UA110746C2 - Method of producing 2- (2,3-dimethyl phenyl) -1-propanol - Google Patents

Abstract

The invention discloses a process for the preparation of 2- (2,3-dimethylphenyl) -1-propanol from 1-bromo-2,3-dimethylbenzene and acetone, its use in perfumery and its use for the preparation of medetomidine.

Description

METHOD OF OBTAINING 2-(2,3-DIMETHYLPHENYL)-1- PROPANAL

The invention discloses a method of obtaining 2-(2,3-dimethylphenyl)-1-propanal from 1-bromo 2,3-dimethylbenzene and acetone, its use in perfumery products, and its use for obtaining medetomidine.

Aromatic aldehydes are widely used as flavoring and flavoring substances in cosmetics, perfumes, and many household chemicals. As you know, alpha-, beta-unsaturated aromatic aldehydes, such as substituted cinnamic aldehydes, have a pronounced aroma and, accordingly, they are used in the perfume industry.

UMO application 98/45237 A discloses some aromatic aldehydes, the method of their preparation, starting from acetophenone acetals, their use as perfumery products and their use as intermediate compounds for the preparation of 3-arylpropanals. They have a musky aroma.

A method of obtaining 2-(dimethylphenyl)upropanaldehydes as a mixture of unidentified isomers is described in MikKkPpegieye-Mosheg ei ai., NeiYimeiisa SpitisAsia, 1977, 60, 1758-1780.

The position of the methyl on the aromatic groups is unknown. These compounds are obtained by a rearrangement reaction in the presence of an acid catalyst (sulfuric acid) from some tricyclic alcohols.

The perfume industry and the household chemical industry feel a constant need for new perfume products with interesting, new and not yet available flavoring substances in order to increase the possible choice of flavoring substances and to adapt the flavoring substances to the ever-changing fashion demand. In addition, the corresponding substances must be synthesized economically and have a stable quality. Preference is given to highly pure and strong flavoring substances. This invention provides a new alpha-; beta-unsaturated aromatic aldehyde, which has a strong and interesting aldehyde smell, intensely spicy and sweet, and an improved method of its preparation.

In the following text, halogen means EN, CI, Bg or I, preferably CI, Bg or I; "alkyl" means linear, branched, cyclic or cycloalkyl, preferably it has the generally accepted meaning of linear or branched alkyl; unless otherwise noted.

Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,

Zo pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, etc.; "cyclic alkyl" or "cycloalkyl" includes cycloaliphatic, bicycloaliphatic and tricycloaliphatic residues; "alkane" means a linear, branched or cyclic alkane, preferably a linear or branched alkane; "alkanol" means hydroxyalkane, with alkane as defined above, including preferred embodiments thereof;

Ac acetyl;

IV is tertiary butyl;

OVIy 1,8-diazabicyclo|5.4.F)undec-7-ene; pАВСО 1 4-diazabicyclo|2.2.2|octane;

PIREA M-ethyl-M, M-diisopropylamine;

OMA M, M-dimethylacetamide;

OME M, M-dimethylformamide;

EOTA-Ma: disodium ethylenediaminetetraacetic acid; hexanes is a mixture of isomeric hexanes;

MMP M-methyl-2-pyrrolidone;

OT trifluorometasulfonate, also known as triflate;

MRB5 KNBZO", also known as potassium peroxomonosulfate or potassium monopersulfate, and commercially available as a triple salt with the formula 2КН5ЗО5КНООхК2г5Ох under the trade names Sagoakyu and OhopeFf), as a result, KНZO" is often used in the form of this triple salt; salen ligand obtained from the condensation of salicylaldehyde or a derivative of substituted salicylaldehyde with ethylenediamine or with substituted ethylenediamine; sulfamic acid HO-502-MN";

TEMRO 2.2,6,6-tetramethylpiperidine-1-oxyl;

THF tetrahydrofuran; xylene 1,2-dimethylbenzene, 1,3-dimethylbenzene, 1,4-dimethylbenzene or their mixture; unless otherwise noted. 60 The object of the invention is a method of obtaining a compound of the formula (XXI);

СНу СН, 6; SN. its CO) method contains stage (M); stage (M) includes a reaction (M-reaction); the reaction (M-reak) represents the reaction of the compound of the formula (XXII) with the catalyst (M-cat); sNnz sn o 3 3

CH psu (ХКП) catalyst (M-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, NCI, НВг, Н25Ох, НМО»z , NzRoh,

NOYU», VSiz, VViz, VEzZOege, VEz5Meg, VEzZTNE, MaosSig, MoaVig, Mai2, AISiz, AO-Si-4 alkyl)»z,

ZPS, TS, P(O-Si-4 alkyl)4,2ySyh, VigOz, VisSyz, 7pSiI2,PsIy", ResSyz, 5sSyz, MiSi", MB(OTO)z, UB(SI)z,

Sasiz, AIVgz, Se(OTI)z, GISI, Stc(VEz)g2, SSHCHOTO», MiVgg(RRНz)2, MiVi», MiSi», RA(OAs)», Rasi», RISI2,

IPS, acid inorganic solid, acid ion exchange resin, carbon treated with inorganic acid and their mixtures.

Predominantly acidic inorganic solids are aluminosilicates.

Preferably, the acidic ion exchange resin is selected from the group consisting of copolymers of styrene and divinylbenzene and perfluorinated branched or linear polyethylenes, these polymers are functionalized with the help of 5OzH groups; more preferably, the acidic ion exchange resin is selected from the group consisting of copolymers of styrene and divinylbenzene, containing more than 5 95 divinylbenzene, which is preferably macroreticulated, and perfluorinated polyethylenes, these polymers are functionalized with

ZON groups.

Preferably, the inorganic acid with which the carbon was treated is selected from the group consisting of NCI, H25Ox and NMO.

