CN103113302B - A kind of method preparing iminostilbene - Google Patents
A kind of method preparing iminostilbene Download PDFInfo
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- CN103113302B CN103113302B CN201310080701.6A CN201310080701A CN103113302B CN 103113302 B CN103113302 B CN 103113302B CN 201310080701 A CN201310080701 A CN 201310080701A CN 103113302 B CN103113302 B CN 103113302B
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Abstract
The invention discloses a kind of method preparing iminostilbene, it is characterized in that, there is intramolecular rearrangement and react a step and obtain iminostilbene in 1-Phenylindole, described acid is sulfuric acid, phosphoric acid, polyphosphoric acid or polyphosphoric acid ester compound etc. in acid system.Synthetic method flow process of the present invention is succinct, and step is simple, and product yield can reach 48%; Participate in reaction without bromine in building-up process, remaining without bromo by product in product, quality is higher.Adopt the inventive method to prepare iminostilbene, the synthesis cost of Carbamzepine can be reduced and improve quality, there is good industrial prospect.
Description
Technical field
The present invention relates to a kind of synthesis of key intermediate iminostilbene of antiepileptic drug Carbamzepine, particularly relate to one with 1-Phenylindole for starting raw material, the method for one-step synthesis Carbamzepine key intermediate iminostilbene, belongs to pharmaceutical synthesis field.
Background technology
Carbamzepine (1), Carbamazepine, chemistry 5H-dibenzo [b, f] azatropylidene-5-methane amide by name, its clinical application is very extensive, can be used for the diseases such as anti-epileptic, anti-peripheral neuralgia, antimanic depression and anti-arrhythmia.The advantage of Carbamzepine mainly contains safety, and effectively, spectrum, does not have the untoward reaction of cognitive function aspect, and cheap, curative effect affirmative etc.
Structural formula
1carbamzepine.
Carbamzepine is industrially prepared by polystep reaction, and in its whole piece route, the technology of most critical obtains midbody compound iminostilbene (or 5-formyl chloride imido stilbene) exactly.Iminostilbene, chemical name 5H-dibenzo [b, f] azepine, molecular weight: 193.25 is orange-yellow powder, odorless, tasteless, water insoluble, can dissolve each other in organic solvent.It is a kind of important medicinal intermediates, is mainly used in synthesis Carbamzepine and oxcarbazepine, also for prevention and therapy hepatitis C (hepatitis C); As anti-hemolysis medicine; Synthesis rhodium catalyst part; And be also the important synthesis material of the aspect such as genetically engineered, materialogy.
The synthetic method of iminostilbene has multiple, and one take iminodibenzyl as raw material, adopts catalytic dehydrogenation process preparation.Relevant dehydrogenating technology, all has large quantity research both at home and abroad, as EP570336, EP0237952 and CN101307021A.Catalytic dehydrogenation process facility investment is large, it is high to require, catalyzer is expensive; The organic solvent toxicity adopted is comparatively large, and quality product is poor.
Another kind of technique adopts the method preparation of bromination, dehydrobromination.It is that starting raw material condensation in three kinds of solvents obtains 2,2 that the firm China of Pu waits (CN 1616433 A, 2005-05-18.) to report with Ortho Nitro Toluene
,-dinitro bibenzyl, then obtain iminodibenzyl through reduction, high temperature cyclization, obtain 5-formyl chloride imido stilbene, whole piece route not only complex steps finally by chlorine formylation, bromo, dehydrobromination, pollute heavy, and yield is low, explosive.Wear (Journal of Chemical Industry and Engineerings such as expounding one's ideas in writing; 2008; 59 (9): 2419-2413.) report with iminodibenzyl is starting raw material; through chlorine formylation; bromo, dehydrobromination, deprotection obtains iminostilbene; although this route comparatively patent synthesis technique improves to some extent, route is still more complicated loaded down with trivial details.And above two kinds of routes all introduce bromine participation reaction, in product, by product is more, and inevitably has the residual of bromo by product, have impact on the quality of iminostilbene, limits the use range of iminostilbene.
