EA043351B1 - 6-CHROMANOL DERIVATIVES AND THEIR SYNTHESIS - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to new compounds that can be used for the synthesis of new chromanol derivatives.

Prior Art

The field of isoprenoids and their derivatives is a branch of chemistry in which a large amount of synthesis research has been carried out. One reason is that they are precursors to vitamin E and alpha-tocopherol, which are very important natural compounds with great value in the food and feed market. In this context, interesting starting compounds are the isoprenoids beta-farnesene and beta-myrcene. Already more than 30 years ago, Rhone-Poulenc has been intensively researching this area, for example see US 4460786, US 4621165 and US 5874636. In CN 105859534 A and WO 2015/165959 A1, beta-farnesene is disclosed as a potential starting material for the synthesis of farnesylacetone.

Myrcene is a naturally occurring compound found in significant quantities in the essential oils of a number of plants, including bay, hemp, ylang-ylang, thyme, parsley, cardamom and hops. In addition, it is produced from beta-pinene, which is obtained from turpentine oil. Thus, myrcene represents a readily available, renewable and interesting starting material for the synthesis of more complex chemicals.

Brief description of the invention

The authors of the present invention unexpectedly discovered a whole series of hitherto unknown compounds with very interesting properties that can be obtained from myrcene. In a series of different reactions involving these new compounds, new chromanol derivatives were eventually discovered. This class of compounds, among other properties, exhibits particularly interesting antioxidant behavior. Given its close structural relationship to tocopherol, this new compound is of great interest to researchers and to the food and feed industry. It is especially important to assess the potential impact on a living organism.

In addition, the intermediates of this synthesis were found to have interesting olfactory characteristics. In particular, they have different odors and provide olfactory sensations that differ from the corresponding previously known compounds.

This opens up new and interesting application possibilities in the field of flavors and fragrances, and especially in the field of perfumery, provided by the compounds that can be obtained according to the present invention. Smells in general, and complex olfactory sensations in particular, are very difficult or even impossible to predict. Therefore, any new fragrance, alone or in combination, is of great value to the fragrance, fragrance and perfume industry.

Other aspects of the present invention are subject to other independent claims. Particularly preferred embodiments are the subject of the dependent claims.

Detailed Description of the Invention

In a first aspect, the present invention relates to a compound of formula (I)

R ¹

where R ¹ , R ³ and R ⁴ independently of each other represent a hydrogen atom or methyl groups;

R ² represents a hydrogen atom or R ² which is a protecting group for a phenolic group;

and wherein each symbol * denotes a chiral/stereogenic center and the symbol # denotes a chiral/stereogenic center.

For the sake of clarity in the text that follows, the following are definitions of some terms used in this text.

As used herein, a C _{x -y} alkyl group is an alkyl group containing from x to y carbon atoms, ie, for example, a C _1-3 -alkyl group is an alkyl group containing from 1 to 3 carbon atoms. The alkyl group may be straight or branched. For example, -CH(CH ₃ )-CH ₂ -CH ₃ is considered a C ₄ -alkyl group.

A C _x-y alkylene group is an alkylene group containing from x to y carbon atoms, ie, for example, a C _1-3 alkylene group is an alkylene group containing from 1 to 3 carbon atoms. The alkylene group may be straight or branched. For example, -CH ₂ -CH ₂ -CH ₂ -, -CH(CH ₃ )-CH ₂ -, -C(CH ₂ -CH ₃ )- and -C(CH ₃ ) ₂ are all considered a C ₃ -alkylene group .

In the event that the same symbol or group designation appears in several claims in this text, the definition of such group or symbol given in the context for one particular claim also applies to other claims that contain that designation.

- 1 043351

The expression process of obtaining is a synonym for the expression method of obtaining, and they can be used interchangeably.

The configuration of an asymmetrically substituted carbon center is designated by the sign R or S according to the rule formulated by R. S. Cahn, C. K. Ingold and V. Prelog. This R/S concept and the rules for determining absolute configuration in stereochemistry are known to those skilled in the art.

In this text, the dotted line in the formulas represents the bond through which the substituent is linked to the rest of the molecule.

The wavy line in any formula herein represents a carbon-carbon bond that bonds to an adjacent carbon-carbon bond such that the double bond is in a Z or E configuration. In other words, a formula containing a wavy bond is a formula that covers both the E and Z isomers.

* and # in any formula in this text mean an asymmetrically substituted carbon atom, which represents a chiral/stereogenic center.

In formula (I), R ² represents a hydrogen atom or a protecting group for a phenolic group. Therefore, formula (I) covers two embodiments. These two embodiments are formula (IA) or (IB), which are discussed below.

In one embodiment of the present invention, R ² represents a hydrogen atom. In this case, the compound of formula (I) is a compound of formula (IA).

R ¹

In another embodiment of the present invention, R ² is R ² which represents a protecting group for a phenolic group. Thus, this version of formula (I) corresponds to formula (IB)

in which R ² represents a protecting group for a phenolic group.

A protecting group for a phenolic group is a group that protects the phenolic group (OH in formula (I-A)), and the protecting group can be easily removed, for example by methods known in the art, again yielding the corresponding compound with a free phenolic group.

The protecting group for the phenolic group is introduced by chemical reaction of a compound of formula (I-A) with a protecting agent.

Protecting agents that provide appropriate protecting groups for the phenolic group are known to those skilled in the art, as are the chemistry and conditions for this reaction. If, for example, the protecting group for the phenolic group forms an ester with the rest of the molecule, then a suitable protecting agent is, for example, an acid, an anhydride or an acyl halide.

The protecting group for the phenolic group R ² is particularly selected from the group consisting of

where R ¹⁰ and R ¹¹ independently of each other represent an O _1-15 alkyl, fluorinated C _1-15 alkyl, C _1-15 cycloalkyl or C _7-15 aralkyl group;

R ¹² represents a C _1-15 alkylene or C _6-15 alkylene group and where

R ¹³ represents a C _1-15 alkyl group, an alkyleneoxyalkyl group or a polyoxyalkylene group;

R ¹⁴ represents a hydrogen atom or a C _1-15 alkyl group;

or

- 2 043351

R ¹³ and R ¹⁴ together represent a C _3-7 alkylene group forming a 5-7 membered ring;

and wherein Y ¹ , Y ² and Y ³ independently represent a hydrogen atom or a group of the formula

and where the dotted line represents the bond by which the substituent is attached to the rest of the molecule.

If R ² is R ¹⁰ , then the compound of formula (I) is an ether, which can be prepared by reacting an appropriate protecting agent with the phenolic group (OH) of the compound of formula (IA). In this case, the protecting agent may be, for example, an alkylating agent such as a corresponding C _1-15 alkyl or fluorinated C _1-15 alkyl or C _1-15 cycloalkyl or C _7-15 aralkyl halide, in particular iodide.

In one preferred embodiment, R ¹⁰ is a methyl group.

In another preferred embodiment, R ¹⁰ represents a C _7-15 aralkyl group, preferably a benzyl group or a substituted benzyl group, particularly preferably a benzyl group.

If R ² represents about oo

Λ Λ J.

R ¹¹ '' or Y ¹ O^ R ¹² '' that compound of formula (I), is an ester of a carboxylic or dicarboxylic acid, which can be prepared by reacting an appropriate protecting agent with the phenolic group (OH) of the compound of formula (IA). In this case, the protecting agent may be, for example, an anhydride or an acid halide of the corresponding carboxylic acid (1) or dicarboxylic acid (2).

o o Λ Λ (2) HO R ¹² OH

If the compound of formula (I) is an ester of a carboxylic acid or a dicarboxylic acid, it is preferred that R ² represents a C _1-7 acyl, preferably an acetyl, trifluoroacetyl, propionyl or benzoyl group, or a substituted benzoyl group.

