WO2001058849A1 - SURFACE ACTIVE AGENTS DERIVED FROM 1-O-Nα-ACETYL-L-AMINOACYL ESTER 3-O-MONOACYL GLYCERIDES AND 1-O-Nα-ACETYL L-AMINOACYL ESTER 2,3-O-DIACYL GLYCERIDES TYPE AMINO ACIDS AND THE PREPARATION THEREOF - Google Patents
SURFACE ACTIVE AGENTS DERIVED FROM 1-O-Nα-ACETYL-L-AMINOACYL ESTER 3-O-MONOACYL GLYCERIDES AND 1-O-Nα-ACETYL L-AMINOACYL ESTER 2,3-O-DIACYL GLYCERIDES TYPE AMINO ACIDS AND THE PREPARATION THEREOF Download PDFInfo
- Publication number
- WO2001058849A1 WO2001058849A1 PCT/ES2001/000040 ES0100040W WO0158849A1 WO 2001058849 A1 WO2001058849 A1 WO 2001058849A1 ES 0100040 W ES0100040 W ES 0100040W WO 0158849 A1 WO0158849 A1 WO 0158849A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acetyl
- aminoacyl
- glycerol
- ester
- process according
- Prior art date
Links
- 239000004094 surface-active agent Substances 0.000 title claims abstract description 19
- 150000001413 amino acids Chemical class 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000002148 esters Chemical class 0.000 title claims description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 6
- 239000004599 antimicrobial Substances 0.000 claims abstract description 3
- 230000000694 effects Effects 0.000 claims abstract description 3
- 238000000746 purification Methods 0.000 claims abstract description 3
- 125000005456 glyceride group Chemical group 0.000 claims abstract 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 60
- 238000000034 method Methods 0.000 claims description 28
- 229940024606 amino acid Drugs 0.000 claims description 20
- 235000001014 amino acid Nutrition 0.000 claims description 19
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- 108090000790 Enzymes Proteins 0.000 claims description 9
- 102000004190 Enzymes Human genes 0.000 claims description 9
- -1 N-acetyl amino Chemical class 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 230000002255 enzymatic effect Effects 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000005917 acylation reaction Methods 0.000 claims description 7
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 7
- 229930195729 fatty acid Natural products 0.000 claims description 7
- 239000000194 fatty acid Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 108090001060 Lipase Proteins 0.000 claims description 5
- 239000004367 Lipase Substances 0.000 claims description 5
- 102000004882 Lipase Human genes 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 150000004665 fatty acids Chemical class 0.000 claims description 5
- 235000019421 lipase Nutrition 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 102000035195 Peptidases Human genes 0.000 claims description 3
- 108091005804 Peptidases Proteins 0.000 claims description 3
- 239000004365 Protease Substances 0.000 claims description 3
- 230000010933 acylation Effects 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000006289 hydroxybenzyl group Chemical group 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims 2
- 238000001311 chemical methods and process Methods 0.000 claims 2
- 238000009833 condensation Methods 0.000 claims 2
- 230000005494 condensation Effects 0.000 claims 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims 1
- 108010048733 Lipozyme Proteins 0.000 claims 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 1
- 238000004458 analytical method Methods 0.000 claims 1
- 229960001230 asparagine Drugs 0.000 claims 1
- 235000009582 asparagine Nutrition 0.000 claims 1
- 239000011942 biocatalyst Substances 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 239000007809 chemical reaction catalyst Substances 0.000 claims 1
- 239000003480 eluent Substances 0.000 claims 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims 1
- FCCDDURTIIUXBY-UHFFFAOYSA-N lipoamide Chemical compound NC(=O)CCCCC1CCSS1 FCCDDURTIIUXBY-UHFFFAOYSA-N 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 125000005480 straight-chain fatty acid group Chemical group 0.000 claims 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims 1
- 239000007788 liquid Substances 0.000 abstract description 6
- 238000002425 crystallisation Methods 0.000 abstract description 3
- 230000008025 crystallization Effects 0.000 abstract description 3
- 239000007787 solid Substances 0.000 abstract description 3
- 238000000605 extraction Methods 0.000 abstract description 2
- 238000004255 ion exchange chromatography Methods 0.000 abstract description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 7
- 239000002609 medium Substances 0.000 description 6
- 239000012429 reaction media Substances 0.000 description 4
- 239000000084 colloidal system Substances 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Substances OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 150000002313 glycerolipids Chemical class 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- CNDHHGUSRIZDSL-UHFFFAOYSA-N 1-chlorooctane Chemical compound CCCCCCCCCl CNDHHGUSRIZDSL-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 1
- OTCCIMWXFLJLIA-BYPYZUCNSA-N N-acetyl-L-aspartic acid Chemical compound CC(=O)N[C@H](C(O)=O)CC(O)=O OTCCIMWXFLJLIA-BYPYZUCNSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 108010084311 Novozyme 435 Proteins 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000002216 antistatic agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000003084 food emulsifier Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000005908 glyceryl ester group Chemical group 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 239000000976 ink Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 150000002759 monoacylglycerols Chemical class 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010517 secondary reaction Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000012610 weak anion exchange resin Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/48—Medical, disinfecting agents, disinfecting, antibacterial, germicidal or antimicrobial compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D1/00—Detergent compositions based essentially on surface-active compounds; Use of these compounds as a detergent
- C11D1/02—Anionic compounds
- C11D1/04—Carboxylic acids or salts thereof
- C11D1/10—Amino carboxylic acids; Imino carboxylic acids; Fatty acid condensates thereof
Definitions
- Surfactant compounds are amphiphilic organic products composed of a hydrophilic part (-COO ⁇ , -S0 3 , -O-, quaternary ammonium) and a hydrophobic (a fatty chain of 8-18 carbon atoms). These products have an extraordinary interest in their wide and versatile application in preparations with a strong impact in our immediate surroundings (food emulsifiers, cleaning and personal hygiene products, drugs, cosmetics, paints, inks, fiber antistatic agents, etc.). Although today it can be considered that the industrial sectors have adequate surfactants for the functions they must perform, current European regulations require the search and study of new alternatives in which the following requirements converge: safety, multifunctionality, efficiency and competitiveness
- the object of the present invention is the synthesis of a new family of amino acid-derived surfactants with a mimetic structure to mono acyl glycerides and diacylglycerides.
- These surfactants consist of a central glycerol skeleton that joins the hydrophobic part formed by one or two fatty chains of variable length to the hydrophilic part formed by an amino acid.
