CN102276530A - Method for preparing 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one - Google Patents
Method for preparing 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one Download PDFInfo
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Abstract
The invention belongs to the field of medicinal preparations and provides a method for preparing a key intermediate of ivabradine, namely 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one. The method is characterized in that: a form of active ester is obtained by activating a carboxyl group of 3,4-dimethoxyphenylacetic acid under the catalysis of alkali, and then the active ester and 2,2-dimethoxyethylamine are ammoniated and cyclized to form a target product, so that the conditions such as adoption of thionyl chloride, high-temperature distillation and the like which are not suitable for industrialized production are avoided, the yield of the reaction is remarkably improved and reaches 75 to 80 percent, and the method is more suitable for large-scale industrialized production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of S 16257-2 key intermediate 7,8-dimethoxy-1, the preparation method of 3-dihydro-2H-3-benzazepine-2-ketone.
Background technology
7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-ketone are the key intermediates of synthetic angina pectoris treatment medicine S 16257-2, and its structural formula is as follows:
US4584293A, CN101607939A and document Spec I f Ic Bradycard I cAgents.1.Chem I stry, Pharmacology, and Structure-Ac I v I ty Relat I onshI ps of Subst I tuted Benzazep I nones, a New Class of Compounds ExertIng Ant II schem I c Propert I es (has medicine and the chemistry thereof of the novel cpd of inhibition ischemic performance as a kind of reducing heart rate, pharmacology and structure activity relationship) J.Med.Chem.1990,33 (5), all disclose 7 among the 1496-1504,8-dimethoxy-1, the preparation method of 3-dihydro-2H-3-benzo-aza-2-ketone.In the above-mentioned document all with 3,4-dimethoxyphenylacetic acid and sulfur oxychloride prepared in reaction 3,4-dimethoxy phenyllacetyl chloride, then with 2, the 2-dimethoxy-ethylamine carries out amination reaction and prepares N-(2, the 2-dimethoxy)-3,4-dimethoxy phenylacetamide, the N-(2 that obtains, the 2-dimethoxy)-3, the cyclisation under the effect of Glacial acetic acid and concentrated hydrochloric acid of 4-dimethoxy phenylacetamide, thus obtain Compound I, yield 58% (with 3,4-dimethoxyphenylacetic acid meter).
In the route of above-mentioned document, because the existence of sulfur oxychloride during reaction, preparation 3, can produce a large amount of hydrogen chloride gas during 4-dimethoxy phenyllacetyl chloride, equipment is had stronger corrodibility and pollutes the environment, and need to carry out operation such as high temperature underpressure distillation in the process of aftertreatment and could obtain comparatively purified product, be unfavorable for so very much suitability for industrialized production, reduced the efficient of producing, and had that environmental pollution is serious, the production cycle long, yield is low and shortcoming such as cost height.
Summary of the invention
The present invention is directed to the deficiency that above-mentioned technology exists, a kind of preparation S 16257-2 key intermediate 7 is provided, 8-dimethoxy-1, the method of 3-dihydro-2H-3-benzazepine-2-ketone, the characteristics of this method are by with 3, the 4-dimethoxyphenylacetic acid activates carboxyl the form that obtains active ester under base catalysis, and then with 2, the 2-dimethoxy-ethylamine carries out ammonification, cyclisation etc. obtain target product, thereby avoided adopting sulfur oxychloride reaction and pyrogenic distillation etc. to be not suitable for carrying out the condition of suitability for industrialized production, reaction yield is obviously improved, reached 75-80%, simultaneously, be fit to technical scale production more.
Concrete technical scheme provided by the invention is: at first make compound ii carboxyl be activated the compound III that obtains the active ester form under base catalysis.
For convenience of description, among the present invention, with 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-ketone abbreviates chemical compounds I as; With 3, the 4-dimethoxyphenylacetic acid is called for short compound ii; Abbreviate the product after the compound ii activation as the compound III; With N-(2, the 2-dimethoxy)-3,4-dimethoxy phenylacetamide abbreviates the compound IV as.
