METHOD FOR PREPARATION OF 2-(2,3-DIMETHYLPHENYL)-l-PROPANAL
The invention discloses a method for preparation of 2-(2,3-dimethylphenyl)-l-propanal from
1-bromo 2,3-dimethylbenzene and aceton, its use in perfumes 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, beta-unsaturated aromatic aldehydes, such as
substituted cinnamic aldehydes, are known 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
preparation of 3-arylpropanals. They have a musky fragrance.
The perfume and household product industry has a constant 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 fragrances 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 provides a new alpha,
beta-unsaturated aromatic aldehyde, which has strong and interesting, aldehydic fragrance,
intensely spicy and sweet, and an improved process for the production thereof.
In the following text,
halogen means F, CI, Br or I, preferably CI, 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 methyl, 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 intended to include cyclo aliphatic, bicyclo aliphatic and
tricycle aliphatic residues;
"alkane" means a linear, branched or cyclic alkane, 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 l,8-diazabicyclo[5.4.0]undec-7-ene;
DABCO 1,4-diazabicyclo[2.2.2]octane;
DIPEA N-ethyl-N,N-diisopropylamine;
DMA N,N-dimethylacetamide;
DMF N,N-dimethylformamide;
EDTA-Na2 ethylene diamine tetraacetic acid disodium;
hexanes mixture of isomeric hexanes;
NMP N-methyl-2-pyrrolidone;
OTf trifluoromethanesulfonate, also known as triflate;
MPS KHSO 5, also known as potassium peroxymonosulfate or potassium
monopersulfate, and marketed as a triple salt with the formula 2 KHSO 5 KHSO 4
K2SO4 under the trade names Caroat® and Oxone®, therefore KHSO 5 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
diamine;
sulfamic acid HO-S0 2-NH2;
TEMPO 2,2,6,6-tetramethylpiperidine 1-oxyl;
THF tetrahydrofuran;
xylene 1,2-dimethylbenzene, 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);
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, H2S0 4, HN0 3, H3P0 4, HC10 4, BC13, BBr3, BF3OEt2,
BF3SMe2, BF3THF, MgCl 2, MgBr 2, Mgl 2, A1C13, Al(0-Ci_ 4 alkyl) 3, SnCl4, TiCl 4,
Ti(0-Ci_ 4 alkyl) 4, ZrCl 4, Bi20 3, BiCl 3, ZnCl 2, PbCl 2, FeCl 3, ScCl3, NiCl 2, Yb(OTf) 3,
Yb(Cl) 3, GaCl 3, AlBr 3, Ce(OTf) 3, LiCl, Cu(BF 4)2, Cu(OTf) 2, NiBr 2(PPh 3)2, NiBr 2, NiCl 2
Pd(OAc) 2, PdCl 2, PtCl 2, InCl 3, acidic inorganic solid substance, acidic ion exchange
resin, carbon treated with inorganic acid and mixtures thereof.
Preferably, the acidic inorganic 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 polyethylenes,
these polymers being functionalized with S0 3H 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 functionalized with S0 3H groups.
Preferably, the inorganic acid, with which the carbon was treated, is selected from the group
consisting of HCl, H2S0 4 and HN0 3.
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, H2S0 4,
H3PO4, BCI3, BF3OEt2, MgCl 2, MgBr 2, A1C13, ZnCl 2, Cu(BF 4)2, aluminosilicates, acidic
ion exchange resins, carbon treated with HC1, H2S0 4 or FfN0 3,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, HC1, H2S0 4, BF3OEt2,
Cu(BF 4)2, aluminosilicates, acidic ion exchange 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,
acetonitrile, 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-methyl-THF, 1,2-dimethoxyethane,
dichloromethane, 1,2-dichloroethane, chloroform, toluene, cyclohexane, ethyl acetate,
acetic acid, formic acid and mixtures thereof;
more preferably from water, acetonitrile, propionitrile, THF, 2-methyl-THF, 1,2-
dimethoxyethane, dichloromethane, 1,2-dichloroethane, toluene, ethyl acetate and
mixtures thereof;
even more preferably from acetonitrile, THF, 2-methyl-THF, dichloromethane, toluene, ethyl
acetate 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 (N-solv).
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,
especially from 1:10 to 1:2.
