CN102040507B - 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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- CN102040507B CN102040507B CN200910196951XA CN200910196951A CN102040507B CN 102040507 B CN102040507 B CN 102040507B CN 200910196951X A CN200910196951X A CN 200910196951XA CN 200910196951 A CN200910196951 A CN 200910196951A CN 102040507 B CN102040507 B CN 102040507B
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- 0 *CCCCCOC1OCCCC1 Chemical compound *CCCCCOC1OCCCC1 0.000 description 1
- CSHMODDFNBAYFB-UHFFFAOYSA-N CC(C)(CCOC1OCCCC1)C#Cc1ccccc1 Chemical compound CC(C)(CCOC1OCCCC1)C#Cc1ccccc1 CSHMODDFNBAYFB-UHFFFAOYSA-N 0.000 description 1
- LMUWFXQGRIPPJK-UHFFFAOYSA-N CCCCCCOC1OCCCC1 Chemical compound CCCCCCOC1OCCCC1 LMUWFXQGRIPPJK-UHFFFAOYSA-N 0.000 description 1
- ADDXPYNQJQNEPZ-UHFFFAOYSA-N OC(CC#Cc1ccccc1)=O Chemical compound OC(CC#Cc1ccccc1)=O ADDXPYNQJQNEPZ-UHFFFAOYSA-N 0.000 description 1
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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 capsaicin midbody 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 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 capsaicin (phenylcapsaicin).The concrete structure of phenyl capsaicin as shown in Equation 2, is mainly used in the production of antifouling varnish at present.
The characteristic that the main additive TBT (tributyl tin) of tradition antifouling varnish poisons environment is proved fully, and was started forbidding comprehensively, the substitute products that market in urgent need is new in 2008.At present, had the antifouling varnish manufacturer to use the natural capsicine of synthetic or its analogue to substitute TBT, its anti-pollution function gets the nod.But currently marketed these capsicine products are due to the inherent nature of itself, and the effect that substitutes TBT is not very desirable, and the technical actual requirement that can not meet well the client is as large as the desired additives amount, loss excessive velocities etc.And phenyl capsaicin possesses the anti-fouling effect ideal, be difficult for to run off, the characteristics that effect is lasting, be rare outstanding TBT substitute in the market, 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 Lalezari etc. delivers, 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.The method obviously is not suitable for suitability for industrialized production.
Within 2005, International Patent Application WO 2005025314 has been reported a kind of synthetic method, and reaction formula is as follows.
The method take the 5-chlorine amylalcohol of less stable as starting raw material altogether through 5 steps reactions, prepare 7-phenyl-6-heptynoic acid.This method synthetic route is long, and cost is high.Wherein the 5th step oxidizing reaction is difficult to realize suitability for industrialized production, because use human body, the great chromium of environmental hazard, is oxygenant.To other a lot of oxidising agent sensitivities, by other method, realize that this conversion is difficult to obtain promising result due to the phenylacetylene group.
The 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.
The 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, and cost is high; Very big to human body, environmental hazard, test effect is poor; Raw material is difficult to obtain, and there is no 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,
By DMSO or the solvent treatment that contains DMSO for NaH or KH, obtain 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, through acid adjustment, process and obtain 7-phenyl-6-heptynoic acid, 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 obtains 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, reach purpose and effect is easy to understand, below in conjunction with specific embodiment, further set forth the present invention.
Embodiment 1
The preparation method of 7-phenyl-6-heptynoic acid, use sodium salt or the sylvite of phenylacetylene to react with 5-bromine valeric acid, and acidifying obtains 7-phenyl-6-heptynoic acid, and concrete steps are as follows:
10.0g 60%NaH is added in 100ml DMSO and 100ml glycol dimethyl ether mixed solution, be heated to 65～70 ℃ of insulation reaction 45min, then be cooled to room temperature.Frozen water is cooling slowly adds the 15.3g phenylacetylene down in gained solution, obtains phenylacetylene sodium suspension.
Then add 5-bromine valeric acid 18.1g in batches.Add complete, stirring at room reaction 3 hours.Reclaim under reduced pressure DMSO, add 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, be concentrated into the about 25ml of volume after filtration, and the cooling lower crystallization of frozen water 2 hours is filtered and obtained 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, use sodium salt or the sylvite of phenylacetylene to react with 5-bromine natrium valericum, and acidifying obtains 7-phenyl-6-heptynoic acid, and concrete steps are as follows:
6.0g 60%NaH is added in 100ml DMSO and 100ml glycol dimethyl ether mixed solution, be heated to 65～70 ℃ of insulation reaction 45min, then be cooled to room temperature.Frozen water is cooling slowly adds the 15.3g phenylacetylene down in gained solution, obtains phenylacetylene sodium suspension.
Then add 5-bromine natrium valericum 20.3g in batches.Add complete, stirring at room reaction 3 hours.Reclaim under reduced pressure DMSO, add 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, be concentrated into the about 25ml of volume after filtration, and the cooling lower crystallization of frozen water 2 hours is filtered and obtained 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, the use Sodium isooctanoate is raw material, with 5-bromine valeric acid, carries out the sodium ion exchange, concrete steps are as follows:
The 250ml methyl acetate solution of 16.3g Sodium isooctanoate is cooled to 0～5 ℃ in stirring lower frozen water, adds 5-bromine valeric acid 17.0g in batches, separate out a large amount of white solids, filtration is drained, methyl acetate drip washing, and vacuum-drying obtains 5-bromine natrium valericum 18.1g, yield 95%.
With existing open synthetic method, compare, 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.
Above demonstration 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 in above-described embodiment and specification sheets, describes 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 (3)
1. the preparation method of 7-phenyl-6-heptynoic acid, is characterized in that,
By DMSO or the solvent treatment that contains DMSO for NaH or KH, obtain sodium/sylvite of DMSO, slowly add phenylacetylene under frozen water is cooling, obtain phenylacetylene sodium/potassium suspension;
Add 5-bromine natrium valericum to described suspension, generate 7-phenyl-6-heptynoic acid sodium/potassium, through acid adjustment, process and obtain 7-phenyl-6-heptynoic acid, reaction formula is as follows:
The preparation method of described 5-bromine natrium valericum is cooled to 0～5 ℃ by the methyl acetate solution of Sodium isooctanoate in stirring lower frozen water, adds 5-bromine valeric acid in batches, separates out a large amount of white solids, and filtration is drained, methyl acetate drip washing, and vacuum-drying obtains 5-bromine natrium valericum.
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 natrium valericum is 1:1-5:1.
3. the preparation method of 7-phenyl according to claim 1-6-heptynoic acid, is characterized in that, the ratio of described Sodium isooctanoate and 5-bromine valeric acid is 1:2-2:1.
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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 |
| 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 |
Non-Patent Citations (4)
| Title |
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| 5-溴戊酸的合成研究;曲富军;《化工矿物与加工》;20050415(第4期);第20-22页，尤其是第20页右栏最后1段 * |
| Lactam Synthesis via the Intramolecular Hydroamidation of Alkynes Catalyzed by Palladium Complexes;Nitin T.Patil等;《J.Org.Chem.》;20060329;第71卷(第9期);第3612-3614页 * |
| Nitin T.Patil等.Lactam Synthesis via the Intramolecular Hydroamidation of Alkynes Catalyzed by Palladium Complexes.《J.Org.Chem.》.2006,第71卷(第9期),第3612-3614页. |
| 曲富军.5-溴戊酸的合成研究.《化工矿物与加工》.2005,(第4期),第20-22页. |
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