CN102040507A - Preparation methods of 7-phenyl-6-heptynoic acid and reactant of sodium 5-bromo-pentanoate - Google Patents
Preparation methods of 7-phenyl-6-heptynoic acid and reactant of sodium 5-bromo-pentanoate Download PDFInfo
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- CN102040507A CN102040507A CN200910196951XA CN200910196951A CN102040507A CN 102040507 A CN102040507 A CN 102040507A CN 200910196951X A CN200910196951X A CN 200910196951XA CN 200910196951 A CN200910196951 A CN 200910196951A CN 102040507 A CN102040507 A CN 102040507A
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Abstract
The invention provides a preparation method of 7-phenyl-6-beptynoic acid, characterized by comprising processing NaH or KH with DMSO or a solvent containing DMSO therefore to obtain a sodium salt or a sylvite of DMSO, adding phenylacetylene to obtain a sodium phenylacetylide suspension or a potassium phenylacetylide suspension, adding 5-bromo pentanoic acid or sodium 5-bromo-pentanoate to generate 7-phenyl-6-beptynoic acid sodium or potassium, and processing the resultant by adjusting the pH value with acid therefore to obtain 7-phenyl-6-beptynoic acid. The invention also provides a preparation method for a reactant of 7-phenyl-6-beptynoic acid sodium 5-bromo-pentanoate, characterized by comprising: cooling a methyl acetate solution of sodium iso-octoate using ice water under stirring to a temperature of 0 DEG C to 5 DEG C, adding 5-bromo pentanoic acid by batch, stirring for 5 to 20 minutes, precipitating a large quantity of white solid, filtering, pumping the resultant till dry, leaching by using methyl acetate, and drying under vacuum therefore to obtain sodium 5-bromo-pentanoate. The invention is advantageous in that: the raw materials are cheap and easily available, the synthesis route is short, the cost is low, the quality of the product is good, and the invention is economical and efficient.
Description
Technical field
The present invention relates to a kind of phenyl capsicine intermediate preparation method, be specifically related to the preparation method of a kind of 7-phenyl-6-heptynoic acid, the present invention also relates to the preparation method of the reactant 5-bromine natrium valericum in preparation 7-phenyl-6-heptynoic acid.
Background technology
The compound that the present invention relates to is 7-phenyl-6-heptynoic acid, this Compound C AS registration number 49769-28-0, concrete structure as shown in Equation 1:
This compound is the key intermediate of phenyl capsicine (phenylcapsaicin).The concrete structure of phenyl capsicine is mainly used in the production of antifouling varnish as shown in Equation 2 at present.
The characteristic that the main additive TBT (tributyl tin) of tradition antifouling varnish poisons environment is proved fully, and is forbidden the substitute products that market in urgent need is new in beginning in 2008 comprehensively.At present, had the antifouling varnish manufacturer to use artificial synthetic natural capsicine or its analogue to substitute TBT, its anti-pollution function gets the nod.But currently marketed these capsicine products are owing to the inherent nature of itself, and the effect that substitutes TBT is not very desirable, and the technical actual requirement that can not satisfy the client well is big as the desired additives amount, loss excessive velocities etc.And the phenyl capsicine possesses the anti-fouling effect ideal, is difficult for running off, and renders a service persistent characteristics, is rare in the market outstanding TBT substitute, and market outlook are good.
The key intermediate of synthesis of phenyl capsicine is 7-phenyl-6-heptynoic acid, existing many pieces of documents and patent its synthetic method of having reported for work.
About synthesizing of 7-phenyl-6-heptynoic acid, report the earliest is seen in Journalof Heterocyclic Chemistry Vol 10 (1973) pp 655 that deliver in Lalezari etc., this article author adopts the method for the assorted imdazole derivatives of pyrolysis 3-selenium to obtain 7-phenyl-6-heptynoic acid, and reaction formula is as follows.This method obviously is not suitable for suitability for industrialized production.
International Patent Application WO 2005025314 had been reported a kind of synthetic method in 2005, and reaction formula is as follows.
This method is that starting raw material reacts through 5 steps altogether with the 5-chlorine amylalcohol of less stable, prepares 7-phenyl-6-heptynoic acid.This method synthetic route is long, the cost height.Wherein the 5th step oxidizing reaction is difficult to realize suitability for industrialized production, is oxygenant because use human body, the great chromium of environmental hazard.Because the phenylacetylene group to other a lot of oxidising agent sensitivities, realizes that with other method this conversion is difficult to obtain promising result.
People such as Yamamoto in 2006 reported another kind of synthetic method (J.Org.Chem.2006,71,3612-3614), concrete synthetic method is as follows.
This method desired raw material is difficult to obtain, and does not have commercial 6-alkynes enanthic acid Industrial products to sell.
