Method for producing thioether

Abstract

The present invention relates to the field of organic synthesis, and more particularly to a method for preparing a compound of formula (I).Furthermore, the present invention also includes an analytical method for determining the amount of thiol or thioether compounds with less than 6 carbon atoms in a thiol of formula R-SH, and a composition of matter containing at most 50 μg / kg of thiol or thioether compounds with less than 6 carbon atoms and at most 1 ppm of a compound of formula (I').

Description

[Technical Field]

[0001] The present invention relates to the field of organic synthesis, and more specifically to a method for producing the compound of formula (I). Furthermore, the present invention also includes an analytical method for determining the amount of a thiol or thioether compound having fewer than 6 carbon atoms in a thiol of formula R-SH, and a material composition containing at most 50 μg / kg of a thiol or thioether compound having fewer than 6 carbon atoms and at most 1 ppm of the compound of formula (I').

[0002] Background of the Invention In the fragrance industry, there is particular interest in compositions or additives that can extend or enhance the fragrance effect over a certain period of time. Achieving lasting properties is especially desirable to enhance the consumer experience. Long-lasting fragrances are desirable for a variety of applications, such as fine perfumery, functional fragrances, or cosmetics. Textile washing and softening is a specialized field where it is always necessary for the effects of active substances, particularly fragrances or fragrance compositions, to remain effective for a certain period after washing, softening, and drying. In fact, many active substances particularly suitable for this type of application are known to lack adhesion to laundry or not remain on the laundry after rinsing, resulting in a short-lived and not very strong fragrance effect. Given the importance of this type of application in the fragrance industry, research in this field has continued, particularly with the aim of finding novel and more effective solutions to the aforementioned problems.

[0003] From this perspective, delivery systems have been developed that release active materials by chemical reactions during or after application (using O2, light, enzymes, water (pH), or temperature as release triggers), such as precursor compounds also called profragrances or properfumes. To this end, β-thiocarbonyl profragrance derivatives of formula (I), described below herein and reported in International Publication No. 03 / 049666, have been developed, in particular 3-(dodecylthio)-1-[(1RS,2SR)-2,6,6-trimethyl-3-cyclohexen-1-yl]-1-butanone, also known as Haloscent® D (supplier: Firmenich SA).

[0004] However, the olfactory quality of the compound of formula (I) can be significantly affected by trace amounts of impurities that are undetectable by common analytical methods, making it unsuitable for use in consumer products. On the other hand, the compound of formula (I) may decompose during common purification methods, making further purification steps counterproductive.

[0005] Therefore, it is necessary to develop an approach to the compound of formula (I) while limiting the occurrence of off-notes, and to develop an analytical method that can detect impurities present in the starting materials that cause off-notes in the final product.

[0006] The present invention provides a solution to the above problem by producing the compound of formula (I) by reacting the compound of formula (III) with a thiol of formula R-SH that contains at most 50 μg / kg of thiol or thioether compounds with fewer than 6 carbon atoms. Furthermore, an analytical method has been developed to detect even trace amounts of thiol or thioether compounds with fewer than 6 carbon atoms.

[0007] Summary of the Invention The present invention relates to a novel method that enables the production of a compound of formula (I) by 1,4-addition (Michael-type addition) of a thiol of formula R-SH to an enal, enone or α,β-unsaturated carboxylic acid ester of formula (III) without the presence of off-notes while restricting the purification step that causes decomposition of the compound of formula (I).

[0008] Therefore, a first main subject of the present invention is a method for measuring the amount of a thiol or thioether compound having less than 6 carbon atoms in a thiol of formula R-SH [wherein R represents a linear or branched alkyl group having 8 to 15 carbon atoms, and the group may contain a carboxylic acid or C1-C8 carboxylic acid ester functional group not directly bonded to the sulfur atom] by gas chromatography-mass spectrometry (GC-MS) combined with solid-phase microextraction (SPME), the method comprising performing SPME while cooling the sample to a temperature of -100°C to -50°C.