- These new structures have advantages over the mono and diacylglycerides described above: a) the introduction of an amino acid as a polar part of the surfactant increases the solubility in aqueous medium and b) compounds with antimicrobial activity can be obtained depending on the amino acid present
- Amino acid derived surfactants are compounds of high interest due to their multifunctionality and safety (Takehara, M. 1989, Colloids and Surfaces, 38: 149; Selve, C, Mansuy, L., Allouch, M., 1992, J Chem. Res. 22: 401). These characteristics have been responsible for the synthesis and study of properties of a wide variety of surfactants of this type, ionic, cationic, non-ionic and amphoteric in nature in recent years (Takehara, M. 1989, Colloids and Surfaces, 38: 149; Sagawa, K., Yokota, H., Ueno, I., Miyosi, T., Takehara, M., XIV IFSCC Congress, 1986).
- lipase type enzymes In relation to the acylation of glycerol hydroxyl groups, the use of lipase type enzymes has been described (Valivety, R., Gill, IS, Vulfson, EN (1998) J. Surf. Deterg. L 177-185) as catalysts of the esterification reaction.
- the main novelties of the present invention are the combination in the same molecule of mono-type surfactants and diacylglycerides and surfactants derived from amino acids with minimal protection as well as the use of enzymes as substitutes for conventional chemical catalysts. DESCRIPTION OF THE INVENTION
- the present invention relates to a new family of amino acid derived surfactants with a glycerol skeleton esterified by one or two fatty acid chains as well as to the methods of synthesis of these compounds.
- the structural formula of these compounds is indicated (I).
- Ri is an acetyl group.
- R may be an optionally substituted, saturated or unsaturated linear or branched chain or an optionally substituted aromatic group.
- R 3 and ⁇ can be a hydrogen or a preferably long saturated or unsaturated linear chain.
- X can be: Br “ , Cl “ , HSO 4 " , CH 3 COO “ , CF 3 COO “ , Na + , K +
- R is preferably a group: amide, hydroxybenzyl, imidazole and carboxyl.
- R 3 and Rj can be selected from a group of linear chains of 8, 9,10, 12, 14,16 and 18 pure saturated or unsaturated carbon atoms or mixtures thereof.
- the starting materials can be:
- the number of alkyl chains (lo 2), the degree of unsaturation, the length thereof and the amino acid present are varied in the molecules which gives rise to compounds with a different behavior in the biological and physicochemical properties of adsorption and self-aggregation . Due to the origin of renewable and safe raw materials, these compounds are expected to be degradable and non-toxic both from a biological and environmental point of view.
- the use of the acetyl group as a protective group of the amino function makes it possible to avoid possible secondary reactions of the Maillard type, in food applications, without altering the biocompatible nature of the final products obtained.
- Enzymatic procedure the synthesis via enzyme has been carried out in two stages: a) Condensation reaction of glycerol and the free or esterified carboxyl group of N ⁇ -acetyl-L-amino acid, using hydrolytic enzymes, proteases type catalysts and lipases, in a medium in the absence of solvent and with low aqueous content. b) Acylation reaction of the OOaa (Ac) free alcohol groups with free fatty acids or esters of these acids, using as lipase catalysts. The reaction takes place in a medium in the absence of solvent and with a low aqueous content.
- the present invention relates to novel surfactant compounds derived from mono and diacylglyceride type amino acids designed to act as surface and antimicrobial agents.
- the variations in activity will be a function of the number of fatty chains, their length and the amino acid present in the structure.
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- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Wood Science & Technology (AREA)
- Dispersion Chemistry (AREA)
- Emergency Medicine (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Mattresses And Other Support Structures For Chairs And Beds (AREA)
- Invalid Beds And Related Equipment (AREA)
Abstract
The invention concerns novel surface active compounds derived from monoacyl and diacyl glyceride type amino acids according to general formula (I) designed to act as surface active and antimicrobial agents. Activity will vary depending on the number of fatty chains, their length and the amino acid present in the structure. Purification of the intermediate and final products is carried out by means of liquid/liquid, liquid/solid extractions, crystallizations and ion exchange chromatography and preparation HPLC.
Description
TÍTULOTITLE
TENSIOACTIVOS DERIVADOS DE AMINOÁCIDOS DEL TIPO l-O-Nα- ACETIL-L-AMINOACIL ESTER 3-O-MONOACIL GLICÉRIDOS Y l-O-Nα- ACETIL L-AMINOACIL ESTER 2,3-O-DIACIL GLICÉRIDOS Y SU PREPARACIÓN.TENSIOACTIVE DERIVATIVES OF AMINO ACIDS OF THE TYPE lON α - ACETIL-L-AMINOACIL ESTER 3-O-MONOACIL GLICÉRIDOS AND lON α - ACETIL L-AMINOACIL ESTER 2,3-O-DIACIL GLICÉRIDOS AND ITS PREPARATION.
IntroducciónIntroduction
Los compuestos tensioactivos son productos orgánicos anfífilos compuestos por una parte hidrófíla ( -COO~, -S03, -O-, amonio cuaternario) y una hidrófoba (una cadena grasa de 8-18 átomos de carbono). Estos productos presentan un extraordinario interés por su amplia y versátil aplicación en preparados de fuerte incidencia en nuestro más inmediato entorno(emulsionantes alimentarios, productos de limpieza e higiene personal, fármacos, cosméticos, pinturas, tintas, antiestáticos de fibras, etc). Si bien hoy en día se puede considerar que los sectores industriales disponen de los tensioactivos adecuados para las funciones que deben realizar, las actuales normativas europeas exigen la búsqueda y estudio de nuevas alternativas en las que converjan los siguientes requisitos: inocuidad, multifuncionalidad, eficacia y competitividad.Surfactant compounds are amphiphilic organic products composed of a hydrophilic part (-COO ~ , -S0 3 , -O-, quaternary ammonium) and a hydrophobic (a fatty chain of 8-18 carbon atoms). These products have an extraordinary interest in their wide and versatile application in preparations with a strong impact in our immediate surroundings (food emulsifiers, cleaning and personal hygiene products, drugs, cosmetics, paints, inks, fiber antistatic agents, etc.). Although today it can be considered that the industrial sectors have adequate surfactants for the functions they must perform, current European regulations require the search and study of new alternatives in which the following requirements converge: safety, multifunctionality, efficiency and competitiveness
Una de las estrategias que existe actualmente para conseguir tensioactivos ecológicamente aceptables es la preparación de moléculas cuya estructura molecular mimetiza la de los tensioactivos naturales: lipoaminoácidos, fosfolípidos y glicerolípidos (J.H. Fendler, 1989 " Membrane Mimetic Chemislry, John Wiley & Son) Los glicerolípidos (mono y diacilglicéridos) constituyen actualmente (Zhu, Y., Masuyama, A., Kirito, Y.. Okahara, M., Rosen, M.J., 1992, J. Am. OH. Chem. Soc, 69:6269), el 75% de los emulsionantes empleados en la industria alimenticia debido a sus excelentes propiedades interfaciales y vehiculizantes, siendo los monoacilglicéridos los más importantes debido a su gran funcionalidad. Dentro de este grupo, los compuestos más estudiados y empleados son los esteres alquílicos de glicerol ya que se obtienen fácilmente mediante glicerolisis de triacilglicéridos o por esterificación del glicerol con ácidos grasos (Lipid Technologies and Applications, 1997. Ed. Gunstone, F.D., Padley. F.B., New York.). Los monoacilglicéridos son compuestos con muy baja solubilidad en agua, por lo que generalmente se añaden a las formulaciones junto con otros emulsionantes de carácter más polar.
