WO1998056748A1 - Method for the synthesis of anti-microbial hydroxybenzoats - Google Patents
Method for the synthesis of anti-microbial hydroxybenzoats Download PDFInfo
- Publication number
- WO1998056748A1 WO1998056748A1 PCT/BE1998/000084 BE9800084W WO9856748A1 WO 1998056748 A1 WO1998056748 A1 WO 1998056748A1 BE 9800084 W BE9800084 W BE 9800084W WO 9856748 A1 WO9856748 A1 WO 9856748A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- benzene
- approximately
- acid
- reaction
- synthesis
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
Definitions
- the present invention relates to a method for synthesizing antimicrobial hydroxybenzoates .
- 4-hydroxybenzoates is already known, but here it mainly concerns 4 -hydroxybenzoates, the ester of which partially contains a small number of carbon atoms.
- the latter was preferred to the higher order derivatives with a greater number of carbon atoms because of problems and costs associated with the production of the higher order derivatives.
- the existing syntheses are based on the reaction between a benzoic acid halide and an alcohol, on the one hand, or on transesterification of a lower order derivative and an alcohol with a greater number of carbon atoms, on the other hand.
- parahydroxybenzoates also called parabens
- PHB parahydroxybenzoates
- Esterification of the carboxyl group of benzoic acid increased the antimicrobial activity of these molecules .
- Later studies showed that as the length of the alkyl group increased, there was also an increase in the antimicrobial activity.
- the PHB are active both against bacteria and against fungi and yeasts. As a result these PHB have a wide area of application. Thus they are used for antifungal treatment of wood and textiles or as preservatives in food, cosmetics and pharmaceutical products.
- methyl and propyl PHB are often used in bakery products such as cakes, tarts, jams, fillings and the like.
- a number of drinks such as wines, beers and so-called soft drinks, are also treated with lower or higher
- PHB are used in many creams, lotions, ointments and lipsticks.
- PHB are mainly used as preservatives. In some cases they are even described as an active medicinal substance.
- the PHB can also be used to control mould growth in materials, especially in the case of materials which because of their use are intended to come frequently into contact with water or moisture, such as sails, folding roofs in cars etc., work clothing and the like.
- the higher homologues of the parabens are usually produced or synthesized as follows.
- the lower n-alkyl esters of parahydroxybenzoic acid are produced by putting equimolar quantities of the n- alcohol with hydroxybenzoic acid in a reactor in the presence of p-toluenesulphonyl chloride as catalyst. The mixture is refiuxed until the complete reaction has taken place, after which the mixture is cooled. Any free acid still present is then neutralized by means of a base solution.
- the ester (PHB) is then extracted from the aqueous solution by means of petroleum ether.
- Surplus alcohol is removed by treatment of the petroleum ether solution with a sodium hydroxide solution, followed by separation of the water-soluble sodium salt from the ester with the alcohol which remains dissolved in the petroleum ether layer.
- the basic solution of the ester is then acidified with concentrated hydrochloric acid and extracted with petroleum ether.
- the ester is crystallized out by evaporation of the ether solution. Recrystallizations are then required to obtain a pure product .
- Yet another method of synthesis involves performing a transesterification of a lower order derivative and an alcohol with a greater number of carbon atoms.
- Desr-ripf -inn of the invention is to provide a method for synthesizing antimicrobial hydroxybenzoates which offers a solution to the abovementioned problems.
- the method of synthesis according to the invention solves the abovementioned problems.
- a method as defined in Claim 1 is proposed according to the invention.
- Equimolar quantities of parahydroxybenzoic acid and the relevant alcohol are put into a reactor in the presence of benzene, or toluene, and an acid as catalyst.
- the mixture is refiuxed and the water formed is removed by means of a so-called Dean-Stark apparatus. After refluxing, the mixture is neutralized with a base.
- the remaining water and solvent still present in the reactor are then distilled over.
- the solvent can thus be reused in a subsequent production batch.
- the desired ester which already has a very high degree of purity, remains in the reactor.
- butanol is an alcohol with a relatively low boiling point and this alcohol moreover forms an azeotrope with water and separates at lower temperature
- butanol can serve as a reagent and as an azeotrope- forming solvent for the synthesis of butyl PHB.
- the synthesis according to the invention thus offers the advantage of using a closed system.
- the production material also involves only a low investment and a double-walled reactor with a Dean-Stark apparatus is sufficient.
- the solvent can be reused.
- the cost price of the paraben is low and the yield from the reaction high.
- a method is also proposed for synthesizing antimicrobial hydroxybenzoates with hexyl-4-hydroxybenzoate as mycostatic.
