METHOD FOR PREPARATION OF MEDETOMIDINE
The invention discloses a method for the preparation of medetomidine starting from 1-bromo
2,3-dimethylbenzene and acetone.
Medetomidine is the 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.
Medetomidine is a 4-alkylimidazole. 4-Alkylimidazoles without additional substituents at the
nitrogen moiety are usually mixtures of two tautomers. For instance, in the case of
medetomidine, two tautomeric forms, represented by compound of formula (XX) and
compound of formula (XX-T),
will usually interconvert if medetomidine is dissolved or in a non-crystalline state. If one of
the tautomeric forms prevails or if they are present in equal amounts is dependent on various
factors, such as pH, solvent or temperature.
In the text, formula (XX) is used for medetomidine, and is meant to comprise both tautomeric
forms as well as their mixture.
US 2010/0048915 A discloses a method for the preparation of medetomidine by reaction of
halogenated imidazoles with 2,3-dimethylbenzaldehyde using Grignard reagents.
Cordi et al, Synth. Commun. 1996, 26, 1585-1593, discloses the preparation of
medetomidine by reaction of 4-imidazolcarboxaldehyde with 2,3-dimethylphenylmagnesium
bromide.
WO 00/4285 1A discloses the use of medetomidine for inhibition of marine biofouling on
surfaces.
The known methods of preparation of medetomidine often use protecting groups, for example
triphenylmethyl (trityl) residues, which entails high material consumption and the need for
protection/deprotection steps. Consequently, these syntheses are long and expensive.
Furthermore rather expensive and non-readily available starting materials are used.
There was a need for a synthetic route, which does not need protecting groups, starts with less
expensive substrates, avoids large amounts of waste and has satisfying yields.
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 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 medetomidine,
the method comprises a step (N) and a step (Ml);
step (Ml) comprises a reaction (Ml-reac);
reaction (Ml-reac) is a reaction between a compound of formula (XXI),
a reagent (M-reag) and a reagent (M-A) in a solvent (M-solv);
reagent (M-reag) is selected from the group consisting of p-toluenesulfonylmethyl isocyanide,
trifluoromethanesulfonylmethyl isocyanide, methanesulfonylmethyl isocyanide,
benzenesulfonylmethyl isocyanide, 4-acetamidobenzenesulfonylmethyl isocyanide
and mixtures thereof;
reagent (M-A) is selected from the group consisting of ammonia, sulfamic acid, ptoluenesulfonamide,
benzenesulfonamide, 4-acetamidobenzenesulfonamide,
tritylamine, formamide, urea, urotropine, ethyl carbamate, acetamide and mixtures
thereof;
solvent (M-solv) is selected from the group consisting of N ,N -dimethylformamide, Ci_
alkanol, formamide, 1,2-dimethoxyethane, NMP, toluene, acetonitrile, propionitrile,
ethyl carbamate, N ,N -dimethylacetamide, water, acetamide and mixtures thereof;
and wherein compound of formula (XXI) is prepared in the 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, HC1, 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, reagent (M-reag) is selected from the group consisting of p-toluenesulfonylmethyl
isocyanide, benzenesulfonylmethyl isocyanide and mixtures thereof;
more preferably, reagent (M-reag) is p-toluenesulfonylmethyl isocyanide.
Preferably, reagent (M-A) is selected from the group consisting of ammonia, sulfamic acid, ptoluenesulfonamide,
benzenesulfonamide, 4-acetamidobenzenesulfonamide,
tritylamine, formamide and mixtures thereof;
more preferably, reagent (M-A) is selected from the group consisting of ammonia, ptoluenesulfonamide,
benzenesulfonamide, formamide, 4-
acetamidobenzenesulfonamide, tritylamine and mixtures thereof;
even more preferably, reagent (M-A) is selected from the group consisting of ammonia, ptoluenesulfonamide,
formamide, and mixtures thereof;
especially, reagent (M-A) is ammonia or formamide.
