CN103183629A - Process of effectively synthesizing important pharmaceutical and chemical intermediate 5-bromoindole - Google Patents
Process of effectively synthesizing important pharmaceutical and chemical intermediate 5-bromoindole Download PDFInfo
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- CN103183629A CN103183629A CN2013100822302A CN201310082230A CN103183629A CN 103183629 A CN103183629 A CN 103183629A CN 2013100822302 A CN2013100822302 A CN 2013100822302A CN 201310082230 A CN201310082230 A CN 201310082230A CN 103183629 A CN103183629 A CN 103183629A
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- bromo indole
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- sodium sulfonate
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Abstract
The invention relates to a process of synthesizing an important pharmaceutical and chemical intermediate 5-bromoindole, and belongs to the technical field of organic synthesis. Step 1, the sodium sulfonate substitution reaction is carried out to indole used as the raw material to obtain 2-sodium sulfonate-indole, step 2, the 2-sodium sulfonate-indole reacts with an acylation reagent to obtain 2-sodium sulfonate-1-chloracetylindole, and step 3, finally, the 2-sodium sulfonate-1-chloracetylindole is subject to addition reaction with bromine to produce 5-bromoindole; the process is mainly characterized in that the atom utilization ratio in the reaction process is high, the solvent can be reused, and is environment-friendly; and in the addition reaction in step 2 and step 3, water is used as the reaction medium, therefore, the cost is reduced, and the after-treatment is simple. The preparation method is easily obtained in raw material, mild in conditions, high in process operability and controllability, low in cost and high in yield, and the high-purity 5-bromoindole can be obtained without complex after-treatment.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to a kind of high-efficiency synthesis method of 5-bromo indole.
Background technology
The 5-bromo indole, it is a kind of intermediate very widely that in preventing and treating medicines such as cardiovascular disorder, sacred disease, tumour and strengthening immunity, uses, one of its important use is the combination colour aminated compounds, wherein melatonin and derivative thereof are being regulated circadian rhythm and sleep, and anti-tumor aspect is very effective.5-methoxyl group-2-phenyl tryptamines has antitumous effect.Serotonine is having special effect aspect the control craving for tobacco, at aspects such as cardiovascular disorder and mental disorder control and anti-genovariations obvious effect is arranged also.
At present 5-bromo indole production technique have that solvent-oil ratio is big, Atom economy is low, cost is high, to many deficiencies such as environment are unfriendly.It does not still have mass-producing at home and abroad and produces report; we are on the basis of reference lot of documents, and having designed improved is the synthetic method of the synthetic 5-bromo indole of raw material with the indoles, has improved the friendliness to environment greatly; reduce production cost, be fit to suitability for industrialized production.
Summary of the invention
It is big to the objective of the invention is to overcome the solvent-oil ratio that exists in the prior art, the cost height, problems such as environmental pollution, provide a kind of easy to operate, raw material is easy to get, the efficient synthesis technique of the 5-bromo indole of yield height, purity is good, energy consumption is low suitable suitability for industrialized production, wherein synthetic route is seen accompanying drawing 1.
Concrete, a kind of efficient synthesis technique of 5-bromo indole, it comprises following a few step:
The first step, the preparation of 2-sodium sulfonate-indoles: it is that indoles is dissolved in the polar aprotic solvent, with Potassium hydrogen sulfite or aqueous solution of sodium bisulfite at 35 ℃ of reaction 10～15h, after reaction finishes, suction filtration dry 2-sodium sulfonate-indoles (hereinafter to be referred as intermediate compound I); Wherein polar aprotic solvent is advisable with alcohols, and its consumption is 2～3 times of indoles weight.
Second step, the preparation of 2-sodium sulfonate-1-chloracetyl indoles: intermediate compound I is mixed afterwards 60～70 ℃ react 1.5～2.5h with acyl chlorides, be cooled to room temperature after having reacted, suction filtration, dry 2-sodium sulfonate-1-chloracetyl indoles (hereinafter to be referred as intermediate II); Wherein the amount of acyl chlorides is 5～6 times of intermediate compound I weight.