El objeto de la presente invención es la síntesis de una nueva familia de tensioactivos derivados de aminoácidos con una estructura mimética a los monoacilglicéridos y diacilglicéridos. Estos tensioactivos están constituidos por un esqueleto central de glicerol que une la parte hidrófoba formada por una o dos cadenas grasas de longitud variable a la parte hidrófila formada por un aminoácido. Estas nuevas estructuras presentan ventajas sobre los mono y diacilglicéridos anteriormente descritos: a) la introducción de un aminoácido como parte polar del tensioactivo aumenta la solubilidad en medio acuoso y b) se pueden obtener compuestos con actividad antimicrobiana dependiendo del aminoácido presenteOne of the strategies that currently exists to achieve ecologically acceptable surfactants is the preparation of molecules whose molecular structure mimics that of natural surfactants: lipoamino acids, phospholipids and glycerolipids (JH Fendler, 1989 "Membrane Mimetic Chemislry, John Wiley & Son) Glycerolipids ( mono and diacylglycerides) currently constitute (Zhu, Y., Masuyama, A., Kirito, Y .. Okahara, M., Rosen, MJ, 1992, J. Am. OH. Chem. Soc, 69: 6269), 75 % of the emulsifiers used in the food industry due to their excellent interfacial and vehicular properties, with monoacylglycerides being the most important due to their great functionality.In this group, the most studied and used compounds are glycerol alkyl esters since easily obtained by glycerolysis of triacylglycerides or by esterification of glycerol with fatty acids (Lipid Technologies and Applications, 1997. Ed. Gunstone, FD, Padley. FB, New York.). Monoacylglycerides are compounds with very low water solubility, so they are generally added to the formulations together with other more polar emulsifiers. The object of the present invention is the synthesis of a new family of amino acid-derived surfactants with a mimetic structure to mono acyl glycerides and diacylglycerides. These surfactants consist of a central glycerol skeleton that joins the hydrophobic part formed by one or two fatty chains of variable length to the hydrophilic part formed by an amino acid. These new structures have advantages over the mono and diacylglycerides described above: a) the introduction of an amino acid as a polar part of the surfactant increases the solubility in aqueous medium and b) compounds with antimicrobial activity can be obtained depending on the amino acid present
ESTADO DE LA TÉCNICASTATE OF THE TECHNIQUE
Los tensioactivos derivados de aminoácido son compuestos de elevado interés debido a su multifuncionalidad e inocuidad (Takehara, M. 1989, Colloids and Surfaces, 38: 149;Selve,C, Mansuy, L., Allouch, M., 1992, J Chem. Res. 22:401). Estas características han sido las responsables de que en los últimos años se haya llevado a cabo la síntesis y estudio de propiedades de una gran variedad de tensioactivos de este tipo, de carácter iónico, catiónico, no iónico y anfótero (Takehara, M. 1989, Colloids and Surfaces, 38:149; Sagawa, K., Yokota, H.,Ueno, I., Miyosi, T., Takehara, M.,XIV Congreso IFSCC, 1986). En esta línea nuestro equipo ha sintetizado mediante metodologías química y enzimática derivados monocatenarios Nα-acil aminoácido, aminoacil N-alquil amidas, aminoacil alquil esteres, así como tensioactivos gemínales de arginina. Este estudio ha dado lugar a un gran número de patentes y publicaciones (ES9500061(1995);PI 9500027(1995); PCT/ES96/00026(1996); ES 9700520 (1997); ES 9900739 (1999); M.R. Infante, J.Molinero, P.Erra, (1992), JAOCS, vol.69, n°7; J.Molinero, M.R.Juliá, P.Erra, M.Robert, M.R.Infante, 1988, JAOCS, Vol.65, n°6; C.Solans, M.A.Pés, N.Azemar,M.R.Infante, 1990, Prog. Colloid Polym Sci 81 ,pp 144- 150; L.Pérez, J.L.Torres, A.Manresa,C.Solans,M.R.Infante, 1996, Langmuir, 12(22), pp 5296-5301 , Clapés, P., Moran, C, Infante, M.R. (1999) Biotechnol. Bioeng. 63 3 pp333- 343).