Preferably, solvent (M-solv) is selected from the group consisting of N,Ndimethylformamide,
methanol, ethanol, n-propanol, isopropanol, butanol, pentanol,
hexanol, water, formamide, 1,2-dimethoxyethane, NMP, toluene, acetonitrile,
propionitrile, ethyl carbamate, N,N-dimethylacetamide, acetamide and mixtures
thereof;
more preferably, solvent (M-solv) is selected from the group consisting of N,Ndimethylformamide,
methanol, ethanol, ethyl carbamate, formamide, acetamide and
mixture thereof.
Preferably, reaction (Ml-reac) is done in the presence of a compound (M-comp), compound
(M-comp) is selected from the group consisting of ammonia, tritylamine, NaCN,
KCN, piperidine, DBU, DABCO, triethylamine, tributylamine, 4-
dimethylaminopyridine, pyridine, tBuOK, tBuONa, NaHC0 3,Na2C0 3, (NH4)HC0 3,
(NH4)2C0 3, KHC0 3, K2C0 3, NaOAc, KOAc, NaOH, KOH, Ca(OH)2, KF and
mixtures thereof;
preferably, compound (M-comp) is selected from the group consisting of ammonia,
tritylamine, NaCN, KCN, piperidine, tBuOK, tBuONa, KOH, K2C0 3,Na2C0 3, KF
and mixtures thereof;
more preferably, compound (M-comp) is selected from the group consisting of ammonia,
NaCN, KCN, piperidine, tBuOK, tBuONa, K2C0 3,Na2C0 3, KF and mixtures thereof;
even more preferably, compound (M-comp) is selected from the group consisting of
ammonia, NaCN, K2C0 3, tBuOK, tBuONa, Na2C0 3 and mixtures thereof;
especially, compound (M-comp) is selected from the group consisting of ammonia, NaCN,
tBuOK, tBuONa, Na2C0 3 and mixtures thereof;
more especially, compound (M-comp) is NaCN or ammonia.
The reagent (M-A) can be used as such or in form of a solution in a solvent (M-A). Solvent
(M-A) is identical or different from solvent (M-solv), preferably identical, and comprises the
same group of solvents as solvent (M-solv), also with respect to all of the preferred
embodiments of solvent (M-solv).
When reagent (M-A) is ammonia, then reagent (M-A) is preferably used in form of a solution,
preferably in form of a solution in methanol.
In case of ethyl carbamate, formamide and acetamide, reagent (M-A) can be identical with
solvent (M-solv) and can be used as solvent (M-solv).
Preferably, the reaction temperature of reaction (Ml-reac) is from -10 to 250 °C, more
preferably from 0 to 200 °C, even more preferably from 10 to 180 °C.
The reaction (Ml-reac) can be done in a system, that is closed or open to the atmosphere;
preferably the reaction (Ml-reac) is done in a closed system.
In a closed system, the pressure depends mainly on the boiling point of the solvent (M-solv),
on the amount of ammonia used, and on the reaction temperature of reaction (Mlreac);
preferably, the reaction (Ml-reac) is done at a pressure of from atmospheric pressure to 20
bar, more preferably of from atmospheric pressure to 10 bar, even more preferably of from
atmospheric pressure to 5 bar.
Preferably, the reaction time of reaction (Ml-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.
Reaction (Ml-reac) may be conducted at a constant temperature, or the temperature may be
modified during the progress of the reaction. For instance, the reaction may be run for a
certain time at first temperature, and then for a given time at second temperature different
from the first temperature;
alternatively, the temperature may be modified continuously during the reaction.
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 (M-reag) are used, the mol
equivalents being based on the mol of compound of formula (XXI).
When one or more reagents (M-A) different from ammonia, formamide and ethyl carbamate
are used, the total amount of substances different from ammonia, formamide and ethyl
carbamate used as reagent (M-A) is 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,
the mol equivalents being based on the mol of compound of formula (XXI).
When ammonia, formamide, ethyl carbamate or mixtures thereof are used as reagent (M-A),
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 ammonia, formamide, ethyl
carbamate or mixtures thereof are used, the mol equivalents being based on the mol of
compound of formula (XXI).
When one or more substances selected from the group ammonia, formamide and ethyl
carbamate, and one or more substances different from ammonia, formamide and ethyl
carbamate are used as reagent (M-A), the given amounts for ammonia, formamide and ethyl
carbamate, and the given amounts for the one or more substances different from ammonia,
formamide and ethyl carbamate, add up to the total amount of reagent (M-A); the total
amount of reagent (M-A) is 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, the mol
equivalents being based on the mol of compound of formula (XXI).
