FR2906531A1 - Making 5,5-dimethyl-3-ethyl-3,4-dihydro-furan-2-one by reacting sodium methylate and dimethyl malonate with 3-chloro-2-methylprop-1-ene, reacting the product with tert-potassium butylate and ethyl bromide then with soda and phosphoric acid - Google Patents

Abstract

Synthesis of 5,5-dimethyl-3-ethyl-3,4-dihydro-furan-2-one (I), comprises: reacting sodium methylate and dimethyl malonate with 3-chloro-2-methylprop-1-ene; reacting obtained product with tert-potassium butylate and ethyl bromide; and reacting obtained product with soda and phosphoric acid.

Description

Process for the preparation of 5,5-dimethyl-3-ethyl-3,4-dihydro-furan-2-one

  The present invention relates to a new process for preparing 5,5-dimethyl-3-ethyl-3,4-dihydro-furan-2-one.

The terms fragrance, fragrance, fragrance are used interchangeably herein for any organoleptic compound that pleasantly stimulates the sense of smell. The terms aroma and aromatic are used interchangeably herein for any taste-stimulating organoleptic compound. The term organoleptic compound is used herein for any compound stimulating the senses of smell and taste, and therefore being perceived as having a characteristic smell and / or taste.

By hiding or masking is meant to reduce or eliminate the perception of a bad odor or bad taste generated by one or more molecules involved in the composition of a product.

Odorous molecules belong to various chemical classes. There may be mentioned lactones widely used in nature and constituting a family of odorous molecules very important in perfumery.

Lactones are known for their fruity notes, such as the y-Nonanoic lactone (coconut fragrance), described in Bunce, R.A .; Reeves, H.D .; J.Chem.Ed. 1990, 67, 69-70. Other well-known fragrances of lactones are 2906531 2 described with terms such as grass, hay, spicy, woody, almond, milk, sweet fruits such as peach or apricot ... The lactones are present in the form of traces in the 5 fruit, dairy products and alcoholic beverages but contribute substantially to their aromas (Duffosé L. et al, Food Sciences 1994, 14, 17-50). The low threshold of olfactory detection of lactones is compensated by a large use of these in the field of: LO perfumes and aromas (Zope D.D. et al., Fafai Journal 2004, 43-54). Some lactones bring the main note of a given aroma; it is often pleasant and persistent. The Applicant has shown during its research that 5,5-dimethyl-3-ethyl-3,4-dihydro-furan-2-one, belonging to the family of tri-substituted y-lactones, referred to as Noxolide, has such characteristics.

To the knowledge of the Applicant, 5,5-dimethyl-3-ethyl-3,4-dihydro-furan-2-one has been reported twice in the literature. First, in a study of the effects of substituents in 1,2-hydride transfer reactions (Kirmse W. et al Chem Chem., 1975, 108, 1839 & M. de Campos M. et al., Arch. Pharm., (Weinheim) 1965, 298, 92). More recently, 5,5-dimethyl-3-ethyl-3,4-dihydro-furan-2-one has been described as one of the products of the reaction of anoic acid with the organometallic complex naphthalene / lithium followed by condensation with isobutene oxide (Fujita et al., J. Appl., Biotechnol., 1977, 27, 539).