Con respecto a los mono y diacilglicéridos, la bibliografía describe con gran detalle sus propiedades y aplicaciones (K.Larsson,1994, "Lipids: Molecular Organization, Phisical Functions and Technical Applications " The Oily Press LTD . Estas propiedades se ven sensiblemente modificadas cuando el/los extremos hidroxilos libres de la molécula se funcionalizan con ácidos orgánicos del tipo ácido láctico, cítrico y acético ( "Food Emulsions ", 1997, Ed. by Stig E.Friberg and K.LarssoηAmino acid derived surfactants are compounds of high interest due to their multifunctionality and safety (Takehara, M. 1989, Colloids and Surfaces, 38: 149; Selve, C, Mansuy, L., Allouch, M., 1992, J Chem. Res. 22: 401). These characteristics have been responsible for the synthesis and study of properties of a wide variety of surfactants of this type, ionic, cationic, non-ionic and amphoteric in nature in recent years (Takehara, M. 1989, Colloids and Surfaces, 38: 149; Sagawa, K., Yokota, H., Ueno, I., Miyosi, T., Takehara, M., XIV IFSCC Congress, 1986). In this line our team has synthesized by means of chemical and enzymatic methodologies single-chain derivatives N α -acrylic amino acid, aminoacyl N-alkyl amides, aminoacyl alkyl esters, as well as arginine gemine surfactants. This study has resulted in a large number of patents and publications (ES9500061 (1995); PI 9500027 (1995); PCT / ES96 / 00026 (1996); ES 9700520 (1997); ES 9900739 (1999); MR Infante, J .Molinero, P.Erra, (1992), JAOCS, vol.69, no.7; J.Molinero, MRJuliá, P.Erra, M.Robert, MRInfante, 1988, JAOCS, Vol.65, n ° 6; C .Solans, MAPés, N. Azzemar, MRInfante, 1990, Prog. Colloid Polym Sci 81, pp 144-150; L. Pérez, JLTorres, A.Manresa, C. Solns, MRInfante, 1996, Langmuir, 12 (22), pp 5296-5301, Clapés, P., Moran, C, Infante, MR (1999) Biotechnol. Bioeng. 63 3 pp333-343). With respect to mono and diacylglycerides, the literature describes in great detail their properties and applications (K. Larson, 1994, "Lipids: Molecular Organization, Phisical Functions and Technical Applications" The Oily Press LTD. These properties are noticeably modified when the / the free hydroxyl ends of the molecule are functionalized with organic acids of the lactic, citric and acetic acid type ("Food Emulsions", 1997, Ed. by Stig E. Friedrich and K. Larsoη
La síntesis de derivados de aminoácidos mono y diacilglicéridos requiere la obtención previa de los derivados del tipo 1 -O-L-aminoacil esteres de glicerol. La bibliografía describe la síntesis de estos intermedios utilizando catalizadores químicos. Valivety et al. (Valivety, R., Gill, I.S., Vulfson, E.N. (1998) J Surf. Deterg í 177-185). prepararon diversos compuestos del tipo 1 -O-L-aminoacil esteres de glicerol a partir de Nα-Z- aminoácidos y glicerol en presencia de BF3-eterato. Asimismo son numerosas las publicaciones basadas en la síntesis enzimática de enlaces esteres ( Cantacuzene, D., Guerreiro, C. (1987) Tetrahedron Letters 28, 5153-5156; Kawashiro,K., Inhizaki, H., Sugiyama, S., Hayashi, H. (1993) Biotechnol. Bioeng.Al 309-314; Kise, H., Hayakawa, A., Noritomi, H. (1987) Biotechnol. Lett. 9 543-548). Sin embargo, la obtención de gliceril esteres con aminoácidos N-protegidos como productos de partida está muy poco desarrollada. Mitin et al. (Mitin, Y.V., Braun, K., Kuhl, P. (1997) Biotech. and Bioeng 54, 287) describen la obtención de gliceril esteres de aminoácidos para su utilización en la síntesis de péptidos. En todos los casos, el extremo α-amino de los aminoácidos así como las funciones reactivas de sus cadenas laterales está protegido por grupos del tipo benziloxicarbonil (Z) y tert-butiloxicarbonil (Boc).The synthesis of mono and diacylglyceride amino acid derivatives requires prior obtaining of the derivatives of the 1 -OL-aminoacyl esters of glycerol. The literature describes the synthesis of these intermediates using chemical catalysts. Valivety et al. (Valivety, R., Gill, IS, Vulfson, EN (1998) J Surf. Determined 177-185). prepared various compounds of the type 1 -OL-aminoacyl glycerol esters from N α -Z-amino acids and glycerol in the presence of BF 3 -eterate. There are also numerous publications based on the enzymatic synthesis of esters (Cantacuzene, D., Guerreiro, C. (1987) Tetrahedron Letters 28, 5153-5156; Kawashiro, K., Inhizaki, H., Sugiyama, S., Hayashi , H. (1993) Biotechnol. Bioeng. Al 309-314; Kise, H., Hayakawa, A., Noritomi, H. (1987) Biotechnol. Lett. 9 543-548). However, obtaining glyceryl esters with N-protected amino acids as starting products is very poorly developed. Mitin et al. (Mitin, YV, Braun, K., Kuhl, P. (1997) Biotech. And Bioeng 54, 287) describe obtaining glyceryl amino acid esters for use in peptide synthesis. In all cases, the α-amino end of the amino acids as well as the reactive functions of their side chains is protected by groups of the benzyloxycarbonyl (Z) and tert-butyloxycarbonyl (Boc) type.
En relación con la acilación de los grupos hidróxilo del glicerol se ha encontrado descrito la utilización de enzimas del tipo lipasas (Valivety, R., Gill, I.S., Vulfson, E.N. (1998) J. Surf. Deterg. l 177-185) como catalizadores de la reacción de esterificación.In relation to the acylation of glycerol hydroxyl groups, the use of lipase type enzymes has been described (Valivety, R., Gill, IS, Vulfson, EN (1998) J. Surf. Deterg. L 177-185) as catalysts of the esterification reaction.
Las principales novedades de la presente invención son la combinación en una misma molécula de tensioactivos tipo mono y diacilglicéridos y tensioactivos derivados de aminoácido con mínima protección así como la utilización de enzimas como sustitutos de los catalizadores químicos convencionales.
DESCRIPCIÓN DE LA INVENCIÓNThe main novelties of the present invention are the combination in the same molecule of mono-type surfactants and diacylglycerides and surfactants derived from amino acids with minimal protection as well as the use of enzymes as substitutes for conventional chemical catalysts. DESCRIPTION OF THE INVENTION
La presente invención se refiere a una nueva familia de tensioactivos derivados de aminoácido con un esqueleto de glicerol esterificado por una o dos cadenas de ácido graso así como a los procedimientos de síntesis de estos compuestos. La fórmula estructural de estos compuestos se indica (I).The present invention relates to a new family of amino acid derived surfactants with a glycerol skeleton esterified by one or two fatty acid chains as well as to the methods of synthesis of these compounds. The structural formula of these compounds is indicated (I).
(i)(i)
Donde: Ri es un grupo acetil.Where: Ri is an acetyl group.
R puede ser una cadena lineal o ramificada opcionalmente sustituida, saturada o no saturada o un grupo aromático opcionalmente sustituido.R may be an optionally substituted, saturated or unsaturated linear or branched chain or an optionally substituted aromatic group.