Adopt this preparation technology, with carboxyl is carried out the activatory mode, replaced available technology adopting sulfur oxychloride preparation 3, the mode of 4-dimethoxy phenyllacetyl chloride, make that the technology of preparation is more succinct, and owing to needn't adopt sulfur oxychloride again as reactant, avoided in reaction process, generating a large amount of hydrogen chloride gas, both reduced corrodibility, reduced pollution again, and yield had been higher for environment for equipment, during late phase reaction, needing to avoid operation such as high temperature underpressure distillation could obtain the problem of product, reduced the difficulty of energy consumption and production technique, helped the preparation of chemical compounds I.
After preparing the compound III, again with 2, the 2-dimethoxy-ethylamine carries out aminating reaction and obtains the compound IV with resulting compound III; Annulation takes place with acid in the compound IV, obtains chemical compounds I.Its whole preparation technology's equation is as follows:
Except not adopting this advantage of material of high pollution in preparation compound III, since obtained the compound III have with 3,4-dimethoxy phenyllacetyl chloride is compared better activity, and the compound III that is obtained is without any need for processing, can directly in reacted mixed system, directly carry out next step reaction, thereby be more convenient for and 2, the reaction of 2-dimethoxy-ethylamine, and in the prior art by 3 of sulfur oxychloride preparation, 4-dimethoxy phenyllacetyl chloride need behind the purifying could and 2, the reaction of 2-dimethoxy-ethylamine adopts method of the present invention both to shorten the time of reaction, has improved the yield of reaction again.
In the described step (1) carboxyl being carried out activatory reagent is 2,4-dimethoxy-6-chloro-1,3,5-s-triazine or N, N-two cyclohexyl diimines (DCC) or 1-ethyl-3-(3-dimethylamine propyl) carbodiimide (EDCI) or N, N-carbonyl dimidazoles (CD I), adopt this class activator energy and carboxylic acid to form the higher intermediate product of a kind of activity, such as forming active ester, the intermediate product that obtains can carry out next step reaction again, thereby improved the efficient of reaction, and this activator can not produce other high pollution material, play important role for the environmental protection of whole production technology.
In above-mentioned activating reagent, the contriver has determined when use 2 at last through long-felt, 4-dimethoxy-6-chloro-1,3, and during the 5-s-triazine, the activatory best results.
The described alkali of above-mentioned steps (1) is selected from N-methylmorpholine, triethylamine, Trimethylamine 99, pyridine, piperidines, N, one or more in the N-Dimethylamino pyridine; The reaction solvent of step (1) is selected from one or more in methylene dichloride, ethyl acetate, acetone, tetrahydrofuran (THF), dioxane, methyl alcohol, ethanol or the acetonitrile; The temperature of reaction of step (1) is-20～35 ℃, more preferably adopts-10～20 ℃.
Under above-mentioned temperature, activator, solvent can better contact and react with reactant, prevents the generation of side reaction, thereby improves the efficient of producing.
Comprehensive above-mentioned various alternative conditions, the contriver provides a kind of preparation 7,8-dimethoxy-1, the preferred plan of 3-dihydro-2H-3-benzazepine-2-ketone is as follows:
(1) with 2,4-dimethoxy-6-chloro-1,3, the 5-s-triazine is dissolved in the methylene dichloride, adds compound ii, stirs and cool to 0～10 ℃;
(2) N-methylmorpholine is dissolved in the methylene dichloride, is added drop-wise in the solution of step (1) and reacts, obtain the compound III;
(3) with 2, the 2-dimethoxy-ethylamine is dissolved in the methylene dichloride, is added drop-wise in the reaction solution of completing steps (2), is stirred to reaction and finishes;
(4) with the reacting liquid filtering of step (3), filtrate is used saturated NaHCO successively
3Solution, the NaCl solution washing, drying, suction filtration, underpressure distillation gets the compound IV;
(5) the compound IV is dissolved in the concentrated hydrochloric acid, to wherein dripping Glacial acetic acid, stirring reaction;
(6) reaction solution with step (5) is poured onto in the frozen water, separates out solid, and suction filtration gets chemical compounds I: 7, and 8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-ketone.
