minutes.Then 1,3- dihydro -5- chloro-1-phenyl -2H- 2-ketone benzimidaozoles 21.1g (100mmol) are added portionwise, heat up
To 160 DEG C, stirring reaction 9 hours, TLC tracking reactions.Reaction is finished, slightly cold, is poured into frozen water, is extracted with ethyl acetate while stirring
Take, merge organic layer and washed successively with water and common salt aqueous solution, dried with anhydrous magnesium sulfate, filtered, vacuum rotary steam reclaims acetic acid
Ethyl ester, obtains 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone crude products, with absolute ethyl alcohol and oil
Mixed solvent 240mL (the volume ratios 5 of ether:1) recrystallize, obtain 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzo two
Azepine -6- ketone finished product 20.8g, yield 98.6%, purity 99.5% (GC).
Example 2
Argon gas is protected, and the sulfuric acid 274.3mL that mass concentration is 95% is added into 500mL four-hole boiling flasks, and stirring is heated to
90-100 DEG C, kept for 10 minutes.Then 1,3- dihydro -5- chloro-1-phenyl -2H- 2-ketone benzimidaozoles 21.1g is added portionwise
(100mmol), is warming up to 170 DEG C, stirring reaction 10 hours, TLC tracking reactions.Reaction is finished, slightly cold, and frozen water is poured into while stirring
In, it is extracted with ethyl acetate, merges organic layer and washed successively with water and common salt aqueous solution, dried with anhydrous magnesium sulfate, filter, subtract
Pressure revolving reclaims ethyl acetate, obtains 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone crude products, uses
Mixed solvent 240mL (the volume ratios 5 of absolute ethyl alcohol and petroleum ether:1) recrystallize, obtain 5,11- dihydro -6H- pyridos [2,3-
B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone finished product 20.89g, yield 99.00%, purity 99.4% (GC).
Example 3
Argon gas is protected, and polyphosphoric acids 295.4mL is added into 500mL four-hole boiling flasks, and stirring is heated to 90-100 DEG C, guarantor
Hold 10 minutes.Then 1,3- dihydro -5- chloro-1-phenyl -2H- 2-ketone benzimidaozoles 21.1g (100mmol) are added portionwise, heat up
To 180 DEG C, stirring reaction 11 hours, TLC tracking reactions.Reaction is finished, slightly cold, is poured into while stirring in frozen water, is used ethyl acetate
Extraction, merges organic layer and is washed successively with water and common salt aqueous solution, dried with anhydrous magnesium sulfate, filtered, vacuum rotary steam reclaims second
Acetoacetic ester, obtains 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone crude products, with absolute ethyl alcohol and stone
Mixed solvent 240mL (the volume ratios 5 of oily ether:1) recrystallize, obtain 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzo
Diaza -6- ketone finished product 20.99g, yield 99.48%, purity 99.7% (GC).
Example 4
Argon gas is protected, and the sulfuric acid 316.5mL that mass concentration is 95% is added into 500mL four-hole boiling flasks, and stirring is heated to
90-100 DEG C, kept for 10 minutes.Then 1,3- dihydro -5- chloro-1-phenyl -2H- 2-ketone benzimidaozoles 21.1g is added portionwise
(100mmol), is warming up to 180 DEG C, stirring reaction 11 hours, TLC tracking reactions.Reaction is finished, slightly cold, and frozen water is poured into while stirring
In, it is extracted with ethyl acetate, merges organic layer and washed successively with water and common salt aqueous solution, dried with anhydrous magnesium sulfate, filter, subtract
Pressure revolving reclaims ethyl acetate, obtains 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone crude products, uses
Mixed solvent 240mL (the volume ratios 5 of absolute ethyl alcohol and petroleum ether:1) recrystallize, obtain 5,11- dihydro -6H- pyridos [2,3-
B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone finished product 21.04g, yield 99.72%, purity 99.9% (GC).
Example 5
Argon gas is protected, and polyphosphoric acids 316.5mL is added into 500mL four-hole boiling flasks, and stirring is heated to 90-100 DEG C, guarantor
Hold 10 minutes.Then 1,3- dihydro -5- chloro-1-phenyl -2H- 2-ketone benzimidaozoles 21.1g (100mmol) are added portionwise, heat up
To 180 DEG C, stirring reaction 10 hours, TLC tracking reactions.Reaction is finished, slightly cold, is poured into while stirring in frozen water, is used ethyl acetate
Extraction, merges organic layer and is washed successively with water and common salt aqueous solution, dried with anhydrous magnesium sulfate, filtered, vacuum rotary steam reclaims second
Acetoacetic ester, obtains 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone crude products, with absolute ethyl alcohol and stone
Mixed solvent 240mL (the volume ratios 5 of oily ether:1) recrystallize, obtain 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzo
Diaza -6- ketone finished product 21.00g, yield 99.52%, purity 99.7% (GC).
Example 6
Argon gas is protected, and the sulfuric acid 316.5mL that mass concentration is 95% is added into 500mL four-hole boiling flasks, and stirring is heated to
90-100 DEG C, kept for 10 minutes.Then 1,3- dihydro -5- chloro-1-phenyl -2H- 2-ketone benzimidaozoles 21.1g is added portionwise
(100mmol), is warming up to 170 DEG C, stirring reaction 9 hours, TLC tracking reactions.Reaction is finished, slightly cold, and frozen water is poured into while stirring
In, it is extracted with ethyl acetate, merges organic layer and washed successively with water and common salt aqueous solution, dried with anhydrous magnesium sulfate, filter, subtract
Pressure revolving reclaims ethyl acetate, obtains 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone crude products, uses
Mixed solvent 240mL (the volume ratios 5 of absolute ethyl alcohol and petroleum ether:1) recrystallize, obtain 5,11- dihydro -6H- pyridos [2,3-
B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone finished product 20.97g, yield 99.38%, purity 99.8% (GC).