Preferably from 1 to 15 mol equivalents, more preferably from 1 to 10 mol equivalents, even
more preferably from 1 to 5 mol equivalents of compound (M-comp) are used, the mol
equivalents being based on the mol of compound of formula (XXI).
Preferably, the amount of solvent (M-solv) is from 0.5 to 20 fold, more preferably from 1 to
10 fold, even more preferably of from 2 to 5 fold, of the weight of compound of formula
(XXI).
Preferably, the reaction (Ml-reac) is done under inert atmosphere.
When tritylamine is used as reagent (M-A), the product of reaction (Ml-reac) may be N-trityl
medetomidine and the trityl residue would have to be removed.
Preferably in this case, the method for preparation of medetomidine comprises a further step
(M2); step (M2) is done after step (Ml); step (M2) comprises a reaction (M2-reac);
reaction (M2-reac) is the treatment of the product of reaction (Ml-reac) with an acid (M-acid
detrit). Acid (M-acid detrit) is preferably selected from the group consisting of acetic acid,
propionic acid, formic acid, HC1 or mixtures thereof.
Acid (M-acid detrit) can be used as an aqueous solution.
Any sequence of the reaction of reagent (M-reag) and of reagent (M-A) with the compound of
formula (XXI) in reaction (Ml-reac) can be used:
compound of formula (XXI) can first be reacted with reagent (M-reag) and then reagent (MA)
added;
or
compound of formula (XXI) can first be reacted with reagent (M-A) and then reagent (Mreag)
added;
or
compound of formula (XXI) can simultaneously be reacted with reagent (M-reag) and with
reagent (M-A), this embodiment is preferably suited for the case that reagent (M-A) and
solvent (M-solv) are identical and are formamide, ethyl carbamate or acetamide; preferably
formamide.
Preferably, compound of formula (XXI) is first reacted with reagent (M-reag) and then
reagent (M-A) added;
or
compound of formula (XXI) is simultaneously reacted with reagent (M-reag) and with reagent
(M-A).
Step (Ml) can therefore be done in three alternatives, the three alternatives are alternative
(Ml-Al), alternative (M1-A2) and alternative (M1-A3).
Alternative (Ml-Al) comprises two steps, a step (Ml-Al-1) and a step (Ml-Al-2);
step (Ml-Al-1) comprises a reaction (Ml-Al-1);
reaction (Ml-Al-1) is a reaction of compound of formula (XXI) with reagent (M-reag) in the
presence of compound (M-comp) and in a solvent (M-solv);
step (Ml-Al-2) comprises a reaction (Ml-Al-2).
reaction (Ml-Al-2) is a reaction of the reaction product of reaction (Ml-Al-1) with reagent
(M-A) in the presence of compound (M-comp) and in a solvent (M-solv).
Preferably, the reaction temperature of reaction (Ml-Al-1) is from -10 to 250 °C, more
preferably from 0 to 200 °C, even more preferably from 10 to 180 °C.
Preferably, the reaction temperature of reaction (Ml-Al-2) is from 20 to 250 °C, more
preferably from 50 to 200 °C, even more preferably from 80 to 180 °C.
Preferably from 0.01 to 1 mol equivalents, more preferably from 0.1 to 0.5 mol equivalents,
even more preferably from 0.2 to 0.3 mol equivalents of compound (M-comp) are used in
reaction (Ml-Al-1), the mol equivalents being based on the mol of compound of formula
(XXI).
Preferably from 1 to 10 mol equivalents, more preferably from 1 to 5 mol equivalents, even
more preferably from 1 to 3 mol equivalents of compound (M-comp) are used in reaction
(Ml-Al-2), the mol equivalents being based on the mol of compound of formula (XXI).
Alternative (M1-A2) comprises two steps, a step (M1-A2-1) and a step (M1-A2-2);
step (M1-A2-1) comprises a reaction (M1-A2-1);
reaction (M1-A2-1) is a reaction of compound of formula (XXI) with reagent (M-A) in a
solvent (M-solv);
step (M1-A2-2) comprises a reaction (M1-A2-2).
reaction (M1-A2-2) is a reaction of the reaction product of reaction (M1-A2-1) with reagent
(M-reag) in the presence of compound (M-comp) and in a solvent (M-solv).