Ester deprotection can be easily accomplished by exposure to an acid or base.

If ^R2 represents ^R \

R ¹³ '' that compound of formula (I) is an acetal which can be prepared by reacting an appropriate protecting agent with the phenolic group (OH) of the compound of formula (IA). In this case, the protecting agent may be, for example, the corresponding aldehyde, an alkyl halide, for example MeO(CH ₂ ) ₂ OCH ₂ Cl, or an enol ester, for example 3,4-dihydro-2H-pyran. In this case, the substituent R ² is preferably

where n=0 or 1.

In some cases, acetals are also called ethers, especially in the above cases: methoxymethyl ether (MOM ether), β-methoxyethoxy methyl ether (MEM ether) or tetrahydropyranyl ether (THP ether).

Acetal protection can be easily removed by acid action.

In another preferred embodiment, the compound of formula (I) is

- 3 043351 ester of phosphoric acid, pyrophosphoric acid, phosphorous acid, sulfuric acid or sulfurous acid.

Depending on the reaction conditions, esterification can be complete or partial, leaving some residual acid groups of the corresponding acid unesterified (ie Y ¹ and/or Y ² and/or Y ³ = H).

Most preferably, the protecting group R ² is a benzoyl group or a C _1-4 acyl group, in particular an acetyl or trifluoroacetyl group, more preferably an acetyl group. Molecules in which R ² represents an acyl group, in particular an acetyl group, can be easily obtained from the corresponding unprotected molecule by esterification, and the unprotected phenolic compound can be obtained from the corresponding ester by ester hydrolysis.

R ¹ , R ³ and R ⁴ independently of each other represent a hydrogen atom or methyl groups.

In all formulas in the present invention, the following combinations of R ¹ , R ³ and R ⁴ are preferred:

R ¹ = R ³ = R ⁴ = CH3 or

R ¹ = R ⁴ = CH3, R ³ = H or

R ¹ = H, R ³ = R ⁴ = CH3 or

R ¹ = R ³ = H, R ⁴ = CH ₃ .

Most preferably R ¹ = R ³ = R ⁴ = CH3.

As stated above, a compound of formula (I) in which the R ² residue is R ² being a protecting group can be prepared from a compound of formula (IA). Thus, in another aspect, the present invention relates to a process for preparing a compound of formula (IB), comprising the steps of:

a1) providing a compound of formula (I-A)

a2) reacting a compound of formula (I-A) with a protecting agent to obtain a compound of formula (IB)

The compound of formula (I-A) can be prepared in various ways. Particularly preferably it is synthesized from a compound of formula (II-A) or (II-B) by reaction with a compound of formula (III).

Thus, in another aspect, the present invention relates to a process for preparing a compound of formula (I-A), comprising the steps of:

b1) providing a compound of formula (II-A) or (II-B)

b2) condensation of a compound of formula 4 (II-A) or (II-B) with a compound of formula (III) to obtain a compound of formula (I-A)

- 4 043351

It has been found that the condensation reaction in step b2) can be carried out analogously to the condensation of methyl, dimethyl or, respectively, trimethylhydroquinone and the corresponding isophytol or phytol alcohol, as described, for example, in Ullmann's Encyclopedia of Industrial Chemistry, Release 2010, ^7th Edition, Vitamins, pages 44-46.

For this condensation reaction (step b2)) a number of catalysts can be used, such as ZnCl ₃ /mineral acid, BF ₃ /AlCl ₃ , Fe/HCl, trifluoroacetic acid or boric acid/carboxylic acid, as well as indium(III) or scandium salts (III) as described in WO 2005/121115 A1. In addition, heteropolyacids are suitable catalysts, in particular 12-tungstophosphoric acid or 12-tungsten silicic acid, as described in EP 0970953 A1.

In condensation step b2) a new compound of formula (I-C) is obtained as an intermediate

The compound of formula (I-C) represents another aspect of the present invention.

Another method for preparing a compound of formula (I-B) represents another aspect of the present invention. This method includes the stages:

b1) providing a compound of formula (II-A) or (II-B)

b3) condensation of a compound of formula (II-A) or (II-B) with a compound of formula (III-A) to obtain a compound of formula (I-B)

In condensation step b3) a new compound of formula (I-D) is obtained as an intermediate

The compound of formula (I-D) represents another aspect of the present invention.

The reactions described above are not stereospecific and therefore a mixture of isomers is formed

- 5 043351 formula (I-A) or (I-B) with R- and S-configuration at the chiral/stereogenic center indicated by the symbol # at C-2. Typically, a diastereomeric mixture is formed with a ratio of about 50% 2S- and

50% 2R isomers at C-2 in formula (I-A).

The different stereoisomers can in principle be separated and isolated by chromatographic methods, in particular using chiral stationary phases, in particular as described in WO 2016/188945 A1 or WO 2012/152779 A1, the entire contents of which are incorporated herein by reference.

It is therefore possible to obtain a specific stereoisomer corresponding to formula (I) or (I-A), in which the chiral/stereogenic centers marked with * and/or #, in particular the chiral/stereogenic center marked with #, have the desired configuration.

Therefore, this methodology facilitates/gives access to compounds having formula (I) or (I-A) in a specific configuration, in particular (2R,3'R,7'R), as shown below in the formulas

The compounds having formula (II-A) and (II-B) mentioned above are new and represent two additional aspects of the present invention.

In addition to being intermediates in the synthesis of the compound of formula (I), respectively (I-A), they can also be used in the field of flavorings and fragrances, in particular in perfumery, due to their odor.

The present inventors have discovered that the above compound of formula (II-B) can be prepared from the compound of formula (II-A) by isomerization. Therefore, in another aspect, the present invention relates to a process for preparing a compound of formula (II-B)

by isomerization of a compound of formula (II-A)

where the wavy line represents a carbon-carbon bond, which when bonded to a carbon-carbon double bond corresponds to the Z- or E-configuration.

Isomerization methods may be methods known to those skilled in the art for isomerizing isophytol to phytol via acid-catalyzed rearrangement, as described, for example, in Ullmann's Encyclopedia of Industrial Chemistry, Release 2010, ^7th Edition, Vitamins, pages 44-46.

The present inventors have discovered that the compound of formula (II-A) described above can be prepared from the compound of formula (IV). Therefore, in another aspect, the present invention relates to a process for preparing a compound of formula (II-A)

including the stage:

b) providing a compound of formula (IV);

- 6 043351 followed by the steps of either c1) ethynylation of a compound of formula (IV), using ethylene in the presence of a base material, to obtain a compound of formula (V)

c2) hydrogenating a compound of formula (V) with molecular hydrogen in the presence of a Lindlar catalyst to obtain a compound of formula (II-A);

or c3) vinylating a compound of formula (IV) by adding a vinyl Grignard reagent to obtain a compound of formula (II-A).

Details of the reaction types and conditions that can be used for the option using steps c1) are described in EP 1532092 B1, in particular in example 2, or in WO 2003/029175 A1 (use of a basic anion exchange resin), the full contents of which are included in this text via link. Hydrogenation with molecular hydrogen in the presence of a Lindlar catalyst can be used for step c2). For example, the method and conditions described in A. Ofner et al, Helv. Chim. Acta 1959, 42, 2577-2584, can be used for a combination of steps c1) and c2), the entire contents of which are incorporated herein by reference.