- 4-hydroxybenzoic acid (50 g; 0.36 mmol) and hexanol together with sulphuric acid p. a. (5 ml) are boiled in particular proportions and with reflux cooling in benzene (300 ml) .
- the water released during this reaction is removed with a so- called Dean-Stark apparatus, for example, via azeotrope formation with benzene.
- the mixture is washed with a saturated sodium bicarbonate solution in water (2 x 100 ml) and with a brine solution, so that the reaction mixture obtains a neutral pH.
- the antimicrobial activity of the hydroxybenzoates synthesized according to the invention is thus much greater than the antimicrobial activity of these products according to the prior art, for example against fungi.
- the active dose of the hydroxybenzoates obtained according to the invention is also much smaller than the active dose of the existing hydroxybenzoates.
- the toxicity to man of the hydroxybenzoates synthesized according to the invention is extremely low, as the hydroxybenzoates already known are already being widely used in food.
- the synthesis according to the invention differs markedly from the existing synthesis, which is based on the reaction between a benzoic acid halide and an alcohol . In view of the cheaper and more readily available raw materials, the synthesis according to this invention is clearly economically more advantageous.
- This invention includes the synthesis, based on the reaction between the hydroxybenzoic acid and the alcohol via azeotropic removal of the water released, and the use of the 4 -hydroxybenzoates thus synthesized, the carbon side chain of which contains a greater number of carbon atoms .
- this invention covers the synthesis and the use of hydroxybenzoates whose boiling point, and the boiling point of the alcohol from which the ester is synthesized, is higher than the boiling point of benzene.
- H 2 S0 4 p. a . (2 ml) is slowly added, while stirring, to a suspension of p-hydroxybenzoic acid (250 g; 1.81 mmol) in b-butanol (400 ml) in a 1-litre flask with a stirrer, bulb condenser and Dean-Stark apparatus in accordance with a set-up as shown in the figure.
- the suspension is refiuxed until a clear solution is obtained.
- the degree of progress in this procedure is monitored via the amount of water formed, which is collected in the Dean-Stark apparatus.
- the warm oil can also be poured out into an excess of cold water so as to obtain white crystals immediately.
- IR (KBr, film): 3360, 2920, 1666, 1580, 1455, 1271, 1215, 1159, 850, 775, 635.
- the suspension so obtained is refiuxed until the reaction is completed. It is monitored via the volume of water formed, which is collected with the aid of the Dean-Stark apparatus. After completion of the reaction a clear solution is obtained. The mixture is then neutralized until the pH reaches the neutral point 7, with 50% NaOH in water (11.7 g) .
- IR (KBr, film): 3288, 2912, 1680, 1590, 1440, 1275, 1215, 1100, 850, 760, 615.
- IR (KBr, film): 3260, 2901, 1676, 1590, 1428, 1275, 1100, 850, 770, 606.
- this product can also be used in other applications or sectors, such as paints, timber treatment, damp-proofing of cellars, and also in textiles, paper production, food and the like.
- an additional, third, identical piece of wood can be taken as a specimen and treated with a solution of 2.2 g of butyl-4-hydroxybenzoate in 1 litre of glycerol.
- the test is performed on a similar basis, with the growth of the fungus being determined after a month, both on the untreated piece of wood and on the piece of wood which has been treated with butyl-4-hydroxybenzoate .
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU77526/98A AU7752698A (en) | 1997-06-09 | 1998-06-09 | Method for the synthesis of anti-microbial hydroxybenzoats |
EP98925340A EP0970037A1 (en) | 1997-06-09 | 1998-06-09 | Method for the synthesis of anti-microbial hydroxybenzoats |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BE9700491 | 1997-06-09 | ||
BE9700491A BE1011198A6 (en) | 1997-06-09 | 1997-06-09 | Method for synthesizing of antimicrobial hydroxybenzoates. |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998056748A1 true WO1998056748A1 (en) | 1998-12-17 |
Family
ID=3890556
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/BE1998/000084 WO1998056748A1 (en) | 1997-06-09 | 1998-06-09 | Method for the synthesis of anti-microbial hydroxybenzoats |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0970037A1 (en) |
AU (1) | AU7752698A (en) |
BE (1) | BE1011198A6 (en) |
