NZ700641B2 - Method for preparation of 2-(2,3-dimethylphenyl)-1-propanal - Google Patents

Method for preparation of 2-(2,3-dimethylphenyl)-1-propanal Download PDF

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NZ700641B2
NZ700641B2 NZ700641A NZ70064112A NZ700641B2 NZ 700641 B2 NZ700641 B2 NZ 700641B2 NZ 700641 A NZ700641 A NZ 700641A NZ 70064112 A NZ70064112 A NZ 70064112A NZ 700641 B2 NZ700641 B2 NZ 700641B2
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reaction
acid
reac
compound
formula
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NZ700641A
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NZ700641A (en
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Robert Bujok
Stephan Elzner
Anna Kulesza
Krzysztof Wojciechowski
Zbigniew Wrobel
Doerwald Florencio Zaragoza
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Lonza Ltd
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Priority claimed from PCT/EP2012/070873 external-priority patent/WO2012172120A2/en
Application filed by Lonza Ltd filed Critical Lonza Ltd
Priority claimed from PCT/EP2012/072797 external-priority patent/WO2013011156A2/en
Publication of NZ700641A publication Critical patent/NZ700641A/en
Publication of NZ700641B2 publication Critical patent/NZ700641B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C07C1/20—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms
    • C07C1/22—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms by reduction
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C07C1/20—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms
    • C07C1/24—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms by elimination of water
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/40—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals
    • C07C15/42—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals monocyclic
    • C07C15/44—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals monocyclic the hydrocarbon substituent containing a carbon-to-carbon double bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • C07C2531/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • C07C2531/025—Sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/18—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part
    • C07C33/20—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part monocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
    • C07C45/58—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in three-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/86—Use of additives, e.g. for stabilisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/228—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing six-membered aromatic rings, e.g. phenylacetaldehyde
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
    • C07D301/12—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with hydrogen peroxide or inorganic peroxides or peracids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/24—Synthesis of the oxirane ring by splitting off HAL—Y from compounds containing the radical HAL—C—C—OY
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/04—Compounds containing oxirane rings containing only hydrogen and carbon atoms in addition to the ring oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B9/00—Essential oils; Perfumes
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B9/00—Essential oils; Perfumes
    • C11B9/0061—Essential oils; Perfumes compounds containing a six-membered aromatic ring not condensed with another ring

Abstract

The invention discloses a method for preparation of a compound of formula (XXI); the method comprises a step (N); step (N) comprises a reaction (N-reac); reaction (N-reac) is a reaction of compound of formula (XXII) with a catalyst (N-cat); catalyst (N-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, HCl, HBr, H2SO4, HNO3, H3PO4, HClO4, BCl3, BBr3, BF3OEt2, BF3SMe2, BF3THF, MgCl2, MgBr2, MgI2, AlCl3, Al(O C1 4 alkyl)3, SnCl4, TiCl4, Ti(O C1 4 alkyl)4, ZrCl4, Bi2O3, BiCl3, ZnCl2, PbCl2, FeCl3, ScCl3, NiCl2, Yb(OTf)3, Yb(Cl)3, GaCl3, AlBr3, Ce(OTf)3, LiCl, Cu(BF4)2, Cu(OTf)2, NiBr2(PPh3)2, NiBr2, NiCl2, Pd(OAc)2, PdCl2, PtCl2, InCl3, acidic inorganic solid substance, acidic ion exchange resin, carbon treated with inorganic acid and mixtures thereof. The invention is also directed towards the use of the compound of formula (XXI), its use in perfumes and its use for the preparation of medetomidine. cetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, HCl, HBr, H2SO4, HNO3, H3PO4, HClO4, BCl3, BBr3, BF3OEt2, BF3SMe2, BF3THF, MgCl2, MgBr2, MgI2, AlCl3, Al(O C1 4 alkyl)3, SnCl4, TiCl4, Ti(O C1 4 alkyl)4, ZrCl4, Bi2O3, BiCl3, ZnCl2, PbCl2, FeCl3, ScCl3, NiCl2, Yb(OTf)3, Yb(Cl)3, GaCl3, AlBr3, Ce(OTf)3, LiCl, Cu(BF4)2, Cu(OTf)2, NiBr2(PPh3)2, NiBr2, NiCl2, Pd(OAc)2, PdCl2, PtCl2, InCl3, acidic inorganic solid substance, acidic ion exchange resin, carbon treated with inorganic acid and mixtures thereof. The invention is also directed towards the use of the compound of formula (XXI), its use in perfumes and its use for the preparation of medetomidine.

Description

METHOD FOR ATION OF 2-(2,3-DIMETHYLPHENYL)PROPANAL The invention discloses a method for ation of 2-(2,3-dimethylphenyl)propanal from 1-bromo 2,3-dimethylbenzene and acetone, its use in es and its use for the preparation of medetomidine.
Aromatic aldehydes are widely used as flavours and fragrances in cosmetics, perfumes, and numerous household products. Alpha, nsaturated ic aldehydes, such as substituted cinnamic aldehydes, are disclosed to have distinct fragrance and are therefore used in the perfume industry.
WO 98/45237 A discloses certain aromatic aldehydes, a method for producing them starting from acetophenone acetals, their use as perfumes and their use as intermediates for the ation of 3-arylpropanals. They have a musky fragrance.
Mukherjee-Müller et al., Helvetica Chimica Acta, 1977, 60, 1758-1780, discloses a process for the preparation of 2-(dimethylphenyl) propanaldehydes as a mixture of 3 unidentified isomers.
The position of the methyl on the aromatic groups is unknown. These compounds are prepared by a ngement reaction in the presence of an acidic catalyst (sulfuric acid) from certain tricyclic alcohols.
The perfume and household product industry has a nt need for new perfumes with interesting, new and not yet available fragrances in order to increase the available choice of fragrances and to adapt the nces to the ever changing demand of fashion. Furthermore the respective substances need to be synthesized economically and with consistent quality.
High purity and strong fragrances are desired. The present invention es a new alpha, beta-unsaturated aromatic aldehyde analogue, which has strong and interesting, aldehydic fragrance, ely spicy and sweet, and an improved process for the production f.