US 4,028,385, for example, describes details of the reaction types and conditions for the embodiment using step c3), as well as for steps c1) and c2), the entire contents of this reference are incorporated herein by reference.

The compound having the above formula (V) is new and represents another aspect of the present invention

As described above, the compound of formula (V) can be prepared by reaction c1), i.e. ethynylation of a compound of formula (IV), using ethylene in the presence of a basic substance.

The compound having the above formula (IV) is also new and represents another aspect of the present invention.

The inventors of the present invention have discovered that this compound of formula (IV) can be prepared from the compound of formula (VI). Therefore, in another aspect, the present invention relates to a process for preparing a compound of formula (IV)

including the stage

d) hydrogenating a compound of formula (VI) to obtain a compound of formula (IV)

where the dotted line indicates a carbon-carbon double bond that is located in one of the two positions indicated.

In other words, the formula of this compound (VI) shown above is a schematic representation of the following two formulas (VI-a) and (VI-b)

Indeed, not only pure molecules having the formula (VI-a) or (VI-b), but also a mixture

- 7 043351 formulas (VI-a) and (VI-b) can be used as a starting compound for hydrogenation at the stage

d). They both yield the same product, namely the compound of formula (IV).

It is preferable for this reaction to use a mixture of compounds of formulas (VI-a) and (VI-b) as the compound of formula (VI) in the above-described step d).

The above-mentioned compound of formula (VI) is also new and represents another aspect of the present invention.

The hydrogenation of a compound of formula (VI), respectively (VI-a) and/or (VI-b), to a compound of formula (IV) can be carried out in step d) according to a method generally known to those skilled in the art. Typically, this hydrogenation involves reaction with molecular hydrogen in the presence of a noble metal catalyst. Preferably, the hydrogenation is carried out using molecular hydrogen in the presence of palladium on an inorganic support. Particularly preferred is a noble metal catalyst selected from the group consisting of palladium on carbon, palladium on silica gel (SiO ₂ ), palladium on TiO2 and palladium on alumina (Al2O ₃ ).

The hydrogenation in step d) is preferably carried out under pressure, in particular under a pressure of 1 to 20 bar, more preferably 1 to 6 bar.

It has been shown that a compound of formula (VI) or respectively (VI-a) or (VI-b) can be prepared from a compound of formula (VII) by reaction e).

The dotted line in formula (VII) indicates a carbon-carbon double bond that is in one of the two positions indicated.

In other words, the formula of this compound (VII) shown above is a schematic representation of the following two formulas (VII-a) and (VII-b)

Said reaction e) is in particular a Wittig reaction, which is the reaction of a compound of formula (VII) or (VTII-a) or (VII-b) with 1(triphenylphosphoranylidene)-2-propanone.

The compound having the above formula (VII) is also new and represents another aspect of the present invention.

It has been shown that a compound of formula (VII) or (VII-a) or (VII-b) can be prepared from a compound of formula (VIII) or (VIII-a) or (VIII-b) by reaction f )

(VIII)

The dotted line in formula (VIII) indicates a carbon-carbon double bond that is in one of the two positions indicated.

In other words, the formula of this compound (VIII) shown above is a schematic representation of the following two formulas (VIII-a) and (VIII-b)

(VIII-a) (VIII-b)

Reaction f) consists of a Wittig reaction of the ketones of formula (VIII), with an (alkoxymethyl)triarylphosphonium salt in the presence of a base, followed by hydrolysis of the resulting enol ester under acidic conditions to the corresponding aldehyde.

It has been shown that a compound of formula (VIII) or (VIII-a) or (VIII-b) can be prepared from a compound of formula (IX) or (IX-a) or (IX-b) by reaction g )

The dotted line in formula (IX) indicates a carbon-carbon double bond that is in one of the two positions indicated.

- 8 043351

In other words, the formula of this compound (IX) shown above is a schematic representation of the following two formulas (IX-a) and (IX-b)

Reaction g) involves decarboxylation in the presence of water. Details of this reaction for similar compounds are given in US 5874636.

It has been shown that a compound of formula (IX) or, respectively, (IX-a) or (IX-b), can be prepared from myrcene (formula (X)) and a compound of formula (XI)

in the presence of a noble metal catalyst, in particular a rhodium(I) catalyst, most preferably a rhodium(I) complex with a suitable diene or ethine as ligand, in particular in the presence of a water-soluble phosphine. Suitable dienes are in particular 1,5-cyclooctadiene or norbornadiene. The preferred ligand is 1,5-cyclooctadiene.

This reaction is preferably carried out according to the methods described in RhonePoulenc patents: US 4460786 and US 4621165, the entire contents of which are incorporated herein by reference.

In formulas (IX), (IX-a), (IX-b) and (XI), the radical R ⁵ represents a C1-1 ₀ alkyl group, preferably a C _1-5 alkyl group, more preferably a methyl group.

In fig. 1 and 2 show a schematic diagram of the described synthesis route for the compound of formula (I). This synthesis scheme starts with the commercially available starting compounds myrcene (formula (X)) and alkyl 3oxovalerate (XI), and uses various intermediates, in particular those of formula (VII), (VI), (IV), (V) , (II-A), (II-B) and (I-A). Details for these substances and the method of obtaining them at specific stages are described in the text above.

It has been found that the substances described above, in particular compounds having formulas (IV), (V), (VI), (VII), (VIII), (IX), (II-A) or (II-B), in particular having formulas (IV), (VI), (VII), (V), (II-A) or (II-B), or in particular having formulas (IV), (VI), (VII), ( VIII) or (IX), have a number of interesting properties and can be used for various purposes. In particular, they are very interesting for use in the field of flavors and fragrances, especially in perfumery, or as starting materials for molecules from the field of pharmaceuticals, food and feed additives. They have very interesting aroma, particularly woody, fruity and even floral notes, which makes them very attractive for use in the field of fragrances, fragrances and perfumes. These compounds are especially interesting for use with other olfactory active substances to create new aromatic compositions.

The compounds mentioned above can be used in a wide range of aromatic applications, for example in any field of fine and functional perfumery such as perfumes, household products, laundry products, body care products and cosmetics. These compounds can be used in a wide range of concentrations, depending on the specific application and the nature and amount of other aromatic components.

These compounds can be used in fragrance compositions simply by mixing them with the formulation, or they can be pre-applied to a carrier material such as, for example, polymers, capsules, microcapsules and nanocapsules, liposomes, film formers, adsorbents such as carbon or zeolites, cyclic oligosaccharides and mixtures thereof, or they can be chemically coupled to substrates that are designed to release these new compounds upon exposure to an external stimulus such as light, enzyme, etc., and then use them in a given application. As used herein, use in a fragrance composition means any product comprising a fragrance, such as perfume and eau de toilette; household chemicals, such as dishwasher detergents and hard surface cleaners; laundry detergents, such as softener, bleach, laundry detergent; body products, such as shampoo, shower gel; and cosmetics, such as deodorant, cream. This product listing is for illustrative purposes only and should not be construed as limiting in any way.

In addition, it was unexpectedly discovered that the compound of formula (I) has a very interesting

- 9 043351 antioxidant behavior. Given its close structural relationship to tocopherol, this new compound is of great interest to researchers and to the food and feed industry. It is especially important to assess the potential impact on a living organism.

Particularly interesting is any combination of a compound of formula (I) with other antioxidants. A suitable other antioxidant is, in particular, one selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), propyl gallate, vitamin A and vitamin E.

Of particular interest are compositions containing a compound of formula (I) and a compound of formula (XI)

R ¹

R ¹

R ⁴

Examples

The present invention is further illustrated by the following examples.

Example 1.