[0009] A second main subject of the present invention is a formula [Chemical formula] [wherein The wavy line indicates the position of the bond between said P and the sulfur atom; P represents a group capable of forming an aromatic α,β-unsaturated ketone, aldehyde or carboxylic acid ester, and the formula [Chemical formula] [wherein The wavy line indicates the position of the bond between said P and S; R is a hydrogen atom, a C1-C6 alkoxyl group, or a linear, cyclic or branched alkyl, alkenyl or alkadienyl group of C1-C 15 which group may optionally be substituted with 1 to 4 C1-C4 alkyl groups; R 2 R 3 and R 4 are each independently a hydrogen atom, an aromatic ring, or a C1-C 15represents a linear, cyclic or branched alkyl, alkenyl or alkadienyl group, which may be substituted with a C1-C4 alkyl group; or the group R 1 ~R 4 where two or three of them are joined together to form a saturated or unsaturated ring, the ring having 5 to 20 carbon atoms and containing the carbon atom to which the R 1 、R 2 、R 3 or R 4 group is attached, and the ring may be substituted with a C1-C8 linear, branched or cyclic alkyl or alkenyl group〕, and is represented by; R represents a linear or branched alkyl group having 8 to 15 carbon atoms, which may contain a carboxylic acid or a C1-C8 carboxylic acid ester functional group not directly bonded to a sulfur atom] A process for producing a compound of The process comprises reacting a compound of the formula [[ID=I9]]

Chemical formula

[0010] The third subject of the present invention comprises a compound of formula (I), containing at most 50 μg / kg of a thiol or thioether compound having less than 6 carbon atoms, and of the formula

Chemical formula

[0011] Description of the Invention The present invention relates to a novel method for producing a compound of formula (I) without off-notes while maintaining high yield. The method of the present invention represents an efficient route to the compound of formula (I) that is free from impurities that adversely affect the functional properties of the compound of formula (I). In fact, it was surprisingly discovered that the presence of thiols or thioether compounds with fewer than 6 carbon atoms in the thiol of formula R-SH used in the production of the compound of formula (I) was the cause of undesirable off-notes in the final compound of formula (I), which could not be removed without reducing the product yield.

[0012] Therefore, the first subject of the present invention is the formula [ka] [In the formula, The dashed line indicates the position of the bond between P and the sulfur atom; P represents a group capable of producing aromatic α,β-unsaturated ketones, aldehydes, or carboxylic acid esters, and the formula [ka] [During the ceremony, The wavy line indicates the location of the connection between P and S; R 1 This is a hydrogen atom, a C1-C6 alkoxyl group, or a C1-C6 group. 15 Represents a linear, cyclic, or branched alkyl, alkenyl, or alkadienyl group, which may be substituted with 1 to 4 C1-C4 alkyl groups; R 2 , R 3 and R 4 These are, independently of each other, hydrogen atoms, aromatic rings, or C1-C 15Represents a linear, cyclic, or branched alkyl, alkenyl, or alkadienyl group, wherein the group may be substituted with a C1-C4 alkyl group; or group R 1 ~R 4 Two or three of these are bonded together to form a saturated or unsaturated ring, the ring having 5 to 20 carbon atoms, and the R 1 , R 2 , R 3 Or R 4 [The ring may contain carbon atoms to which the group is bonded, and the ring may be substituted with linear, branched, or cyclic alkyl or alkenyl groups of C1 to C8]; R represents a linear or branched alkyl group having 8 to 15 carbon atoms, and the group may include a carboxylic acid or C1-C8 carboxylic acid ester functional group that is not directly bonded to a sulfur atom. A method for producing the compound, The method is, [ka] [In the formula, R 1 , R 2 , R 3 and R 4 A method comprising the step of reacting a compound of the formula R-SH [wherein R has the same meaning as defined above] with a thiol of the formula R-SH [wherein R has the same meaning as defined above], The method is characterized in that the thiol contains no more than 50 μg / kg of thiols or thioether compounds with fewer than 6 carbon atoms.

[0013] To clarify, “thiol or thioether compounds with fewer than 6 carbon atoms” or similar expressions mean, in the ordinary sense understood by those skilled in the art, that is, organosulfur compounds with fewer than 6 carbon atoms containing an -SH functional group, or organosulfur compounds with fewer than 6 carbon atoms containing an -S- functional group.