Preferably, the catalyst (M-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, НС, НВг, Нег5О», НзРО»з, ВСиз, БезОе, МаСи», MoaVig .

More preferably, the catalyst (M-cat) is selected from the group consisting of acetic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, HCI, H25bO.

БезЗОЕе, Суц(БЕ4)», aluminosilicates, acidic ion-exchange resins, and their mixtures.

Preferably, the reaction (M-reak) is carried out in a solvent (M-solution); the solvent (M-solvent) is selected from the group consisting of water, tert-butanol, isopropanol, acetonitrile, propionitrile, THF, methyl-THF, MMR, dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, chloroform , toluene, benzene, chlorobenzene, hexane, cyclohexane, ethyl acetate, acetic acid, formic acid, trifluoroacetic acid and their mixtures; preferably from water, acetonitrile, propionitrile, THF, 2-methyl-THF, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, chloroform, toluene, cyclohexane, ethyl acetate, acetic acid, formic acid and their mixtures; more preferably from water, acetonitrile, propionitrile, THF, 2-methyl-THF, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, toluene, ethyl acetate and their mixtures; even more preferably from acetonitrile, THF, 2-methyl-THF, dichloromethane, toluene, ethyl acetate and their mixtures.

The catalyst (M-cat) can be used in its pure form or in the form of a hydrate.

The catalyst (M-cat) can be used as a solution in a solvent (M-solution).

Preferably, the molar ratio between the catalyst (M-cat) and the compound of the formula (XXIII) is from 1:1000 to 10:1, more preferably from 1:100 to 5:1, even more preferably from 1:20 to

BO 171, especially from 1:10 to 1:2.

Preferably, the reaction temperature of the reaction (M-reak) is from -20 to 200 "C, more preferably from 0 to 150 "C, even more preferably from 10 to 100 "C.

The reaction (M-reak)u can be carried out in a system that is closed or communicates with the atmosphere.

In a closed system, the pressure mainly depends on the boiling point of the solvent (M-solvent) and on the reaction temperature of the reaction (M-reak).

Preferably, the reaction (M-reak) is carried out under pressure from 0.01 bar to 20 bar, more preferably from 0.1 to 10 bar, even more preferably from atmospheric pressure to 5 bar. more preferably, the reaction (M-reak) is carried out in an open system.

Mostly, the reaction time of the reaction (M-reak) is from 30 min. up to 72 hours, more preferably from 1 hour. up to 48 hours, even more preferably from 2 hours. up to 24 hours

Alternatively, the reaction (M-reak)u can be carried out as a continuous gas-phase reaction by passing the vaporized compound of formula (XXI) through the catalyst (M-cat). This gas-phase reaction can be carried out in the presence of an inert gas, the inert gas preferably being selected from the group consisting of nitrogen, noble gas and carbon dioxide.

After the reaction (M-reak), the compound of formula (XXI) can be isolated by standard methods, such as evaporation of volatile components, extraction, washing, drying, concentration, filtration, crystallization, distillation, chromatography and any combination thereof, which themselves known to a specialist in this field of technology.

Preferably, any volatile components of the reaction mixture either added or formed during the separation can be removed by evaporation under reduced pressure.

Preferably, the reaction mixture obtained from the reaction (M-react) or any aqueous phase during separation after the reaction (M-react) can be extracted with a solvent (M-extract), the solvent (M-extract) is preferably selected from the group that consists of water, toluene, benzene, xylene, chlorobenzene, dichloromethane, chloroform, C:i-C alkyl ester of acetic acid and their combinations;

The gray alkyl ester of acetic acid is preferably a C:-4 alkyl ester of acetic acid, more preferably selected from the group consisting of ethyl acetate, isopropyl acetate and butyl acetate;

The solvent (M-extract) is preferably selected from the group consisting of toluene, dichloromethane, ethyl acetate, isopropyl acetate and their mixtures.

Preferably, any washing of any organic phase after the reaction (M-react) can be carried out using water, a base (M-basing), using an aqueous solution of a base (M-basing), using an aqueous acid solution (M- acid) or brine.

Preferably, the base (M-base) is selected from the group consisting of ManNso»z,

MagSO", Mahon and their mixtures.

Preferably, the base (M-alkalization) is added in such an amount that the pH of the resulting mixture is from 7 to 12, more preferably from 8 to 10, even more preferably from 8 to 9.

Preferably, the acid (M-acid) is selected from the group consisting of oxalic acid, citric acid, maleic acid, fumaric acid, tartaric acid, MNAaSi, NOI,

NVg, Ne50x, NzRoh and their mixtures.

Any extraction or washing may be followed by filtration and concentration of the extract or washed mixture.

In another preferred embodiment, the compound of formula (XXI) is purified after the reaction (M-reak) by means of chromatography.

Any organic phase can be dried, preferably over Mda5O»: or Ma?»5Ox.

Any concentration is preferably carried out by distillation, preferably under reduced pressure.

The compound of formula (XXI) can be obtained in step (M) as an aldehyde as depicted in formula (XXI), but also in the form of its hydrate or hemiacetal. The hemiacetal of a compound of formula (XXI), which may be obtained as a product of step (M), may be the product of an addition reaction between an aldehyde as depicted in formula (XXI) and an alcohol selected from the group consisting of tert-butanol and isopropanol, or between an aldehyde as depicted in formula (XXI) and any alcohol used in the isolation after the reaction (M-reak).

Consequently, formula (XXI) for the purposes of this invention includes aldehyde, hydrate and hemiacetal.

If the compound of formula (XXI) is obtained from the reaction (M-reak) in the form of its hydrate or hemiacetal, then the hydrate or hemiacetal can be converted to an aldehyde using standard reactions known to a person skilled in the art.