Example of a compound of formula (IX): methyl 2-geranyl-3-oxovalerate

Stage h)

A 200 mL four-neck sulfonylation flask equipped with a magnetic stirrer, reflux condenser, thermometer and argon adapter was filled with argon and then charged with Na ₂ CO ₃ (42 mg, 0.40 mmol, 99.8%, 0.4 mol%), chlorine (1,5-cyclooctadiene)rhodium(I) dimer (60 mg, 0.12 mmol, 0.24 mol% [Rh]), sodium 3,3',3-phosphantriyltribenzenesulfonate (3.56 g, 5.95 mmol, 95%, 6 mol. %), after which the contents were dissolved in water (26 ml) and MeOH (6 ml). Methyl 3-oxovalerate (15 mL, 15.7 g, 119 mmol, 1.2 eq.) and myrcene (19.0 mL, 15 g, 99 mmol, 90%, 1.0 eq.) were added and the resulting biphasic mixture was heated to 100°C (oil bath ) for 23 hours. The resulting mixture was left to cool to 23 °C and the phases were separated. The organic phase was diluted with hexane (50 ml), then washed with saturated sodium chloride solution (2x50 ml), dried over MgSO ₄ , filtered and evaporated in vacuo to give 24.0 g of crude colorless product. The resulting product was then purified by vacuum distillation at 145°C (oil bath)/0.35 mbar to obtain a mixture of two isomers of methyl 2-geranyl-3-oxovalerate (methyl (E)-5,9-dimethyl-2-propionyldeca-4,8 -dienoate and methyl 9methyl-5-methylene-2-propionyldec-8-enoate) as a colorless liquid (18.63 g, 95.7% purity by quantitative NMR, 68% yield). The resulting two isomers were characterized by MS and NMR.

Characteristics of methyl 2-geranyl-3-oxovalerate

GC-MS method. GC: HP-5MS column, 30m x 0.25 mm, 0.25 µm; temperature range: 70°C, +10°C/min to 315°C, holding time 15 minutes. Total analysis time 39.5 min. MS: quadrupole mass spectrometer, EI.

GC-MS: 51.5 area% (methyl 9-methyl-5-methylene-2-propionyldec-8-enoate), 41.7 area% (methyl (E)-5,9-dimethyl-2-propionyldeca-4,8-dienoate ).

m/z (methyl 9-methyl-5-methylene-2-propionyldec-8-enoate, %) 266 (2, M ⁺ ), 248 [5, (MH ₂ O) ⁺ ], 205 (6), 136 ( 22), 121 (21), 109 (26), 93 (78), 69 (100), 57 (43), 41 (45), 29 (20).

m/z (methyl (E)-5,9-dimethyl-2-propionyldeca-4,8-dienoate, %) 266.1 (2, M ⁺ ), 248 [1, (M-H ₂ O) ⁺ ], 197 (10), 137 (29), 136 (29), 121 (19), 109 (58), 93 (19), 81 (20), 69 (71), 57 (100), 41 (44), 29 (22).

¹ H NMR (mixture of isomers, 300 MHz, chloroform-d) δ 1.05 (t, J = 7.3 Hz, 1.4H), 1.06 (t, J = 7.3 Hz, 1.6H), 1.56-1.63 (m, 4.5H) , 1.64-1.70 (m, 3H), 1.92-2.15 (m, 6.5H), 2.40-2.68 (m, 3H), 3.43-3.52 (m, 1H), 3.70 (s, 1.3H), 3.72 (s, 1.7Н), 4.72 (b.s, 0.56Н), 4.77 (d, J = 1.3 Hz, 0.57Н), 4.97-5.14 (m, 1.5Н) ppm.

¹³ C NMR (mixture of isomers, 75 MHz, chloroform-d) δ 7.53, 7.59, 16.0, 17.63, 17.64, 25.6, 26.19, 26.28, 26.5, 27.1, 33.7, 35.4, 35.6, 39.6, 52. 22, 52.27, 57.8, 58.5 , 110.2, 119.7, 123.86, 123.93, 131.5, 131.7, 138.4, 147.9, 170.08, 170.28, 205.64, 205.66 ppm

Example 2.

Compound of formula (VIII): Synthesis of 11-methyl-7-methylenedodec-10-en-3-one and (E)-7,11-dimethyldodeca-6,10-dien-3-one

Stage g):

Methyl 2-geranyl-3-oxovalerate (Example 1) was charged into a 100-mL four-neck flask equipped with a magnetic stirrer, reflux condenser, Dean-Stark adapter, thermometer, argon adapter, syringe pump, and oil bath. mixture of two olefin isomers, 17.6 g, 63.3 mmol, 95.7% by quantitative NMR). The flask was heated to 190°C (oil bath), after which water (2.0 ml, 1.75 eq.) was slowly added below the surface using a syringe pump over 8 hours. The reaction was continued for another 13 hours at 190°C (oil bath), then crude the product was cooled to room temperature and diluted with hexane (50 ml). The resulting solution was washed with water (3x50 ml) and the combined aqueous phases were again extracted with hexane (30 ml). The combined organic phases were dried over MgSO ₄ , filtered and evaporated in vacuo (40°C, 120 to 1 mbar) to obtain a colorless residue (12.9 g). The resulting crude product was purified by distillation to give a mixture of 11-methyl-7methylendodec-10-en-3-one and (E)-7,11-dimethyldodeca-6,10-dien-3-one (10.2 g, 48.7 mmol, 99.3% according to quantitative NMR data, ratio ~54:46, 77% yield).

Characteristics of the compound of formula (VIII)

GC-MS: 53.6 area% (11-methyl-7-methylenedodec-10-en-3-one), 44.2 area% ((E)-7,11dimethyldodeca-6,10-dien-3-one);

m/z (11-methyl-7-methylendodec-10-en-3-one, %) 208 (2, M ⁺ ), 190 [3, (M-H ₂ O) ⁺ ], 175 (2), 165 (9), 147 (9), 136 (16), 121 (15), 109 (30), 93 (42), 85 (15), 79 (9), 69 (100), 57 (38), 41 (49), 29 (16).

m/z ((E)-7,11-dimethyldodeca-6,10-dien-3-one, %) 208 (2, M ⁺ ), 190 [1, (M-H ₂ O) ⁺ ], 175 ( 0.5), 165 (15), 147 (2), 136 (14), 121 (11), 109 (7), 93 (10), 81 (5), 69 (40), 57 (100), 41 ( 27), 29 (14).

1H NMR (mixture of isomers at the double bond, 300 MHz, chloroform-d) δ 1.06 (t, J = 7.3 Hz, 3H), 1.60 (br.s, 1.5H), 1.61 (b.s, 3H), 1.69 ( br.s, 3H), 1.70-1.79 (m, 1H), 1.93-2.16 (m, 5H), 2.21-2.33 (m, 1H), 2.36-2.47 (m, 4H), 4.72 (b.s, 0.55 N), 4.75 (b.s, 0.55H), 5.04-5.14 (m, 1.5H) ppm.

¹³ C NMR (mixture of isomers at the double bond, 75 MHz, chloroform-d) δ 7.80, 7.84, 15.9, 17.65, 17.68, 21.7, 22.6, 25.7, 26.4, 26.6, 35.5, 35.8, 35.92, 35.97, 39.6, 41.7, 42.4, 109.5, 122.7, 124.0, 124.2, 131.4, 131.6, 136.2, 148.8, 211.5, 211.6 ppm

Example 3.