The 3rd step, synthesizing of 5-bromo indole: the water that intermediate II is dissolved in 3～5 times of amounts, not being higher than 5 ℃ of dropping bromines maintenance 1～1.5h, rise to room temperature, continue reflection 0.5～1h, after adding sodium bisulfite or Potassium hydrogen sulfite reactant aqueous solution 5～10min, add sodium hydroxide or potassium hydroxide aqueous solution backflow 15～20h, reaction solution cooling, suction filtration, washing, oven dry had both got product 5-bromo indole; Wherein bromine refers to liquid bromine simple substance (Br
2).Sodium bisulfite or bisulfite potassium application rate are 0.2～0.25 times of intermediate II weight.
The above, the mass concentration of the first step and employed sodium bisulfite of the 3rd step or bisulfite aqueous solutions of potassium is 10%～30%, addition is 1～3 times of indoles weight, the mass concentration of employed sodium hydroxide of the 3rd step or potassium hydroxide aqueous solution is 5%～15%, and addition is 1～1.5 times of intermediate II weight.
Polar aprotic solvent described in the first step can be selected from one or more in methyl alcohol, ethanol, propyl alcohol, the glycerol; second step, employed acylating reagent was chloroacetyl chloride; chlorpromazine chloride; in the tert-Butyl dicarbonate etc. one or both; more than second step and the 3rd go on foot described wet concentration and get final product from tap water; by using alcohols and water to be reaction solvent; significantly reduced the pollution to environment; reduction is to the requirement of production unit; simultaneously; the first step mother liquor can recycle, has reduced production cost.
The sodium bisulfite or the bisulfite aqueous solutions of potassium amount that add in the 3rd step have great effect to reaction, and through experimental results demonstrate, as if consumption very little, then the cooling back easily produces bulk, is unfavorable for reaction.
Step involved in the present invention is easy to operate, mild condition, by using methyl alcohol, water etc. be simple and easy to solvent as reaction system, greatly reduced and produced the requirement of going up for equipment, methyl alcohol can also recycle, has reduced production cost, has reduced environmental pollution.This technology can realize large-scale industrial production, the product production height, and the purity height, energy consumption is low.
Description of drawings
Fig. 1 is the building-up reactions formula of 5-bromo indole.
Embodiment
Below by several preferred embodiments synthetic method of the present invention is elaborated, but protection scope of the present invention is not limited thereto.
Embodiment 1:
The preparation of 5-bromo indole
The first step, preparation 2-sodium sulfonate-indoles: the bisulfite aqueous solutions of potassium that adds 80mL massfraction 23% in the there-necked flask of 250ml, slowly drip under the room temperature and be dissolved in the 25ml ethanolic soln by 11.7g (0.1mol) indoles, dropwise the back in 35 ℃ the reaction 12h, the reaction finish afterreaction liquid through suction filtration, washing, dry 23.3g silver yellow look intermediate compound I.
Second step; preparation 2-sodium sulfonate-1-chloracetyl indoles: add the 150ml chloroacetyl chloride in the 250ml there-necked flask, 23.9g intermediate compound I (0.1mol) is warming up to 68 ℃ of reaction 2.5h; be cooled to room temperature after reaction finishes, filter, wash, dry 29g white solid intermediate II.
The 3rd step, preparation 5-bromo indole: in the 500ml there-necked flask, add 85ml water, 20.6g (0.0675mol) intermediate II, 0 ℃ drips 11.9g (0.01438mol) bromine, drips off with 45min, and maintenance reaction 40min, the bisulfite aqueous solutions of potassium that adds 28g massfraction 10% behind the reaction 5min, adds the potassium hydroxide aqueous solution backflow 16h of 30g massfraction 6% again, reaction finishes after-filtration, washing, dry 12.8g grey crystal, be 5-bromo indole (purity 99.7%).