In the following text, halogen means F, Cl, Br or I, preferably Cl, Br or I; "alkyl" means linear, branched, cyclic or cyclo alkyl, preferably it means the commonly accepted meaning linear or branched alkyl; if not otherwise stated. Examples of "alkyl" include , ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, and the like; "cyclic alkyl" or "cyclo alkyl" are ed to include cyclo aliphatic, bicyclo aliphatic and tricycle aliphatic residues; "alkane" means a linear, branched or cyclic , preferably linear or branched alkane; "alkanol" means a hydroxyalkane, with alkane having the meaning as defined above also with its preferred embodiments; Ac acetyl; tBu tertiary butyl; DBU 1,8-diazabicyclo[5 .4.0]undecene; DABCO l,4-diazabicyclo[2.2.2]octane; DIPEA N-ethyl-N,N—diisopropylamine; DMA N,N—dimethylacetamide; DMF N,N—dimethylformamide; EDTA—Nag ethylene diamine tetraacetic acid disodium; hexanes mixture of isomeric hexanes; NMP N—methyl-Z—pyrrolidone; OTf trifluoromethanesulfonate, also known as triflate; MPS KHSOs, also known as potassium peroxymonosulfate or potassium monopersulfate, and marketed as a triple salt with the formula 2 KH805 KHSO4 K2804 under the trade names ® and , therefore KH805 is often used in form of this triple salt; salen ligand obtained from a condensation of salicylaldehyde or of a substituted salicylaldehyde derivative with ethylene diamine or with a substituted ethylene e; sulfamic acid HO-SOg-NHzg TEMPO 6—tetramethylpiperidine l-oxyl; THF tetrahydrofuran; xylene methylbenzene, 1,3-dimethylbenzene, 1,4-dimethylbenzene or a mixture thereof; if not otherwise stated.
Subject of the invention is a method for preparation of compound of formula (XXI); CH3 CH3 0 CH3 (XXI) WO 11156 2012/072797 the method comprises a step (N); step (N) comprises a reaction (N—reac); reaction (N-reac) is a on of compound of formula (XXII) with a catalyst (N-cat); CH3 CH3 (xx11) catalyst (N-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, rsulfonic acid, HCl, HBr, H2804, HNO3, H3PO4, HClO4, BC13, BBr3, BFgoEtz, BngMez, BFgTHF, MgClz, MgBrz, Mglz, AlClg, Al(O-C1_4 alkyl)3, SnCl4, TiCl4, Ti(O-C1_4 alkyl)4, ZrCl4, B1203, B1Cl3, ZnClz, PbClz, FCCl3, SCCl3,N1C12, Yb(OTf)3, Yb(Cl)3, GaClg, AlBrg, Ce(OTf)3, LiCl, Cu(BF4)2, Cu(OTf)2,NiBr2(PPh3)2,NiBr2,NiC12, Pd(OAc)2, PdClz, PtClz, InC13, acidic inorganic solid substance, acidic ion exchange resin, carbon treated with inorganic acid and mixtures thereof.
Preferably, the acidic nic solid substance is aluminosilicates.
Preferably, the acidic ion exchange resin is selected from the group consisting of copolymers of styrene and divinylbenzene and of perfluorinated branched or linear hylenes, these polymers being functionalized with SO3H groups; more preferably, the acidic ion exchange resin is ed from the group consisting of copolymers of styrene and divinylbenzene containing more than 5% of divinylbenzene, preferably being macroreticular, and ofperfluorinated polyethylenes, these polymers being functionalized with SOgH groups. ably, the inorganic acid, with which the carbon was treated, is selected from the group consisting of HCl, H2804 and HNO3.
Preferably, the catalyst (N-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, HCl, HBr, H2804, W0 20131011156 H3PO4, BC13, BF30Et2, MgClg, MgBrg, AlCl3, ZnClg, Cu(BF4)2, osilicates, acidic ion exchange , carbon treated with HCl, H2804 or HNO3,and mixtures thereof; more preferably, the catalyst (N-cat) is selected from the group consisting of acetic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, HCl, H2804, BF30Et2, Cu(BF4)2, aluminosilicates, acidic ion ge resins, and mixtures thereof.
Preferably, reaction (N-reac) is done in a solvent (N-solv); solvent (N-solv) is selected from the group consisting of water, tert—butanol, isopropanol, itrile, propionitrile, THF, methyl-THF, NMP, dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, chloroform, toluene, benzene, chlorobenzene, hexane, cyclohexane, ethyl acetate, acetic acid, formic acid, trifluoroacetic acid and mixtures thereof; preferably from water, acetonitrile, propionitrile, THF, 2-methy1-THF, 1,2—dimethoxyethane, dichloromethane, 1,2-dichloroethane, chloroform, toluene, cyclohexane, ethyl acetate, acetic acid, formic acid and mixtures thereof; more preferably from water, itrile, propionitrile, THF, yl-THF, 1,2- dimethoxyethane, dichloromethane, 1,2—dichloroethane, toluene, ethyl acetate and es thereof; even more preferably from acetonitrile, THF, 2-methyl-THF, dichloromethane, toluene, ethyl e and mixtures thereof.
The catalyst (N-cat) can be used in a pure form or as hydrate.
The catalyst (N-cat) can be used as a solution in solvent v).
Preferably, the molar ratio between catalyst (N-cat) and compound of formula (XXII) is from 1:1000 to 10:1, more preferably from 1:100 to 5:1, even more preferably from 1:20 to 1:1, ally from 1:10 to 1:2.
Preferably, the reaction temperature of on (N—reac) is from —20 to 200 0C, more preferably from 0 to 150 °C, even more preferably from 10 to 100 °C.
The reaction (N-reac) can be done in a system, that is closed or open to the atmosphere.
In a closed system, the pressure depends mainly on the boiling point of a solvent (N-solv) and on the reaction temperature of reaction (N-reac).
Preferably, the reaction (N-reac) is done at a pressure of from 0.0] bar to 20 bar, more preferably of from 0.1 to 10 bar, even more ably of from atmospheric pressure to 5 bar.
More preferably, the reaction (N—reac) is done in an open system.