Preferably, the reaction temperature of reaction (N-reac) is from -20 to 200 °C, 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 0.01 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, 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 preferably 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 formula (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 selected from the group
consisting of nitrogen, a noble gas and carbon dioxide.
After reaction (N-reac), 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 are
known per se to the person skilled in the art.
Preferably, any volatile 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 extracted with a solvent (M-extract),
solvent (M-extract) is preferably selected from the group consisting of water, toluene,
benzene, xylene, chlorobenzene, dichloromethane, chloroform, acetic acid Ci_8 alkyl ester and
combinations thereof;
the acetic acid Ci_8 alkyl ester is preferably an acetic acid Ci_4 alkyl ester, more preferably
selected from the group consisting of ethyl acetate, isopropyl acetate and butyl acetate;
preferably solvent (M-extract) is selected from the group consisting of toluene,
dichloromethane, ethyl acetate, isopropyl acetate and mixtures thereof.
Preferably, any washing of any organic phase after reaction (N-reac) can be done with water,
with a base (M-basify), with an aqueous solution of a base (M-basify), with an aqueous
solution of an acid (M-acid) or with brine.
Preferably base (M-basify) is selected from the group consisting of NaHC0 3, Na2C0 3, 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, NH4C1, HC1, HBr, H2SO4, H3P0 4 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 (Nreac)
by chromatography.
Any organic phase can be dried, preferably over MgS0 4 or Na2S0 4.
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
reaction between the aldehyde as depicted in formula (XXI) and an alcohol selected from the
group consisting of tert-butanol 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 hydrate
or of a hemiacetal, the hydrate or the hemiacetal can be converted into the aldehyde by
standard reactions known to the person skilled in the art.
Preferably, compound of formula (XXII) is prepared in a step (O) or in two steps, the two
steps are step (01) and step (02);
step (O) comprises a reaction (O-reac);
reaction (O-reac) is a reaction of compound of formula (XXIII), with a reagent (O-reag);
(XXIII)
reagent (O-reag) 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, KHS0 ,Na20 2, aqueous H20 2, H20 2 dissolved in acetic acid, H20 2
dissolved in trifluoroacetic acid, and mixtures thereof;
step (01) comprises a reaction (01-reac);
reaction (01-reac) is a reaction of compound of formula (XXIII) with water and with a
compound (01-comp);
compound (01-comp) is selected from the group consisting of bromine, N-bromosuccinimide,
chlorine, N-chlorosuccinimide, iodine, N-iodosuccinimide, IBr, BrCl, and mixtures
thereof;
step (02) comprises a reaction (02-reac);
reaction (02-reac) is a reaction of the reaction product from reaction (01-reac) with a base
(02-base);
base (02-base) is selected from the group consisting of sodium hydroxide, potassium
hydroxide, calcium hydroxide and mixture thereof.
Preferably, reagent (O-reag) is selected from the group consisting of peracetic acid, tertbutylhydroperoxide,
oxygen, air, sodium hypochlorite, aqueous H20 2, H20 2 dissolved in
acetic acid, H20 2 dissolved in trifluoroacetic acid, and mixtures thereof;
more preferably, reagent (O-reag) is aqueous H20 2.
Preferably, reaction (O-reac) is done in a solvent (O-solv);
solvent (O-solv) is selected from the group consisting of water, aqueous solutions of
NaHC0 3, Na2C0 3, (NH4)HC0 3, (NH4)2C0 3, KHC0 3 or K2C0 3, benzene, toluene, NMP,
dioxane, acetone, ethyl acetate, methylethylketone, tert-butanol, acetonitrile, chloroform,
dichloromethane and mixtures thereof;
preferably from water, aqueous solutions of NaHC0 3, Na2C0 3, KHC0 3 or K2C0 3, toluene,
dioxane, 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
1-oxyl and mixtures thereof;
aldehydes are preferably isobutyraldehyde or benzaldehyde.
Reaction (O-reac) can be done in the presence of a buffer (O-buff);
preferably, buffer (O-buff) is an aqueous buffer and is selected from the group consisting of
K2C0 3 / EDTA-Na2 buffer, phosphate buffer and other buffers known by the skilled person;
more preferably, buffer (O-buff) is an K2C0 3 / EDTA-Na2 buffer.
Preferably, the reaction temperature of reaction (O-reac) is from -20 to 100 °C, more
preferably from -10 to 80 °C, even more preferably from 0 to 50 °C.