Preferably, the compound of formula (XXI) is obtained in stage (OO) or in two stages, the two stages being stage (01) and stage (02); stage (0) contains a reaction (O-reak); the reaction (O-react) represents the reaction of the compound of the formula (XXIII) with the reagent (O-react);

SNz SNU

CH ns (HCP) reagent (O-reagent) is selected from the group consisting of peracetic acid, trifluoroperacetic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid, dimethyldioxirane, tert-butyl hydroperoxide, dibenzoyl peroxide, cumene hydroperoxide, oxygen , air, sodium hypochlorite, KNZO", MagO", aqueous HgO", HgO", dissolved in acetic acid, HgO", dissolved in trifluoroacetic acid, and their mixtures; stage (01) contains a reaction (О1-reak); the reaction (O1-reak) represents the reaction of the compound of the formula (XXIII) with water and with the compound (O1-spol); the compound (01-spol) is selected from the group consisting of bromine, M-bromosuccinimide, chlorine,

M-chlorosuccinimide, iodine, M-iodosuccinimide, IVg, VgSii, and their mixtures; stage (02) contains a reaction (О02-reak); the reaction (02-react) represents the reaction of the reaction product from the reaction (O1-react) with the base (O2-base); the base (02-base) is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, and mixtures thereof.

Preferably, the reagent (O-reagent) is selected from the group consisting of peracetic acid, tert-butyl hydroperoxide, oxygen, air, sodium hypochlorite, aqueous HgO», H2O», dissolved in acetic acid, HgO»2, dissolved in trifluoroacetic acid and their mixtures; more preferably, the reagent (O-reagent) is aqueous HgO".

Preferably, the reaction (O-reaction) is carried out in a solvent (O-solution); the solvent (O-solvent) is selected from the group consisting of water, aqueous solutions of ManNso»z,

MagSoOz, (MNa)HSO", (MNa)2COz, KHSO»z or K»COz, benzene, toluene, MMP, dioxane, acetone, ethyl acetate, methyl ethyl ketone, tert-butanol, acetonitrile, chloroform, dichloromethane and their mixtures;

Z is mainly from water, aqueous solutions of ManСО3, MagСО3, КНСО»3 or KСО», toluene, dioxane, acetone, ethyl acetate, methyl ethyl ketone, tert-butanol, acetonitrile, dichloromethane and their mixtures.

The reaction (O-reak) can be carried out in the presence of a catalyst (O-cat); the catalyst (O-cat) is selected from the group consisting of trifluoroacetic acid, trifluoroacetone, Mp(salen) complex, aldehydes, M-methylmorpholine-M-oxide, 2,2,6,6-tetramethylpiperidine-1-oxyl and their mixtures ; aldehydes are preferably isobutyraldehyde or benzaldehyde.

The reaction (O-reak) can be carried out in the presence of a buffer (O-buf);

Preferably, the buffer (O-buf) is an aqueous buffer and is selected from the group consisting of K»bOz / EOTA-Ma?» buffer, phosphate buffer and other buffers known to a specialist in this field of technology; more preferably, the buffer (O-buffer) is a K»CO3 / EOTA-Ma» buffer.

Preferably, the reaction temperature of the reaction (O-react) is from -20 to 100 "C, more preferably from -10 to 80 "C, even more preferably from 0 to 50 "C.

The reaction (O-reak) can be carried out in a system that is closed or communicates with the atmosphere.

In a closed system, the pressure depends on the boiling point of the solvent (O-solvent) and on the reaction temperature of the reaction (O-reaction).

Preferably, the reaction (M-reak) is carried out under pressure from 0.01 bar to 20 bar, more preferably from 0.1 to 10 bar, even more preferably from atmospheric pressure to 5 bar. more preferably, the reaction (O-reaction) is carried out in an open system.

Mostly, the reaction time of the reaction (O-reak) is from 30 min. up to 72 hours, more preferably from 1 hour. up to 48 hours, even more preferably from 2 hours. up to 24 hours

After the reaction (O-reak), the compound of formula (XXIII) can be isolated by standard methods such as evaporation of volatile components, extraction, washing, drying, concentration, crystallization, distillation, chromatography and any combination thereof.

Preferably, the reaction (O1-react) and the reaction (O2-react) are carried out in a solvent (O-solvent), with a solvent (O-solvent) as defined above, also with all its preferred implementation options.

Preferably, the reaction temperatures of the reaction (01-react) and the reaction (02-react) are the same or different and independently of each other are from -20 to 100 "C, more preferably from -10 to 80 "C, even more preferably from 0 to 50 "S.

Reaction (01-reak) and reaction (02-reak) can be carried out independently of each other in systems that are closed or communicate with the atmosphere.

In a closed system, the pressure depends on the boiling point of the solvent (O-react) and on the reaction temperature of the reaction (O1-react) and, accordingly, the reaction (O-react).

Preferably, the reaction (O1-reaction) and the reaction (O2-reaction) are carried out independently of each other under pressure from 0.01 bar to 20 bar, more preferably from 0.1 to 10 bar, even more preferably from atmospheric pressure to 5 bar. more preferably, the reaction (O1-reak) and the reaction (O2-reak) are carried out in an open system.

Mostly, the reaction time of the reaction (O1-reak) and reaction (02-reak) independently of each other is from 30 min. up to 72 hours, more preferably from 1 hour. up to 48 hours, even more preferably from 2 hours. up to 24 hours

The reaction product from the reaction (О01-reak) and the compound of formula (XXII) from the reaction (O2-reak) can be isolated by standard methods, such as evaporation of volatile components, extraction, washing, drying, concentration, filtration, crystallization, distillation, chromatography and any combination of them.

The reaction (O1-reak) and the reaction (02-reak) can be carried out sequentially without separating the reaction product from the reaction (O1-reak), it can be carried out in one reactor.