[0014] According to any embodiment of the present invention, the method of the present invention comprises the step of measuring the amount of a thiol or thioether compound having fewer than 6 carbon atoms in the thiol of formula R-SH by gas chromatography-mass spectrometry (GC-MS) combined with solid-phase microextraction (SPME), wherein the SPME is performed with the neat sample cooled to a temperature of -100°C to -50°C. The SPME fiber is preferably 50 / 30 μm divinylbenzene / carboxene on polydimethylsiloxane on a StableFlex fiber (part number 57329-U, Supelco), or 50 / 30 μm divinylbenzene / carboxene on polydimethylsiloxane on a 2 cm StableFlex fiber. Other usable fibers are 65 μm polydimethylsiloxane / divinylbenzene or 75 μm / 85 μm carboxene / polydimethylsiloxane.

[0015] According to any embodiment of the present invention, the thiol or thioether compound having fewer than 6 carbon atoms can be selected from the group consisting of 1-propantheol, 2-propantheol, 2-methyl-1-propantheol, 2-methyl-2-propantheol, 1-butanethiol, tetrahydrothiophene, and mixtures thereof.

[0016] According to any embodiment of the present invention, the thiol of formula R-SH is a) 1-propanethol with a maximum of 5 μg / kg b) A maximum of 5 μg / kg of 2-propanethol c) A maximum of 5 μg / kg of 2-methyl-1-propanethol d) 2-methyl-2-propanethol, at most 20 μg / kg e) 1-butanethiol at a maximum of 5 μg / kg, and f) Tetrahydrothiophene, up to a maximum of 10 μg / kg It only contains that.

[0017] In a particular embodiment of the present invention, the thiol of formula R-SH is, a) 1-propanethol at a maximum of 2.5 μg / kg b) 2-propanethol with a maximum concentration of 3.5 μg / kg c) A maximum of 2.5 μg / kg of 2-methyl-1-propanethol d) A maximum of 18 μg / kg of 2-methyl-2-propanethol e) 1-butanethiol at a maximum of 2.5 μg / kg, and f) Tetrahydrothiophene, up to a maximum of 5 μg / kg It only contains that.

[0018] In a particular embodiment of the present invention, the thiol of formula R-SH is, a) A maximum of 1 μg / kg of 1-propanethol b) A maximum of 3 μg / kg of 2-propanethol c) A maximum of 1 μg / kg of 2-methyl-1-propanethol d) A maximum of 18 μg / kg of 2-methyl-2-propanethol e) A maximum of 1 μg / kg of 1-butanethiol, and f) Tetrahydrothiophene, up to a maximum of 3 μg / kg It only contains that.

[0019] In one particular embodiment, the thiol of formula R-SH does not contain trace amounts of 1-propantheol, 2-propantheol, 2-methyl-1-propantheol, 2-methyl-2-propantheol, 1-butanethiol, or tetrahydrothiophene.

[0020] According to any embodiment of the present invention, the thiol of formula R-SH can be purified by distillation before reacting with the compound of formula (III). In particular, the distillation may be batch distillation or continuous distillation, and may be batch distillation in particular. Distillation can be carried out by removing low-boiling fractions (topping), selecting a desired fraction (fractional distillation), or by flash distillation using a flow-down (wipe-type) thin-film evaporator.

[0021] According to any embodiment of the present invention, R may be a linear alkyl group having 8 to 15 carbon atoms. In particular, R may be a linear alkyl group having 10 to 14 carbon atoms, especially an n-dodecyl group; that is, R-SH may be a 1-dodecanethiol.

[0022] The expression "fragrant α,β-unsaturated ketone, aldehyde, or carboxylic acid ester" used in the definition of P is understood to refer to α,β-unsaturated ketones, aldehydes, or carboxylic acid esters that are recognized by those skilled in the art as being used as fragrance components in fragrances. Generally, the aforementioned fragrant α,β-unsaturated ketones, aldehydes, or carboxylic acid esters are compounds having 8 to 20 carbon atoms, more preferably 10 to 15 carbon atoms.