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 solvent (O-solv) and on the
reaction temperature of reaction (O-reac).
Preferably, the reaction (N-reac) is done at a pressure 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 the reaction (O-reac) is done in an open system.
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 components, extraction, washing, drying,
concentration, crystallization, distillation, chromatography and any combination thereof.
Preferably, reaction (Ol-reac) and reaction (02-reac) are conducted in solvent (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 (02-reac) are
identical or different and independently from each other from -20 to 100 °C, more preferably
from -10 to 80 °C, even more preferably from 0 to 50 °C.
Reaction (Ol-reac) and reaction (02-reac) can independently from each other be done in
systems, that are closed or open to the atmosphere.
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 (02-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 (02-reac) are done in a open system.
Preferably, the reaction times of reaction (Ol-reac) and of reaction (02-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 (02-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 (02-reac) can be done consecutively without isolation of the
reaction 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
(O) 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 (02-reac) respectively.
Preferably, compound of formula (XXIII) is prepared in a step (P);
step (P) comprises a reaction (P-reac);
in reaction (P-reac) the compound of formula (XXIV) is exposed to a temperature (P-temp);
temperature (P-temp) is from 0 to 300 °C.
Preferably, temperature (P-temp) is from 5 to 200 °C, more preferably from 100 to 150 °C.
Reaction (P-reac) can be done in a solvent (P-solv);
solvent (P-solv) is selected from the group consisting of benzene, toluene, xylene, hexane,
heptane, 1,2-dichloroethane, NMP, dichloromethane, chloroform and mixtures thereof;
preferably from benzene, toluene, xylene, dichloromethane and mixtures thereof.
Preferably, reaction (P-reac) is done in the presence of a catalyst (P-cat);
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, HC1, HBr, H2S0 4, KOH, NaOH, KHS0 4, HN0 3, H3P0 4, HC10 4,
BC13, BBr3, BF3OEt2, BF3SMe2, BF3THF, MgCl 2, MgBr 2, Mgl 2, A1C13, Al(0-Ci_ 4 alkyl) 3,
I2, A 120 3, SnCl4, TiCl 4, Ti(0-Ci_ 4 alkyl) 4, ZrCl 4, Bi20 3, BiCl 3, ZnCl 2, PbCl 2, FeCl 3,
Yb(OTf) 3, Yb(Cl) 3, GaCl 3, AlBr 3, Ce(OTf) 3, LiCl, acidic insoluble inorganic solid, acidic
ion exchange resins, carbon treated with an inorganic acid, and mixtures thereof;
preferably from methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, H2S0 4,
KHS0 4, H3P0 4, 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 HC1, H2S0 4 and HN0 3.
Preferably, the acidic ion exchange resin is selected from the group consisting of copolymers
of styrene and divinylbenzene and of perfluorinated branched or linear polyethylenes,
these polymers being functionalized with S0 3H 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 functionalized with S0 3H groups.
When reaction (P-reac) is done in the presence of a catalyst (P-cat), 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.
Reaction (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 (P-reac), 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
(Ql), a step (Q2) and a step (Q3);
step (Ql) comprises a reaction (Ql-reac) by a reaction of compound of formula (XXV) with a
reagent (Ql-reag);
Q is Br, CI, or I;
reagent (Ql-reag) is selected from the group consisting of lithium, magnesium, aluminum,
zinc, calcium, isopropylmagnesium chloride, isopropylmagnesium bromide, butyllithium,
sec-butyllithium and mixtures thereof;
step (Q2) comprises a reaction (Q2-reac);
reaction (Q2-reac) is a reaction of the reaction product of reaction (Ql-reac) with acetone;
in step (Q3) comprises a reaction (Q3-reac);
reaction (Q3-reac) is a reaction of the reaction product of reaction (Q2-reac) with a reagent
(Q3-reag);
reagent (Q3-reag) is selected from the group consisting of water, methanol, ethanol, oxalic
acid, citric acid, NH4C1, HCl, HBr, HN0 3, H2S0 4, H3P0 4, 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,
aluminum, isopropylmagnesium chloride, isopropylmagnesium bromide and mixtures thereof.
Reaction (Ql-reac) can be catalyzed with a catalyst (Ql-cat).
Catalyst (Ql-cat) is selected from the group consisting of iodine, 1,2-dibromoethane, TiCl 4,
A1C13, PbCl 2, BiCl 3, LiCl and mixtures thereof.