Preferably, the compound of formula (XXII) is not isolated, stage (M) is carried out directly after stage (0) or stage (02), respectively, in one reactor. For this, the catalyst (M-cat) is simply added to the reaction mixture obtained from the reaction (O-reak) or, respectively, from the reaction (02-

From reality).

Preferably, the compound of formula (XXI) is obtained in stage (P); stage (P) contains a reaction (P-reak); in the reaction (P-reak), the compound of the formula (XXIM) is exposed to temperature (P-temp);

СНз СН,

BUT.

SN

Io) su (XXIX) temperature (P-temp) is from 0 to 300 "С.

Preferably, the temperature (P-temp) is from 5 to 200 °C, more preferably from 100 to 15076.

The reaction (P-react) can be carried out in a solvent (P-solution); the solvent (P-solvent) is selected from the group consisting of benzene, toluene, xylene, hexane, heptane, 1,2-dichloroethane, MMP, dichloromethane, chloroform and their mixtures; mainly from benzene, toluene, xylene, dichloromethane and their mixtures.

Preferably, the reaction (P-react) is carried out in the presence of a catalyst (P-cat); the catalyst (P-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, HCI, HBg, Hg5O", KOH, Maon, Knzoh,

NMO", NzROx", NOYU", Vsiz, VViz, VEZOE", VEz5Meg, VEZTNE, Masi", MoVi", Mag, AiISiz, AKO-Sch-4 alkyl)z, Ig2, AI2Oz, ZpSih, TiSii, T(O -Sh.-4 alkyl)4, 2gSyh, Vig2Oz, ViSyz, 2pSi", РІСІ", ЕРеSyz, MB(OTI",

UB(СИ)z, Sasiz, AIViz, Se(OTI)z, ISI, acid insoluble inorganic solid matter, acid ion exchange resins, carbon treated with inorganic acid and their mixtures; mainly from methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Не5О»х, КНБО», НзРоОх, acid insoluble inorganic solid matter, acid ion exchange resins, carbon treated with inorganic acid and their mixtures.

Preferably, the acid insoluble inorganic solid is acidic aluminosilicates or silica gel.

Preferably, the inorganic acid with which the carbon was treated is selected from the group consisting of NCI, H25Ox and NMO.

Preferably, the acidic ion exchange resin is selected from the group consisting of copolymers of styrene and divinylbenzene and perfluorinated branched or linear polyethylenes, these polymers are functionalized with the help of 5OzH groups; more preferably, the acidic ion exchange resin is selected from the group consisting of copolymers of styrene and divinylbenzene, containing more than 5 95 divinylbenzene, which is preferably macroreticulated, and perfluorinated polyethylenes, these polymers are functionalized with

ZON groups.

If the reaction (P-react) is carried out in the presence of a catalyst (P-cat), then the temperature (P-temp) is preferably from 0 to 200 C, more preferably from 10 to 150 C, even more preferably from 10 to 100 "C.

The reaction (P-reak) can be carried out in the gas phase by passing the vaporized compound of the formula (XXIM) through a heated tube, the heated tube can be loaded with a catalyst (P-cat).

After the reaction (P-reak), the compound of formula (XXI) can be isolated by standard methods such as evaporation of volatile components, extraction, washing, drying, concentration, crystallization, distillation, chromatography and any combination thereof.

Preferably, the compound of formula (XXIM) is obtained in three stages, the three stages are stage (01), stage (02) and stage (03); stage (O1) includes a reaction (O1-react) using the reaction of a compound of the formula (XXU) with a reagent (01-react);

SNU about SN (XXU)

O means Vg, SI, or I; the reagent (01-reagent) is selected from the group consisting of lithium, magnesium, aluminum, zinc, calcium, isopropylmagnesium chloride, isopropylmagnesium bromide, butyllithium, sec-butyllithium and their mixtures; stage (02) contains a reaction (02-reak); the reaction (02-reak) represents the reaction of the reaction product from the reaction (01-reak) with acetone; stage (03) contains a reaction (03-reak); the reaction (03-reak) represents the reaction of the reaction product from the reaction (02-reak) with the reagent (03-reak); the reagent (03-reagent) is selected from the group consisting of water, methanol, ethanol, oxalic acid, citric acid, МНАСИ, NOСИ, НВг, НМО3, Н25О», НзРоОх, acetic acid, propionic acid, formic acid and their mixtures.

Mostly O means Vg.

Preferably, the reagent (01-reagent) is selected from the group consisting of lithium, magnesium, aluminum, isopropylmagnesium chloride, isopropylmagnesium bromide and their mixtures.

The reaction (O1-reak) can be catalyzed by a catalyst (01-cat).

The catalyst (01-cat) is selected from the group consisting of iodine, 1,2-dibromoethane, Tisich,

AISiz, РСИ", ViSiz, ISI and their mixtures.

Preferably, the reagent (03-reagent) is water or aqueous MNaCl.

Preferably, the reaction (01-reak) is carried out in a solvent (01-solution).

Preferably, the reaction (02-react) is carried out in a solvent (02-solvent).

Preferably, the reaction (O3-reaction) is carried out in a solvent (O3-solution).

Preferably, the solvent (01-solvent), the solvent (02-solvent) and the solvent (03-solvent) are the same or different and are independently selected from THF, methyl-THF, MMP, diethyl ether, methyl-tert-butyl ether , methoxycyclopentane, diisopropyl ether, 1,2-dimethoxyethane, tri-C, and 4-alkylamine and their mixtures; more preferably from THF, 2-methyl-THF, 1,2-dimethoxyethane, methyl-tert-butyl ether, methoxycyclopentane, tri-C.-4 alkylamine and their mixtures; even more preferably from the group consisting of THF, 2-methyl-THF, 1,2-dimethoxyethane, triethylamine and their mixtures.

Preferably, the solvent (21-vol), the solvent (02-vol) and the solvent (203-vol) are the same.