[0023] Similarly, it is impossible to provide a comprehensive list of currently known aromatic compounds of formula (III) that can be used in the synthesis of compounds of formula (I). However, preferred examples include: α-Damascone, β-Damascone, γ-Damascone, δ-Damascone, α-Ionone, β-Ionone, γ-Ionone, δ-Ionone, β-Damascenone, 1-[6-ethyl-2,6-dimethyl-3-cyclohexen-1-yl]-2-buten-1-one, 3-methyl-5-propyl-2-cyclohexen-1-one, 2- Methyl-5-(1-propen-2-yl)-2-cyclohexen-1-one, 2,5-dimethyl-5-phenyl-1-hexen-3-one, 1-(5,5-dimethyl-1-cyclohexen-1-yl)-4-penten-1-one, 3,7-dimethylocta-2,6-dienal, 8-methyl-α-ionone or 10-methyl-α-ionone, 2-octenal, 1-(2,2,3, 6-Tetramethylcyclohexyl)buta-2-en-1-one, 4-(2,2,3,6-Tetramethylcyclohexyl)buta-3-en-2-one, 2-Cyclopentadecene-1-one, 4,4a-Dimethyl-6-(1-propen-2-yl)-4,4a,5,6,7,8-Hexahydro-2(3H)-naphthalenone, (E)-3-phenylpropane-2-enal, 2,6,6-tri Methylspiro[bicyclo[3.1.1]heptan-3,1'-cyclohexane]-2'-en-4'-one, ethyl 2,4-decadienone, ethyl 2-octenone, methyl 2-nonenoate, ethyl 2,4-undecadienone, 4-methylpenta-3-en-2-one, octa-2-en-4-one, and methyl 5,9-dimethyl-2,4,8-decatrienoate.

[0024] According to any embodiment of the present invention, the compound of formula (I) may be in the form of one of its stereoisomers or a mixture thereof, and the compound of formula (III) may be in the form of one of its stereoisomers or a mixture thereof. To clarify, “one of its stereoisomers or a mixture thereof” or similar expression means in the usual sense understood by those skilled in the art, i.e., the compounds of formulas (I) and (III) may be pure enantiomers or diastereomers. In other words, the compounds of formulas (I) and (III) may have multiple stereocenters, each of which may have two different configurations (e.g., R or S). The compounds of formulas (I) and (III) may be in the form of pure enantiomers or a mixture of enantiomers or diastereomers. The compounds of formulas (I) and (III) may be racemic or scaremic. Thus, the compounds of formulas (I) and (III) may be a single stereoisomer or may be in the form of a composition of substances containing or comprising various stereoisomers.

[0025] According to any one of the above embodiments of the present invention, the compound of formula (III) may be in the form of its E-isomer or Z-isomer, or a mixture thereof. For example, the present invention includes a material composition comprising one or more compounds of formula (III) having the same chemical structure but different arrangements of double bonds.

[0026] According to any embodiment of the present invention, P is given by formulas (P-1) to (P-14): [ka] [In the formula, the dashed line has the meaning shown above, and the dotted line represents a single bond or a double bond. R a R is a hydrogen atom or a methyl group, b R represents a hydrogen atom, a hydroxyl group or a methoxy group or a linear or branched alkyl group of C1-C4, cP is a group selected from the group consisting of a hydrogen atom or a linear or branched alkyl group of C1-C4, and is one of their isomers. Therefore, the compound of formula (I) [wherein P is selected from the group consisting of formulas (P-1) to (P-14)] is a compound of formula [ka] [In the formula, dotted line, R a , R b and R c It is produced by reacting compounds of the same meaning as defined above.

[0027] To clarify, the expression "In the formula, the dotted line represents a single or double bond" or similar expression means, in the ordinary sense understood by those skilled in the art, that is, the entire bond between carbon atoms connected by the dotted line (solid and dotted lines) is either a carbon-carbon single bond or a carbon-carbon double bond.

[0028] In one particular embodiment, P is a formula [ka] [In the formula, the dashed line has the meaning shown above, and the dotted line represents a single bond or a double bond. R a P represents a group selected from the group consisting of a hydrogen atom or a methyl group. Therefore, the compound of formula (I) [wherein P is selected from the group consisting of formulas (P-1)', (P-2)', (P-3), (P-5), (P-6), (P-7), (P-13), and (P-14)'] is a compound of formula [ka] [In the formula, dotted lines and R a It is produced by reacting compounds of the same meaning as defined above.

[0029] In a particular embodiment, P represents a group selected from the group consisting of the formulas (P-1), (P-2), (P-1)', (P-2)', (P-3), (P-7), (P-13), (P-14), or (P-14)' as defined above. In particular, P may be (P-1), (P-2), (P-3), (P-7), (P-13), or (P-14). Preferably, P represents a group selected from the group consisting of the formulas (P-1), (P-1)', (P-2), (P-2)', (P-3), or (P-14)' as defined above.