Preferably, reagent (Q3-reag) is water or aqueous NH4C1.
Preferably, reaction (Ql-reac) is performed in a solvent (Ql-solv).
Preferably, reaction (Q2-reac) is performed in a solvent (Q2-solv).
Preferably, reaction (Q3-reac) 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 selected from THF, methyl-THF, NMP,
diethylether, methyl-tert-butylether, methoxycyclopentane, diisopropylether, 1,2-
dimethoxyethane, tri Ci_4 alkyl amine and mixtures thereof;
more preferably from THF, 2-methyl-THF, 1,2-dimethoxyethane, methyl-tert-butylether,
methoxycyclopentane, tri Ci_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 temperatures of reaction (Ql-reac), of reaction (Q2-reac) and of reaction (Q3-
reac) are identical or different and idependently from each other preferably from -100 to 150
°C, more preferably from -60 to 100 °C, and even more preferably from -20 to 80 °C.
Reaction (Ql-reac), reaction (Q2-reac) and reaction (Q3-reac) can be done at a constant
temperature, or the temperature may be modified during the progress 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 solvent (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 reaction product of reaction (Ql-reac) and
of the weight of the reaction product of reaction (Q2-reac) respectively.
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).
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 acetone 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 (Ql-reac), reaction (Q2-reac) and reaction (Q3-reac) are done at
atmospheric pressure.
Preferably, reaction (Ql-reac), reaction (Q2-reac) and reaction (Q3-reac) 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 preferably a Ci_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, extraction, washing, drying, concentration, crystallization, distillation,
chromatography and any combination thereof.
Preferably, the reaction product of reaction (Ql-reac) and the reaction product of reaction
(Q2-reac) are not isolated.
Preferably, reaction (Ql-reac), reaction (Q2-reac) 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 reagent (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 components, hydrolysis and optional acidification of the higherboiling
residue, extraction, and distillation.
Any aqueous phase can be extracted, preferably the extraction is done with a solvent (Qextract).
Solvent (Q-extract) is benzene, toluene, ethyl acetate, or isopropyl 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 reduced pressure.
Compounds of formula (XXI) and (XXII) are chiral compounds, and the formulae 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 reactions reaction (N-reac), reaction (O-reac), reaction (Ol-reac),
reaction (02-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 (LCMS), or Thin Layer
Chromatography (TLC), and work-up of the reaction mixture can start, when the conversion
of the starting material exceeds 95%, or when no more starting 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 MgS0 4 or Na2S0 4, 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.
Further subject of the invention is the use of compound of formula (XXI) for the preparation
of medetomidine.
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.
WO201 1/070069A discloses a process for the preparation of medetomidine, in which the
imidazole ring is built up during a multi-step process starting from commercially affordable
2,3-dimethyl benzoic acid.
Compound of formula (XX) is preferably prepared from compound of formula (XXI) by a
method, that comprises a reaction (Ml);
reaction (Ml) 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 selected from the group consisting
of p-toluenesulfonylmethyl isocyanide, trifluoromethanesulfonylmethyl isocyanide,
methanesulfonylmethyl isocyanide, benzenesulfonylmethyl isocyanide, 4-
acetamidobenzenesulfonylmethyl isocyanide and mixtures thereof;
the compound acting as a nitrogen 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, tritylamine, formamide, urea,
urotropine, ethyl carbamate, acetamide and mixtures thereof;
preferably the reaction (Ml) is done in a solvent (M), preferably solvent (M) is selected from
the group consisting of N ,N -dimethylformamide, Ci_ alkanol, formamide, 1,2-
dimethoxyethane, NMP, toluene, acetonitrile, propionitrile, ethyl carbamate, N,Ndimethylacetamide,
water, acetamide and mixtures thereof.
Any sequence of the reaction of reagent (M) and of reagent (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 reagent (M-A)
added;
or
compound of formula (XXI) can first be first reacted with reagent (M-A) and then reagent
(M) added;
or
compound of formula (XXI) can simultaneously be reacted with reagent (M) and with reagent
(M-A), this embodiment is preferably suited for the case that reagent (M-A) and solvent (M)
are identical and are formamide, ethyl carbamate or acetamide; preferably formamide.
Further subject of the invention is the use of compound of formula (XXII) for the preparation
of compound of formula (XXI).