Preferably, the reaction temperature of reaction (M1-A2-1) is from 0 to 250 °C, more
preferably from 10 to 200 °C, even more preferably from 20 to 180 °C.
Preferably, the reaction temperature of reaction (M1-A2-2) is from -10 to 250 °C, more
preferably from 0 to 200 °C, even more preferably from 20 to 180 °C.
In case of reagent (M-A) not being ammonia and tritylamine, reaction (M1-A2-1) can be done
in the presence of an acid (M1-A2-1); acid (M1-A2-1) is selected from the group
consisting of p-toluenesulfonic acid, methanesulfonic acid and benzenesulfonic acid;
preferably from 0.01 to 1 mol equivalents, more preferably from 0.05 to 0.5 mol equivalents,
even more preferably from 0.1 to 0.3 mol equivalents of acid (M1-A2-1) are used in
reaction (M1-A2-1), the mol equivalents being based on the mol of compound of formula
(XXI).
Preferably from 1 to 10 mol equivalents, more preferably from 1 to 5 mol equivalents, even
more preferably from 1 to 3 mol equivalents of compound (M-comp) are used in reaction
(M1-A2-2), the mol equivalents being based on the mol of compound of formula (XXI).
Alternative (M1-A3) comprises a step (M1-A3-1)
step (M1-A3-1) comprises a reaction (M1-A3-1);
reaction (M1-A3-1) is a reaction of compound of formula (XXI) with reagent (M-reag) and
with with reagent (M-A) in a solvent (M-solv).
Preferably, the reaction temperature of reaction (M1-A3-1) is from 0 to 250 °C, more
preferably from 20 to 200 °C, even more preferably from 50 to 180 °C.
Reaction (M1-A3-1) can be done in the presence of compound (M-comp); preferably from 1
to 10 mol equivalents, more preferably from 1 to 5 mol equivalents, even more preferably
from 1 to 3 mol equivalents of compound (M-comp) are used in reaction (M1-A3-1), the
mol equivalents being based on the mol of compound of formula (XXI).
In case of all these three alternatives, reagent (M-reag), reagent (M-A), compound (M-comp)
and solvent (M-solv) are as defined herein, also with all their preferred embodiments.
When the reaction (Ml-reac) is completed, medetomidine can be isolated by standard
methods such as evaporation of volatile components, extraction, washing, drying,
concentration, filtration, crystallization, distillation, chromatography and any combination
thereof.
Preferably, the volatile components of the reaction mixture are removed by evaporation under
reduced pressure.
Preferably, the reaction mixture resulting from reaction (Ml-reac) or the reaction mixture
resulting from reaction (M2-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_s 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.
The extraction can be followed by filtration and concentration of the extract.
Preferably, after an extraction with a solvent (M-extract), the extract resulting from the
extraction with solvent (M-extract) can be extracted with an aqueous solution of an acid (Macid).
Acid (M-acid) is preferably selected from the group consisting of oxalic acid, citric
acid, maleic acid, fumaric acid, tartaric acid, NH4C1, HCl, HBr, H2SO4, H3PO4 and mixtures
thereof.
The extract resulting from the extraction with an aqueous solution of acid (M-acid) can be
washed with a solvent (M-wash).
Preferably, solvent (M-wash) is selected from the group consisting of toluene, benzene,
xylene, chlorobenzene, dichloromethane, chloroform, acetic acid Ci_8 alkyl ester and
mixtures 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.
The product can be isolated by concentration of the extract, that was washed with solvent (Mwash).
In another preferred embodiment, the reaction mixture resulting from reaction (Ml-reac) or
the reaction mixture resulting from reaction (M2-reac) can be, without above mentioned
extraction with solvent (M-extract), acidified by mixing with an aqueous solution of acid (Macid).
The mixture, that is thereby obtained, can be washed with solvent (M-wash), and the
product can be isolated by concentration.