Summary of the invention
Technical problem to be solved by this invention is to provide the preparation method of a kind of 7-phenyl-6-heptynoic acid, and to solve the existing many weak points of preparation of existing 7-phenyl-6-heptynoic acid: synthetic route is long, the cost height; Very big to human body, environmental hazard, test effect is poor; Raw material is difficult to obtain, and does not have commercialization.The present invention is the synthetic method of a kind of phenyl of 7-cheaply-6-heptynoic acid, is applicable to suitability for industrialized production.
The technical problem that will solve required for the present invention can be achieved through the following technical solutions:
As a first aspect of the present invention, the preparation method of a kind of 7-phenyl-6-heptynoic acid is characterized in that,
NaH or KH with DMSO or contain the solvent treatment of DMSO, are obtained sodium/sylvite of DMSO, add phenylacetylene, obtain phenylacetylene sodium/potassium suspension;
Add 5-bromine valeric acid or 5-bromine natrium valericum to described suspension, generate 7-phenyl-6-heptynoic acid sodium/potassium, handle promptly getting 7-phenyl-6-heptynoic acid through acid adjustment, reaction formula is as follows:
The ratio of described phenylacetylene and described 5-bromine valeric acid or 5-bromine natrium valericum is 1: 1-5: 1.
Described acid is 30% concentrated hydrochloric acid.
As a second aspect of the present invention, a kind of preparation method who prepares the reactant 5-bromine natrium valericum of 7-phenyl-6-heptynoic acid, it is characterized in that, the methyl acetate solution of Sodium isooctanoate is cooled to 0～5 ℃, add 5-bromine valeric acid in batches, separate out a large amount of white solids, filtration is drained, methyl acetate drip washing, vacuum-drying get 5-bromine natrium valericum.
The ratio of described Sodium isooctanoate and 5-bromine valeric acid is 1: 2-2: 1.
Beneficial effect of the present invention:
Method raw material of the present invention is cheap and easy to get, and synthetic route is short, and cost is low, good product quality, economical and efficient.
Embodiment
In order to make technique means of the present invention, creation characteristic, to reach purpose and effect is easy to understand,, further set forth the present invention below in conjunction with specific embodiment.
Embodiment 1
The preparation method of 7-phenyl-6-heptynoic acid uses sodium salt or the sylvite and the reaction of 5-bromine valeric acid of phenylacetylene, and acidifying obtains 7-phenyl-6-heptynoic acid, and concrete steps are as follows:
10.0g 60%NaH is added in 100ml DMSO and the 100ml glycol dimethyl ether mixed solution, be heated to 65～70 ℃ of insulation reaction 45min, be cooled to room temperature then.The frozen water cooling slowly adds the 15.3g phenylacetylene down in gained solution, obtain phenylacetylene sodium suspension.
Then add 5-bromine valeric acid 18.1g in batches.Adding finishes, stirring at room reaction 3 hours.Reclaim under reduced pressure DMSO adds 150ml water, stir process 15min, and 30% concentrated hydrochloric acid is regulated pH to 1.0～3.0, adds the 200ml isopropyl ether, stirs extraction 10min.Wash three times, anhydrous sodium sulfate drying is concentrated into the about 25ml of volume after the filtration, and crystallization is 2 hours under the frozen water cooling, filters and obtains 7-phenyl-6-heptynoic acid sodium white crystalline solid 7.7g, 69.5～73 ℃ of fusing points, HPLC content 99.6%, yield 44%.
Embodiment 2
The preparation method of 7-phenyl-6-heptynoic acid uses sodium salt or the sylvite and the reaction of 5-bromine natrium valericum of phenylacetylene, and acidifying obtains 7-phenyl-6-heptynoic acid, and concrete steps are as follows:
6.0g 60%NaH is added in 100ml DMSO and the 100ml glycol dimethyl ether mixed solution, be heated to 65～70 ℃ of insulation reaction 45min, be cooled to room temperature then.The frozen water cooling slowly adds the 15.3g phenylacetylene down in gained solution, obtain phenylacetylene sodium suspension.
Then add 5-bromine natrium valericum 20.3g in batches.Adding finishes, stirring at room reaction 3 hours.Reclaim under reduced pressure DMSO adds 150ml water, stir process 15min, and 30% concentrated hydrochloric acid is regulated pH to 1.0～3.0, adds the 200ml isopropyl ether, stirs extraction 10min.Wash three times, anhydrous sodium sulfate drying is concentrated into the about 25ml of volume after the filtration, and crystallization is 2 hours under the frozen water cooling, filters and obtains 7-phenyl-6-heptynoic acid sodium white crystalline solid 7.1g, HPLC content 99.5%, yield 35%.