In addition, can also adopt activator N, N-dicyclohexyl diimine (DCC) prepares chemical compounds I, and prepared is as follows:
(1) with N, N-dicyclohexyl diimine is dissolved in the methylene dichloride, adds compound ii, stirs and cool to 0～20 ℃, adds 2, and the 2-dimethoxy-ethylamine continues stirring and finishes until reaction;
(2) with the reacting liquid filtering of step (1), filtrate is used saturated NaHCO3 solution successively, the NaCl solution washing, and drying, suction filtration, underpressure distillation gets the compound IV;
(3) the compound IV is dissolved in the concentrated hydrochloric acid, to wherein dripping Glacial acetic acid, stirring reaction;
(4) reaction solution with step (3) is poured onto in the frozen water, separates out solid, and suction filtration gets chemical compounds I.
The compound III can directly be carried out next step reaction among the preparation method of above-claimed cpd I, carries out next step reaction after also can separating again, specifically decides on production technique.
In sum, characteristics of the present invention are to adopt 3, and the 4-dimethoxyphenylacetic acid prepares active ester, and then with 2, the 2-dimethoxy-ethylamine carries out ammonification, cyclisation synthesizes target product under the condition of acid.This method used 2,4-dimethoxy-6-chloro-1,3,5-s-triazine etc. are the conventional reagent that arrives commonly used in producing, be simple and easy to, and working condition is simple, replaced the working condition harshness, the sulfur oxychloride that environmental pollution is serious, and avoided high temperature underpressure distillation etc. to be not suitable for industrialized condition, be a kind of novelty suitable industrialization operation synthetic 7,8-dimethoxy-1, the method for 3-dihydro-2H-3-benzazepine-2-ketone is because its yield height is that route selection is reasonable, reactive behavior is high, reaction yield is obviously improved, reach 75-95%.
Embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
With 2,4-dimethoxy-6-chloro-1,3,5-s-triazine (210.6g) is dissolved in the methylene dichloride of 2L, 3.4-dimethoxyphenylacetic acid (196g) is joined in the above-mentioned dichloromethane solution, stir and lower the temperature 0～10 ℃, N-methylmorpholine (121.2g) is dropped in the above-mentioned system, TLC analyzes raw material 3 after finishing continuation stirring 3h, the 4-dimethoxyphenylacetic acid disappears substantially, and with 2,2-dimethoxy-ethylamine (105g) drops in the reaction solution, finish and continue to stir 2h, TLC analyzes the intermediate activity ester and disappears.Suction filtration, filtrate are used saturated NaHCO successively
3Solution, NaCl solution washing, anhydrous Na
2SO
4Drying, suction filtration, be lower than 45 ℃ subtract steam light yellow blocks of solid 261g (compound IV), yield 92.3%.
Embodiment 2
With N, N-dicyclohexyl diimine (250g) is dissolved in the methylene dichloride of 2L, adds 2 then, and 2-dimethoxy-ethylamine (130g) is lowered the temperature 0～20 ℃ then.Add 3.4-dimethoxyphenylacetic acid (250g) in batches, stir and lower the temperature 10～20 ℃, be stirred to raw material and disappear.Suction filtration with a spot of washed with dichloromethane filter cake, is placed on filtrate static 12h under 0～5 ℃ of condition then, separates out a little white precipitate, filters, and the filtrate evaporate to dryness is obtained (compound IV) 206g, yield 74%.
Embodiment 3
With 2,4-dimethoxy-6-chloro-1,3,5-s-triazine (5.25kg) is dissolved in the methylene dichloride of 30L, 3.4-dimethoxyphenylacetic acid (5kg) is joined in the above-mentioned dichloromethane solution, stir and lower the temperature 0～10 ℃, N-methylmorpholine (3.0kg) is dropped in the above-mentioned system, TLC analyzes raw material 3 after finishing continuation stirring 3h, the 4-dimethoxyphenylacetic acid disappears substantially, and with 2,2-dimethoxy-ethylamine (2.6kg) drops in the reaction solution, finish and continue to stir 2h, TLC analyzes the intermediate activity ester and disappears.Suction filtration, filtrate are used saturated NaHCO successively
3Solution, NaCl solution washing, anhydrous Na
2SO
4Drying, suction filtration, be lower than 45 ℃ subtract steam light yellow blocks of solid 6.579kg (compound IV), yield 93.0%.