Embodiment 2:
The preparation of 5-bromo indole
The first step, preparation 2-sodium sulfonate-indoles: the bisulfite aqueous solutions of potassium that adds 160mL massfraction 24% in the there-necked flask of 500ml, slowly drip the solution that is dissolved in 52ml ethanol by 23.4g (0.2mol) indoles under the room temperature, dropwise the back in 35 ℃ the reaction 12h, the reaction finish afterreaction liquid through suction filtration, washing, dry 46.4g silver yellow look intermediate compound I.
Second step; preparation 2-sodium sulfonate-1-propionyl indoles: add the 300ml propionyl chloride in the 500ml there-necked flask, 47.8g intermediate compound I (0.2mol) is warming up to 68 ℃ of reaction 2.5h; be cooled to room temperature after reaction finishes, filter, wash, dry 57.8g white solid intermediate II.
The 3rd step, preparation 5-bromo indole: in the 1000ml there-necked flask, add 160ml water, 41.2g (0.135mol) intermediate II, 0 ℃ drips 23.8g (0.02876mol) bromine, drips off with 45min, and maintenance reaction 40min, the bisulfite aqueous solutions of potassium that adds 57g massfraction 10% behind the reaction 5min, adds the potassium hydroxide aqueous solution backflow 16h of 58g massfraction 6% again, reaction finishes after-filtration, washing, dry 25.3g lead crystal, be 5-bromo indole (purity 99.4%).
Embodiment 3:
The preparation of 5-bromo indole
The first step, preparation 2-sodium sulfonate-indoles: the aqueous solution of sodium bisulfite that adds 160mL massfraction 22% in the there-necked flask of 5L, slowly drip the solution that is dissolved in 500ml methyl alcohol by 234g (2mol) indoles under the room temperature, dropwise the back in 35 ℃ the reaction 12h, the reaction finish afterreaction liquid through suction filtration, washing, dry 465g silver yellow look intermediate compound I.
Second step; preparation 2-sodium sulfonate-1-ethanoyl indoles: add the 3000ml Acetyl Chloride 98Min. in the 5L there-necked flask, 478g intermediate compound I (2mol) is warming up to 68 ℃ of reaction 2.5h; be cooled to room temperature after reaction finishes, filter, wash, dry 579g white solid intermediate II.
The 3rd step, preparation 5-bromo indole: in the 10L there-necked flask, add 1700ml water, 412.5g (1.35mol) intermediate II, 0 ℃ drips 238g (0.2876mol) bromine, drips off with 45min, and maintenance reaction 40min, the aqueous solution of sodium bisulfite that adds 560g massfraction 10% behind the reaction 5min, adds the aqueous sodium hydroxide solution backflow 16h of 145g massfraction 6% again, reaction finishes after-filtration, washing, dry 253.2g canescence crystal, be 5-bromo indole (purity 99.5%).
Each raw material and solvent that the present invention is cited can both be realized the present invention, and yield is between 88%-93%, and purity＞98% (HPLC normalization method) is not just enumerated one by one at this.
Claims (7)
1. the efficient synthesis technique of an important pharmaceutical-chemical intermediate 5-bromo indole; it is characterized in that it being that indoles is dissolved in the polar aprotic solvent; under 35 ℃ of conditions with sodium bisulfite or Potassium hydrogen sulfite reactant aqueous solution 10～15h; then suction filtration dry 2-sodium sulfonate-indoles (hereinafter to be referred as intermediate compound I); intermediate compound I is mixed with acylating reagent; at 65～75 ℃ of reaction 1.5～2.5h; cooling then; suction filtration; dry 2-sodium sulfonate-1-chloracetyl indoles (hereinafter to be referred as intermediate II); intermediate II is dissolved in the water of 3～5 times of amounts; not being higher than 5 ℃ of dropping bromines maintenance 1～1.5h, rise to room temperature, continue reaction 0.5～1h; after adding sodium bisulfite or Potassium hydrogen sulfite reactant aqueous solution 5～10min; add sodium hydroxide or potassium hydroxide aqueous solution backflow 15～20h, reaction solution cooling, suction filtration; washing, oven dry namely gets product 5-bromo indole.