Preferably, the reaction time of reaction (N-reac) is from 30 min to 72 h, more preferably from 1 h to 48 h, even more ably from 2 h to 24 h.
Alternatively, reaction (N-reac) can be done as a continuous gas-phase reaction by passing the evaporated compound of a (XXII) over the catalyst (N-cat). This gas-phase reaction can be done in the presence of an inert gas, the inert gas is preferably ed from the group consisting of nitrogen, a noble gas and carbon e.
After reaction (N-reac), compound of formula (XXI) can be isolated by standard methods such as evaporation of volatile components, extraction, washing, , concentration, filtration, crystallization, distillation, chromatography and any combination thereof, which are known per se to the person skilled in the art.
Preferably, any le components of the reaction mixture or added or generated during work up can be removed by evaporation under reduced pressure.
Preferably, the reaction mixture resulting from reaction (N-reac) or any aqueous phase during the work up after reaction (N—reac) can be ted with a solvent (M-extract), solvent ract) is preferably selected from the group consisting of water, toluene, benzene, xylene, chlorobenzene, romethane, chloroform, acetic acid C1_g alkyl ester and combinations thereof; the acetic acid CH; alkyl ester is preferably an acetic acid C1_4 alkyl ester, more preferably selected from the group consisting of ethyl acetate, isopropyl acetate and butyl acetate; preferably solvent ract) is selected from the group consisting of toluene, romethane, ethyl acetate, isopropyl acetate and mixtures thereof.
WO 11156 Preferably, any washing of any organic phase after reaction (N-reac) can be done with water, with a base ify), with an aqueous solution of a base (M-basify), with an aqueous solution of an acid d) or with brine. ably base (M-basify) is selected from the group consisting ofNaHCOg, N32C03, NaOH and mixtures thereof.
Preferably, base (M—basify) 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, acid (M—acid) is selected from the group consisting of oxalic acid, citric acid, maleic acid, fumaric acid, tartaric acid, NH4Cl, HCl, HBr, H2804, H3PO4 and mixtures thereof.
Any extraction or washing can be followed by filtration and concentration of the extract or of the washed mixture.
In another preferred embodiment, compound of formula (XXI) is purified after reaction (N- reac) by chromatography.
Any organic phase can be dried, ably over MgSO4 or NaZSO4.
Any concentration is preferably done by distillation, preferably under reduced pressure.
Compound of formula (XXI) can be obtained in step (N) as the aldehyde as depicted in formula (XXI), but also in form of its hydrate or hemiacetal. The hemiacetal of compound of formula (XXI), which can result as product from step (N), can be the product of an addition on between the aldehyde as depicted in formula (XXI) and an alcohol selected from the group consisting of utanol and isopropanol, or between the aldehyde as depicted in formula (XXI) and any alcohol which is used during the isolation after reaction (N-reac).
Therefore formula (XXI) for the purpose of this invention encompasses the aldehyde, hydrate and the hemiacetal.
When compound of formula (XXI) is obtained from reaction (N-reac) in form of its e or of a hemiacetal, the hydrate or the hemiacetal can be ted into the aldehyde by standard reactions known to the person skilled in the art.
WO 11156 Preferably, compound of formula (XXII) is prepared in a step (0) or in two steps, the two steps are step (01) and step (02); step (0) comprises a reaction c); reaction (O-reac) is a reaction of nd of formula (XXIII), with a reagent (O-reag); CH3 CH3 reagent (O-reag) is selected from the group consisting of tic acid, trifluoroperacetic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid, dimethyldioxirane, utylhydroperoxide, dibenzoyl peroxide, cumenehydroperoxide, oxygen, air, sodium hypochlorite, KHSOs, Na202, aqueous H202, H202 ved in acetic acid, H202 dissolved in trifluoroacetic acid, and mixtures thereof; step (01) comprises a reaction (Ol-reac); reaction (Ol—reac) is a reaction of compound of formula (XXIII) with water and with a compound (01-comp); compound (Ol-comp) is selected from the group consisting of bromine, N-bromosuccinimide, chlorine, rosuccinimide, iodine, N—iodosuccinimide, IBr, BrCl, and mixtures thereof; step (02) comprises a reaction (OZ-reac); reaction (02—reac) is a reaction of the reaction product from reaction (Ol-reac) with a base (OZ-base); base se) is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide and e thereof.
Preferably, reagent (0-reag) is selected from the group consisting of peracetic acid, tertbutylhydroperoxide , oxygen, air, sodium hypochlorite, aqueous H202, H202 dissolved in acetic acid, H202 dissolved in trifluoroacetic acid, and mixtures thereof; more preferably, reagent (0-reag) is aqueous H202.
Preferably, on (O-reac) is done in a solvent (O-solv); solvent v) is selected from the group consisting of water, aqueous solutions of NaHC03, N32C03, (NH4)HC03, (NH4)2C03, KHC03 or K2C03, benzene, toluene, NMP, dioxane, acetone, ethyl acetate, methylethylketone, tert-butanol, acetonitrile, chloroform, dichloromethane and mixtures thereof; ably from water, aqueous solutions ofNaHCOg, N32C03, KHC03 or K2C03, toluene, e, acetone, ethyl acetate, methylethylketone, tert—butanol, acetonitrile, dichloromethane and mixtures thereof.
Reaction (O-reac) can be done in the presence of a catalyst (O-cat); catalyst (O—cat) is selected from the group consisting of trifluoroacetic acid, trifluoroacetone, Mn(salen) complex, aldehydes, N—methylmorpholine N-oxide, 2,2,6,6-tetramethylpiperidine l-oxyl and mixtures thereof; aldehydes are preferably isobutyraldehyde or benzaldehyde.
Reaction (O-reac) can be done in the presence of a buffer f); preferably, buffer (O-buff) is an aqueous buffer and is selected from the group consisting of K2C03 / EDTA-Naz buffer, phosphate buffer and other buffers known by the skilled ; more preferably, buffer (O-buff) is an K2C03 / EDTA-Naz buffer.
Preferably, the reaction temperature of reaction (O—reac) is from -20 to 100 CC, more ably from -10 to 80 °C, even more preferably from 0 to 50 OC.