Embodiment 4
With 2,4-dimethoxy-6-chloro-1,3,5-s-triazine (210.6g) is dissolved in the methylene dichloride of 2L, 3.4-dimethoxyphenylacetic acid (196g) is joined in the above-mentioned dichloromethane solution,-10～0 ℃ of stirring and cooling, N-methylmorpholine (121.2g) is dropped in the above-mentioned system, TLC analyzes raw material 3 after finishing continuation stirring 3h, the 4-dimethoxyphenylacetic acid disappears substantially, and with 2,2-dimethoxy-ethylamine (105g) drops in the reaction solution, finish and continue to stir 2h, TLC analyzes the intermediate activity ester and disappears.Suction filtration, filtrate are used saturated NaHCO successively
3Solution, NaCl solution washing, anhydrous Na
2SO
4Drying, suction filtration, be lower than 45 ℃ subtract steam light yellow blocks of solid 257.5g (compound IV), yield 91%.
Embodiment 5
With 2,4-dimethoxy-6-chloro-1,3,5-s-triazine (210.6g) is dissolved in the tetrahydrofuran (THF) of 2L, 3.4-dimethoxyphenylacetic acid (196g) is joined in the above-mentioned dichloromethane solution,-10～0 ℃ of stirring and cooling, triethylamine (121.2g) is dropped in the above-mentioned system, TLC analyzes raw material 3 after finishing continuation stirring 3h, the 4-dimethoxyphenylacetic acid disappears substantially, and with 2,2-dimethoxy-ethylamine (105g) drops in the reaction solution, finish and continue to stir 2h, TLC analyzes the intermediate activity ester and disappears.Suction filtration, filtrate are used saturated NaHCO successively
3Solution, NaCl solution washing, anhydrous Na
2SO
4Drying, suction filtration, be lower than 45 ℃ subtract steam light yellow blocks of solid 263g (compound IV), yield 93%.
Embodiment 6
Adopt the foregoing description 3 synthetic compound IV to be dissolved in the 30L concentrated hydrochloric acid, to wherein dripping the 30L Glacial acetic acid, stir 24h then.Reaction solution is poured onto in the 100L frozen water, separates out a large amount of pulverulent solids, suction filtration promptly gets chemical compounds I 4.4kg.Yield 75.0% (in compound ii).
Embodiment 7
With 2,4-dimethoxy-6-chloro-1,3,5-s-triazine (210.6g) is dissolved in the ethyl acetate of 2L, 3.4-dimethoxyphenylacetic acid (196g) is joined in the above-mentioned dichloromethane solution,-20～-10 ℃ of stirring and coolings, Dimethylamino pyridine (244.4g) is dropped in the above-mentioned system, TLC analyzes raw material 3 after finishing continuation stirring 3h, the 4-dimethoxyphenylacetic acid disappears substantially, and with 2,2-dimethoxy-ethylamine (105g) drops in the reaction solution, finish and continue to stir 2h, TLC analyzes the intermediate activity ester and disappears.Suction filtration, filtrate are used saturated NaHCO successively
3Solution, NaCl solution washing, anhydrous Na
2SO
4Drying, suction filtration, be lower than 45 ℃ subtract steam light yellow blocks of solid 263g (compound IV), yield 92.5%.