[0030] In a particular embodiment, the compound of formula (I) is a) to d) [ka] The compound is selected from the group consisting of [wherein R has the same meaning as defined above].

[0031] The compound of formula a) is obtained from the reaction of the compound of formula (III), where the compound of formula (III) is δ-damascone. The compound of formula a) is preferably (±)-trans-3-(dodecylthio)-1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-butanone. δ-damascone is also known as 1-[(1RS,2SR)-2,6,6-trimethyl-3-cyclohexen-1-yl]-2-buten-1-one.

[0032] The compound of formula b) or c) is obtained from the reaction of the compound of formula (III), where the compound of formula (III) is an ionone. The compound of formula b) or c) may exist as an isomer mixture of formulas b) and c). The isomer mixture may have a weight ratio of formula b) to formula c) of 40:60 to 60:40. In particular, the isomer mixture may have a weight ratio of formula b) to formula c) of about 55:45. In particular, the compound of formula b) or c) releases two isomers of ionone as a fragrance compound.

[0033] In particular, the compound of formula b) is obtained from the reaction of the compound of formula (III), where the compound of formula (III) is α-ionone. The compound of formula b) is preferably (±)-4-(dodecylthio)-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-butanone. α-ionone is also known as (±)-(3E)-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one.

[0034] In particular, the compound of formula c) is obtained from the reaction of the compound of formula (III), where the compound of formula (III) is β-ionone. The compound of formula c) is preferably (±)-4-(dodecylthio)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butanone. β-ionone is also known as (3E)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-one.

[0035] The compound of formula d) is obtained from the reaction of the compound of formula (III), where the compound of formula (III) is octa-2-en-4-one. The compound of formula d) is preferably (±)-2-(dodecylthio)octan-4-one. Octa-2-en-4-one can be used as its (E) or (Z) isomer, or as a mixture thereof, but the (E) isomer is preferred.

[0036] According to any embodiment of the present invention, non-limiting examples of compounds of formula (I) include: 3-(dodecylthio)-1-(2,6,6-trimethylcyclohexa-3-en-1-yl)butan-1-one, 2-(dodecylthio)-4-octanone, 3-(dodecylthio)-1-(2,6,6-trimethylcyclohexa-2-en-1-yl)butan-1-one, 4-(dodecylthio)-4-(2,6,6-trimethylcyclohexa-2-en-1-yl)butan-2-one, and 4-(dodecylthio)-4-(2,6,6-trimethylcyclohexa-1-en-1-yl)butan-2-one and 4-(dodecylthio)-4-methylpentan-2-one.

[0037] According to any embodiment of the present invention, the reaction of the compound of formula (III) with the thiol of formula R-SH can be carried out in the presence of any reagent commonly used for 1,4 addition, such as a base, Lewis acid, transition metal, or organocatalyst. In particular, the reaction can be carried out in the presence of a base. In particular, the base is a tertiary amine. Non-limiting examples of suitable bases include triethylamine, trimethylamine, urotropin, N,N-diisopropylethylamine, 1,8-diazobicyclo(5.4.0)undeca-7-ene, or mixtures thereof.

[0038] To form the compound of formula (I), a base can be added to the reaction medium of the method of the present invention at a wide range of concentrations. As a non-limiting example, the base concentration can range from 0.001 to 2 equivalents relative to the total amount of the compound of formula (III). In particular, the base concentration may be 0.005 to 1.5 equivalents relative to the total amount of the compound of formula (III). Needless to say, the method will also be successful when using larger amounts of base. However, as those skilled in the art will know, the optimal base concentration depends on the properties of the base, the properties of the compound of formula (III) and the thiol of formula R-SH, the temperature, and the desired reaction time.

[0039] To form the compound of formula (I), thiols of formula R-SH can be added to the reaction medium of the method of the present invention at a wide range of concentrations. Non-limiting examples include thiol concentrations ranging from 0.5 to 5 equivalents relative to the total amount of compound (III). In particular, the thiol concentration may be 0.75 to 3 equivalents relative to the total amount of compound (III). Needless to say, the method will also be successful when using larger amounts of thiols of formula R-SH. However, as those skilled in the art will know, the optimal concentration of thiols of formula R-SH depends on the properties of the thiol of formula R-SH, the properties of compound (III) and the base, the temperature, and the desired reaction time.