The reaction (O-reac) can be done in a system, that is closed or open to the atmosphere.
In a closed system, the pressure depends on the boiling point of a t (O-solv) and on the reaction temperature of reaction (O-reac).
Preferably, the reaction (N—reac) is done at a pressure of from 0.0] bar to 20 bar, more preferably of from 0.1 to 10 bar, even more preferably of from atmospheric re to 5 bar.
More ably the reaction (O-reac) is done in an open .
Preferably, the reaction time of reaction (O-reac) is from 30 min to 72 h, more preferably from 1 h to 48 h, even more preferably from 2 h to 24 h.
After the reaction (O—reac), the compound of formula (XXII) can be isolated by standard methods such as evaporation of volatile ents, tion, washing, drying, concentration, crystallization, lation, tography and any combination thereof.
Preferably, reaction ac) and reaction (OZ-reac) are conducted in t (O—solv), with solvent (O-solv) as defined above, also with all its preferred embodiments.
Preferably, the reaction temperatures of reaction (Ol-reac) and of reaction (O2-reac) are identical or different and ndently from each other from -20 to 100 °C, more preferably from —10 to 80 °C, even more preferably from 0 to 50 oC.
Reaction (Ol-reac) and reaction (O2-reac) can independently from each other be done in systems, that are closed or open to the here.
In a closed system, the pressure depends on the boiling point of a solvent (O-solv) and on the reaction temperature of reaction (Ol-reac) and reaction (O-reac) respectively.
Preferably, reaction (Ol-reac) and reaction (O2-reac) are independently from each other done at pressures of from 0.01 bar to 20 bar, more preferably of from 0.1 to 10 bar, even more preferably of from atmospheric pressure to 5 bar.
More preferably, reaction (Ol-reac) and reaction (O2-reac) are done in a open system.
Preferably, the reaction times of reaction (Ol-reac) and of reaction (O2-reac) are independently from each other from 30 min to 72 h, more preferably from 1 h to 48 h, even more preferably from 2 h to 24 h.
The reaction product of reaction (Ol-reac) and the compound of formula (XXII) from reaction (O2-reac) can be isolated by standard methods such as evaporation of volatile components, extraction, washing, drying, concentration, filtration, crystallization, distillation, chromatography and any combination thereof.
Reaction (Ol-reac) and reaction (O2-reac) can be done consecutively t isolation of the on product of reaction (Ol-reac), they can be done in one pot.
Preferably, compound of formula (XXII) is not isolated, step (N) is done directly after step (0) or step (02) respectively in one pot. For this, catalyst (N—cat) is simply added to the reaction mixture resulting from reaction (O-reac) or from reaction (OZ-reac) respectively.
Preferably, compound of formula (XXIII) is prepared in a step (P); step (P) ses a reaction (P-reac); in reaction (P-reac) the compound of formula (XXIV) is exposed to a temperature (P-temp); CH3 CH3 (XXIV) temperature (P-temp) is from 0 to 300 °C.
Preferably, temperature (P-temp) is from 5 to 200 CC, more preferably from 100 to 150 °C.
Reaction (P-reac) can be done in a solvent (P-solv); solvent v) is selected from the group consisting of benzene, toluene, xylene, hexane, heptane, 1,2-dichloroethane, NMP, dichloromethane, chloroform and es thereof; preferably from benzene, toluene, xylene, dichloromethane and mixtures thereof.
Preferably, reaction (P-reac) is done in the presence of a st (P-cat); catalyst (P-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, enesulfonic acid, camphorsulfonic acid, HCl, HBr, H2804, KOH, NaOH, KHSO4, HNO3, H3PO4, HClO4, BClg, BBI'3, BF30Et2, BngMez, BFgTHF, MgClz, MgBrz, MgIz, AlClg, Al(O-C1_4 alkyl)3, 12, A1203, SnCl4, TiC14, 1_4 alkyl)4, ZrCl4, B1203, B1Cl3, ZIIClz, PbClz, FGCl3, )3, Yb(Cl)3, GaClg, AlBI'g, Ce(OTf)3, LiCl, acidic insoluble inorganic solid, acidic ion ge , carbon treated with an inorganic acid, and es f; preferably from methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, H2804, KHSO4, H3PO4, acidic insoluble inorganic solid, acidic ion exchange resins, carbon treated with an inorganic acid, and mixtures thereof.
Preferably, the acidic 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 HCl, H2804 and HNOg. ably, the acidic ion exchange resin is selected from the group consisting of copolymers of styrene and divinylbenzene and of perfluorinated ed or linear polyethylenes, these polymers being functionalized with SO3H groups; more preferably, the acidic ion exchange resin is selected from the group consisting of copolymers of styrene and divinylbenzene containing more than 5% of divinylbenzene, preferably being macroreticular, and of perfluorinated polyethylenes, these polymers being nalized with SO3H .
When reaction (P-reac) is done in the presence of a catalyst ), ature (P-temp) is preferably from 0 to 200 CC, more preferably from 10 to 150 CC, even more preferably from to 100 °C. on (P-reac) can be done in gas phase by passing evaporated compound of formula (XXIV) through a heated tube, the heated tube can be charged with a catalyst (P-cat).
After reaction c), 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, compound of formula (XXIV) is prepared in three steps, the three steps are a step (Q1), a step (Q2) and a step (Q3); step (Q1) comprises a reaction (Ql—reac) by a on of compound of formula (XXV) with a reagent (Q 1—reag); (XXV) Q is Br, C1, or I; reagent (Ql-reag) is selected from the group consisting of lithium, magnesium, um, zinc, calcium, isopropylmagnesium chloride, pylmagnesium bromide, butyllithium, sec-butyllithium and mixtures thereof; step (Q2) ses a reaction (Q2-reac); reaction (Q2—reac) is a reaction of the reaction product of on (Ql-reac) With e; in step (Q3) comprises a reaction (Q3-reac); reaction (Q3-reac) is a reaction of the reaction product of reaction ac) with a reagent (Q3-reag); reagent (Q3-reag) is selected from the group consisting of water, methanol, ethanol, oxalic acid, citric acid, NH4Cl, HCl, HBr, HN03, H2804, H3PO4, acetic acid, propionic acid, formic acid and mixtures thereof.