R3 y ι pueden ser un hidrógeno o una cadena lineal preferentemente larga saturada o no saturada. X puede ser : Br ", Cl ", HSO4 ", CH3COO ", CF3COO " ,Na +, K + R 3 and ι can be a hydrogen or a preferably long saturated or unsaturated linear chain. X can be: Br " , Cl " , HSO 4 " , CH 3 COO " , CF 3 COO " , Na + , K +
En la fórmula general R es preferentemente un grupo: amida, hidroxibencil, imidazol y carboxilo.In the general formula R is preferably a group: amide, hydroxybenzyl, imidazole and carboxyl.
R3 y Rj pueden ser seleccionados de un grupo de cadenas lineales de 8, 9,10, 12, 14,16 y 18 átomos de carbono saturadas o no saturadas puras o sus mezclas.
Los materiales de partida pueden ser:R 3 and Rj can be selected from a group of linear chains of 8, 9,10, 12, 14,16 and 18 pure saturated or unsaturated carbon atoms or mixtures thereof. The starting materials can be:
Aminoácidos Nα-acetil protegidos de calidad técnica GlicerolProtected N α- acetyl amino acids of technical quality Glycerol
Ácidos y esteres grasos lineales saturados o no saturados de distinta longitud - Cloruros de ácidos grasos lineales saturados o no saturados de distinta longitudSaturated or unsaturated linear fatty acids and esters of different lengths - Saturated or unsaturated linear fatty acid chlorides of different lengths
Catalizadores químicos de calidad técnica. Proteasas y lipasas de calidad técnicaChemical catalysts of technical quality. Proteases and lipases of technical quality
Se varia en las moléculas el n° de cadenas alquílicas (ló 2), el grado de insaturación, la longitud de las mismas y el aminoácido presente lo cual da lugar a compuestos con un diferente comportamiento en las propiedades biológicas y fisicoquímicas de adsorción y autoagregación. Debido a la procedencia de materias primas renovables e inocuas es de esperar que estos compuestos sean degradables y no tóxicos tanto desde el punto de vista biológico como medioambiental. La utilización del grupo acetil como grupo protector de la función amino permite evitar posibles reacciones secundarias del tipo Maillard, en aplicaciones alimenticias, sin alterar el carácter biocompatible de los productos finales obtenidos.The number of alkyl chains (lo 2), the degree of unsaturation, the length thereof and the amino acid present are varied in the molecules which gives rise to compounds with a different behavior in the biological and physicochemical properties of adsorption and self-aggregation . Due to the origin of renewable and safe raw materials, these compounds are expected to be degradable and non-toxic both from a biological and environmental point of view. The use of the acetyl group as a protective group of the amino function makes it possible to avoid possible secondary reactions of the Maillard type, in food applications, without altering the biocompatible nature of the final products obtained.
La obtención de estos compuestos se ha llevado a cabo por metodología química y/o enzimática. A continuación se describen las etapas involucradas en cada uno de los procedimientos:The obtaining of these compounds has been carried out by chemical and / or enzymatic methodology. The stages involved in each of the procedures are described below:
1) Procedimiento químico: la síntesis de estos compuestos por vía química ha tenido lugar en 2 etapas: a) Formación de los derivados l-0-Nα-acetil-aminoacil-glicerol éster (a los cuales se designará como OOaa(Ac) a partir del Nα-acetil L-aminoácido y glicerol utilizando BF3-eterato como catalizador de la reacción de esterificación. b) Formación de los derivados l-0-Nα-acetil-aminoacil éster 3-0- monoacilglicéridos o l -0-Nα-acetil-aminoacil éster 2,3-O-diacilglicéridos o (a los cuales se designará como nnaa(Ac)) a partir de OOaa(Ac) utilizando cloruros de ácidos grasos lineales de 8 a 18 átomos de carbono como agentes acilantes en un medio de piridina.
2) Procedimiento enzimático: la síntesis vía enzimática se ha llevado a cabo en dos etapas: a) Reacción de condensación del glicerol y el grupo carboxilo libre o esterificado del Nα-acetil-L-aminoácido, empleando como catalizadores enzimas hidrolíticos, tipo proteasas y lipasas, en un medio en ausencia de disolvente y con bajo contenido acuoso. b) Reacción de acilación de el/los grupos alcoholes libres del OOaa(Ac) con ácidos grasos libres o esteres de estos ácidos, empleando como catalizadores lipasas. La reacción tiene lugar en un medio en ausencia de disolvente y con un bajo contenido acuoso.1) Chemical procedure: the synthesis of these compounds by chemical route has taken place in 2 stages: a) Formation of the derivatives l-0-N α -acetyl-aminoacyl-glycerol ester (which will be designated as OOaa (Ac) from N α -acetyl L-amino acid and glycerol using BF 3 -eterate as catalyst for the esterification reaction b) Formation of the derivatives l-0-N α -acetyl aminoacyl ester 3-0- monoacylglycerides ol -0 -N α -acetyl-aminoacyl ester 2,3-O-diacylglycerides or (which will be designated as nnaa (Ac)) from OOaa (Ac) using linear fatty acid chlorides of 8 to 18 carbon atoms as agents acylating agents in a pyridine medium. 2) Enzymatic procedure: the synthesis via enzyme has been carried out in two stages: a) Condensation reaction of glycerol and the free or esterified carboxyl group of N α -acetyl-L-amino acid, using hydrolytic enzymes, proteases type catalysts and lipases, in a medium in the absence of solvent and with low aqueous content. b) Acylation reaction of the OOaa (Ac) free alcohol groups with free fatty acids or esters of these acids, using as lipase catalysts. The reaction takes place in a medium in the absence of solvent and with a low aqueous content.
La presente invención se refiere a nuevos compuestos tensioactivos derivados de aminoácidos del tipo mono y diacilglicéridos diseñados para que actúen como agentes de superficie y antimicrobianos. Las variaciones en la actividad serán función del n° de cadenas grasas, la longitud de éstas y el aminoácido presente en la estructura.The present invention relates to novel surfactant compounds derived from mono and diacylglyceride type amino acids designed to act as surface and antimicrobial agents. The variations in activity will be a function of the number of fatty chains, their length and the amino acid present in the structure.
La purificación de los productos intermedios y finales se lleva a cabo mediante extracciones líquido/líquido, líquido/sólido, cristalizaciones, cromatografía de intercambio iónico y HPLC preparativo.Purification of intermediate and final products is carried out by liquid / liquid, liquid / solid extractions, crystallizations, ion exchange chromatography and preparative HPLC.