Further 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 (XXIV).
Compared to prior art, the method of the present invention offers several advantages:
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
example a trityl or acetal protecting group is used. The method has good yields.
Compound 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 destined
for use as fragrance.
The product is distinguished by a very special fragrance sought after in the fragrance industry.
Examples
Methods
1H and 1 C NMR spectra were recorded on a Varian VNMRS 500 (500 MHz for 1H and 125
MHz for 1 C) 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 spectra (70 eV), they were obtained on an AMD-604
spectrometer.
ESI means Electron spray ionization mass spectra
THF was distilled from sodium/benzophenone ketyl prior to use; the obtained anhydrous THF
is called "dry THF" in the following text.
Example 1: 2-(2,3-Dimethylphenyl)propan-2-ol, compound of formula (XXIV), prepared
via an organomagnesium intermediate
l-Bromo-2,3-dimethylbenzene (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 stirrer, and a reflux condenser. The l-bromo-2,3-
dimethylbenzene solution ( 1.0 mL) was added via a dropping funnel and the reaction was
initiated by the addition of 1,2-dibromoethane (3 drops), and then the rest of the l-bromo-2,3-
dimethylbenzene solution was added. The content of the dropping funnel 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 °C. A solution of dry acetone (4.2 mL, 58 mmol) in dry THF (15 mL)
was added dropwise and the mixture was stirred at a temperature between 0 and 20 °C for 3 h.
The mixture was poured into saturated NH4C 1 aqueous solution (100 mL) extracted with
hexane (5 times with 50 mL each), dried with Na2S0 4 and evaporated under reduced pressure.
The main product was isolated via silica gel column chromatography with hexane: ethyl
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).
1 C NMR: 17.72, 21.08, 31.24 , 73.71, 123.1 1, 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)propan-2-ol, compound of formula (XXIV), prepared
via an organolithium intermediate
1-Bromo-2,3-dimethylbenzene (compound of formula (XXV), wherein Q is Br; 4.25 g, 23.0
mmol) was dissolved in dry THF (20 mL) in a flask equipped with a thermometer and a
stirring bar. The mixture was cooled to -78 °C. n-Butyllithium (1.6 M in hexane, 17.5 mL,
28.0 mmol) was added dropwise via a syringe, 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. 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 NH4C 1 solution (100 mL), extracted with hexane (4 times with 50 mL
each), dried over Na2S0 4, and purified by via silica gel column chromatography using
hexane: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 : l,2-Dimethyl-3-(2-propenyl)benzene, compound of formula (XXIII)
2-(2,3-Dimethylphenyl)propan-2-ol, compound of formula (XXIV), prepared according to
either 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 3 h. Silica gel (200 mg) was added, and stirring 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 K2C0 3 solution, conventionally
dried, and concentrated 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 K2C0 3 (20.7 g) and EDTA-Na2 ( 11.5 mg) in water (100
mL). l,2-Dimethyl-3-(2-propenyl)benzene, compound of formula (XXIII), 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 ) and then hydrogen
peroxide (30% in water, 6.2 mL, 60.7 mmol) were added and the mixture was stirred at room
temperature for 2 h. The reaction 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 Na2S0 4, concentrated under reduced
pressure, and the residue was purified by via silica gel column chromatography using
hexane:ethyl acetate as eluent (v/v 32: 1) to give 85 1mg (85%) of the title compound.
1H NMR: 1.59 (s, 3H), 2.28 (s, 3H), 2.31 (s, 3H), 2.83 (br d, J = 5.4, 1H), 2.98 (d, J = 5.4 Hz,
1H), 7.08 (m, 2H), 7.21 (m, 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 (XXII), prepared according to
example 4 (0.84 g, 5.18 mmol), was dissolved in dry dichloromethane (50 mL) and powdered
Cu(BF4)2 hydrate (318 mg) was added at room temperature. After 2 h at room temperature,
the mixture was washed with water, dried over Na2S0 4 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).
Example 6: Medetomidine, compound 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 isocyanide (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 °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%> (w/w) aqueous Na2C0 3 (200 mL) and then with water (200
mL), conventionally dried, evaporated under reduced pressure and purified by via silica gel
column chromatography using dichloromethane : 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 xyclohexane, 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).
1 C NMR: 14.65, 20.72, 20.88, 14.12, 117.61, 124.62, 125.53, 127.91, 134.05, 134.60,
136.76, 141.1 1, 143.23.