Compound of formula (VII): Synthesis of (±)-2-ethyl-10-methyl-6-methylundec-9-enal and (E)-2-ethyl-6,10dimethylundec-5,9-dienal

Stage f):

A 350 mL four-neck flask equipped with a magnetic stirrer, reflux condenser, dropping funnel, thermometer, argon adapter, syringe pump, and oil bath was filled with argon, (methoxymethyl)triphenylphosphonium chloride (45.2 mmol, 99.7% (2.0 eq.)) was added and suspended in dry THF (100 ml).The resulting suspension was then cooled to 15° C. n-Butyllithium (29.4 ml of a 1.54 M solution in hexane, 45.2 mmol, 2.0 eq.) was slowly added over 35 min, at which time the solution turned orange The mixture was left to warm to 0°C and stirred for 1 hour. A solution of a mixture of 11-methyl-7-methylenedodec-10-en-3-one and (E)-7,11dimethyldodeca-6,10-dien-3- was added dropwise. she (example 2) (5.0 g, 22.6 mmol, 94.2% purity by quantitative NMR, 1.0 eq.) in THF (20 ml) for 45 min, maintaining the temperature at 0-5 ° C. The reaction mixture was stirred for another 30 min at 0° C. The mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was then cooled to 0° C. and quenched by adding saturated sodium chloride solution (100 ml), obtaining two liquid phases and a colorless precipitate. When water (50 ml) was added, the precipitate dissolved; the aqueous phase was extracted with ethyl acetate (3x100 ml). The combined organic phases were washed with saturated sodium chloride solution (2x50 ml), dried over MgSO ₄ , filtered and evaporated in vacuo to give a dark red oil, which precipitated overnight at 4°C. The mixture was dissolved in heptane/ethyl acetate 95:5 and then the solution was filtered through a pad of silica gel. The silica gel layer on the filter was washed with additional heptane/ethyl acetate 95:5 and the combined filtrates were evaporated in vacuo to give crude enol ester (7.85 g, 18.5 mmol, 55.7% qNMR purity, 82% yield).

A 100 mL four-neck flask equipped with a thermometer, magnetic stirrer, argon adapter, reflux condenser, and oil bath was charged with the above-described crude enol ether (2.25 g, 5.30 mmol, 55.7%, 1.0 eq.) and dissolved in acetone (48 ml) and water (12 ml). p-Toluenesulfonic acid monohydrate (102 mg, 0.53 mmol, 10 mol%, 98.5%) was added and the resulting yellow solution was heated to 62°C (boiling) for 10 h. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2x30 ml). The combined organic phases were washed with saturated sodium chloride solution (2x20 ml), dried over MgSO4, filtered and evaporated in vacuo to give the crude product as a yellow liquid (2.20 g, 3.66 mmol, 37.0% qNMR purity, 69% yield), which purified by chromatography.

Characteristics of the compound of formula (VII)

GC-MS: 92.3 area%;

m/z (%) 222 (2, M ⁺ ), 204 [3, (M-H ₂ O) ⁺ ], 179 (8), 161 (16), 150 (3), 135 (9), 109 ( 27), 95 (13), 81 (14), 69

- 11 043351 (100), 55 (11), 41 (45), 29 (7).

1H NMR (300 MHz, chloroform-d) δ 0.92 (t, J = 7.4 Hz, 3H), 1.40-1.75 (m, 12H), 1.97-2.24 (m, 7H), 4.72 (b.s, 1H), 4.74 (b.s, 1H), 5.06-5.16 (m, 1H), 9.59 (d, J = 3.1 Hz, 1H) ppm.

¹³ C NMR (75 MHz, chloroform-d) δ 11.5, 17.7, 21.9, 25.1, 25.7, 26.4, 28.1, 35.9, 36.1, 53.3, 109.2, 124.1,

131.6, 149.0, 205.5 ppm

Example 4.

Compound of formula (VI): Synthesis of (±)-(E)-5-ethyl-13-methyl-9-methylenetetradeca-3,12-dien-2-one

Stage e):

A 100-mL four-neck flask equipped with a magnetic stirrer, reflux condenser, thermometer, argon adapter, and oil bath was filled with argon and charged with a mixture of 2-ethyl-10-methyl-6-methylenundec-9-enal and (E)-2- ethyl 6,10-dimethylundec-5,9-dienal (example 3) (6.50 g, 24.7 mmol, 84.6% purity by quantitative NMR, ratio ~95:5, 1.0 eq.) and 1(triphenylphosphoranylidene)-2-propanone (11.9 g, 37.1 mmol, 99%, 1.5 eq.) and dissolved in toluene (60 ml). The resulting colorless suspension was heated to 125°C (oil bath) for 26 hours. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was suspended in heptane (50 ml) and stirred for 30 min at 23°C. The resulting suspension was filtered and the filtrate was evaporated in vacuo to obtain a yellow liquid (7.85 g). The resulting crude product was purified by flash chromatography on silica gel (220 g), eluting with heptane/t-butyl methyl ether 100:0 to 90:10 (v/v), flow rate 150 ml/min. Some mixture fractions were again purified by flash chromatography and the combined product fractions gave (±)-(E)-5ethyl-13-methyl-9-methylenetetradeca-3,12-dien-2-one (4.88 g, 17.5 mmol, 94.3 % purity by quantitative NMR, 71% yield).

Characteristics of the compound of formula (VI)

GC-MS: 96.3 area% ((E)-5-ethyl-13-methyl-9-methylenetetradeca-3,12-dien-2-one) m/z (%) 262 (3, M ⁺ ), 244 [ 1, (M-H2O) ⁺ ], 233 [1, (M-C2H ₅ ) ⁺ ], 219 (3), 201 (3), 189 (3), 178 (5), 161 (13), 149 ( 7), 135 (21), 122 (17), 109 (49), 95 (36), 81 (23), 69 (100), 55 (19), 41 (59), 29 (4).

1H NMR (300 MHz, chloroform-d) δ 0.86 (m, J = 7.3 Hz, 3H), 1.25-1.59 (m, 6H), 1.61 (s, 3H), 1.69 (d, J = 0.9 Hz, 3H) , 1.93-2.16 (m, 7H), 2.25 (s, 3H), 4.70 (broads.s, 1H), 4.72 (broads.s, 1H), 5.05-5.16 (m, 1H), 6.04 (dd, J = 15.9, 0.7 Hz, 1H), 6.56 (dd, J = 15.9, 9.1 Hz, 1H) ppm.

¹³ C NMR (75 MHz, chloroform-d) δ 11.64 (s, 1 C), 17.7 (1 C), 25.3 (1 C), 25.7 (1 C), 26.4 (1 C), 26.9 (1 C), 27.2 (1 C), 33.7 (1 C), 35.9 (1 C), 36.1 (1 C), 44.5 (1 C), 109.0 (1 C), 124.1 (1 C), 131.2 (1 C), 131.5 ( 1 C), 149.2 (1 C), 152.4 (1 C), 198.6 (1 C) ppm.

Example 5.

(IV): Synthesis of (full racemate)-5-ethyl-9,13-dimethyltetradecan-2-one

Stage d):

(E)-5-ethyl-13-methyl-9-methylenetetradeca-3,12-dien-2-one (example 4) (3.18 g, 11.3 mmol, 93.5%) was dissolved in heptane (10 g) and carbon was added ( 1.00 g). After stirring for 5 minutes, the suspension was filtered and the filter cake was washed with heptane (10 g). The filtrate was transferred to a 125 ml autoclave, diluted with heptane (10 g) and Pd/C (150 mg, 5% Pd, 0.071 mmol, 0.6 mol%) was added. The reactor was filled with argon, stirred at 500 rpm, heated to 80°C and then filled with hydrogen under a pressure of 2 bar for 2 hours. The reaction mixture was left to cool to room temperature, the resulting suspension was filtered through a syringe filter (0.45 μm) and the filter cake washed with heptane (21.7 g). The filtrate was evaporated in vacuo to give (total racemate)-5-ethyl-9,13-dimethyltetradecan-2-one as a colorless oil (3.00 g, 96.4% qNMR, 10.8 mmol, 95% yield).