SíntesisSynthesis
A modo de ejemplo y sin que ello limite el procedimiento, a continuación se detalla un ejemplo de la obtención de un tensioactivo derivado del ácido aspártico (D) del tipo diacil glicerol éster con cadenas grasas de 8 átomos de carbono por vía química (8 8 D(Ac)) y uno del tipo monoacil glicerol éster de cadena grasa de 12 átomos de carbono por vía enzimática(12 0 D(Ac)). En ambos casos el aminoácido utilizado es aspártico.
1 ) Procedimiento químicoBy way of example and without limiting the process, an example of obtaining a surfactant derived from aspartic acid (D) of the diacyl glycerol ester type with fatty chains of 8 carbon atoms by chemical route (8 8 D (Ac)) and one of the monoacyl glycerol fatty chain ester type of 12 carbon atoms enzymatically (12 0 D (Ac)). In both cases the amino acid used is aspartic. 1) Chemical procedure
Ia) Preparación de 88D(Ac)I a ) Preparation of 88D (Ac)
Se prepara una disolución 1 Molar de OOD(Ac) en piridina a la cual se añade cantidades catalíticas de una base orgánica terciaria (dimetil amino piridina, DMAP). A esta mezcla se le añade lentamente cloruro de octilo en una concentración 2.5-3 Molar. La mezcla de reacción se mantiene en agitación durante 4-6 horas a temperatura ambiente. Posteriormente se elimina el disolvente al vacío y la mezcla se purifica mediante extracciones líquido-líquido, MPLC y HPLC preparativa.A 1 Molar solution of OOD (Ac) in pyridine is prepared to which catalytic amounts of a tertiary organic base (dimethyl amino pyridine, DMAP) are added. To this mixture is added slowly octyl chloride in a concentration 2.5-3 Molar. The reaction mixture is kept under stirring for 4-6 hours at room temperature. The solvent is then removed in vacuo and the mixture is purified by liquid-liquid extractions, MPLC and preparative HPLC.
2) Procedimiento enzimático2) Enzymatic procedure
Como se ha mencionado en la memoria, el proceso consta de dos etapas: Ia) Preparación de 0 0 D(Ac) En un reactor con cierre hermético se disuelve Nα-acetil-L-aspártico (1 eq) en glicerol (5 eq) conteniendo un 10 % de agua. La homogeneización del medio tiene lugar mediante la introducción de agitación magnética. A la disolución se añade la preparación comercial de lipasa Novozym 435. La mezcla de reacción se mantiene en agitación de tipo vaivén (200 rpm) o equivalente y termostatizada a 50 °C en un baño de agua. La reacción se sigue por cromatografía líquida de alta eficacia (HPLC) hasta que todo el N -acetil-L-aspártico se ha consumido; aproximadamente unas 48 horas. El rendimiento en este punto y por HPLC es del 90 %. A continuación se añade al medio de reacción un volumen igual de una mezcla metano 1/ ácido acético 4: 1 y se filtra para separar el enzima del medio de reacción con el producto. El filtrado previamente evaporado se disuelve en agua y se adsorbe sobre resina de intercambio aniónico débil. En una primera etapa tiene lugar la elución selectiva del glicerol presente en el medio por tratamiento con agua. Seguidamente se procede a la elución de l-Nα-acetil aspártico-sn-glicerol por tratamiento con HAc 400 mM. Tras evaporación y liofilización se obtiene un sólido pardo que se identifica por espectrometría de masas y resonancia magnética nuclear de protón y carbono. El rendimiento final es del 70 %.
2a) Preparación de 12 C D(Ac)As mentioned in the report, the process consists of two stages: I a ) Preparation of 0 0 D (Ac) In a tightly sealed reactor N α -acetyl-L-aspartic (1 eq) is dissolved in glycerol (5 eq) containing 10% water. The homogenization of the medium takes place by the introduction of magnetic stirring. To the solution is added the commercial preparation of lipase Novozym 435. The reaction mixture is kept under stirring of the reciprocating type (200 rpm) or equivalent and thermostated at 50 ° C in a water bath. The reaction is followed by high efficiency liquid chromatography (HPLC) until all the N-acetyl-L-aspartic acid has been consumed; About 48 hours. The yield at this point and by HPLC is 90%. An equal volume of a methane 1/4: 1 acetic acid mixture is then added to the reaction medium and filtered to separate the enzyme from the reaction medium with the product. The previously evaporated filtrate is dissolved in water and adsorbed on weak anion exchange resin. In a first stage the selective elution of the glycerol present in the medium takes place by treatment with water. It then proceeds to the elution of lN aspartic α -acetyl-sn-glycerol by treatment with 400 mM HAc. After evaporation and lyophilization a brown solid is obtained which is identified by mass spectrometry and nuclear magnetic resonance of proton and carbon. The final yield is 70%. 2 a ) Preparation of 12 CD (Ac)
En un reactor abierto conteniendo OOD(Ac) (1 eq) y ácido laúrico (2 eq) a 55 C conteniendo un 4 % (w/w) de agua, se añade la preparación comercial NovozymIn an open reactor containing OOD (Ac) (1 eq) and lauric acid (2 eq) at 55 C containing 4% (w / w) of water, the commercial preparation Novozym is added
435 manteniendo el medio en agitación y termostatizado a 55 C. La reacción se sigue por cromatografía líquida de alta eficacia (HPLC) hasta que todo el 1 -Nα- acetil-aspártico-sn-glicerol se haya consumido; aproximadamente unas 72 horas. El rendimiento en este punto y por HPLC es de un 65 %. A continuación se añade al medio de reacción un volumen igual de una mezcla acetonitrilo/agua/ácido acético 80:19: 1 y se filtra para separar el soporte que contiene el enzima del medio de reacción con el producto. La obtención del producto final se consigue mediante técnicas convencionales de cristalización y/o de cromatografía.
435 keeping the medium under stirring and thermostatized at 55 C. The reaction is followed by high efficiency liquid chromatography (HPLC) until all 1-N α -acetyl-aspartic-sn-glycerol has been consumed; approximately 72 hours. The yield at this point and by HPLC is 65%. An equal volume of an 80:19: 1 acetonitrile / water / acetic acid mixture is then added to the reaction medium and filtered to separate the enzyme-containing support from the reaction medium with the product. Obtaining the final product is achieved by conventional crystallization and / or chromatography techniques.