The reaction temperatures of reaction (01-reak), reaction (02-reak) and reaction (03-reak) are the same or different and independently of each other are preferably from -100 to 150 "C, more preferably from -60 to 100 "C , and even more preferably from -20 to 80 "s.

Reaction (01-reak), reaction (02-reak) and reaction (03-reak) can be carried out at a constant temperature, or the temperature can be changed during the progress of the reactions. For example, reactions can proceed for a certain period of time at one temperature, and then for a subsequent period of time at another temperature, different from the first temperature. Alternatively, the temperature may change continuously during the reaction.

The reaction time periods of reaction (01-reak), reaction (02-reak) and reaction (03-reak) are the same or different and, independently of each other, preferably consist of 30 minutes or more. up to 48 hours, more preferably from 1 to 24 hours, even more preferably from 2 to 12 hours.

The amounts of solvent (01-fold), solvent (02-fold) and solvent (23-fold) are the same or different and independently of each other are preferably in the 2- to 40-fold range, more preferably in the 3- to 10-fold range , even more preferably in the 5- to 7-fold range, from the mass of the compound of the formula (XXU), from the mass of the reaction product from the reaction (01-react) and from the mass of the reaction product from the reaction (02-react), respectively.

It is preferable to use from 1.0 to 10 mol equivalents, more preferably from 1.1 to 5 mol equivalents, even more preferably from 1.1 to 3 mol equivalents of the reagent (01-reag), mol equivalents per mol of the compound of the formula (XXM).

It is preferable to use from 1.0 to 10 mol equivalents, more preferably from 1.1 to 5 mol equivalents, even more preferably from 1.1 to 3 mol equivalents of acetone, mol equivalents per mol of the compound of the formula (XXM).

It is preferable to use from 1.0 to 100 mol equivalents, more preferably from 1.1 to 50 mol equivalents, even more preferably from 1.1 to 30 mol equivalents of the reagent (03-reag), mol equivalents per mol of the compound of the formula (XXM) or per mol of the reaction product from the reaction (02-reakyuk).

Preferably, reaction (01-reak), reaction (02-reak) and reaction (03-reak) are carried out under atmospheric pressure.

Preferably, reaction (01-reaction), reaction (02-reaction) and reaction (03-reaction) are carried out under inert

With atmosphere. Preferably, an inert atmosphere is achieved by using an inert gas selected from the group consisting of argon, another noble gas, a low-boiling alkane, nitrogen, and mixtures thereof.

A low-boiling alkane is mainly a C:-z alkane, i.e. methane, ethane or propane.

After the reaction (01-react), the reaction (02-react) and the reaction (03-react), the reaction product from the reaction (01-react), the reaction product from the reaction (02-react) and the compound of the formula (XXIM), respectively, can be isolated by standard methods such as evaporation of volatile components, extraction, washing, drying, concentration, crystallization, distillation, chromatography and any combination thereof.

Preferably, the reaction product from the reaction (C1-react) and the reaction product from the reaction (02-react) are not isolated.

Preferably, reaction (01-reaction), reaction (02-reaction) and reaction (03-reaction) are carried out sequentially; preferably reaction (01-react), reaction (O2-react) and reaction (C03-react) are carried out in one reactor.

In another preferred embodiment, the reaction (O1-react) and the reaction (02-react) can be carried out in one reactor by adding the reagent (01-react) to a mixture of the compound of the formula (XXM) and acetone in a solvent (CO1-solvent) ; after that, the reaction (C3-reak) is carried out, preferably in the same reactor.

The compound of the formula (XXIM) is preferably isolated using conventional methods, such as evaporation of volatile components, hydrolysis and optional acidification of the high-boiling residue, extraction and distillation.

Any aqueous phase can be extracted, extraction is preferably carried out with a solvent (O-extract). The solvent (O-extract) is benzene, toluene, ethyl acetate or isopropyl acetate.

Any organic phase can be dried, preferably with magnesium sulfate.

Any concentration is preferably carried out by distillation, preferably under reduced pressure.

The compound of formula (XXIM) can be purified, preferably by crystallization or distillation under reduced pressure.

The compounds of formula (XXI) and (XXII) are chiral compounds, and the formulas contain any enantiomer, as well as any mixture of enantiomers of the compounds of formula (XXI) or formula (XXIII), respectively.

Compounds of the formula (XXM) are known compounds and can be obtained according to known methods.

The development of any of the reactions reaction (M-reaction), reaction (O-reaction), reaction (O1-reaction), reaction (O2-reaction), reaction (P-reaction), reaction (OО1-reaction), reaction ( 02-react) and reactions (03Z-react) can be monitored using standard techniques such as nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), high performance liquid chromatography (HPLC), liquid chromatography mass spectrometry (LCMS), or thin-layer chromatography (TLC), and separation of the reaction mixture can begin when the conversion of the starting material exceeds 95 95, or if the starting material is no longer detectable. The time required for this to occur will depend on the exact reaction temperature and the exact concentrations of all reagents, and may vary from batch to batch.

As a rule, any organic phase can be dried, preferably over Moa 5 O 4 or Mag 5 O , unless otherwise specified.

In addition, the object of the invention is the use of the compound of formula (XXI) as a fragrance, preferably in perfumery products or household chemical products.

In addition, the object of the invention is the use of the compound of formula (XXI) for the production of medetomidine.

Medetomidine is a compound of the formula (XX)

CH, CH,

M SN,

OR o)

M

H is an alpha-2-adrenergic agonist, which is currently used in veterinary medicine as a sedative and analgesic, and is considered an analgesic.

ММО2011/070069А discloses a method of obtaining medetomidine, in which the imidazole ring is formed during a multistage process, starting from commercially available 2,3-dimethylbenzoic acid.