However, none of the documents of the prior art describe or suggest that 5,5-dimethyl-3-ethyl-3,4-dihydrofuran-2-one has organoleptic properties, and a fortiori it The use which could be made of this molecule as an odorant compound, in particular a fragrance or as a flavoring, or as a masking agent for an odor or a flavor, is neither described nor suggested. . Moreover, the proposed syntheses are difficult to apply on an industrial scale, involving in particular the use of alkali metals which are very reactive with respect to water and oxygen in the air. Thus, the technical problem that the Applicant proposes to solve by the present invention is the provision of new molecules with high odor power, stable, having a long shelf life, and prepared according to a simple embodiment and from cheap and abundant raw materials. The simplicity of implementation of the reactions and the low cost of the raw materials used represent important advantages for the industrial implementation of the invention. The present invention relates to the use of 5,5-dimethyl-3-ethyl-3,4-dihydro-furan-2-one (or Noxolide) as an odorant agent or compound, especially as a fragrance or aroma . An evaluation panel composed of several professionals qualitatively evaluated the compound of the invention. Noxolide, represented below by the formula (A), has been described as iodized marine with walnut facets, aniseed slightly licorice, patchouli, damascenone. Because of its olfactory qualities, Noxolide finds a wide variety of use in perfumery for the preparation of perfume compositions, perfume bases or concentrates, perfumes or eau de toilette, as well as in the preparation of scented articles. various, such as soaps, bubble bath, shower or bath gels, aftershave lotions, shampoos or other hair products including hair hygiene or hair care, cosmetic preparations, deodorants 7.0 body or ambient air, or detergents or fabric softeners or products for the maintenance or purification of ambient air. In particular, the subject of the invention is a hygiene or hair care product, characterized in that it comprises 5,5-dimethyl-3-ethyl-3,4-dihydro-furan-2 -one. In these applications, the compound according to the invention can be used alone or, as is more common in perfumery, in admixture with other perfuming ingredients, solvents or adjuvants commonly used in perfumery and that the man of the craft is able to choose according to the desired effect and the nature of the product to be perfumed. The present invention also relates to the use of 5,5-dimethyl-3-ethyl-3,4-dihydro-furan-2-one (Noxolide) as a flavor. Noxolide is useful as a food flavoring, particularly for the preparation of food compositions, food additives, flavoring bases and concentrates as well as in the preparation of various flavored products, such as beverages, dairy products, ice creams, soups and the like. sauces, ready meals, meat products, cooking aids, biscuits or savory snacks. Noxolide can also be used as an aroma in wines, beers and / or tobaccos.

The present invention also relates to the use of 5,5-dimethyl-3-ethyl-3,4-dihydro-furan-2-one (Noxolide) as a masking agent for a taste and / or odor, especially in a food composition, or cosmetic, or pharmaceutical. In these applications, the compound according to the invention can be used alone or, as is more common in aromatics, in admixture with other flavoring ingredients, solvents or adjuvants of common use in food flavoring and that the Those skilled in the art are able to choose according to the desired effect and the nature of the product to be flavored. The concentrations in which 5,5-dimethyl-3-ethyl-3,4-dihydro-furan-2-one (Noxolide) can be used to achieve the desired scenting, aromatizing and / or masking effects vary within a range of very broad value, from 0.001% to 99% by weight, preferably from 0.001% to 20% by weight, very preferably from 0.1% to 10% by weight, it being well known that these values depend on the nature of the perfume article, the desired odor effect, and the nature of the other ingredients in a given composition. The invention also relates to a new process for the synthesis of 5,5-dimethyl-3-ethyl-3,4-dihydro-furan-2-one, (Noxolide) comprising - a first step [1] reacting sodium methoxide and dimethyl malonate with 3-clhoro-2-methylprop-1-ene, resulting in the formation of methyl 4-methyl-2-methoxycarbonyl-pent-4-enoate (I), - a second step [2] reacting the product (I) with potassium t-butoxide and ethyl bromide, resulting in the formation of 2-ethyl-4-methyl-2-methoxycarbonyl-pent-4-enoate methyl (II), - a third step [3] reacting the product (I: I) with sodium hydroxide and phosphoric acid, resulting in the formation of 5,5-dimethyl-3-ethyl-3, 4-dihydro-furan-2-one (A). The following examples further illustrate the various methods of making novel compounds according to the invention as well as their use, and their utility. These examples are presented for illustrative purposes only and can not be considered as limiting the invention.

Example 1: Production of Noxolide or methyl 5,5-dimethyl-3-ethyl-3,4-dihydro-furan-2-one methyl 4-methyl-2-methoxycarbonyl-pent-4-enoate (I) COOMe COOMe The reaction is carried out in a three-neck flask equipped with a plunging thermometer, an ascending condenser equipped with a potash drying guard and an isobaric 250 mL dropping funnel. .