Characteristics of the compound of formula (IV)

GC-MS: 98.4 area%;

m/z (%) 268 (1, M ⁺ ), 253 [2, (M-CH3) ⁺ ], 239 [1, (M-C ₂ H ₅ ) ⁺ ], 210 (14), 155 (4) , 141 (5), 124 (15), 113 (10), 95 (11), 85 (20), 71 (100), 57 (36), 43 (80), 29 (7).

1H NMR (300 MHz, chloroform-d) δ 0.81-0.90 (m, 12H), 0.99-1.44 (m, 16H), 1.45-1.60 (m, 3H), 2.15 (s, 3H), 2.34-2.46 (m , 2H) ppm

¹³ C NMR (75 MHz, chloroform-d) δ 10.73, 10.77, 19.69, 19.71, 22.61, 22.71, 24.0, 24.8, 25.61, 25.68, 27.06, 27.11, 28.0, 29.8, 32.8 , 33.3, 37.3, 37.5, 38.5, 39.4, 41.26, 41.29, 209.6 ppm

Example 6.

Compound of formula (II-A): Synthesis of (complete racemate)-6-ethyl-3,10,14-trimethylpentadec-1-en-3-ol Step c3):

Vinyl magnesium chloride (2.1 ml of a 1.6 M solution in THF, 3.35 mmol, 1.5 eq.) was loaded into an oven-dried 25-mL three-neck round-bottom flask. A solution of 5ethyl-9,13-dimethyltetradecan-2-one (Example 5) (0.65 g, 2.24 mmol, 92.3% by quantitative NMR) in dry THF (2.2 ml) was added dropwise at 23°C for 30 min. The reaction mixture was stirred for another 2 hours at 23°C, after which it was quenched by adding a saturated aqueous solution of NH ₄ Cl (1 ml). Heptane (10 ml) and saturated sodium chloride solution (10 ml) were added. The aqueous phase was extracted with heptane (2x10 ml).

- 12 043351

The combined organic phases were washed with saturated sodium chloride solution (2x10 ml), dried over MgSO ₄ , filtered and evaporated in vacuo to give (complete racemate)-6-ethyl-3,10,14trimethylpentadec-1-en-3-ol as colorless oil (0.70 g, 2.0 mmol, 84.7% purity by quantitative NMR, 89% yield).

Characteristics of the compound of formula (II-A)

GC-MS: 97.4 area%;

m/z (%) 296 (0.1, M ⁺ ), 278 [1, (M-H ₂ O) ⁺ ], 236 (2), 207 (2), 193 (2), 151 (3), 137 ( 3), 123 (9), 109 (5), 95 (5), 81 (6), 71 (100), 57 (13), 43 (23), 29 (2).

^1H NMR (300 MHz, chloroform-d) δ 0.79-0.90 (m, 12H), 1.06-1.44 (m, 22H), 1.46-1.65 (m, 3H), 5.05 (dd, J = 10.7, 1.3 Hz, 1H), 5.21 (dd, J = 17.3, 1.3 Hz, 1H), 5.92 (dd, J = 17.3, 10.7 Hz, 1H) ppm.

¹³ C NMR (75 MHz, chloroform-d) δ 10.82, 10.85, 10.88, 14.1, 19.7, 22.61, 22.69, 22.71, 24.10, 24.12, 24.8, 25.78, 25.84, 26.87, 26. 93, 27.64, 27.67, 28.0, 29.0, 31.9, 32.7, 33.4, 37.3, 37.5, 39.1, 39.28, 39.30, 39.37, 73.4, 111.5, 145.3 ppm

Example 7.

Compound of formula (I-A): Synthesis of (full racemate)-2-(3-ethyl-7,11-dimethyldodecyl)-2,5,7,8tetramethylchroman-6-ol

Stage b2):

2,3,5-trimethylhydroquinone (0.21 g, 1.34 mmol, 98%, 1.0 eq.), ZnCl ₂ (0.16 g, 1.13 mmol, 98 %, 0.84 eq.) and suspended in ethyl acetate (1 ml) and conc. HCl (22 mg, 0.22 mmol, 0.17 eq.). The reaction mixture was heated to 35°C (oil bath). Add 6-ethyl-3,10,14-trimethylpentadec-1-en-3-ol (Example 6) (0.47 g, 1.34 mmol, 84.7% qNMR, 1.0 eq.) via syringe over 30 min. Then the reaction mixture was stirred for 2 hours at 35°C. After this, the mixture was diluted with heptane (5 ml) and water (2.5 ml). The aqueous phase was extracted with heptane (5 ml). The combined organic phases were washed with water (2x2.5 ml), 10% aqueous NaHCO ₃ solution (2.5 ml) and saturated sodium chloride solution (2.5 ml). The organic phases were dried over MgSO ₄ , filtered and evaporated in vacuo to give (total racemate)-2-(3-ethyl-7,11-dimethyldodecyl)-2,5,7,8-tetramethylchroman-6-ol as a brown oil (0.51 g, 1.05 mmol, 88.8% by quantitative NMR, 78% yield).

Characteristics of the compound of formula (I-A)

GC-MS: 99.5 area%;

m/z (%) 430 (89, M ⁺ ), 205 (13), 165 (100), 121 (6), 91 (2), 71 (3), 57 (6), 43 (14).

1H NMR (300 MHz, chloroform-d) δ 0.84 (t, J = 7.4 Hz, 3H), overlaps with 0.85 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 6.8 Hz, 6H), 1.03 -1.42 (m, 18H), overlaps with 1.23 (s, 3H), 1.44-1.63 (m, 3H), 1.69-1.93 (m, 2H), 2.12 (s, 6H), 2.17 (s, 3H), 2.61 (t, J = 6.9 Hz, 2H), 4.17 (s, 1H, OH) ppm.

¹³ C NMR (75 MHz, chloroform-d) δ 10.81, 10.86, 10.89, 10.93, 11.3, 11.8, 12.2, 19.7, 20.8, 22.6, 22.7, 23.7, 24.07, 24.16, 24.8, 25 .78, 25.85, 25.90, 25.97, 26.45, 26.51, 28.0, 31.37, 31.39, 32.78, 33.43, 33.54, 36.50, 36.53, 36.57, 37.4, 37.5, 39.2, 39.4, 74.6, 117.3, 118.4, 1 21.0, 122.6, 144.5, 145.6 ppm

Example 8.

Example of a compound of formula (I-B): Synthesis of (full racemate)-2-(3-ethyl-7,11-dimethyldodecyl)2,5,7,8-tetramethylchroman-6-yl acetate

Stage a2):

2-(3-ethyl-7,11-dimethyldodecyl)-2,5,7,8tetramethylchroman-6-ol (Example 7) was charged into a 5-mL round-bottom flask equipped with a magnetic stirrer, reflux condenser, and argon adapter. 0.41 g, 0.85 mmol, 88.8% according to quantitative NMR, 1.0 eq.) and dissolved in acetic anhydride (0.23 ml, 0.24 g, 99%, 2.8 eq.) and pyridine (13.7 μl, 13.4 mg, 0.17 mmol, 99.8% , 0.2 eq) and heated to 90°C (oil bath) for 1.5 h. The reaction mixture was allowed to cool to room temperature and then evaporated in vacuo to give the crude product (476 mg).