The compound of the formula (XX) is preferably obtained from the compound of the formula (XXI) by a method that includes the reaction (M11);

Zo reaction (MI) is a reaction between a compound of formula (XXI), an isocyanide and a compound that acts as a source of nitrogen; isocyanide is preferably reagent (M), reagent (M) is selected from the group consisting of p-toluenesulfonylmethyl isocyanide, trifluoromethanesulfonylmethyl isocyanide, methanesulfonylmethyl isocyanide, benzenesulfonylmethyl isocyanide, 4-acetamidobenzenesulfonylmethyl isocyanide and their mixtures; the compound acting as a source of nitrogen is mainly a reagent (М-А), a reagent (М-

A) is chosen from the group consisting of ammonia, sulfamic acid, p-toluenesulfonamide, benzenesulfonamide, 4-acetamidobenzenesulfonamide, tritylamine, formamide, urea, urotropin, ethyl carbamate, acetamide and their mixtures; preferably, the reaction (M1) is carried out in a solvent (M), preferably the solvent (M) is selected from the group consisting of M, M-dimethylformamide, Si-alkanol, formamide, 1,2-dimethoxyethane, MMP, toluene, acetonitrile, propionitrile, ethyl carbamate, M, M-dimethylacetamide, water, acetamide and their mixtures.

In the reaction (MI), any sequence of reaction reagent (M) and reagent (M-A) with the compound of formula (XXI) can be used: the compound of formula (XXI) can first react with reagent (M) and then add reagent (М-А); or the compound of the formula (XXI) may first react with the reagent (М-А) and then add the reagent (M); or the compound of the formula (XXI) can simultaneously react with the reagent (M) and with the reagent (M-A), this embodiment is preferably suitable in the case when the reagent (M-A) and the solvent (M) are the same and represent is formamide, ethyl carbamate or acetamide; mainly formamide.

In addition, the object of the invention is the use of a compound of the formula (XXI!) to obtain a compound of the formula (XXI).

In addition, the object of the invention is the use of the compound of the formula (XXI) to obtain the compound of the formula (XXII).

In addition, the object of the invention is the use of the compound of the formula (XXII) to obtain the compound of the formula (XXIII).

In addition, the object of the invention is the use of a compound of the formula (XXM) to obtain a compound of the formula (XXIM).

Compared to the state of the art, the method according to the present invention offers several advantages: it is important to note that the entire carbon skeleton of the compound of formula (XXI) is formed in several chemical steps, using only inexpensive reagents. There is no need for protecting groups and as a result the total amount of applicable compound is reduced, the batch size in terms of molar amounts is increased.

In particular, trityl or acetal protecting groups are not used and imidazole protection is not required. Thus, the number and volume of required reagents is reduced, and there is no need for the stages of introduction of protection or removal of protection, the amount of waste is reduced, unlike, for example, when a protective group of trityl or acetal is used. The method provides good yields.

The compound of formula (XXI) can be easily purified and obtained in the form of a strongly fragrant aroma with aroma purity or high aroma purity. This is especially important for products intended for use as a fragrance.

The product has a rather special aroma, which the perfume industry is looking for.

Examples

Methods "NizZS NMR spectra were recorded on Magiap MMME5 500 devices (500 MHz for "H and 125 MHz for "ZS) in SOSIz. Chemical shifts are expressed in parts per million relative to TMS and constants

From interaction (U) in hertz.

EI means mass spectra with electron impact ionization (70 em), they were obtained on an AMO-604 spectrometer.

ESI stands for Electrospray Ionization Mass Spectra.

THF is distilled from sodium/benzophenone-ketyl before use; obtained anhydrous

THF is referred to as "dry THF" in the text below.

Example 1: 2-(2,3-Dimethylphenyl)upropan-2-ol, a compound of the formula (XXIM), obtained with the help of the organomagnesium intermediate compound 1-Bromo-2,3-dimethylbenzene (a compound of the formula (XXM), where OO means Bg ; 8.43 g, 45.6 mmol) was dissolved in dry THF (15 ml) and placed in a dropping funnel. Separately, Ma wire (1.10 g, 45.3 mmol) in dry THF (5 mL) was placed in a flask equipped with the above-mentioned dropping funnel, a stirrer, and a reflux condenser. A solution of 1-bromo-2,3-dimethylbenzene (1.0 mL) was added through a drop funnel and the reaction was initiated by adding 1,2-dibromoethane (3 drops), and then the remainder of the 1-bromo-2,3-dimethylbenzene solution was added. The contents of the dropping funnel were added at a rate sufficient to maintain gentle heating in the reflux flask. After the addition was complete, the mixture was refluxed for 1 h. and then cooled to 0 °C. A solution of dry acetone (4.2 mL, 58 mmol) was added dropwise to dry THF (15 mL) and the mixture was stirred at a temperature between 0 and 207 for 3 h. The mixture was poured into a saturated MNACI aqueous solution ( 100 ml), extracted with hexane (5 times with 50 ml each), dried with Ma250x and evaporated under reduced pressure. The major product was isolated by silica gel column chromatography with hexane:ethyl acetate as eluent (v/v from 15: 1 to 10:1 gradient) to give 3.50 g (47 95) of the title compound.

IN NMR: 1.68 (5, 6H), 1.70 (5, 1H), 2.29 (5, ЗН), 2.50 (5, ЗН), 7.03 to 7.10 (t, 2Н), 7.29 to 7.32 (t, 1Н). 136 NMR: 17.72, 21.08, 31.24, 73.71, 123.11, 125.02, 129.02, 135.09, 138.69, 145.47.

MS (EI): 164 (12), 149 (35), 146 (100), 131, 116, 105, 91.

Example 2: 2-(2,3-Dimethylphenyl)upropan-2-ol, a compound of the formula (XXIM), obtained using the organolithium intermediate compound 1-Bromo-2,3-dimethylbenzene (a compound of the formula (XXM), where O means Bg ; 4.25 g, 23.0 bo mmol) was dissolved in dry THF (20 mL) in a flask equipped with a thermometer and a magnetic stirrer.