How participate in being obtained by reacting midbody compound iminostilbene (or 5-formyl chloride imido stilbene) without bromine by easy steps, determine the synthesis cost of Carbamzepine.
Summary of the invention
For the technology of solving the problem, namely in prior art iminostilbene synthetic method step long, pollute heavy, the problem such as have bromine residual, the invention provides that a kind of cost is low, step is short, synthesize the method for iminostilbene without bromine method.
The present invention is by the following technical solutions:
Prepare a method for iminostilbene, it is characterized in that, with 1-Phenylindole for starting raw material, under acid effect, 1-Phenylindole generation intramolecular rearrangement obtains iminostilbene.
The inventive method is in acid system, and 1-Phenylindole intramolecular rearrangement one-step synthesis obtains object, is that a kind of step is simple, the method for high yield synthesis iminostilbene.Building-up reactions formula is as follows:
。
The synthetic method of iminostilbene of the present invention, specifically carry out according to following step:
(1) in four-hole boiling flask, add appropriate amount of acid, stir, be heated to 80-100 DEG C of maintenance;
(2) drip 1-Phenylindole, be warming up to 105-115 DEG C, reaction 36-72 hour;
(3) after reaction product cooling (to about 30 ~ 40 DEG C), pour in the frozen water of appropriate saturated sodium bicarbonate, with dichloromethane extraction after vigorous stirring, merge organic layer and use water and saturated common salt solution washing successively, with anhydrous sodium sulfate drying, filter, vacuum rotary steam recycling design, obtain yellow iminostilbene crude product, with petroleum ether dissolution, insolubles is iminostilbene finished product.
Described acid is sulfuric acid, phosphoric acid, polyphosphoric acid or polyphosphoric acid ester compound etc., preferred polyphosphoric acid and polyphosphoric acid ethyl ester.
Described 1-Phenylindole and the weightmeasurement ratio of sour add-on are 1g/10-30mL.1-Phenylindole can be obtained by substitution reaction by indoles and halogeno-benzene.
Preferably, in described method, wherein step (1) and (2) can in an inert atmosphere, as carried out in nitrogen, inert gas atmosphere.
In described method, wherein the saturated sodium bicarbonate described in step (3) and sour add-on volume ratio are 20-40mL/1mL.
Synthetic method of the present invention overcomes many deficiencies of prior art, and flow process is succinct, and step is simple, and product yield can reach 48%; Participate in reaction without bromine in building-up process, remaining without bromo by product in product, quality product is high, solvent recoverable.Adopt the inventive method to prepare iminostilbene, the synthesis cost of Carbamzepine can be made generally greatly to reduce, there is good industrial prospect.
Embodiment
Hereafter describe the present invention with specific embodiment.Protection scope of the present invention is not limited with embodiment, but is limited by claim.
Embodiment 1
(1) in 100mL four-hole boiling flask, add polyphosphoric acid 50mL, stir, be heated to 80 DEG C, keep 30 minutes.
(2) 1-Phenylindole 5g(26mmol is dripped), be warming up to 105 DEG C, stirring reaction 36 hours, TLC follows the tracks of reaction.
(3) reaction is finished, and is cooled to 30 DEG C-40 DEG C, pours in the frozen water of 1000mL saturated sodium bicarbonate, vigorous stirring 1 hour, with dichloromethane extraction, merges organic layer successively with water and common salt aqueous solution washing, with anhydrous sodium sulfate drying, filter, vacuum rotary steam recycling design, obtain yellow iminostilbene crude product, with petroleum ether dissolution, insolubles is iminostilbene, filter, dry, obtain bright yellow solid 1.40g, productive rate 28%, purity >=98%.
1HNMR(400MHz, DMSO, TMS, δ): 6.07(s, 2H), 6.58-6.60(d, 2H, J=8.0Hz ), 6.66-6.69(m, 2 H),6.73-6.75(d, 2H, J=8.0Hz), 6.93-6.97(m, 3H)。
Embodiment 2
(1) in 250mL four-hole boiling flask, add polyphosphoric acid 150mL, stir, be heated to 100 DEG C, keep 30 minutes.