[0040] According to any one embodiment of the present invention, the method for forming the compound of formula (I) is carried out at a temperature of -10°C to 150°C. In particular, the temperature is in the range of 30°C to 70°C. Naturally, those skilled in the art may also select a preferred temperature depending on the melting and boiling points of the starting materials and the final product, as well as the desired reaction time or conversion time.

[0041] The method of the present invention for forming the compound of formula (I) can be carried out with or without a solvent. Where a solvent is required or used for practical reasons, any solvent currently used in such types of reactions can be used for the purposes of the present invention. Non-limiting examples include C6-C6 compounds such as xylene, toluene, 1,3-diisopropylbenzene, cumene or pseudocumene or mixtures thereof. 12 Examples of solvents include aromatic solvents, hydrocarbon solvents such as cyclohexane, heptane, or mixtures thereof, nitrile solvents such as acetonitrile, ester solvents such as ethyl acetate, or ether solvents such as tetrahydrofuran, diethyl ether, methyltetrahydrofuran, or mixtures thereof. The choice of solvent depends on the properties of the substrate and / or base, and those skilled in the art can easily select the most suitable solvent in each case to optimize the reaction. In particular, the method of the present invention for forming the compound of formula (I) is carried out in the absence of a solvent.

[0042] The method of the present invention for forming the compound of formula (I) can be carried out under batch, semi-batch, or continuous conditions.

[0043] The present invention's method for forming the compound of formula (I) may further include a step of purifying the compound of formula (I). Those skilled in the art will be familiar with the most suitable purification methods. Non-limiting examples of suitable purification methods include washing and drying, vacuum distillation, vacuum distillation in particular using wipe thin film distillation, or chromatography.

[0044] The presence of trace amounts of sulfur-containing hydrocarbon impurities in the compound of formula (I) must be minimized because they cause undesirable off-notes in the final product. Surprisingly, a correlation was found between the presence of thiols or thioether compounds with fewer than 6 carbon atoms in the thiol of formula R-SH and the presence of off-notes in the final product, and this off-note, surprisingly, could not be removed even by purification at the end of this method. Detection of thiols or thioether compounds with fewer than 6 carbon atoms in the thiol of formula R-SH cannot be performed by simple GC methods because these very strong odorants cannot be detected with adequate sensitivity. For this specific purpose, a novel analytical method was developed.

[0045] Therefore, another subject of the present invention is a method for measuring the amount of thiols or thioether compounds having fewer than 6 carbon atoms in a thiol of formula R-SH [wherein R has the same meaning as defined above] by gas chromatography-mass spectrometry (GC-MS) combined with solid-phase microextraction (SPME), wherein SPME is performed with a neat sample cooled to a temperature of -100°C to -50°C. The SPME fiber is 50 / 30 μm DVB / CAR / PDMS Stableflex (part number 57329-U, Supelco).

[0046] According to any embodiment of the present invention, the thiol or thioether compound having fewer than 6 carbon atoms detected by this method is selected from the group consisting of 1-propantheol, 2-propantheol, 2-methyl-1-propantheol, 2-methyl-2-propantheol, 1-butanethiol, and tetrahydrothiophene.

[0047] According to any embodiment of the present invention, the MS in GC / MS is a triple quadrupole, quadrupole time-of-flight (Q-TOF), or quadrupole orbit trap. The gas used is helium.

[0048] According to any embodiment of the present invention, the GC-MS data acquisition mode is selected ion monitoring (SIM) or selected reaction monitoring (SRM).

[0049] According to one particular embodiment, GC chromatography uses a non-polar GC column (DB-1, SPB-1) or, optionally, a moderately polar GC column (DB-5). The GC gradient oven needs to be started at a low temperature to adequately separate volatile sulfur compounds.

[0050] A further subject of the present invention is a compound comprising formula (I) and containing no more than 50 μg / kg of thiol or thioether compounds having fewer than 6 carbon atoms, and formula [ka] This is a substance composition containing at most 1 ppm of the compound [wherein the formula, the dashed line indicates the position of the bond between P and the sulfur atom; P has the same meaning as defined above, and R' represents an alkyl group having 1 to 5 carbon atoms].