Preferably, Q is Br.
Preferably, reagent (Ql-reag) is selected from the group consisting of lithium, magnesium, um, isopropylmagnesium chloride, isopropylmagnesium e and mixtures thereof.
Reaction (Ql-reac) can be catalyzed with a catalyst (Ql-cat). st (Ql—cat) is selected from the group consisting of iodine, 1,2—dibromoethane, TiCl4, A1C13, PbClZ, B1C13, LiCl and mixtures thereof.
Preferably, reagent (Q3-reag) is water or aqueous NH4Cl.
Preferably, reaction (Ql-reac) is performed in a solvent (Ql-solV).
Preferably, reaction (Q2-reac) is performed in a solvent (Q2-solV).
WO 11156 Preferably, reaction ac) is performed in a solvent (Q3 —solv).
Preferably, solvent (Ql-solv), solvent (Q2-solv) and solvent (Q3-solv) are identical or different and independently from each other ed from THF, methyl-THF, NMP, diethylether, methyl-tert-butylether, methoxycyclopentane, diisopropylether, 1,2- dimethoxyethane, tri C1_4 alkyl amine and mixtures thereof; more preferably from THF, 2-methyl-THF, l,2-dimethoxyethane, methyl—tert-butylether, methoxycyclopentane, tri C1_4 alkyl amine and mixtures thereof; even more preferably from the group consisting of THF, 2-methyl-THF, 1,2- dimethoxyethane, triethylamine, and mixtures thereof.
Preferably the solvent (Ql—solv), solvent (Q2-solv) and solvent (Q3-solv) are identical.
The reaction atures of reaction (Ql—reac), of reaction (Q2-reac) and of on (Q3- reac) are cal or different and idependently from each other preferably from -100 to 150 0C, more preferably from -60 to 100 oC, and even more preferably from -20 to 80 oC.
Reaction (Ql-reac), on (Q2-reac) and reaction (Q3-reac) can be done at a constant temperature, or the temperature may be modified during the ss of the reactions. For instance, the reactions can run for a certain time at first temperature, and then for a subsequent time at a second temperature different from the first temperature. Alternatively, the temperature may be modified continuously during the reaction.
The reaction times of reaction (Ql-reac), of reaction (Q2-reac) and of reaction (Q3—reac) are identical or different and idependently from each other preferably from 30 min to 48 h, more preferably from 1 to 24 h, even more preferably from 2 to 12 h.
The amounts of solvent (Ql-solv), of t (Q2—solv) and of solvent (Q3-solv) are are identical or different and idependently from each other preferably from 2 to 40 fold, more preferably from 3 to 10 fold, even more preferably from 5 to 7 fold, of the weight of compound of formula (XXV), of the weight of the on product of reaction (Ql—reac) and of the weight of the reaction product of reaction (Q2-reac) respectively. 2012/072797 Preferably, 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 reagent (Ql-reag) are used, the mol equivalents being based on the mol of compound of formula (XXV). ably, from 1.0 to 10 mol equivalents, more ably from 1.1 to 5 mol equivalents, even more preferably from 1.1 to 3 mol equivalents of e are used, the mol equivalents being based on the mol of compound of formula (XXV).
Preferably, 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 reagent (Q3 —reag) are used, the mol equivalents being based on the mol of compound of formula (XXV) or of the mol of the reaction product of reaction (Q2—reac).
Preferably, reaction ac), reaction (Q2-reac) and reaction (Q3-reac) are done at atmospheric pressure.
Preferably, reaction (Ql-reac), reaction (Q2—reac) and reaction ac) are done under inert atmosphere. Preferably, the inert atmosphere is achieved by the use if an inert gas selected from the group consisting of argon, another noble gas, lower boiling alkane, nitrogen and mixtures thereof.
The lower boiling alkane is ably a C1_3 alkane, i.e. methane, ethane or propane.
After reaction (Ql-reac), reaction (Q2-reac) and reaction (Q3-reac), the reaction product of reaction (Ql—reac), the reaction product of reaction (Q2-reac) and compound of formula (XXIV) respectively can be isolated by standard methods such as evaporation of volatile components, tion, washing, drying, tration, crystallization, distillation, chromatography and any combination thereof.
Preferably, the reaction product of reaction ac) and the reaction product of reaction (Q2-reac) are not isolated.
Preferably, reaction ac), reaction ac) and reaction (Q3-reac) are done consecutively; preferably, reaction (Ql-reac), reaction (Q2—reac) and reaction (Q3—reac) are done in one pot.
In another preferred embodiment, reaction (Ql-reac) and reaction (Q2-reac) can be done in one pot by adding t (Ql-reag) to a mixture of compound of formula (XXV) and acetone in a solvent (Ql-solv); reaction (Q3-reac) is done thereafter, preferably in the same pot.
Compound of formula (XXIV) is preferably isolated using conventional methods, such as evaporation of volatile ents, hydrolysis and optional acidification of the higher- boiling residue, extraction, and distillation.
Any aqueous phase can be extracted, preferably the extraction is done with a solvent (Q- extract). Solvent (Q—extract) is benzene, e, ethyl acetate, or pyl acetate.
Any organic phase can be dried, preferably with magnesium sulphate.
Any concentration is preferably done by distillation, preferably under reduced pressure.
The compound of formula (XXIV) can be purified, preferably by crystallization or distillation under d pressure.
Compounds of formula (XXI) and (XXII) are chiral nds, and the ae comprise any enantiomer as well as any mixture of enantiomers of the compounds of formula (XXI), or of formula (XXII) respectively.
Compounds of formula (XXV) are known compounds and can be prepared according to known methods.
The progress of any of the ons reaction (N-reac), reaction (O-reac), reaction (Ol-reac), on (O2—reac), reaction (P-reac), reaction (Ql-reac), reaction (Q2-reac) and reaction (Q3- reac) can be monitored by standard techniques, such as nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), High performance Liquid Chromatography (HPLC), Liquid Chromatography Mass Spectrometry , or Thin Layer Chromatography (TLC), and p of the on mixture can start, when the conversion of the starting material exceeds 95%, or when no more ng material can be detected. The time required for this to occur will depend on the precise reaction temperature and the precise concentrations of all reagents, and may vary from batch to batch.