Embodiment 8
With 2,4-dimethoxy-6-chloro-1,3,5-s-triazine (210.6g) is dissolved in the dioxane of 2L, (196g) joins in the above-mentioned dichloromethane solution with the 3.4-dimethoxyphenylacetic acid, stirs and lowers the temperature 20～35 ℃, and pyridine (160g) is dropped in the above-mentioned system, TLC analyzes raw material 3 after finishing continuation stirring 2h, the 4-dimethoxyphenylacetic acid disappears substantially, and with 2,2-dimethoxy-ethylamine (105g) drops in the reaction solution, finish and continue to stir 2h, TLC analyzes the intermediate activity ester and disappears.Suction filtration, the purified water that adds 5L in the filtrate is mixed, and uses the ethyl acetate extraction twice of 2L then, and the combined ethyl acetate phase is used saturated NaHCO then successively
3Solution, NaCl solution washing, anhydrous Na
2SO
4Drying, suction filtration, be lower than 45 ℃ subtract steam light yellow blocks of solid 263g (compound IV), yield 93.4%.
Comparative example
3.4-dimethoxyphenylacetic acid (196g) is dissolved in the methylene dichloride of 1.5L, stirs, be partly dissolved.10-20 ℃ drips thionyl chloride (258.7g) down, continues at 10-20 ℃ after finishing and stirs 12h down, and the TLC detection reaction is complete, is lower than 45 ℃ of vacuum rotary steams to remove low boiler cut, obtains yellow liquid 188.5g (crude product).Use the oil pump underpressure distillation again, collect 5mmHg/138 ℃ of cut, get garnet oily matter 98.44g, yield 46%.
With above-mentioned obtain 3,4-dimethoxy phenyllacetyl chloride (98.44g) is dissolved in the methylene dichloride of 0.2L, then it is added drop-wise in the dichloromethane solution of the 1L that is made up of triethylamine (69.4g), dimethoxy-ethylamine (58.3g).Dropping temperature 0-10 ℃, TLC analyzes raw material and disappears.With reaction solution water (600ml * 2) washing, collected organic layer adds anhydrous sodium sulfate drying, filters, and filtrate removes solvent under reduced pressure for 45 ℃, gets orange red blocks of solid 124.3g (compound IV), yield 43.9%.(with 3,4-dimethoxyphenylacetic acid meter)
The contrast embodiments of the invention can be seen, the employing sulfur oxychloride that adopts in the comparative example prepares the method for target product, need to adopt steps such as " oil pump underpressure distillation ", than the present invention, step complex operations difficulty, and the final product yield that obtains is lower, and owing in preparation process, can produce a large amount of hydrogen chloride gas, can cause bigger influence to conversion unit, thereby improve production cost, be unfavorable for development of technology and development.
Claims (10)
1. one kind 7,8-dimethoxy-1, the preparation method of 3-dihydro-2H-3-benzazepine-2-ketone comprises the preparation of compound III, it is characterized in that the preparation process of described compound III is as follows:
Wherein compound ii activates carboxyl the compound III that obtains the active ester form under alkaline matter catalysis.
2. according to claim 17,8-dimethoxy-1, the preparation method of 3-dihydro-2H-3-benzazepine-2-ketone is characterized in that: resulting compound III is again with 2, and the 2-dimethoxy-ethylamine carries out aminating reaction and obtains the compound IV; Annulation takes place with acid in the compound IV, obtains chemical compounds I.
3. according to claim 1 and 27,8-dimethoxy-1, the preparation method of 3-dihydro-2H-3-benzazepine-2-ketone, it is characterized in that: in the described step (1) carboxyl being carried out activatory reagent is 2,4-dimethoxy-6-chloro-1,3,5-s-triazine or N, N-dicyclohexyl diimine or 1-ethyl-3-(3-dimethylamine propyl) carbodiimide or N, the N-carbonyl dimidazoles.
4. according to claim 37,8-dimethoxy-1, the preparation method of 3-dihydro-2H-3-benzazepine-2-ketone is characterized in that: in the described step (1) carboxyl being carried out activatory reagent is 2,4-dimethoxy-6-chloro-1,3,5-s-triazine.
5. according to claim 1 and 27,8-dimethoxy-1, the preparation method of 3-dihydro-2H-3-benzazepine-2-ketone, it is characterized in that: the described alkaline matter of described step (1) is N-methylmorpholine or triethylamine or Trimethylamine 99 or pyridine or piperidines or N, in the N-Dimethylamino pyridine or its mixture.