[0051] The analytical methods used to measure the amount of the product of formula (I') in the compound of formula (I) are HPLC / MS or UPLC / MS. The product of formula (I) is usually C 18The product is injected into the column at a maximum concentration of 10% and eluted with water / acetonitrile. The flow to the MS is typically diverted when the main product (I) is eluted, which is always done with a higher retention time than for the smaller amount of product (I'). The MS can be selected from the group consisting of triple quadrupoles, Q-Tof, and Q-orbitrap. If no signal corresponding to the molecular ion of (I') is observed, the corresponding product is generally less than 10 μg / kg. [Examples]

[0052] The present invention will be described in further detail below with reference to the following examples, where abbreviations have their usual meaning in the art, and temperatures are given in degrees Celsius (°C). The solvent was dried by a standard procedure and distilled under an argon atmosphere. NMR spectra were recorded at 20°C using a Bruker AV 300, AV 400, or AV 500 MHz spectrometer. Chemical shifts were used to determine the solvent signal (chloroform, δ). H =7.26 ppm, δ C It is reported in ppm (=77.0 ppm). The signal assignment is, 1 H, 1 H-COSY, -NOESY, 13 C, 1 This was confirmed by recording H-HSQC and -HMBC experiments.

[0053] [Example 1] (Measurement of the amount of thiols or thioethers with fewer than 6 carbon atoms in dodecanethiol) Three batches of dodecanethiol were analyzed by solid-phase microextraction (SPME) and GC / MS as follows. Batch 3 was obtained by distillation of batch 2, as reported below.

[0054] a) Typical distillation procedure for dodecanethiol 600 g of dodecanethiol was placed in a round-bottom flask equipped with a thermowell and magnetic stirrer bar, connected to a fractionation column. The fractionation column was packed with ordered packing with an efficiency of approximately 15 theoretical plates. Distillation was started under reduced pressure (2-3 mmHg), and the pot was heated to a maximum temperature of 161°C. The following fractions were obtained.

[0055] [Table 1]

[0056] b) SPME method SPME was performed using gray fibers (50 / 30 μm DVB / CAR / PDMS Stableflex, part number 57329-U, Supelco). Manual SPME extraction was performed at -80°C (15 minutes) by manually swirling a 20 mL headspace vial containing dodecanethiol (1 g) in a dry ice / ethanol bath until the dodecanethiol adhered to the glass wall of the vial. Subsequently, the fibers were exposed to the sample headspace for 15 minutes while the vial remained partially immersed in the dry ice / ethanol bath. This SPME method ensured the highest sensitivity. SPME can also be performed at room temperature using an autosampler (combi-PAL, CTC), but the sensitivity will be lower.

[0057] c)GC / MS method A 7890 / 7000B triple quadrupole GC / MS system (Agilent) was used. The column was SPB-1, 30 m, inner diameter 0.25 mm, film thickness 0.25 μm (Supelco). Elution was performed at 0.7 mL / min using He as the carrier gas, and the oven was set to 40°C for 5 minutes, then to 60°C at 5°C / min, and finally to 250°C at 20°C / min for 1.5 minutes. The parent / product ions and collision energies (expressed in eV) of the different products were as follows: 1-Butanethiol: 90 / 56 (3 eV) and 90 / 41 (6 eV); 1-Propanchiol: 76 / 60 (3 eV) and 76 / 47 (6 eV); 2-Methyl-1-Propanchiol: 90 / 56 (4 eV) and 90 / 41 (6 eV); 2-Propanchiol: 76 / 60 (2 eV) and 76 / 43 (6 eV); 2-Methyl-2-Propanchiol: 90 / 57 (2 eV) and 90 / 41 (2 eV); Tetrahydrothiophene: 88 / 60 (14 eV) and 88 / 54 (9 eV).

[0058] SPME protruding fibers were exposed for 5 minutes before GC / MS injection using the PAL autosampler automated procedure. Splitless injection was used.

[0059] d) Results [Table 2]

[0060] The later distillates of batch 1 and batch 3 represent the dodecanethiol batches used in the method of the present invention. The first and middle distillates of batch 2, and batch 3, represent the dodecanethiol batches used in the production of comparative examples.