(2) 1-Phenylindole 5g(26mmol is dripped), be warming up to 115 DEG C, stirring reaction 72 hours, TLC follows the tracks of reaction.
(3) reaction is finished, and is cooled to 30 DEG C-40 DEG C, pours in the frozen water of 2000mL saturated sodium bicarbonate, vigorous stirring 1 hour, with dichloromethane extraction, merges organic layer successively with water and common salt aqueous solution washing, with anhydrous sodium sulfate drying, filter, vacuum rotary steam recycling design, obtain yellow iminostilbene crude product, with petroleum ether dissolution, insolubles is iminostilbene, filter, dry, obtain bright yellow solid 1.55g, productive rate 31%, purity >=98%.
1HNMR(400MHz, DMSO, TMS, δ): 6.07(s, 2H), 6.58-6.60(d, 2H, J=8.0Hz ), 6.66-6.69(m, 2 H),6.73-6.75(d, 2H, J=8.0Hz), 6.93-6.97(m, 3H)。
Embodiment 3
(1) in 100mL four-hole boiling flask, add polyphosphoric acid ethyl ester 50mL, stir, be heated to 80 DEG C, keep 30 minutes.
(2) 1-Phenylindole 5g(26mmol is dripped), be warming up to 105 DEG C, stirring reaction 36 hours, TLC follows the tracks of reaction.
(3) reaction is finished, and is cooled to 30 DEG C-40 DEG C, pours in the frozen water of 1000mL saturated sodium bicarbonate, vigorous stirring 1 hour, with dichloromethane extraction, merges organic layer successively with water and common salt aqueous solution washing, with anhydrous sodium sulfate drying, filter, vacuum rotary steam recycling design, obtain yellow iminostilbene crude product, with petroleum ether dissolution, insolubles is iminostilbene, filter, dry, obtain bright yellow solid 1.65g, productive rate 33%, purity >=98%.
1HNMR(400MHz, DMSO, TMS, δ): 6.07(s, 2H), 6.58-6.60(d, 2H, J=8.0Hz ), 6.66-6.69(m, 2 H),6.73-6.75(d, 2H, J=8.0Hz), 6.93-6.97(m, 3H)。
Embodiment 4
(1) argon shield, adds polyphosphoric acid ethyl ester 150mL in 250mL four-hole boiling flask, stirs, is heated to 100 DEG C, keeps 30 minutes.
(2) 1-Phenylindole 5g(26mmol is dripped), be warming up to 115 DEG C, stirring reaction 72 hours, TLC follows the tracks of reaction.
(3) reaction is finished, and is cooled to 30 DEG C-40 DEG C, pours in the frozen water of 2000mL saturated sodium bicarbonate, vigorous stirring 1 hour, with dichloromethane extraction, merges organic layer successively with water and common salt aqueous solution washing, with anhydrous sodium sulfate drying, filter, vacuum rotary steam recycling design, obtain yellow iminostilbene crude product, with petroleum ether dissolution, insolubles is iminostilbene, filter, dry, obtain bright yellow solid 1.85g, productive rate 37%, purity >=98%.
1HNMR(400MHz, DMSO, TMS, δ): 6.07(s, 2H), 6.58-6.60(d, 2H, J=8.0Hz ), 6.66-6.69(m, 2 H),6.73-6.75(d, 2H, J=8.0Hz), 6.93-6.97(m, 3H)。
Embodiment 5
(1) argon shield, adds polyphosphoric acid ethyl ester 75mL in 250mL four-hole boiling flask, stirs, is heated to 90 DEG C, keeps 30 minutes.
(2) 1-Phenylindole 5g(26mmol is dripped), be warming up to 110 DEG C, stirring reaction 60 hours, TLC follows the tracks of reaction.