In general, any organic phase can be dried, preferably over MgSO4 or NaZSO4, if not stated otherwise.
Further subject of the invention is the use of compound of formula (XXI) as a fragrance, preferably in perfumes or house hold products. r t of the invention is the use of compound of a (XXI) for the preparation of midine.
Medetomidine is compound of formula (XX) and is an alpha2 adrenergic agonist, which is currently being used as veterinary sedative and analgesic and is evaluated as anesthetic.
WOZOl l/O70069A discloses a process for the preparation of medetomidine, in which the imidazole ring is built up during a multi-step process ng from commercially affordable methy1 benzoic acid.
Compound of formula (XX) is preferably prepared from compound of formula (XXI) by a method, that comprises a reaction (Ml); reaction (M1) is a reaction between a compound of formula (XXI), an isocyanide and a compound acting as nitrogen source; the isocyanide is preferably a reagent (M), reagent (M) is ed from the group consisting of p-toluenesulfonylmethyl isocyanide, trifluoromethanesulfonylmethyl nide, methanesulfonylmethyl isocyanide, benzenesulfonylmethyl isocyanide, 4- acetamidobenzenesulfonylmethyl isocyanide and mixtures thereof; the compound acting as a en source is preferably a reagent (M-A), reagent (M-A) is selected from the group consisting of ammonia, sulfamic acid, p-toluenesulfonamide, benzenesulfonamide, 4—acetamidobenzenesulfonamide, amine, formamide, urea, urotropine, ethyl carbamate, acetamide and mixtures thereof; preferably the reaction (M1) is done in a solvent (M), preferably solvent (M) is selected from the group ting ofN,N—dimethylformamide, C1_6 alkanol, formamide, 1,2- dimethoxyethane, NMP, toluene, acetonitrile, propionitrile, ethyl carbamate, N,N- dimethylacetamide, water, acetamide and mixtures thereof.
Any sequence of the reaction of reagent (M) and ofreagent (M-A) with the compound of formula (XXI) in reaction (Ml) can be used: compound of formula (XXI) can first be reacted with reagent (M) and then t (M-A) added; compound of formula (XXI) can first be first d with reagent (M-A) and then reagent (M) added; or compound of a (XXI) can simultaneously be reacted with reagent (M) and with reagent (M-A), this embodiment is ably suited for the case that reagent (M-A) and solvent (M) are identical and are formamide, ethyl ate or acetamide; preferably formamide.
Further subject of the invention is the use of compound of formula (XXII) for the preparation of nd of formula (XXI). r subject of the invention is the use of compound of formula (XXIII) for the preparation of compound of formula (XXII).
Further subject of the invention is the use of compound of formula (XXIV) for the preparation of compound of formula (XXIII).
Further subject of the invention is the use of compound of formula (XXV) for the preparation of compound of formula .
Compared to prior art, the method of the present invention offers several ages: Importantly, the whole carbon framework of compound of formula (XXI) is built in few chemical steps, using cheap reagents only. No protecting groups are needed and the overall amount of material used is therefore reduced, the batch size based on molar amounts is increased.
In particular no trityl or acetal protection groups are used and no protection of the imidazoles is necessary. Thereby the number and amount of reagents needed is reduced, and no protecting or deprotecting steps being needed the waste is reduced, contrary to when for e a trityl or acetal protecting group is used. The method has good yields. nd of formula (XXI) can be easily purified and obtained in a form of high odorous of fragrance purity or high fragrance purity. This is particularly important for products ed for use as fragrance.
The product is distinguished by a very special fragrance sought after in the fragrance industry.
Examples Methods 1H and 13C NMR spectra were recorded on a Varian VNMRS 500 (500 MHz for 1H and 125 MHz for 13C) instruments in CDC13. Chemical shifts are expressed in parts per million referred to TMS and coupling constants (J) in hertz.
EI means Electron ionization mass a (70 eV), they were obtained on an AMD-604 spectrometer.
ESI means Electron spray ionization mass spectra THF was led from sodium/benzophenone ketyl prior to use; the obtained ous THF is called "dry THF" in the following text. e 1: 2-(2,3-Dimethylphenyl)propanol, compound of formula (XXIV), prepared via an organomagnesium intermediate 1-Bromo-2,3—dimethy1benzene (compound of formula (XXV), wherein Q is Br; 8.43 g, 45.6 mmol) was dissolved in dry THF (15 mL) and placed in dropping funnel. Separately, Mg 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 r, and a reflux condenser. The l-bromo-2,3- dimethylbenzene solution (1.0 mL) was added Via a ng flannel and the reaction was initiated by the addition of 1,2-dibromoethane (3 drops), and then the rest of the 1—bromo—2,3- dimethylbenzene solution was added. The content of the dropping fiinnel was added at such a rate to maintain slight reflux. After completion of the addition, the mixture was refluxed for 1 h and then cooled to 0 0C. A solution of dry acetone (4.2 mL, 58 mmol) in dry THF (15 mL) was added dropwise and the e was stirred at a temperature between 0 and 20 °C for 3 h.
The mixture was poured into saturated NH4C1 aqueous solution (100 mL) ted with hexane (5 times with 50 mL each), dried with Na2SO4 and ated under reduced pressure.
The main product was isolated via silica gel column chromatography with hexanezethyl acetate as eluent (V/V 15:1 to 10:1 gradient), to yield 3.50 g (47%) of the title compound. 1H NMR: 1.68 (s, 6H), 1.70 (s, 1H), 2.29 (s, 3H), 2.50 (s, 3H), 7.03 to 7.10 (m, 2H), 7.29 to 7.32 (m, 1H). 13C NMR: 17.72, 21.08, 31.24 145.47. , 73.71, 123.11, 125.02, 129.02, 135.09, 138.69, MS (E1): 164 (12), 149 (35), 146 (100), 131, 116, 105, 91.