Claims
1. Tensioactivos del tipo 1 -O-Nα-acetil-L-aminoacil éster 3-O- monoacil glicéridos y 1 - O-Nα-acetil-L-aminoacil éster 2,3-0- diacil glicéridos como agentes antimicrobianos de elevada actividad superficial caracterizados por la fórmula general:1. Surfactants of the type 1 -ON α -acetyl-L-aminoacyl ester 3-O-monoacyl glycerides and 1-ON α -acetyl-L-aminoacyl ester 2,3-0-diacyl glycerides as high surface activity antimicrobial agents characterized by the general formula:
(I)(I)
Donde:Where:
Ri es un grupo acetil. R2 puede ser una cadena lineal o ramificada opcionalmente sustituida, saturada o no saturada o un grupo aromático opcionalmente sustituido.Ri is an acetyl group. R 2 may be an optionally substituted, saturated or unsaturated linear or branched chain or an optionally substituted aromatic group.
R3 y Ri pueden ser un hidrógeno o una cadena lineal preferentemente larga saturada o no saturada.R 3 and Ri can be a hydrogen or a preferably long saturated or unsaturated linear chain.
X puede ser : Br \ Cl ", HSO4 ", CH3COO \ CF3COO " ,Na +, K + En la fórmula general R es preferentemente un grupo: amida, hidroxibencil, imidazol y carboxilo.X may be: Br \ Cl " , HSO 4 " , CH 3 COO \ CF 3 COO " , Na + , K + In the general formula R is preferably a group: amide, hydroxybenzyl, imidazole and carboxyl.
R3 y Rj pueden ser seleccionados de un grupo de cadenas lineales de 8, 9,10, 12, 14,16 γR 3 and Rj can be selected from a group of linear chains of 8, 9,10, 12, 14,16 γ
18 átomos de carbono saturadas o no saturadas puras o sus mezclas. 2- Procedimiento de obtención químico o enzimático de tensioactivos de fórmula general según reivindicación 1 caracterizado por las siguientes etapas:18 pure saturated or unsaturated carbon atoms or mixtures thereof. 2- Procedure for obtaining chemical or enzymatic surfactants of the general formula according to claim 1 characterized by the following steps:
- Formación del l-Nα-acetil-aminoacil-sn-glicerol éster.- Formation of the α- acetyl-aminoacyl-sn-glycerol ester.
- Formación de 1 -O-Nα-acetil-aminoacil éster 3-O-monoacilglicéridos o l-O-Nα- acetil- aminoacil éster 2,3-O-diacilglicéridos- Formation of 1 -ON α -acetyl-aminoacyl ester 3-O-monoacylglycerols or lON α - acetyl aminoacyl ester O-2,3-diacylglycerol
3- Un procedimiento según la reivindicación 1 y 2 caracterizado por utilizar como compuestos de partida N -acetil aminoácidos L puros o mezclas de D y L de: aspártico, asparagina, glutámico, glutamina, tirosina y histidina.3- A process according to claim 1 and 2 characterized by using as pure N-acetyl amino acids starting compounds or mixtures of D and L of: aspartic, asparagine, glutamine, glutamine, tyrosine and histidine.
4- Un procedimiento según la reivindicación 1 y 2 caracterizado por utilizar como grupo protector de la función α-amino del aminoácido el grupoacetil (Ac).4- A process according to claim 1 and 2 characterized in that the acetyl group (Ac) is used as the protecting group for the α-amino function of the amino acid.
5- Un procedimiento de obtención según reivindicación 1 y 2 en el que la primera etapa del procedimiento químico se caracteriza por la obtención de los compuestos 1 -Nα-acetil- aminoacil-sn-glicerol éster a partir de Nα-acetil-L-aminoácidos y glicerol utilizando BF3 como catalizador químico de la reacción.5- A method of obtaining according to claim 1 and 2 in which the first stage of the chemical process is characterized by obtaining the compounds 1 -N α -acetyl-aminoacyl-sn-glycerol ester from N α -acetyl-L -amino acids and glycerol using BF 3 as chemical reaction catalyst.
6- Un procedimiento de obtención según reivindicación 1 y 2 en el que la primera etapa del procedimiento enzimático se caracteriza por la obtención de los compuestos 1-Nα- acetil-aminoacil-sn-glicerol éster a partir de N -acetil-L-aminoácidos y glicerol mediante la catálisis de un enzima hidrolítico, proteasas y lipasas preferentemente, en medios libres de disolvente.6- A method of obtaining according to claim 1 and 2 in which the first stage of the enzymatic process is characterized by obtaining the compounds 1-N α -acetyl-aminoacyl-sn-glycerol ester from N-acetyl-L- amino acids and glycerol by catalysis of a hydrolytic enzyme, proteases and lipases preferably, in solvent free media.
7- Un procedimiento según reivindicación 1, 2, 5 y 6 caracterizado por emplear glicerol puro para la obtención de 1 -Nα-acetil-aminoacil-sn-glicerol éster .7- A method according to claim 1, 2, 5 and 6 characterized by pure glycerol used for the preparation of 1 -N α -acetyl-aminoacyl-sn-glycerol ester.
8- Un procedimiento según reivindicación 1, 2, 5 y 6 caracterizado por que la condensación del glicerol con el aminoácido N-α acetil protegido tiene lugar de forma regioselectiva en el carboxilo en α del derivado Nα-acetil protegido. 9- Un procedimiento según reivindicación 1, 2, 5 y 6 caracterizado por que la condensación del glicerol con el aminoácido N-α protegido tiene lugar de forma regioselectiva en la posición 1(3) del glicerol.8- A process according to claim 1, 2, 5 and 6 characterized in that the condensation of glycerol with the amino acid N-α protected acetyl takes place regioselectively in the carboxyl in α of the derivative N α -acetyl protected. 9- A process according to claim 1, 2, 5 and 6 characterized in that the condensation of glycerol with the protected N-α amino acid takes place regioselectively in position 1 (3) of glycerol.
10- Un procedimiento según la reivindicación 1 y 2, caracterizado por utilizar un lecho combinado de celita/ carbón activo en proporciones 1 a 1 para la purificación de los derivados 1 -Nα-acetil-aminoacil-sn-glicerol éster.A method according to claim 1 and 2, characterized in that a combined bed of celite / activated carbon is used in proportions 1 to 1 for the purification of the 1-N α -acetyl-aminoacyl-sn-glycerol ester derivatives.
1 1 - Un procedimiento según reivindicación 1 y 2 en el que la segunda etapa del procedimiento químico se caracteriza por la acilación de los grupos hidroxilo libres de 1 - Nα -acetil-aminoacil-sn-glicerol éster en un medio de piridina.1 1 - A process according to claim 1 and 2 wherein the second stage of the chemical process is characterized by the acylation of the free hydroxyl groups of 1 - N α -acetyl-aminoacyl-sn-glycerol ester in pyridine medium.