[0061] [Example 2] (Preparation and analysis of the compound of formula (I)) a) Preparation of the compound of formula (I) Solutions of δ-damascone (10.0 g; 52.1 mmol) and 1-dodecanethiol (8.42 g, 41.7 mmol) in THF (150 ml) using five different batches reported below were treated with DBU (7.92 g; 52.1 mmol) and stirred at 45°C for 90 minutes. The reaction mixture was treated with 5% hydrochloric acid, extracted twice with ether, washed with H2O, saturated aqueous NaHCO3, then brine, dried over Na2SO4, and concentrated at 70°C / 0.01 mbar. Yield of crude product: 16.2 g (99%) [ka]

[0062] b) Measurement of the amount of thiols or thioethers with fewer than 6 carbon atoms in the product of formula (I) The amount of thiols with fewer than 6 carbon atoms in the product of formula (I) was measured using the SPME GC / MS method described in Example 1. SPME sampling of (I) was performed at room temperature. The results are shown in Table 2.

[0063] Furthermore, all batches of (I) obtained from different dodecanethiol batches were analyzed by UPLC / MS to evaluate their content in the compound of formula (I'). This system consisted of an Acquity I-Class UPLC system (Waters) and a QExactive Plus mass spectrometer (Thermo). The column was an Acquity BEH C18 (1.7 μm, 2.1 x 100 mm) and eluted with 0.4 ml / min of H2O / ACN 0.1% formic acid. The gradient was as follows: 0% B, 0.5 min; 0-100% B, 10 min; 100% B, 1 min; equilibration for 1 min. The MS was operated in negative ESI mode, voltage 3500 V, probe heater (source) 300 °C, capillary 300 °C, sheath gas 48, and auxiliary gas 11. Qualitative and quantitative analysis was performed using full-scan ddMS2 mode [150-2000 Da] with stepwise NCE at 10, 30, and 45 V. PRM was performed using an inclusion list and a separation width of 1.0 Da (no offset). The results are reported in Table 2.

[0064] [Table 3]

[0065] The presence of 1-propantheol, 2-propantheol, 2-methyl-1-propantheol, 2-methyl-2-propantheol, and 1-butanethiol was not detected in the final product, despite the strong off-note of the compound of formula (I) prepared in these batches, as shown below. These results support the need to pre-analyze low molecular weight thiols against the starting material, dodecanethiol. Indeed, even the presence of these compounds in the final product in undetectable trace amounts can be detrimental.

[0066] [Example 3] (Sensory evaluation of the compound of formula (I)) The batch obtained in Example 2 was evaluated by three trained panelists by smelling the top of the newly opened bottle. The panelists were asked to rate the intensity of the sulfurous odor on a scale of 1 to 10, where 1 corresponds to no odor and 10 to a very strong odor. The results are shown in Table 3.

[0067] [Table 4]

[0068] Only the compound of formula (I) prepared from the post-distillation fractions of batches 1 and 3 of dodecanethiol exhibited a very low level of the undesirable sulfurous odor.

Claims

1. Formula R-SH [wherein R represents a linear or branched alkyl group having 8 to 15 carbon atoms, and the group is a carboxylic acid or C that is not directly bonded to a sulfur atom] １ ~C ８ A method for measuring the amount of thiols or thioether compounds having fewer than 6 carbon atoms in a thiol [which may contain a carboxylic acid ester functional group] by gas chromatography-mass spectrometry (GC-MS) combined with solid-phase microextraction (SPME), wherein the SPME is performed with the sample cooled to a temperature of -100°C to -50°C.

2. The method according to claim 1, wherein the thiol or thioether compound having fewer than six carbon atoms is selected from the group consisting of 1-propantheol, 2-propantheol, 2-methyl-1-propantheol, 2-methyl-2-propantheol, 1-butanethiol, and tetrahydrothiophene.

3. The method according to claim 1 or 2, wherein the MS of the GC / MS is a triple quadrupole, quadrupole time of flight (Q-TOF), or quadrupole orbit trap type.

4. The method according to any one of claims 1 to 3, wherein the GC-MS data acquisition mode is selected ion monitoring (SIM) or selected reaction monitoring (SRM).

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