W0 2013l011156 Example 2: 2-(2,3-Dimethylphenyl)propanol, nd of formula (XXIV), prepared via an organolithium intermediate 1-Brom0-2,3-dimethy1benzene (compound of formula (XXV), wherein Q is Br; 4.25 g, 23.0 mmol) was ved in dry THF (20 mL) in a flask equipped with a thermometer and a stirring bar. The mixture was cooled to —78 CC. llithium (1.6 M in hexane, 17.5 mL, 28.0 mmol) was added se via a syringe, keeping the ature below —70 0C. When the addition was complete, the mixture was ined at —78 CC and stirred at this temperature for 1 h. A solution of dry acetone (1.85 mL, 25.2 mmol) in dry THF (5 mL) was then added at —78 °C. The mixture was stirred at —78 °C for 30 min, the cooling bath was removed, and the mixture was allowed to reach room temperature. The mixture was poured into saturated aqueous NH4Cl solution (100 mL), extracted with hexane (4 times with 50 mL each), dried over Na2SO4, and purified by via silica gel column chromatography using :ethyl acetate as eluent (v/v 32:1) to give 3.45 g (91%) of the title compound.
The measured NMR spectra were identical to those recorded in example 1.
Example 3: 1,2-Dimethyl(2-propenyl)benzene, compound of formula (XXIII) 2-(2,3-Dimethy1pheny1)propanol, compound of formula (XXIV), prepared according to either example 1 or example 2, (1.10 g, 6.70 mmol), was ved in benzene (20 mL), and p-toluenesulfonic acid monohydrate (35 mg, 0.18 mmol) was added. The mixture was stirred at room temperature for 3 h. Silica gel (200 mg) was added, and ng was continued for ca. 16 hours, and then the reaction mixture was refluxed for 30 min. After cooling to room temperature, the mixture was filtered, washed with aqueous K2C03 solution, conventionally dried, and trated under reduced pressure, to yield 0.90 g (92%) of the title compound. 1H NMR: 2.02 (m, 3H), 2.21 (s, 3H), 2.28 (s, 3H), 4.82 (m, 1H), 5.17 (m, 1H), 6.97 (m, 1H), 7.05 (m, 2H).
Example 4: 2-(2,3-Dimethylphenyl)methyloxirane, compound of formula (XXII) A buffer was prepared by dissolving K2C03 (20.7 g) and EDTA-Naz (11.5 mg) in water (100 mL). 1,2-Dimethyl—3-(2-pr0penyl)benzene, compound of formula ), prepared according to example 3 (0.90 g, 6.16 mmol), was dissolved in a mixture of dichloromethane and acetonitrile (v/V 1:1, 60 mL), and the buffer prepared as described above (9.3 mL) was added. To the resulting mixture, first 1,1,1-trifluoroacetone (60 uL) and then hydrogen peroxide (30% in water, 6.2 mL, 60.7 mmol) were added and the mixture was stirred at room 2012/072797 temperature for 2 h. The on mixture was diluted 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 Na2SO4, concentrated under reduced re, and the residue was purified by via silica gel column chromatography using hexane:ethyl acetate as eluent (v/v 32: 1) to give 851 mg (85%) of the title compound. 1H NMR: 1.59 (s, 3H), 2.28 (s, 3H), 2.31 (s, 3H), 2.83 (br (1, J = 5.4, 1H), 2.98 (d, J = 5.4 Hz, 1H), 7.08 (m, 2H), 7.21 (m, 1H).
MS (E1): 162, 147, 133, 117 (100).
Example 5: 2-(2,3-Dimethylphenyl)propanal, compound of formula (XXI) 2-(2,3-Dimethylphenyl)methyloxirane, nd of formula (XXII), prepared according to example 4 (0.84 g, 5.18 mmol), was dissolved in dry dichloromethane (50 mL) and powdered )2 hydrate (318 mg) was added at room temperature. After 2 h at room temperature, the mixture was washed with water, dried over Na2SO4 and concentrated under reduced pressure to yield 0.84 g (100%) of the title product. 1H NMR: 1.40 (d, J = 7.1 Hz, 3H), 2.25 (s, 3H), 2.32 (s, 3H), 3.89 (qd, J = 7.1, 1.0 Hz, 1H), 6.89 to 6.92 (m, 1H), 7.12 (m, 2H), 9.67 (d, J =1.0 Hz, 1H). e 6: Medetomidine, nd of formula (XX) 2-(2,3-Dimethylphenyl)propanal, compound of formula (XXI), prepared according to example 5 (2.43 g, 15.0 mmol) and p-toluenesulfonylmethyl nide (2.73 g, 14.0 mmol) were mixed with EtOH (30 mL). To the stirred suspension powdered NaCN (73 mg, 1.5 mmol) was added. The mixture was stirred for 1 h at room temperature, and then evaporated under reduced pressure to dryness. The residue was placed in an ampoule and treated with MeOH saturated with NH3 (50 mL). The ampoule was heated to 110 CC 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% (w/w) aqueous Na2C03 (200 mL) and then with water (200 mL), conventionally dried, evaporated under reduced pressure and purified by via silica gel column chromatography using romethane : methanol as eluent (v/v 15:1 to 10:1 gradient), to yield 3.0 g (44%) of medetomidine as a sticky oil. Medetomidine was crystallized from toluene:cyclohexane, and then recrystallized from aqueous ethanol. 1H NMR: 1.56 (d, J = 7.2 Hz, 3H), 2.18 (s, 3H), 2.25 (s, 3H), 4.35 (q, J = 7.2 Hz, 1H), 6.66 (s, 1H), 6.93 (dd, J = 6.6, 2.2 Hz, 1H), 6.99 to 7.05 (m, 2H), 7.30 (d, J = 1.1 Hz, 1H), 9.84 (broad s, 1H). 13C NMR: 14.65, 20.72, 20.88, 14.12, , 124.62, 125.53, 127.91, 134.05, 134.60, 136.76,141.11,143.23.