12- Un procedimiento según reivindicación 1, 2 y 1 1 caracterizado por el empleo de cloruros de ácido graso de cadena lineal de 8, 9, 10, 12, 14, 16 y 18 átomos de carbono saturadas o no saturadas en la reacción de acilación de los grupos hidroxilo libres de 1 -Nα -acetil -aminoacil-sn-glicerol éster.12- A process according to claim 1, 2 and 1 1 characterized by the use of linear chain fatty acid chlorides of 8, 9, 10, 12, 14, 16 and 18 saturated or unsaturated carbon atoms in the acylation reaction of the free hydroxyl groups of 1 -N α -acetyl-sn-glycerol -aminoacil ester.
13- Un procedimiento según reivindicación 1 y 2 en el que la segunda etapa del procedimiento enzimático,correspondiente a la reacción de acilación del ácido o éster de ácido graso con los grupos hidroxilo libres del derivado 1 -Nα -acetil-aminoacil-sn-glicerol éster, tiene lugar mediante la mezcla de ambos compuestos sin la necesidad de ningún solvente.13- A process according to claim 1 and 2 wherein the second stage of the enzymatic process, corresponding to the acylation reaction of the fatty acid or ester with the free hydroxyl groups of the derivative 1-N α -acetyl-aminoacyl-sn- Glycerol ester, takes place by mixing both compounds without the need for any solvent.
14- Un procedimiento según reivindicación 1, 2 y 13 caracterizado por el empleo de ácidos grasos o esteres de ácidos grasos de cadena lineal de 8, 9, 10, 12, 14, 16 y 18 átomos de carbono saturadas o no saturadas en la reacción de acilación de los grupos hidroxilo libres de 1-Nα -acetil-aminoacil-sn-glicerol éster. 15- Un procedimiento segur reivindicación 1, 2 y 13 caracterizado por el empleo de enzimas hidrolíticos del tipo ¡ipasas, como ahora las preparaciones comerciales Novozym y/o Lipozyme como biocatalizadores de la reacción de acilación de los grupos hidroxilo libres de l-O- Nα -acetil -aminoacil-sn-glicerol éster.14- A process according to claim 1, 2 and 13 characterized by the use of fatty acids or esters of straight chain fatty acids of 8, 9, 10, 12, 14, 16 and 18 saturated or unsaturated carbon atoms in the reaction acylation of the free hydroxyl groups of N α -acetyl-1-aminoacyl-sn-glycerol ester. 15- A process ax claim 1, 2 and 13 characterized by the use of hydrolytic enzymes of the type ipasas as Novozym now commercial preparations and / or Lipozyme as biocatalysts of the acylation reaction of the free hydroxyl groups of LO- N α -acetyl-aminoacyl-sn-glycerol ester.
16- Un procedimiento según reivindicación 1 y 2 caracterizado por que el progreso de la reacción se realiza mediante análisis por cromatografía líquida de alta eficacia, con una columna de tipo propilciano y Cι8, utilizando como eluyentes agua y acetonitrilo. 16- A process according to claim 1 and 2 characterized in that the progress of the reaction is carried out by analysis by high performance liquid chromatography, with a propylcyan type column and Cι 8 , using as eluents water and acetonitrile.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2001231770A AU2001231770A1 (en) | 2000-02-11 | 2001-02-08 | Surface active agents derived from 1-o-nalpha-acetyl-l-aminoacyl ester 3-o-monoacyl glycerides and 1-o-nalpha-acetyl l-aminoacyl ester 2,3-o-diacyl glycerides type amino acids and the preparation thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES200000318U ES1045340Y (en) | 2000-02-11 | 2000-02-11 | LIFTING WEDGE FOR PNEUMATIC DRIVING BEDS. |
| ESP200000318 | 2000-02-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2001058849A1 true WO2001058849A1 (en) | 2001-08-16 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/ES2001/000040 WO2001058849A1 (en) | 2000-02-11 | 2001-02-08 | SURFACE ACTIVE AGENTS DERIVED FROM 1-O-Nα-ACETYL-L-AMINOACYL ESTER 3-O-MONOACYL GLYCERIDES AND 1-O-Nα-ACETYL L-AMINOACYL ESTER 2,3-O-DIACYL GLYCERIDES TYPE AMINO ACIDS AND THE PREPARATION THEREOF |
Country Status (2)
| Country | Link |
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| ES (1) | ES1045340Y (en) |
| WO (1) | WO2001058849A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003070735A3 (en) * | 2002-02-19 | 2004-03-25 | Novosom Ag | Components for producing amphoteric liposomes |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996021642A1 (en) * | 1995-01-10 | 1996-07-18 | Laboratorios Miret, S.A. | Process for the synthesis of cationic surfactants obtained from the condensation of fatty acids with esterified dibasic aminoacids, and their application as antimicrobial agents |
| ES2130980A1 (en) * | 1997-03-10 | 1999-07-01 | Consejo Superior Investigacion | Enzyme process for the preparation of lipoamino acids of the alkyl amide and ester type |
-
2000
- 2000-02-11 ES ES200000318U patent/ES1045340Y/en not_active Expired - Fee Related
-
2001
- 2001-02-08 WO PCT/ES2001/000040 patent/WO2001058849A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996021642A1 (en) * | 1995-01-10 | 1996-07-18 | Laboratorios Miret, S.A. | Process for the synthesis of cationic surfactants obtained from the condensation of fatty acids with esterified dibasic aminoacids, and their application as antimicrobial agents |
| ES2130980A1 (en) * | 1997-03-10 | 1999-07-01 | Consejo Superior Investigacion | Enzyme process for the preparation of lipoamino acids of the alkyl amide and ester type |
Non-Patent Citations (1)
| Title |
|---|
| R. VALIVETY ET AL.: "Chemo-enzymic synthesis of amino-acid based surfactants", JOURNAL AMERICAN OIL CHEM. SOC., vol. 74, no. 7, 1997, pages 879 - 886 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003070735A3 (en) * | 2002-02-19 | 2004-03-25 | Novosom Ag | Components for producing amphoteric liposomes |
Also Published As
| Publication number | Publication date |
|---|---|
| ES1045340U (en) | 2000-08-16 |
| ES1045340Y (en) | 2001-02-16 |
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