Embodiment 3
The preparation of 5-bromine natrium valericum uses Sodium isooctanoate to be raw material, carries out the sodium ion exchange with 5-bromine valeric acid, and concrete steps are as follows:
250ml methyl acetate solution frozen water under stirring of 16.3g Sodium isooctanoate is cooled to 0～5 ℃, adds 5-bromine valeric acid 17.0g in batches, separate out a large amount of white solids, filtration is drained, and methyl acetate drip washing, vacuum-drying get 5-bromine natrium valericum 18.1g, yield 95%.
Compare with existing open synthetic method, method raw material of the present invention is cheap and easy to get, and synthetic route is short, and cost is low, good product quality, economical and efficient.
More than show and described ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in the foregoing description and the specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (4)
1. the preparation method of 7-phenyl-6-heptynoic acid is characterized in that,
NaH or KH with DMSO or contain the solvent treatment of DMSO, are obtained sodium/sylvite of DMSO, add phenylacetylene, obtain phenylacetylene sodium/potassium suspension;
Add 5-bromine valeric acid or 5-bromine natrium valericum to described suspension, generate 7-phenyl-6-heptynoic acid sodium/potassium, handle promptly getting 7-phenyl-6-heptynoic acid through acid adjustment, reaction formula is as follows:
2. the preparation method of 7-phenyl according to claim 1-6-heptynoic acid is characterized in that, the ratio of described phenylacetylene and described 5-bromine valeric acid or 5-bromine natrium valericum is 1: 1-5: 1.
3. preparation method who prepares the reactant 5-bromine natrium valericum of 7-phenyl-6-heptynoic acid according to claim 1, it is characterized in that, methyl acetate solution frozen water under stirring of Sodium isooctanoate is cooled to 0～5 ℃, add 5-bromine valeric acid in batches, separate out a large amount of white solids, filtration is drained, and methyl acetate drip washing, vacuum-drying get 5-bromine natrium valericum.
4. the preparation method of 5-bromine natrium valericum according to claim 3 is characterized in that, the ratio of described Sodium isooctanoate and 5-bromine valeric acid is 1: 2-2: 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111925285A (en) * | 2019-05-13 | 2020-11-13 | 上海北卡医药技术有限公司 | Preparation method of 7-phenyl-6-heptynoic acid |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3911038A (en) * | 1974-03-25 | 1975-10-07 | American Cyanamid Co | Process for making bis(phenylethylnyl)anthracenes |
| CN1594324A (en) * | 2004-07-07 | 2005-03-16 | 广州白云山医药科技发展有限公司 | Process for preparing cefpiramide sodium |
| CN1849068A (en) * | 2003-09-12 | 2006-10-18 | 阿克西迈德股份有限公司 | Capsaicin derivates and the production and use thereof |
| CN1852707A (en) * | 2003-04-08 | 2006-10-25 | 阿尔高克斯制药公司 | Preparation and purification of synthetic capsaicin |
| CN1995043A (en) * | 2006-12-29 | 2007-07-11 | 珠海联邦制药股份有限公司 | Preparation process of ticarcillin disodium salt |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3911038A (en) * | 1974-03-25 | 1975-10-07 | American Cyanamid Co | Process for making bis(phenylethylnyl)anthracenes |
| CN1852707A (en) * | 2003-04-08 | 2006-10-25 | 阿尔高克斯制药公司 | Preparation and purification of synthetic capsaicin |
| CN1849068A (en) * | 2003-09-12 | 2006-10-18 | 阿克西迈德股份有限公司 | Capsaicin derivates and the production and use thereof |
| CN1594324A (en) * | 2004-07-07 | 2005-03-16 | 广州白云山医药科技发展有限公司 | Process for preparing cefpiramide sodium |
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Non-Patent Citations (2)
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| NITIN T.PATIL等: "Lactam Synthesis via the Intramolecular Hydroamidation of Alkynes Catalyzed by Palladium Complexes", 《J.ORG.CHEM.》 * |
| 曲富军: "5-溴戊酸的合成研究", 《化工矿物与加工》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111925285A (en) * | 2019-05-13 | 2020-11-13 | 上海北卡医药技术有限公司 | Preparation method of 7-phenyl-6-heptynoic acid |
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Effective date of registration: 20170918 Address after: Taizhou City, Zhejiang province 317016 coastal city waterfront Toumen Port District Du Sichuan Road No. 32 Patentee after: Zhejiang state rich Biotechnology Co., Ltd. Address before: 318000 No. 56 Binhai Road, rock head industrial zone, Jiaojiang District, Zhejiang, Taizhou Patentee before: Taizhou City Hwasun Pharmacuetical and Chemical Co., Ltd. |
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