If the deprotonated medetomidine is to be isolated, a suspension or solution of the salt of
medetomidine, preferably an aqueous suspension or solution of the salt of
medetomidine, can be basified by addition of a base (M-basify) or of an aqueous
solution of base (M-basify);
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.
After the addition of base (M-basify), an aqueous phase can be extracted with solvent (Mextract),
followed by isolation of the product by concentration of the extract.
Preferably, any washing of any organic phase after reaction (Ml-reac) or after reaction (M2-
reac) can be done with water, with base (M-basify), with an aqueous solution of base (Mbasify)
or with brine.
Preferably, any extraction of any aqueous phase after reaction (Ml-reac) or after reaction
(M2-reac) is done with solvent (M-extract).
Preferably, the reaction mixture after reaction (Ml-reac) or after reaction (M2-reac) is first
concentrated under reduced pressure, then diluted with water and acidified with acid (M-acid)
as described above, washed with solvent (M-wash), preferably solvent (M-wash) is toluene,
basified with base (M-basify), preferably base (M-basify) is an aqueous solution of NaHC0 3,
and then extracted with solvent (M-extract), preferably solvent (M-extract) is selected from
the group consisting of toluene, dichloromethane, isopropyl acetate and ethyl acetate;
followed by isolation of the product by concentration of the extract.
In another preferred embodiment, medetomidine is purified after reaction (Ml-reac) or after
reaction (M2-reac) 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.
Medetomidine can be purified, preferably by crystallization or distillation under reduced
pressure, more preferably by crystallization from a mixture of cyclohexane and toluene, even
more preferably from cyclohexane :toluene 99:1 v/v .
Medetomidine may also be converted into a salt by mixing with an acid (M-acid salt), acid
(M-acid salt) is preferably used as aqueous solution, acid (M-acid salt) is preferably selected
from the group consisting of acetic acid, oxalic acid, HC1 and H2SO4;
then it can be isolated by filtration and purified by recrystallization in a solvent (M-cryst),
solvent (M-cryst) is preferably selected from the group consisting of water, ethanol, methanol,
isopropanol, acetonitrile, hexane, cyclohexane, heptane, toluene, ethyl acetate and mixtures
thereof; recrystallization can be repeated using a different solvent (Mcryst).
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 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 functionalized with SO3H groups.
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 catalyst (N-cat) is selected from the group consisting of acetic acid, formic
acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, HC1, HBr, H2S0 4,
H3PO4, BCI 3, BF3OEt2, MgCl 2, MgBr 2, A1C13, ZnCl 2, Cu(BF 4)2, aluminosilicates, acidic
ion exchange resins, carbon treated with HC1, H2S0 4 or FiNC^, 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.
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).
Also this hydrate and this hemiacetal can be directly used in step (Ml).
When compound of formula (XXI) is obtained from reaction (N-reac) in form of its hydrate
or of a hemiacetal, the hydrate or the hemiacetale 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)
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.
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-buf);
preferably, buffer (O-buf) is an aqueous buffer and is selected from the group consisting of
K2CO3 / EDTA-Na2 buffer, phosphate buffer and other buffers known by the skilled person;
more preferably, buffer (O-buf) is an K2CO3 / 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, B1CI3, 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-
dimethoxy ethane, 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.
Medetomidine and compounds of formula (XXI) and (XXII) are chiral compounds, and the
formulae comprise any enantiomer as well as any mixture of enantiomers of medetomidine, of
the compounds of formula (XXI), or of formula (XXII) respectively.
Enantiomers can be separated by conventional procedure known in organic chemistry, such as
repeated crystallizations of the (+) tartaric acid salt in alcoholic media, as disclosed for
medetomidine in Cordi et al, Synth. Commun. 1996, 26, 1585-1593.
Compounds of formula (XXV) are known compounds and can be prepared according to
known methods.
The progress of any of the reactions reaction (Ml-reac), reaction (M2-reac), reaction (N-reac),
reaction (O-reac), reaction (Ol-reac), reaction (02-reac), reaction (P-reac), reaction (Qlreac),
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.
Compared to prior art, the method of the present invention offers several advantages:
Importantly, the whole carbon framework of medetomidine 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.