Purification by flash chromatography (silica gel, heptane/ethyl acetate, gradient 100:0 to 90:10 v/v) gave (complete racemate) -2-(3-ethyl-7,11-dimethyldodecyl)-2,5,7 ,8-tetramethylchroman-6-yl acetate as a pale yellow oil (392 mg, 0.79 mmol, 94.9% by quantitative NMR, 93% yield).

Characteristics of the compound of formula (I-B)

GC-MS: 99.7 area%;

m/z (%) 472 (11 M ⁺ ), 430 [100, (M-Ac) ⁺ ], 247 (4), 207 (20), 165 (56), 121 (3), 91 (2), 71 (3), 57 (7), 43 (16).

1H NMR (300 MHz, chloroform-d) δ 0.85 (t, J = 7.2 Hz, 3H), overlaps with 0.86 (d, J = 6.40 Hz, 3H), 0.88 (d, J = 6.6 Hz, 6H), 1.06 -1.42 (m, 18Н), overlaps with 1.24 (s, Zn), 1.45-1.64 (m, 3Н), 1.68-1.90 (m, 2Н), 1.99 (s, 3Н), 2.04 (s, 3Н), 2.11 (s, 3H), 2.34 (s, 3H), 2.60 (t, J = 6.8 Hz, 2H) ppm.

¹³ C NMR (75 MHz, chloroform-d) δ 10.82, 10.84, 10.86, 10.91, 11.8, 12.1, 12.9, 19.7, 20.55, 20.60, 22.62, 22.71, 24.09, 24.15, 24.8 , 25.76, 25.84, 25.87, 25.94, 26.41, 26.48, 28.0, 32.8, 33.42, 33.51, 37.3, 37.5, 39.1, 39.4, 75.2, 117.3, 123.0, 124.9, 126.6, 140.5, 149.4, 169.7 ppm .

- 13 043351

Olfactory properties

The odor of individual substances was assessed by different human testers based on the odor of strips onto which the test compound was pipetted. Olfactory properties are summarized in table. 1.

Table 1. Olfactory properties of compounds

Example Compound Starting note Middle note Example 1 Formula (IX) - Basement, musty Example 2 Formula (VIII) Fruit, pear Fruit, pear Example 3 Formula (VII) raw wood Fruit, pear Example 4 Formula (VI) Aromatic - Example 5 Formula (IV) Chocolate, beans -

Antioxidant properties

a) Assessment of oxidation stability by determining the induction period

Oxidation stability was assessed using Rancimat™ (Metrohm AG, Zofingen, Switzerland). Rancimat™ is designed to monitor the oxidation of liquid products. The principle of operation is that purified heated air is passed through the samples, and volatile oxidation products are transferred to a flask with demineralized water. The conductivity of the water is monitored using an electrode, and volatile oxidation products such as acetic acid or other charged molecules cause the water's conductivity to increase over time. These oxidation processes start slowly but accelerate exponentially after an induction period, which indicates the resistance of the compound or sample to oxidation (DGF Standard Method C-VI 6f (06)). Thus, the longer the induction period, the higher the antioxidant activity.

Approximately 1 g of 2-(3-ethyl-7,11-dimethyldodecyl)-2,5,7,8-tetramethylchroman-6-ol (Example 7) or alpha-tocopherol (Standard 1) was loaded into a Rancimat™ flask and placed in device. Purified air at 80°C was passed through the sample into a plastic flask containing demineralized water (MilliQ water), and the electrical conductivity of the water was monitored continuously. Data were visualized with time on the x-axis and conductivity on the y-axis. The slope of the resulting curve slowly increased until the end of the induction period. The exponential growth of oxidation reactions is reflected in a rapid increase in the slope of the curve. The induction period was determined manually as the point of intersection of the straight section of the curve and entered into the table. 2.

Table 2. Oxidation stability according to Rancimat™ test at 80°C

Example Induction period [hours] Example 7 42 Standard 1 31

Table 2 shows an induction period that is 35% longer than the induction period for alpha-tocopherol, well known for its antioxidant activity.

b) Determination of antioxidant activity by reaction with 2,2'-diphenyl-1-picrylhydrazyl (DPPH)

Determination of antioxidant activity was additionally carried out using a validated colorimetric method (Planck, Szpylka, Sapirstein, Woolard, Zapf, Lee, Chen, Liu, Tsao, Dusterloh, Baugh, Determination of the antioxidant activity by reaction with 2,2'-diphenyl-1-Picrylhydrazyl ( DPPH): Collaborative Study first Action 2012.04, J AOAC, 95, 2012: 1562-9).

The principle of operation is that the antioxidant is dissolved in a water:methanol mixture, and an aliquot of the resulting solution is reacted with the pink-colored DPPH radical. This reaction results in the formation of colorless antioxidant-DPPH adducts, and the decrease in color can be quantified spectrophotometrically at 517 nm. Calibration in this analysis method is carried out using the water-soluble antioxidant Trolox.

Approximately 25 mg of 2-(3-ethyl-7,11-dimethyldodecyl)-2,5,7,8-tetramethylchroman-6-ol (Example 7) or alpha-tocopherol (Standard 1) was dissolved in 50 ml of methanol:water (40:10, v/v). 0.4 ml of the resulting solutions were added to a solution of the DPPH reagent (approximately 40 mg/l), mixed and kept in the dark for 30 min. The solutions were analyzed spectrophotometrically against distilled water at a wavelength of 517 nm. In parallel, a calibration curve was constructed for Trolox (= 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) at concentrations of 100, 200, 300 and 400 μg/ml according to the method described above.

The antioxidant activity of both compounds was calculated in Trolox equivalents and entered into the table. 3.

Table 3. DPPH efficacy analysis compared to Trolox

Example Trolox equivalents Example 7 1.17 Standard 1 1.15

Table 3 shows that Example 7 and Standard 1 have higher antioxidant activity than Trolox, which is a well-known antioxidant.

Table 3 furthermore shows that example 7 has higher antioxidant activity,

-

Claims (17)