6. according to claim 1 and 27,8-dimethoxy-1, the preparation method of 3-dihydro-2H-3-benzazepine-2-ketone is characterized in that: the reaction solvent in the described step (1) is selected from methylene dichloride or ethyl acetate or acetone or tetrahydrofuran (THF) or dioxane or methyl alcohol or ethanol or acetonitrile or its mixture.
7. according to claim 1 and 27,8-dimethoxy-1, the preparation method of 3-dihydro-2H-3-benzazepine-2-ketone is characterized in that: the temperature of reaction of step (1) is-20～35 ℃, preferred-10～20 ℃.
8. according to claim 1 and 27,8-dimethoxy-1, the preparation method of 3-dihydro-2H-3-benzazepine-2-ketone, it is characterized in that: concrete steps are as follows:
(1) with 2,4-dimethoxy-6-chloro-1,3, the 5-s-triazine is dissolved in the methylene dichloride, adds compound ii, stirs and cool to 0～10 ℃;
(2) N-methylmorpholine is dissolved in the methylene dichloride, is added drop-wise in the solution of step (1) and reacts, be stirred to compound ii and disappear and to obtain the compound III;
(3) with 2, the 2-dimethoxy-ethylamine is dissolved in the methylene dichloride, is added drop-wise in the reaction solution of completing steps (2), is stirred to the compound III and disappears;
(4) with the reacting liquid filtering of step (3), filtrate is used saturated NaHCO successively
3Solution, the NaCl solution washing, drying, suction filtration, underpressure distillation gets the compound IV;
(5) the compound IV is dissolved in the concentrated hydrochloric acid, to wherein dripping Glacial acetic acid, stirring reaction;
(6) reaction solution with step (5) is poured onto in the frozen water, separates out solid, and suction filtration gets chemical compounds I: 7, and 8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-ketone.
9. according to claim 27,8-dimethoxy-1, the preparation method of 3-dihydro-2H-3-benzazepine-2-ketone is characterized in that: the compound III can directly prepare the compound IV in solvent, also can separate back refabrication compound IV from solvent.
10. according to claim 27,8-dimethoxy-1, the preparation method of 3-dihydro-2H-3-benzazepine-2-ketone is characterized in that: chemical compounds I is 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-ketone; Compound ii is 3, the 4-dimethoxyphenylacetic acid; The compound III is the product after the compound ii activation; The compound IV is N-(2, the 2-dimethoxy)-3,4-dimethoxy phenylacetamide.
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| CN114324715A (en) * | 2021-01-05 | 2022-04-12 | 海南鑫开源医药科技有限公司 | Method for detecting related substances in 7, 8-dimethoxy-1, 3-dihydro-2H-3-benzazepin-2-ketone |
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| CN1958570A (en) * | 2006-05-25 | 2007-05-09 | 药源药物化学（上海）有限公司 | Method for preparing ropinirole |
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| CN1958570A (en) * | 2006-05-25 | 2007-05-09 | 药源药物化学（上海）有限公司 | Method for preparing ropinirole |
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| HONG-YU LIANG ET AL.: "Synthesis and Biological Activity of Some 1,3-Dihydro-2H-3-benzazepin-2-ones with a Piperazine Moiety as Bradycardic Agents", 《ARCH. PHARM. CHEM. LIFE SCI.》, vol. 343, 28 February 2010 (2010-02-28), pages 114 - 119 * |
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| CN114324715A (en) * | 2021-01-05 | 2022-04-12 | 海南鑫开源医药科技有限公司 | Method for detecting related substances in 7, 8-dimethoxy-1, 3-dihydro-2H-3-benzazepin-2-ketone |
| CN114324715B (en) * | 2021-01-05 | 2023-06-02 | 海南鑫开源医药科技有限公司 | Detection method of related substances in 7, 8-dimethoxy-1, 3-dihydro-2H-3-benzazepin-2-ketone |
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