MS (ESI): 201 [M+H]+
Claims
1. A method for preparation of 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, H2S0 4, HN0 3, H3P0 4, HC10 4, BC13, BBr3, BF3OEt2,
BF3SMe2, BF3THF, MgCl 2, MgBr 2, Mgl 2, A1C13, Al(0-Ci_ 4 alkyl) 3, SnCl4, TiCl 4,
Ti(0-Ci_ 4 alkyl) 4, ZrCl 4, Bi20 3, BiCl 3, ZnCl 2, PbCl 2, FeCl 3, ScCl3, NiCl 2, Yb(OTf) 3, Yb(Cl) 3,
GaCl 3, AlBr 3, Ce(OTf) 3, LiCl, Cu(BF 4)2, Cu(OTf) 2, NiBr 2(PPh 3)2, NiBr 2, NiCl 2, Pd(OAc) 2,
PdCl 2, PtCl 2, InCl 3, acidic inorganic solid substance, acidic ion exchange resin, carbon treated
with inorganic acid and mixtures thereof.
2. Method according to claim 1, wherein the catalyst (N-cat) is selected from the group
consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, ptoluenesulfonic
acid, HCl, HBr, H2S0 4, H3P0 4, BC13, BF3OEt2, MgCl 2, MgBr 2, A1C13, ZnCl 2,
Cu(BF 4)2, aluminosilicates, acidic ion exchange resins, carbon treated with HCl, H2S0 4 or
HN0 3, and mixtures thereof.
3. Method according to claim 1 or 2, wherein reaction (N-reac) is done in a solvent (Nsolv);
solvent (N-solv) is selected from the group consisting of water, tert-butanol, isopropanol,
acetonitrile, 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.
4. Method according to one or more of claims 1 to 3, wherein compound of formula (XXII)
is prepared in a step (O) or in two steps, the two steps are step (01) and step (02);
step (O) comprises a reaction (O-reac);
reaction (O-reac) is a reaction of compound of formula (XXIII), with a reagent (O-reag);
(XXIII)
gent (O-reag) 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, KHS0 ,Na20 2, aqueous H20 2, H20 2 dissolved in acetic acid, H20 2
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 (01-comp) is selected from the group consisting of bromine, N-bromosuccinimide,
chlorine, N-chlorosuccinimide, iodine, N-iodosuccinimide, IBr, BrCl, and mixtures
thereof;
step (02) comprises a reaction (02-reac);
reaction (02-reac) is a reaction of the reaction product from reaction (Ol-reac) with a base
(02-base);
base (02-base) is selected from the group consisting of sodium hydroxide, potassium
hydroxide, calcium hydroxide and mixture thereof.
5. Method according to claim 4, wherein reagent (O-reag) is selected from the group
consisting of peracetic acid, tert-butylhydroperoxide, oxygen, air, sodium hypochlorite,
aqueous H20 2, H20 2 dissolved in acetic acid, H20 2 dissolved in trifluoroacetic acid, and
mixtures thereof.
6. Method according to claim 4 or 5, wherein compound of formula (XXIII) is prepared in a
step (P);
step (P) comprises a reaction (P-reac);
in reaction (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 (Ql), a step (Q2) and a step (Q3);
step (Ql) comprises a reaction (Ql-reac) by a reaction of compound of formula (XXV) with a
reagent (Ql-reag);
is Br, CI, or I;
gent (Ql-reag) is selected from the group consisting of lithium, magnesium, aluminum,
zinc, calcium, isopropylmagnesium chloride, isopropylmagnesium bromide, butyllithium,
sec-butyllithium and mixtures thereof;
step (Q2) comprises a reaction (Q2-reac);
reaction (Q2-reac) is a reaction of the reaction product of reaction (Ql-reac) with acetone;
in step (Q3) comprises a reaction (Q3-reac);
reaction (Q3-reac) is a reaction of the reaction product of reaction (Q2-reac) with a reagent
(Q3-reag);
reagent (Q3-reag) is selected from the group consisting of water, methanol, ethanol, oxalic
acid, citric acid, NH4C1, HCl, HBr, HNO 3, H2S0 4, H3PO4, acetic acid, propionic acid, formic
acid and mixtures 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
compound of formula (XXI) as defined in claim 1.