54 g of sodium methylate, 300 ml of anhydrous methanol, 1 g of potassium iodide and 138.7 g of dimethyl malonate are introduced successively into the dry flask, purged with nitrogen. The resulting solution is stirred for one hour at room temperature and then 95 g of 3-chloro-2-methylpropene-1Lo are slowly added to the dropping funnel. The mixture is stirred for 3 hours at room temperature and then 12 hours under reflux. The refrigerant is replaced by a distillation unit and the solvent is distilled. The residue is taken up in 50 ml of clear water and 300 ml of methylcyclohexane. The organic phase is dried and the solvent is distilled off. The residue is fractionated using a 30 cm Vigreaux column; 3 fractions are collected: - The first fraction, which weighs 15 g, consists of 20 dimethyl malonate (Eb = 85-87 C / 20mm Hg) - The second fraction weighs 138 g and boils at 86 C / 6 mm Hg. of the desired ester, (I), a yield of 74% (80% based on the starting material actually consumed). The product is pure in vapor phase chromatography at more than 98%. - A third fraction is obtained by high vacuum distillation (Eb = 64-68 C / 1 mm Hg). It weighs 36 g and has been identified as dimethyl bis (2-methyl-2-propenyl) -2-malonate. For compound 1 2906531 8 IR: (NaCl, film) 1760, 1740, 1440, 1350, 1295, 1230, 1150, 1050, 1020, 900 cm -1 1H NMR, (CDCl3) 1.73 ppm (m, 3H); 2.50 (d, J = 8 Hz, 2H); 3.20 to 3.70 (m; H); 3.68 (s, 6H); 4.72 (m 2H). MS: 70 eV 186 (M +); 154; 127; 111; 95 uma methyl 2-methyl-4-methyl-2-methoxycarbonyl-4-enanoate (II) The reaction is carried out in a three-neck flask equipped with a dipping thermometer, an ascending condenser equipped with a drying guard potash and a 250mL isobaric dropping funnel. 93 g of methyl 4-methyl-2-methoxycarbonyl-pentenoate (I) and 40 g of anhydrous DMSO are introduced successively into the flask. With the mixture being maintained at 20 ° C. to 30 ° C. using a cooling bath, 59 g of potassium t-butoxide are added and the mixture obtained is stirred for 2 hours at room temperature before 35.5 g of ethyl bromide are added. slowly added to the flask via the dropping funnel so that the temperature does not exceed 30 C in the medium. The solution obtained is stirred for 12 hours at room temperature and then poured into 300 ml of 5% hydrochloric acid. The resulting aqueous phase is extracted 5 times with 100 ml of methylcyclohexane. The combined organic phases are washed with 100 ml of clear water and then dried and concentrated in vacuo.

The residue is rectified under vacuum. The product distils at 95 ° C./4 mm Hg. 91 g of the desired product are isolated, ie a yield of 85%. 1 H NMR (CDCl 3) 0.64 ppm (t, 7.5 Hz, 3H); 1.06 (t, 7.1 Hz, 6H), 1.46 (s, 3H), 1.75 (q, 7.5 HZ, 2H); 2.50 (s, 2H), 4.00 (q, 7.1 Hz, 4H); 4.53 (s, 1H); 4.65 (s, 1H).