The mixture was cooled to -78 "C. n-butyllithium (1.6

M in hexane, 17.5 mL, 28.0 mmol), keeping the temperature below -70 °C. When the addition was complete, the mixture was maintained at -78 °C and stirred at this temperature for 1 h. After that, a solution of dry acetone (1.85 mL, 25.2 mmol) in dry THF (5 mL) was added at -7876. The mixture was stirred at -78 "C for 30 min., the cooling bath was removed, and the mixture was allowed to warm to room temperature. The mixture was poured into a saturated aqueous solution

MNA:CI (100 mL), extracted with hexane (4 times with 50 mL each), dried over

Ma?5O., and purified by column chromatography using hexane:ethyl acetate as eluent (06./06. 32:1) to obtain 3.45 g (91 95) of the title compound.

The measured NMR spectra were identical to the spectra recorded in Example 1.

Example 3: 1,2-Dimethyl-3-(2-propenyl)benzene, compound of formula (XXII) 2-(2,3-Dimethylphenyl)propan-2-ol, compound of formula (XXIM), obtained according to or example 1 , or example 2, (1.10 g, 6.70 mmol) was dissolved in benzene (20 ml), and p-toluenesulfonic acid monohydrate (35 mg, 0.18 mmol) was added. The mixture was stirred at room temperature for three hours. Silica gel (200 mg) was added, stirring was continued for approx. 16 hours, and then the reaction mixture was boiled in a reflux flask for 30 minutes. After cooling to room temperature, the mixture was filtered, washed with aqueous CaCO3 solution, dried in a conventional manner, and concentrated under reduced pressure to give 0.90 g (92 95) of the title compound.

IN NMR: 2.02 (t, ЗН), 2.21 (5, ЗН), 2.28 (5, ЗН), 4.82 (t, 1Н), 5.17 (t, 1Н), 6.97 (t, 1Н), 7.05 (t, 2Н ).

Example 4: 2-(2,3-Dimethylphenyl)methyloxirane, compound of formula (XXII)

The buffer was obtained by dissolving K»2CO3 (20.7 g) and EOTA-Ma» (11.5 mg) in water (100 ml). 1,2-Dimethyl-3-(2-propenyl)benzene, a compound of the formula (XXIII), obtained according to the example

C (0.90 g, 6.16 mmol) was dissolved in a mixture of dichloromethane and acetonitrile (0.06.1:1, 60 ml), and the buffer obtained as described above (9.3 ml) was added. First, 1,1,1-trifluoroacetone (60 μl) and then hydrogen peroxide (30 95 in water, 6.2 ml, 60.7 mmol) were added to the resulting mixture, and the mixture was shaken at room temperature for 2 h. The reaction mixture was diluted with

With water (100 ml), the organic phase was separated, and the aqueous phase was extracted with dichloromethane (2 times with 50 ml each). The combined organic phases were dried over Ma»5Ox, concentrated under reduced pressure, and the residue was purified by column chromatography using hexane:ethyl acetate as eluent (vol./06. 32:71) to give 851 mg (85 95) of the indicated the title of the compound.

IN NMR: 1.59 (5, ZN), 2.28 (5, ZN), 2.31 (5, ZN), 2.83 (Bg and, 9U-5.4, 1H), 2.98 (y, U-5.4 Hz, 1H), 7.08 ( t, 2H), 7.21 (t, 1H).

MS (EI): 162, 147, 133, 117 (100).

Example 5: 2-(2,3-Dimethylphenyl)propanal, compound of formula (XXI) 2-(2,3-Dimethylphenyl)methyloxirane, compound of formula (XXIII), obtained according to example 4 (0.84 g, 5.18 mmol), was dissolved in dry dichloromethane (50 ml) and at room temperature was added powdery hydrate Syc(BE-)2 (318 mg). After 2 hours at room temperature, the mixture was washed with water, dried over Mag2505 and concentrated under reduced pressure to obtain 0.84 g (100 95) of the title product.

IN NMR: 1.40 (y, 9-7.1 Hz, ZN), 2.25 (5, ZN), 2.32 (5, ZN), 3.89 (da, 9-7.1, 1.0 Hz, 1H), from 6.89 to 6.92 (t, 1H), 7.12 (t, 2H), 9.67 (a, 9-1.0 Gu, 1H).

Example 6: Medetomidine, compound of formula (XX) 2-(2,3-Dimethylphenyl)propanal, compound of formula (XXI) obtained according to example 5 (2.43 g, 15.0 mmol) and p-toluenesulfonylmethyl isocyanide (2.73 g, 14.0 mmol) ) was mixed with EUN (30 ml). Powdered Masm (73 mg, 1.5 mmol) was added to the shaken suspension. The mixture was stirred for 1 hour. at room temperature, and then evaporated under reduced pressure to dryness. The residue was placed in an ampoule and treated with Meon saturated with Mn (50 mL). The ampoule was heated to 110 C in an oil bath for three days.

This experiment was repeated once more (2-(2,3-Dimethylphenyl)propanal: 3.24 g, 20.0 mmol; p-toluenesulfonylmethyl isocyanide: 3.90 g, 20.0 mmol).

Both reaction mixtures were combined, evaporated to dryness, dissolved in dichloromethane (150 mL) and washed with 10 95 (w/w) aqueous MgSO3 (200 mL) and then water (200 mL), dried in the usual way, evaporated under reduced pressure and purified by silica gel column chromatography using dichloromethane:methanol as 60 eluent (o0ob6./06.15:1 to 10:1 gradient) to give 3.0 g (44 95) of medetomidine as a viscous oil. Medetomidine was crystallized from toluene:cyclohexane and then recrystallized from aqueous ethanol.