(3) reaction is finished, and is cooled to 30 DEG C-40 DEG C, pours in the frozen water of 1500mL saturated sodium bicarbonate, vigorous stirring 1 hour, with dichloromethane extraction, merges organic layer successively with water and common salt aqueous solution washing, with anhydrous sodium sulfate drying, filter, vacuum rotary steam recycling design, obtain yellow iminostilbene crude product, with petroleum ether dissolution, insolubles is iminostilbene, filter, dry, obtain bright yellow solid 2.40g, productive rate 48%, purity >=98%.
1HNMR(400MHz, DMSO, TMS, δ): 6.07(s, 2H), 6.58-6.60(d, 2H, J=8.0Hz ), 6.66-6.69(m, 2 H),6.73-6.75(d, 2H, J=8.0Hz), 6.93-6.97(m, 3H)。
Claims (5)
1. prepare a method for iminostilbene, it is characterized in that, with 1-Phenylindole for starting raw material, under acid effect, 1-Phenylindole generation intramolecular rearrangement is obtained by reacting iminostilbene;
Described method comprises the following steps:
(1) in four-hole boiling flask, add appropriate amount of acid, stir, be heated to 80-100 DEG C of maintenance;
(2) drip 1-Phenylindole, be warming up to 105-115 DEG C, reaction 36-72 hour;
(3) after reaction product cooling, pour in the frozen water of appropriate saturated sodium bicarbonate, with dichloromethane extraction after vigorous stirring, merge organic layer and use water and saturated common salt solution washing successively, with anhydrous sodium sulfate drying, filter, vacuum rotary steam recycling design, obtain yellow iminostilbene crude product, with petroleum ether dissolution, insolubles is iminostilbene finished product.
2. the method preparing iminostilbene according to claim 1, is characterized in that, described acid is sulfuric acid, phosphoric acid, polyphosphoric acid or polyphosphate.
3. the method preparing iminostilbene according to claim 2, is characterized in that, described acid is polyphosphoric acid or polyphosphoric acid ethyl ester.
4. the method preparing iminostilbene according to claim 1, is characterized in that, described 1-Phenylindole and the weightmeasurement ratio of sour add-on are 1g/10-30mL.
5. the method preparing iminostilbene according to claim 1, is characterized in that, wherein the volume ratio of the saturated sodium bicarbonate described in step (3) and sour add-on is 20-40mL/1mL.
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| CN103483257A (en) * | 2013-09-06 | 2014-01-01 | 江苏同禾药业有限公司 | Method for synthesizing iminostilbene |
| CN113395958A (en) * | 2019-02-01 | 2021-09-14 | H.隆德贝克有限公司 | Injectable carbamazepine compositions substantially free of 10-bromo-carbamazepine |
| CN112457253A (en) * | 2021-01-15 | 2021-03-09 | 浙江工业大学 | Method for synthesizing iminostilbene |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0466972A1 (en) * | 1990-07-18 | 1992-01-22 | ARZNEIMITTELWERK DRESDEN GmbH | Process for the preparation of 5-chlorocarbonyl-5H-dibenzo-[b,f]azepine |
| CN102391182A (en) * | 2011-09-26 | 2012-03-28 | 江苏同禾药业有限公司 | Method for preparing iminodibenzyl |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0466972A1 (en) * | 1990-07-18 | 1992-01-22 | ARZNEIMITTELWERK DRESDEN GmbH | Process for the preparation of 5-chlorocarbonyl-5H-dibenzo-[b,f]azepine |
| US5110923A (en) * | 1990-07-18 | 1992-05-05 | Arzneimittelwerk Dresden Gmbh | Method for preparing 5-chlorocarbonyl-5h-dibenz(b,f)azepine |
| CN102391182A (en) * | 2011-09-26 | 2012-03-28 | 江苏同禾药业有限公司 | Method for preparing iminodibenzyl |
Non-Patent Citations (1)
| Title |
|---|
| Gennadii P. Tokmakov,等.Rearrangement of 1-Arylindoles to 5H-Dibenzlb,flazepines.《Tetrahedron》.1995,第51卷(第7期),第2091-2098页. * |
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