than alpha-tocopherol (Standard 1). c) Redox potential Cyclic voltammetry was performed on a PGSTAT128N device (Metrohm Autolab). The electrochemical cell had a three-electrode system: a glassy carbon working electrode (BASi MF2012), a platinum wire counter electrode, and an Ag/Ag + reference electrode filled with a 0.1 M solution of LiClO4 in an ethanol:acetonitrile mixture (1:1). The working electrode was cleaned with a polishing cloth (Buehler) impregnated with a suspension of 0.05 mm aluminum oxide and treated in an ultrasonic bath. Between measurements, the electrode was washed with solvent and dried with a lint-free cloth. A 10 mM stock solution of 2-(3-ethyl-7,11-dimethyldodecyl)-2,5,7,8-tetramethylchroman-6-ol (example 7) was prepared by dissolving example 7 in a previously prepared 0.1 M buffer solution of LiClO4 in an ethanol mixture :acetonitrile (1:1). The stock solutions described above were then added to a 0.1 M LiClO4 buffer solution in ethanol:acetonitrile (1:1) to obtain the target analyte concentration. Cyclic voltammetry was performed by scanning the potential (scanning speed: 0.05 V/s, potential step: 0.001 V), first recording the anodic wave (from 0 V to 0.7 V) and then cycling the potential back from 0.7 to 0 V to record the cathodic wave. In fig. 3, the x-axis shows the applied potential (E) in volts and the measured electric current (I) in microamps for Example 7 at a concentration of 200 μM (dashed line) or 400 μM (solid line), respectively. The redox potential for Example 7 was calculated from the cathode waveforms in voltammetry as the maximum peak in FIG. 3, and these values are presented in table. 4. Table 4. Redox potential for example 7 Concentration Redox potential 200 µm 0.38 V 400 µm 0.43 V Electrochemically measured redox potential values clearly demonstrate the excellent antioxidant behavior of 2-(3-ethyl-7,11-dimethyldodecyl)-2,5,7,8-tetramethylchroman-6-ol (Example 7). CLAIM 1. Compound of formula (I-B) where R ¹ , R ³ and R ⁴ independently of each other represent a hydrogen atom or methyl groups; R ² is a protecting group for a phenolic group; where each symbol * denotes a chiral/stereogenic center and the symbol # denotes a chiral/stereogenic center; characterized in that the phenol protecting group R ² is selected from the group consisting of where R ¹⁰ and R ¹¹ are independently from each other are C _1-15 alkyl or fluorinated C _1-15 -alkyl or C _3-15 -cycloalkyl or C _7-15 -aralkyl group; R ¹² is C _1-15 alkylene; and wherein either R ¹³ represents a C _1-15 alkyl group, a C _1-15 alkyleneoxyalkyl group or a C _1-15 polyoxyalkylene group; R ¹⁴ represents a hydrogen atom or a C _1-15 alkyl group; or R ¹³ and R ¹⁴ together represent a C _3-7 alkylene group forming a 5-7 membered ring; and wherein Y ¹ , Y ² and Y ³ independently represent a hydrogen atom or a group of the formula - 15 043351 and where the dotted line represents a bond that links said substituent to the rest of the molecule. 2. Compound of formula (I-A) R ¹ but R -A) R ⁴ where R ¹ , R ³ and R ⁴ independently of each other represent a hydrogen atom or methyl groups; where each symbol * denotes a chiral/stereogenic center and the symbol # denotes a chiral/stereogenic center. 3. Compound of formula (IV) where each symbol * denotes a chiral/stereogenic center. 4. Method for preparing the compound of formula (IV) including stage d) hydrogenating a compound of formula (VI) to obtain a compound of formula (IV) where the dotted line denotes a carbon-carbon double bond that occurs at the two positions indicated; and where each symbol * denotes a chiral/stereogenic center. 5. The compound of formula (VI) is one of where the dotted line denotes a carbon-carbon double bond that occurs at the two positions indicated; and where each symbol * denotes a chiral/stereogenic center. 6. The compound of formula (VII) is one of where the dotted line denotes a carbon-carbon double bond that occurs at the two positions indicated; and where each symbol * denotes a chiral/stereogenic center. 7. Method for preparing a compound of formula (II-A) in one of including stage b) obtaining a compound of formula (IV) according to claim 4; - 16 043351 followed by the steps of either c1) ethynylation of a compound of formula (IV) using ethyl in the presence of a basic compound, to obtain a compound of formula (V) c2) hydrogenating a compound of formula (V) with molecular hydrogen in the presence of a Lindlar catalyst to obtain a compound of formula (II-A); or c3) vinylating a compound of formula (IV) by adding a vinyl Grignard reagent to obtain a compound of formula (II-A); where each symbol * denotes a chiral/stereogenic center. 8. Method according to claim 7, characterized in that the compound of formula (IV) is obtained by the method according to claim 4. 9. Compound of formula (V) where each symbol * denotes a chiral/stereogenic center. 10. Compound of formula (II-A) where each symbol * denotes a chiral/stereogenic center. 11. Method for preparing the compound of formula (II-B) by isomerization of a compound of formula (II-A) where each symbol * denotes a chiral/stereogenic center and where the wavy line represents a carbon-carbon bond that, when bonded to a carbon-carbon double bond, is in the Z or E configuration. 12. Compound of formula (II-B) where each symbol * denotes a chiral/stereogenic center and the wavy line represents a carbon-carbon bond that, when bonded to a carbon-carbon double bond, corresponds to the Z- or E-configuration. 13. A method for preparing a compound of formula (I-A), including steps b1) providing a compound of formula (II-A) or (II-B) b2) condensing a compound of formula (II-A) or (II-B) with a compound of formula (III), to obtain a compound of formula (I-A) - 17 043351 where R ¹ , R ³ and R ⁴ independently of each other represent a hydrogen atom or methyl groups; where each symbol * denotes a chiral/stereogenic center and the symbol # denotes a chiral/stereogenic center; and where the wavy line represents a carbon-carbon bond that, when bonded to a carbon-carbon double bond, is in the Z or E configuration. 14. The method according to claim 13, characterized in that the compound of formula (II-A) is obtained by the method according to claim 7 or 8 or the compound of formula (II-B) is obtained by the method according to claim 11. 15. A method for preparing a compound of formula (I-B), comprising steps a1) providing a compound of formula (I-A) a2) reacting a compound of formula (I-A) with a protecting agent to obtain a compound of formula (I-B) where R ¹ , R ³ and R ⁴ independently of each other represent a hydrogen atom or methyl groups and R ² represents a protecting group for a phenolic group; and wherein each symbol * denotes a chiral/stereogenic center and the symbol # denotes a chiral/stereogenic center; characterized in that the phenol protecting group R ² is selected from the group consisting of where R ¹⁰ and R ¹¹ independently of each other represent a C _1-15 alkyl or fluorinated C _1-15 alkyl or C _3-15 cycloalkyl or C _7-15 aralkyl group; R ¹² represents a C _1-15 alkylene group; and anywhere R ¹³ represents a C _1-15 alkyl group, a C _1-15 alkyleneoxyalkyl group or a C _1-15 polyoxyalkylene group; R ¹⁴ represents a hydrogen atom or a C _1-15 alkyl group; or R ¹³ and R ¹⁴ together represent a C _3-7 alkylene group forming a 5-7 membered ring; and where Y ¹ , Y ² and Y ³ independently represent a hydrogen atom or a group of the formula and where the dotted line represents a bond that links said substituent to the rest of the molecule. - 18 043351 16. A composition suitable as a food or feed or antioxidant composition containing a compound of formula (I) and a compound of formula (XII) where R ¹ , R ³ and R ⁴ independently of each other represent a hydrogen atom or methyl groups; R ² represents a hydrogen atom; where each symbol * denotes a chiral/stereogenic center and the symbol # denotes a chiral/stereogenic center. 17. A composition suitable as a food or feed or antioxidant composition containing a compound of formula (I) and a compound of formula (XII) where R ¹ , R ³ and R ⁴ independently of each other represent a hydrogen atom or methyl groups; R ² represents R ² which is a protecting group for a phenolic group; where each symbol * denotes a chiral/stereogenic center and the symbol # denotes a chiral/stereogenic center; characterized in that the phenol protecting group R ² is selected from the group consisting of where R ¹⁰ and R ¹¹ independently of each other represent a C _1-15 alkyl or fluorinated C _1-15 alkyl or C _3-15 cycloalkyl or C _7-15 aralkyl group; R ¹² is C _1-15 alkylene; and wherein either R ¹³ represents a C _1-15 -αalkyl group, a C _1-15 -alkyleneoxyalkyl group or a C _1-15 -polyoxyalkylene group; R ¹⁴ represents a hydrogen atom or a C _1-15 alkyl group; or R ¹³ and R ¹⁴ together represent a C _3-7 alkylene group forming a 5-7 membered ring; and where Y ¹ , Y ² and Y ³ independently represent a hydrogen atom or a group of the formula and where the dotted line represents a bond that links said substituent to the rest of the molecule. -