IN NMR: 1.56 (y, 92-7.2 Hz, ZN), 2.18 (5, ZN), 2.25 (5, ZN), 4.35 (d, 9-7.2 Hz, 1H), 6.66 (5, 1H), 6.93( aa, 9U-6.6, 2.2 Hz, 1H), 6.99 to 7.05 (t, 2H), 7.30 (a, 9-1.1 Gu, 1H), 9.84 (width 5, 1H). 13 NMR: 14.65, 20.72, 20.88, 14.12, 117.61, 124.62, 125.53, 127.91, 134.05, 134.60, 136.76, 141.11, 143.23.

MS (EU): 201|MNI"

Claims (9)

FORMULA OF THE INVENTION 1. The method of obtaining the compound of the formula (XXI) dream sleep, (in) sleep N ; (XXI) where the method includes stage (M); stage (M) includes a reaction (M-reak); reaction (M-reak) is a reaction of a compound of formula (XXII) with a catalyst (M-cat); dream sn, ru sn, ; (XXII) the catalyst (M-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, HCI, Hg, H25Ox, HMO»z, NzRox . . MiVgg, MiSi», RA(OAs)», Rasi», RiISI», Ipsiz, acid inorganic solid, acid ion exchange resin, carbon treated with inorganic acid and their mixtures. 2. The method according to claim 1, which is characterized by the fact that the catalyst (M-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, NCI, НВг, Нг5О», НзРО »z, VSiz, VEZOE, Masig, MaVi», AIISiz, 7pSiI», Suc(ВЕ4)2, aluminosilicates, acid ion-exchange resins, carbon treated with NCI, Hg5Ox or NMOz and their mixtures. Zo 3. The method according to claim 1 or 2, which differs in that the reaction (M-reak) is carried out in a solvent (M-solution); the solvent (M-solvent) is selected from the group consisting of water, tert-butanol, isopropanol, acetonitrile, propionitrile, THF, methyl-THF, MMP, dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, chloroform , toluene, benzene, chlorobenzene, hexane, cyclohexane, ethyl acetate, acetic acid, formic acid, trifluoroacetic acid and their mixtures. 4. The method according to any of paragraphs from 1 to 3, which differs in that the compound of formula (XXII) is obtained in stage (0) or in two stages, where the two stages are stage (01) and stage (02); stage (0) includes a reaction (O-reak); reaction (О-reak) is a reaction of a compound of the formula (XXI) with a reagent (О-reak) сн, сн, dream no; (XXI) reagent (O-reagent) is selected from the group consisting of peracetic acid, trifluoroperacetic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid, dimethyldioxirane, tert-butyl hydroperoxide, dibenzoyl peroxide, cumene hydroperoxide, oxygen, air, sodium hypochlorite, KH5OO", MagO", aqueous HgO", HgO", dissolved in acetic acid, HgO", dissolved in trifluoroacetic acid, and their mixtures; stage (O1) includes a reaction (O1-reaction); the reaction (O1-reak) is a reaction of the compound of the formula (XXIII) with water and with the compound (O1-spol); the compound (O1-spol) is selected from the group consisting of bromine, M-bromosuccinimide, chlorine, M-chlorosuccinimide, iodine, M-iodosuccinimide, IVg, ALL and their mixtures; stage (02) includes reaction (02-reak); the reaction (O2-reak) represents the reaction of the reaction product from the reaction (O1-reak) with the base (02- base); the base (О02-base) is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide and mixtures thereof. 5. The method according to claim 4, which differs in that the reagent (O-reagent) is selected from the group consisting of peracetic acid, tert-butyl hydroperoxide, oxygen, air, sodium hypochlorite, aqueous HgO»5», H2gO»5» dissolved in acetic acid, HgOg dissolved in trifluoroacetic acid, and their mixtures. 6. The method according to claim 4 or 5, which differs in that the compound of the formula (XXIII) is obtained at stage (P); stage (P) includes a reaction (P-reak); in the reaction (P-reak), the compound of the formula (XXIM) is exposed to temperature (P-temp) dream sleep, but sleep, no; (ХХИМ) where the temperature (Р-temp) ranges from О to 300 "С. 7. The method according to claim 6, which differs in that the compound of the formula (XXIM) is obtained in three stages, where the three stages are stage (01), stage (02) and stage (03); stage (01) includes the reaction (01-react) using the reaction of the compound of the formula (XXM) with the reagent (01-react) sn, at. | "сн, ; (ХХУ) O means HV, SI, or I; the reagent (01-reagent) is selected from the group consisting of lithium, magnesium, aluminum, zinc, calcium, isopropylmagnesium chloride, isopropylmagnesium bromide, butyllithium, sec-butyllithium and their mixtures; stage (02) includes the reaction (02-reaction); reaction (02-reaction) is the reaction of the reaction product from the reaction (O1-reaction) with acetone; stage (03) includes the reaction (O3-reaction); reaction (OZ-react) represents the reaction of the reaction product from the reaction (O2-react) with the reagent (O03-react); the reagent (OZ3-react) is selected from the group consisting of water, methanol, ethanol, oxalic acid, citric acid, МНАСИ, НСИ, НВг, НМОз, Н25О», НзРоОх, acetic acid, propionic acid, formic acid and their mixtures. 8. Use of a compound of formula (XXI) as a fragrance, with a compound of formula (XXI) as defined in claim 1. 9. Application of the compound of the formula (XXI) for the preparation of medetomidine, with the compound of the formula (XXI), as defined in claim 1. 00 Komputernaverstka!, Skvortsova.dG (00000000 State Intellectual Property Service of Ukraine, 45 Vasylya Lypkivskoho St., Kyiv , SME, 03680, Ukraine SE "Ukrainian Institute of Intellectual Property", 1 Glazunova St., Kyiv - 42, 01601