2. the synthetic method of 5-bromo indole according to claim 1 is characterized in that described sodium bisulfite or Potassium hydrogen sulfite mass concentration are 10%～30%.
3. the synthetic method of 5-bromo indole according to claim 1 is characterized in that described polar aprotic solvent is methyl alcohol, ethanol, one or more in methyl alcohol, ethanol, propyl alcohol, the glycerol; Every gram indoles adds 3～5ml polar aprotic solvent.
4. the synthetic method of 5-bromo indole according to claim 1 is characterized in that described acylating reagent is chloroacetyl chloride, one or more in chlorpromazine chloride, the tert-Butyl dicarbonate; Its consumption is 5～6 times of intermediate compound I weight.
5. the synthetic method of 5-bromo indole according to claim 1, the mass concentration that it is characterized in that described potassium hydroxide or aqueous sodium hydroxide solution is 5%～15%, addition is 1～1.5 times of intermediate II weight.
6. the synthetic method of 5-bromo indole according to claim 1 is characterized in that sodium bisulfite in the described final step or Potassium hydrogen sulfite amount of aqueous solution used are 0.2～0.25 times of intermediate II weight.
7. the synthetic method of 5-bromo indole according to claim 1 is characterized in that the polar aprotic solvent of the synthetic middle indoles of intermediate compound I adds in sodium bisulfite or the bisulfite aqueous solutions of potassium in the mode that drips in 0.5～1h.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103539720A (en) * | 2013-10-08 | 2014-01-29 | 常州大学 | Method for preparing 1-phenylindole |
| CN106432040A (en) * | 2016-08-09 | 2017-02-22 | 中钢集团鞍山热能研究院有限公司 | Environment-friendly synthesis method for medicine intermediate 5-bromoindole |
| CN107915670A (en) * | 2017-11-03 | 2018-04-17 | 苏州艾缇克药物化学有限公司 | A kind of preparation method of 5 bromo indole |
| CN114149356A (en) * | 2021-11-18 | 2022-03-08 | 安徽益多康尔医药科技有限公司 | Preparation method of methyl indolcarbate compound |
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| CN85101761A (en) * | 1984-08-17 | 1987-02-04 | 特罗本维克有限公司和科隆分公司 | The preparation method of novel tryptamines derivative and application |
| CN102558017A (en) * | 2011-12-27 | 2012-07-11 | 郑州凯美克化学有限公司 | Method for preparing 5-bromoindole |
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| CN85101761A (en) * | 1984-08-17 | 1987-02-04 | 特罗本维克有限公司和科隆分公司 | The preparation method of novel tryptamines derivative and application |
| CN102558017A (en) * | 2011-12-27 | 2012-07-11 | 郑州凯美克化学有限公司 | Method for preparing 5-bromoindole |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103539720A (en) * | 2013-10-08 | 2014-01-29 | 常州大学 | Method for preparing 1-phenylindole |
| CN103539720B (en) * | 2013-10-08 | 2016-06-08 | 常州大学 | A kind of method preparing 1-Phenylindole |
| CN106432040A (en) * | 2016-08-09 | 2017-02-22 | 中钢集团鞍山热能研究院有限公司 | Environment-friendly synthesis method for medicine intermediate 5-bromoindole |
| CN106432040B (en) * | 2016-08-09 | 2019-02-19 | 中钢集团鞍山热能研究院有限公司 | A kind of green synthesis method of medicine intermediate 5- bromo indole |
| CN107915670A (en) * | 2017-11-03 | 2018-04-17 | 苏州艾缇克药物化学有限公司 | A kind of preparation method of 5 bromo indole |
| CN114149356A (en) * | 2021-11-18 | 2022-03-08 | 安徽益多康尔医药科技有限公司 | Preparation method of methyl indolcarbate compound |
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Application publication date: 20130703 |