MS (E81): 201 [M+H]+

Claims (9)

The claims defining the invention are as follows:
1. A method for ation of a compound of formula (XXI): the method comprises a step (N); step (N) comprises a reaction (N-reac); reaction (N-reac) is a reaction of compound of formula (XXII) with a catalyst (N-cat): catalyst (N-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic 15 acid, HCl, HBr, H2SO4, HNO3, H3PO4, HClO4, BCl3, BBr3, BF3OEt2, BF3SMe2, BF3THF, MgCl2, MgBr2, MgI2, AlCl3, Al(O-C1-4 3, SnCl4, TiCl4, Ti(O-C1-4 alkyl)4, ZrCl4, Bi2O3, BiCl3, ZnCl2, PbCl2, FeCl3, ScCl3, NiCl2, Yb(OTf)3, Yb(Cl)3, GaCl3, AlBr3, Ce(OTf)3, LiCl, Cu(BF4)2, Cu(OTf)2, NiBr2(PPh3)2, NiBr2, NiCl2, Pd(OAc)2, PdCl2, PtCl2, InCl3, acidic inorganic solid nce, acidic ion ge resin, carbon treated with inorganic acid and 20 mixtures thereof.
2. Method according to claim 1, wherein the catalyst (N-cat) is selected from the group ting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, ptoluenesulfonic acid, HCl, HBr, H2SO4, H3PO4, BCl3, BF3OEt2, MgCl2, MgBr2, AlCl3, ZnCl2, 25 Cu(BF4)2, aluminosilicates, acidic ion exchange resins, carbon d with HCl, H2SO4 or HNO3, and mixtures thereof.
3. Method according to claim 1 or claim 2, wherein reaction (N-reac) is done in a solvent (N-solv); solvent (N-solv) is selected from the group consisting of water, tert-butanol, isopropanol, acetonitrile, propionitrile, THF, methyl-THF, NMP, dioxane, 1,2-dimethoxyethane, 5 dichloromethane, 1,2-dichloroethane, chloroform, toluene, benzene, benzene, hexane, cyclohexane, ethyl acetate, acetic acid, formic acid, trifluoroacetic acid and mixtures thereof.
4. Method according to any one of claims 1 to 3, n compound of a (XXII) is prepared in a step (O) or in two steps, the two steps are step (O1) and step (O2); 10 step (O) comprises a on (O-reac); reaction (O-reac) is a reaction of nd of formula ), with a reagent (O-reag); 15 reagent g) is selected from the group consisting of peracetic acid, trifluoroperacetic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid, dimethyldioxirane, tert-butylhydroperoxide, dibenzoyl peroxide, cumenehydroperoxide, oxygen, air, sodium hypochlorite, KHSO5, Na2O2, aqueous H2O2, H2O2 dissolved in acetic acid, H2O2 dissolved in trifluoroacetic acid, and mixtures thereof; step (O1) comprises a reaction (O1-reac); on (O1-reac) is a reaction of compound of formula (XXIII) with water and with a compound (O1-comp); nd (O1-comp) is selected from the group consisting of bromine, N-bromosuccinimide, 25 chlorine, N-chlorosuccinimide, , N-iodosuccinimide, IBr, BrCl, and mixtures thereof; step (O2) comprises a reaction (O2-reac); reaction (O2-reac) is a reaction of the reaction product from reaction (O1-reac) with a base 30 (O2-base); base (O2-base) is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium ide and mixture thereof.
5. Method according to claim 4, wherein reagent (O-reag) is selected from the group 5 consisting of peracetic acid, tert-butylhydroperoxide, oxygen, air, sodium hypochlorite, aqueous H2O2, H2O2 dissolved in acetic acid, H2O2 ved in trifluoroacetic acid, and mixtures thereof.
6. Method according to claim 4 or claim 5, wherein compound of formula (XXIII) is 10 prepared in a step (P); step (P) comprises a on (P-reac); in on (P-reac) the compound of formula (XXIV) is exposed to a temperature (P-temp); temperature (P-temp) is from 0 to 300 °C.
7. Method according to claim 6, wherein compound of formula (XXIV) is prepared in three steps, the three steps are a step (Q1), a step (Q2) and a step (Q3); step (Q1) comprises a reaction ac) by a reaction of compound of formula (XXV) with a reagent (Q1-reag); Q is Br, Cl, or I; reagent ag) is selected from the group consisting of lithium, magnesium, aluminum, zinc, calcium, isopropylmagnesium chloride, isopropylmagnesium bromide, butyllithium, sec-butyllithium and mixtures thereof; 5 step (Q2) comprises a reaction (Q2-reac); reaction (Q2-reac) is a reaction of the reaction product of reaction (Q1-reac) with e; in step (Q3) comprises a reaction (Q3-reac); reaction ac) is a reaction of the reaction product of on (Q2-reac) with a reagent 10 ag); reagent (Q3-reag) is selected from the group consisting of water, methanol, ethanol, oxalic acid, citric acid, NH4Cl, HCl, HBr, HNO3, H2SO4, H3PO4, acetic acid, propionic acid, formic acid and es thereof.
8. Use of compound of formula (XXI) as a fragrance, with the compound of formula (XXI) as defined in claim 1.
9. Use of compound of formula (XXI) for the preparation of medetomidine, with the 20 compound of formula (XXI) as defined in claim 1.
NZ700641A 2012-05-08 2012-11-15 Method for preparation of 2-(2,3-dimethylphenyl)-1-propanal NZ700641B2 (en)

Applications Claiming Priority (11)

Application Number Priority Date Filing Date Title
US201261644198P 2012-05-08 2012-05-08
EP12167135 2012-05-08
EP12167135.8 2012-05-08
US61/644,198 2012-05-08
EP12187354 2012-10-05
EP12187354.1 2012-10-05
PCT/EP2012/070873 WO2012172120A2 (en) 2012-05-08 2012-10-22 2-(2,3-dimethylphenyl)-1-propanal and its use as perfume
EPPCT/EP2012/070873 2012-10-22
EP12192621.6 2012-11-14
EP12192621 2012-11-14
PCT/EP2012/072797 WO2013011156A2 (en) 2012-05-08 2012-11-15 Method for preparation of 2-(2,3-dimethylphenyl)-1-propanal

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NZ700641A NZ700641A (en) 2016-02-26
NZ700641B2 true NZ700641B2 (en) 2016-05-27

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