Embodiment 4 and comparison example 1-2 is contrasted it can be found that comparison example 1 is with 2- chlorine-3-aminopyridines and adjacent amino
Methyl benzoate is initiation material, synthesizes 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone, reaction
It is middle to have used palladium and dinaphthalene hexichol phosphorus expensive and that be difficult acquisition, add synthesis cost；Total reaction time is more than
24 hours, high energy consumption, yield only had 95%, and yield is low.Comparison example 2 is that conventional synthesis route is improved, and is with 2-
Amino-N- (2- chloropyridine bases -3-) benzamide is initiation material, although the technique after improvement overcomes high in original technique
Temperature, post processing complexity, the low defect of yield, but initiation material 2- amino-N- (2- chloropyridine bases -3-) benzamide is not big
Ancestor's industrialization product, synthesis is, using 3- aminopyridines as initiation material, (Zhang Yun to be obtained through chlorination, acylation, reduction three-step reaction
A kind of production method of pirenzepine:Jiangsu, CN104744457A [P] .2015-07-01), reaction Central Plains supplementary product kind is more, behaviour
Make complicated, cost is high, yield is low, and this adds increased 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone
Industrial production cost.Embodiment 4 is with 1,3- dihydro -5- chloro-1-phenyl -2H- 2-ketone benzimidaozole initiation materials, a step
Reaction obtains 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone, and high income is up to 99.72%, hence it is evident that high
In existing synthetic method；Acid is both reaction dissolvent in reaction, is also catalyst, can both make raw material 1, the chloro- 1- benzene of 3- dihydros -5-
The reaction of base -2H- 2-ketone benzimidaozoles is complete, improves reaction yield, it also avoid the cost increase that is come using other solvent banks with
Hydrochlorate can be reclaimed and used after environmental pollution, post processing, greatlyd save cost and protected environment.Therefore, by with it is existing
The contrast of technology, it is possible to which obvious to find, instant invention overcomes many deficiencies of prior art, single step reaction obtains 5,11-
Dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone, high income, the supplementary material of reaction is cheap and easy to get, and reaction is easy
In operation, solvent recoverable is the production technology of a strong operability.
Claims (6)
1. a kind of synthetic method of pirenzepine hydrochloride key intermediate, it is characterised in that specific synthetic method is as steps described below
Carry out：
Argon gas is protected, and appropriate amount of acid is added into four-hole boiling flask, is stirred, and is heated to 90-100 DEG C and is maintained 10 minutes；Then add in batches
Enter 1,3- dihydros -3- phenyl -2H- imidazos [4,5-B] pyridin-2-ones, raise thermotonus.TLC tracking reactions, have reacted,
It is slightly cold, pour into appropriate frozen water, be extracted with ethyl acetate while stirring, merge organic layer and use water and the saturated common salt aqueous solution successively
Washing, dried with anhydrous magnesium sulfate, filter, vacuum rotary steam recycling design, obtain 5,11- dihydro -6H- pyridos [2,3-B] [1,
4] benzodiazepine -6- ketone crude product, is recrystallized with the mixed solvent of absolute ethyl alcohol and petroleum ether, obtains 5,11- dihydro -6H- pyrroles
Pyridine simultaneously [2,3-B] [1,4] benzodiazepine -6- ketone finished products.
2. the synthetic method of pirenzepine hydrochloride key intermediate according to claim 1, it is characterised in that described acid
For 95% sulfuric acid (mass concentration) and polyphosphoric acids.
3. the synthetic method of pirenzepine hydrochloride key intermediate according to claim 1, it is characterised in that described 1,
3- dihydro -3- phenyl -2H- imidazos [4,5-B] pyridin-2-ones and the w/v 1g/12-15mL of sour addition.
4. the synthetic method of pirenzepine hydrochloride key intermediate according to claim 1, it is characterised in that described is anti-
It is 160-180 DEG C to answer temperature.
5. the synthetic method of pirenzepine hydrochloride key intermediate according to claim 1, it is characterised in that described is anti-
It is 9-11 hours between seasonable.
6. the synthetic method of pirenzepine hydrochloride key intermediate according to claim 1, it is characterised in that described nothing
Water-ethanol is 5 with petroleum ether addition volume ratio:1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044419A (en) * | 2012-09-04 | 2013-04-17 | 苏州弘森药业有限公司 | Method for synthesizing pirenzepine hydrochloride |
| CN104892596A (en) * | 2015-02-12 | 2015-09-09 | 苏州弘森药业有限公司 | Novel method for synthesizing pirenzepine hydrochloride intermediate |
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- 2016-07-28 CN CN201610609497.6A patent/CN106220625B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044419A (en) * | 2012-09-04 | 2013-04-17 | 苏州弘森药业有限公司 | Method for synthesizing pirenzepine hydrochloride |
| CN104892596A (en) * | 2015-02-12 | 2015-09-09 | 苏州弘森药业有限公司 | Novel method for synthesizing pirenzepine hydrochloride intermediate |
Non-Patent Citations (1)
| Title |
|---|
| Solvolysis, Electrochemistry, and Development of Synthetic Building Blocks from Sawdust;Bichlien H. Nguyen et al.;《The Journal of Organic Chemistry》;20151106;第80卷;第11956页路线3 * |
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