WO (1) | WO1998056748A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1208910A2 (en) * | 2000-11-28 | 2002-05-29 | Nippon Shokubai Co., Ltd. | Process and apparatus for producing a dehydration reaction product |
FR2828808A1 (en) * | 2001-08-24 | 2003-02-28 | Unilever Nv | COMPOSITION |
WO2004047782A1 (en) * | 2002-11-22 | 2004-06-10 | Unilever N.V. | Oral compositions comprising salts of alkyl hydroxybenzoates |
US20140221207A1 (en) * | 2011-08-27 | 2014-08-07 | Marrone Bio Innovations, Inc. | Isolated bacterial strain of the genus burkholderia and pesticidal metabolites therefrom- formulations and uses |
CN104119230A (en) * | 2014-06-25 | 2014-10-29 | 李炳洁 | Synthesis method and application of long-chain methyl p-hydroxybenzoate |
DE102021212696A1 (en) | 2021-11-11 | 2023-05-11 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung eingetragener Verein | Stabilizers based on syringic acid, vanillic acid, isovanillic acid or 5-hydroxyveratric acid, plastic composition, method for stabilizing a plastic composition, and stabilizer composition |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3321509A (en) * | 1964-03-02 | 1967-05-23 | Washine Chemical Corp | Preparation of alkyl esters of parahydroxybenzoic acid |
-
1997
- 1997-06-09 BE BE9700491A patent/BE1011198A6/en not_active IP Right Cessation
-
1998
- 1998-06-09 WO PCT/BE1998/000084 patent/WO1998056748A1/en not_active Application Discontinuation
- 1998-06-09 EP EP98925340A patent/EP0970037A1/en not_active Withdrawn
- 1998-06-09 AU AU77526/98A patent/AU7752698A/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3321509A (en) * | 1964-03-02 | 1967-05-23 | Washine Chemical Corp | Preparation of alkyl esters of parahydroxybenzoic acid |
Non-Patent Citations (3)
Title |
---|
G,W,K, CAVILL ET AL.: "The Esters of Hydroxybenzoic Acid and Related Compounds.Part 2.Relationships between the Fungistatic Activity,and Physical and Chemical Properties of the Esters", JOURNAL OF THE SOCIETY OF CHEMICAL INDUSTRY., vol. 66, June 1947 (1947-06-01), LONDON GB, pages 175 - 182, XP002076502 * |
V. FROSINI ET AL.: "Transitions and Relaxations in Mesophase Polymers:Thermotropic Liquid Crystalline Polyesters with Mesogenic Groups in the Main Chain", MOLECULAR CRYSTALS AND LIQUID CRYSTALS, vol. 98, 1983, READING GB, pages 223 - 242, XP002076503 * |
Y. HARAMOTO ET AL.: "New Liquid Crystal Compounds:(+)-4-Alkoxycarbonylphenyl-4-(5-(2-methylbutyl)-1,3-dioxan-2-yl)benzoate", MOLECULAR CRYSTALS AND LIQUID CRYSTALS, vol. 201, 1991, READING GB, pages 161 - 166, XP002076504 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1208910A2 (en) * | 2000-11-28 | 2002-05-29 | Nippon Shokubai Co., Ltd. | Process and apparatus for producing a dehydration reaction product |
JP2002161071A (en) * | 2000-11-28 | 2002-06-04 | Nippon Shokubai Co Ltd | Method for producing dehydration reaction product and dehydration reaction device used therefor |
EP1208910A3 (en) * | 2000-11-28 | 2003-07-09 | Nippon Shokubai Co., Ltd. | Process and apparatus for producing a dehydration reaction product |
FR2828808A1 (en) * | 2001-08-24 | 2003-02-28 | Unilever Nv | COMPOSITION |
WO2003017962A1 (en) * | 2001-08-24 | 2003-03-06 | Unilever N.V. | Oral composition comprising an alkylhydroxybenzoate |
WO2004047782A1 (en) * | 2002-11-22 | 2004-06-10 | Unilever N.V. | Oral compositions comprising salts of alkyl hydroxybenzoates |
US20140221207A1 (en) * | 2011-08-27 | 2014-08-07 | Marrone Bio Innovations, Inc. | Isolated bacterial strain of the genus burkholderia and pesticidal metabolites therefrom- formulations and uses |
CN104119230A (en) * | 2014-06-25 | 2014-10-29 | 李炳洁 | Synthesis method and application of long-chain methyl p-hydroxybenzoate |
DE102021212696A1 (en) | 2021-11-11 | 2023-05-11 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung eingetragener Verein | Stabilizers based on syringic acid, vanillic acid, isovanillic acid or 5-hydroxyveratric acid, plastic composition, method for stabilizing a plastic composition, and stabilizer composition |
WO2023083884A1 (en) | 2021-11-11 | 2023-05-19 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Stabilizers based on syringic acid, vanillic acid, isovanillic acid or 5-hydroxyveratric acid, plastic composition, method for stabilizing a plastic composition and stabilizer composition |
Also Published As
Publication number | Publication date |
---|---|
AU7752698A (en) | 1998-12-30 |
BE1011198A6 (en) | 1999-06-01 |
EP0970037A1 (en) | 2000-01-12 |
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