IR: (NaCl, film) 3079, 2955, 1736, 1647, 1437, 1301, 1225, 1123, 901 cm -1 MS: 214 (M + +) 185; 155; 139; 123; 95; 85; 79; The reaction is conducted in a 1L 3-neck flask equipped with a dipping thermometer and an ascending condenser. This 20 denier will then be replaced by a conventional distillation system: Vigreaux column, condenser and recipe. 200mL of clear water, 200 mL of methanol, 20 g of flaked sodium hydroxide and 53.5 g of methyl 2-ethyl-4-methyl-2-methoxycarbonyl-pent-4-enanoate (II) are successively introduced into the flask. . The mixture is heated for 4 hours and then the heating is interrupted. The distilling assembly replaces the rising refrigerant and the solvent is distilled until 90 C in the vapors. Hot water is introduced gradually into the flask in order to maintain a fluidity in the distillation mixture. The aqueous phase is brought to 60 ° C., extracted with 2 × 100 ml of toluene and then brought to between 0 ° and 5 ° C. A heavy white precipitate is formed. The suspension is acidified to pH = 3 with a 6N sulfuric acid solution, while maintaining the temperature below 5 C. The white precipitate is filtered, washed with clean water until neutrality is obtained. then it is taken up in 300 ml of dry toluene and refluxed in the presence of 1 g of 85% phosphoric acid for 12 hours. The solution is cooled, washed neutral with saturated sodium bicarbonate solution and dried. The solvent is distilled under partial vacuum and the residue is stripped in vacuo (bp = 86 ° C / 6 mm Hg). The lactone weighs 27.8 g, which represents a yield of 78.2%. It has a strong smell of green nuts. It is named Noxolide (Formula A). 1 H NMR (CDCl 3) 1.0 ppm (t, 7.4 Hz, 3H); 1.4 (s, 3H); 1.5 (s, 3H); 1.4 to 1.6 (m, 1H); 1.7 (m, 1H); 1.8 to 2.0 (m, 1H); 2. 3 (dd, 12.6 / 8.9 Hz, 1H); 2.7 (ddt, 11.2 / 8.9 / 4.7 Hz, 1H) IR: (NaCl, film) 2973, 2935, 2878, 1768, 1461, 1376, 1271, 1168, 1118, 952 cm MS (70 eV) 142 ( M +.); 127; 99; 83; 69 μM 13 C NMR: CDCl 3, 50MHz 12.0, 24.1, 27.5, 29.3, 41.0, 42.4, 82.5, 178.5 ppm Elemental Analyzes% calc. C 67.57 H 9.92 30% obt. C 66.84 H 10.02 Physical Constants: 2906531 N20 = 1.4355 D2o = 0.949 Example 2: Olfactory evaluation of Noxolide in a composition Noxolide has been described olfactively as marine iodized with walnut facets, aniseed a little licorice, patchouli, damascenone .

A perfume composition was created (test 2) in which the olfactory impact of the noxolide was examined by comparison with a composition not containing the compound (test 1). Components Test 1 Test 2 _ (weight) (weight) HS MELON P-99 10.00 10.00 BERGAMOTTE 77 P-99 15.00 15.00 LINALYLE ACETATE HLR 50.00 50.00 CASSIS BASE 345 B 5.00 5.00 LEMON TERPENES USA 50.00 50.00 DIHYDROMYRCENOL 50.00 50.00 ETHYL LINALOL (Givaudan) 90.00 90.00 FLORALOZONE (IFF) 10.00 10.00 GALAXOLIDE without PE in MIP 135.00 135, 00 METHYL DIHYDRO JASMONATE 200.00 200.00 OCTAHYDRO TETRAMETHYL ACETONAPHTONE 40.00 40.00 LILIAL (Givaudan) from MFI 100.00 100.00 LINALOL HLR 50.00 50.00 GAMMA NONALACTONE-PRUNOLIDE 50.00 50.00 ALDEHYDE C14 GAMMA UNDECA (: 10% DPG) 5.00 5.00 DIHYDROFLORIFON (IFF) (10% DPG) 5.00 5.00 FOLIONE (Givaudan) (1% DPG) 20.00 20.00 JASMOLACTONE (Firmenich) ( 10% DPG) 5.00 5.00 _CRIPLAL (IFF) (10% DPG) 5.00 5.00 VANILLIN (Rhone-Poulenc) (: L0% DPG) 5.00 5.00 DPG 2.70 0.00 NOXOLIDE 0, 00 2,70 11 The previous compositions were tested in a type 2 in 1 shampoo application at a rate of 0.5% in the base. The formula of Trial 2 gives more power and 5 grip in the lead. The appearance is greener and more natural than the formula of Trial 1 is remarkable. Noxolide particularly enhances the natural, transparent, green-colored side of the fragrance accord. It highlights sparkling citrus tones and the lactonic, fruity accord. Formula 10 of Trial 1 is soft, musky, flat and featureless. It hides the base with difficulty.

Claims (1)

  A process for synthesizing 5,5-dimethyl-3-ethyl-3,4-dihydro-furan-2-one comprising reacting sodium methylate and dimethyl malonate with 3-clhoro-2- methylprop-1-ene, - reacting the product from the above step with potassium t-butoxide and ethyl bromide, - reacting the product from step 10 above with soda and phosphoric acid.