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-Na 2 ( 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
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 medetomidine,
the method comprises a step (N) and a step (Ml);
step (Ml) comprises a reaction (Ml-reac);
reaction (Ml-reac) is a reaction between a compound of formula (XXI),
a reagent (M-reag) and a reagent (M-A) in a solvent (M-solv);
reagent (M-reag) is selected from the group consisting of p-toluenesulfonylmethyl isocyanide,
trifluoromethanesulfonylmethyl isocyanide, methanesulfonylmethyl isocyanide,
benzenesulfonylmethyl isocyanide, 4-acetamidobenzenesulfonylmethyl isocyanide and
mixtures thereof;
reagent (M-A) is selected from the group consisting of ammonia, sulfamic acid, ptoluenesulfonamide,
benzenesulfonamide, 4-acetamidobenzenesulfonamide, tritylamine,
formamide, urea, urotropine, ethyl carbamate, acetamide and mixtures thereof;
solvent (M-solv) is selected from the group consisting of N,N-dimethylformamide, Ci_
alkanol, formamide, 1,2-dimethoxyethane, NMP, toluene, acetonitrile, propionitrile, ethyl
carbamate, N,N-dimethylacetamide, water, acetamide and mixtures thereof;
and wherein compound of formula (XXI) is prepared in the 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);
(XXII)
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, HC1, 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 reagent (M-reag) is selected from the group
consisting of p-toluenesulfonylmethyl isocyanide, benzenesulfonylmethyl isocyanide and
mixtures thereof.
3. Method according to claim 1 or 2, wherein reagent (M-A) is selected from the group
consisting of ammonia, sulfamic acid, p-toluenesulfonamide, benzenesulfonamide, 4-
acetamidobenzenesulfonamide, tritylamine, formamide and mixtures thereof.
4. Method according to one or more of claims 1 to 3, wherein solvent (M-solv) is selected
from the group consisting of N ,N -dimethylformamide, methanol, ethanol, n-propanol,
isopropanol, butanol, pentanol, hexanol, water, formamide, 1,2-dimethoxyethane, NMP,
toluene, acetonitrile, propionitrile, ethyl carbamate, N ,N -dimethylacetamide, acetamide and
mixtures thereof.
5. Method according to one or more of claims 1 to 4, wherein reaction (Ml-reac) is done in
the presence of a compound (M-comp), compound (M-comp) is selected from the group
consisting of ammonia, tritylamine, NaCN, KCN, piperidine, DBU, DABCO, triethylamine,
tributylamine, 4-dimethylaminopyridine, pyridine, tBuOK, tBuONa, NaHC0 3, Na2C0 3,
(NH4)HC0 3, (NH4)2C0 3, KHC0 3, K2C0 3, NaOAc, KOAc, NaOH, KOH, Ca(OH) 2, KF and
mixtures thereof.
6. Method according to claim 5, wherein compound (M-comp) is selected from the group
consisting of ammonia, tritylamine, NaCN, KCN, piperidine, tBuOK, tBuONa, KOH, K2C0 3,
Na2C0 3, KF and mixtures thereof.
7. Method according to one or more of claims 1 to 6, wherein compound of formula (XXI)
is first reacted with reagent (M-reag) and then reagent (M-A) added;
or
compound of formula (XXI) is first reacted with reagent (M-A) and then reagent (M-reag)
added;
or
compound of formula (XXI) is simultaneously reacted with reagent (M-reag) and with reagent
(M-A).
8. Method according to one or more of claims 1 to 7, wherein 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, 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.
9. Method according to one or more of claims 1 or 8, 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,
dichloromethane, 1,2-dichloroethane, chloroform, toluene, benzene, chlorobenzene, hexane,
cyclohexane, ethyl acetate, acetic acid, formic acid, trifluoroacetic acid and mixtures thereof.
10. Method according to one or more of claims 1 to 9, 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)
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 (Ol-reac);
reaction (Ol-reac) is a reaction of compound of formula (XXIII) with water and with a
compound (Ol-comp);
compound (Ol-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.
11. Method according to claim 10, 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.
12. Method according to claim 10 or 11, 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.
13. Method according to claim 12, 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);
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, HNO 3, H2S0 4, H3PO4, acetic acid, propionic acid, formic
acid and mixtures thereof.