METHOD FOR PREPARATION OF 6-TRIFLUOROMETHYLPYRIDINE-3-
CARBOXYLIC ACID DERIVATIVES FROM TRIFLUOROACETYLACETICACID
The invention discloses a method for the preparation of 6-trifluoromethylpyridine-3-
carboxylic acid derivatives from trifluoroacetylacetic acid and orthoesters, and their use for
the preparation of pharmaceutical, chemical or agro-chemical products.
BACKGROUND OF THE INVENTION
2-Trifluoromethylpyridines and 6-trifluoromethylpyridine-3-carboxylic acid derivatives are
intermediates for the preparation of biologically active compounds. For instance,
WO 00/39094 Al discloses trifluoromethylpyridine as herbicides, WO 2006/059103 A2
discloses trifluoromethylpyridines as intermediates in the production of pharmaceutical,
chemical and agro-chemical products, WO 2008/013414 Al discloses
trifluoromethylpyridines as vanilloid receptor antagonists and WO 2012/061926 Al describes
trifluoromethylpyridines as calcium channel blockers.
The common route for the preparation of 6-trifluoromethylpyridine-3 -carboxylic acid
derivatives was first reported by Okada et al, Heterocycles 1997, 46, 129-132, and has only
been slightly modified by others. The common synthetic strategies are summarized in Scheme
1:
This route has disadvantages for the large scale production of 6-trifluoromethylpyridine-3-
carboxylic acid derivatives, because ethylvinylether is highly flammable and therefore
difficult to handle, and because the trifluoroacetylated enolether and the trifluoroacetylated
enamine intermediates are unstable and cannot be stored for a longer time. Moreover, most
vinyl ethers are mutagenic.
Volochnyuk et al, Synthesis 2003, 10, 1531-1540, discloses a method for the preparation of
pyridines substituted in position 4 with a trifluoromethyl residue. The pyridines are part of a
bicyclic heterocycle. The method starts with aminopyrazole, which is reacted with
trifluoroacetylketones or with the ethyl ester of trifluoroacetylacetic acid. The method is
principally not suited to prepare the desired 6-trifluoromethylpyridine-3-carboxylic acid
derivatives of the instant invention, since position 6 in Volochnyuk is the endocyclic C atom
connecting the pyrazol part with the pyridine part of the bicyclic heterocycle of Volochnuyk.
The disclosure does not mention the use of trifluoroacetylacetic acid at all.
WO 2004/078729 Al discloses the preparation of compound of formula (Xa) from inter alia
4-alkoxy-l,l,l-trifluorobut-3-en-2-ones, which are prepared from vinylethers;
and discloses on page 18 in example P2 the use of 4-ethoxy-l,l,l-trifluorobut-3-en-2-one for
the reparation of compound of formula (1-2).
Compound of formula (Xa) and compound of formula (1-2) are intermediates for the
preparation of herbicides.
F. Swarts, Bulletin de la Classe des Sciences, Academie Royale de Belgique, 1926, 12,
721-725 discloses the preparation of a certain substrate used in instant invention.
There was a need for an improved procedure for the preparation of 6-trifluoromethylpyridine-
3-carboxylic acid derivatives.
This need was met by the method of instant invention as outlined below.
R.W. Leiby, J . Org. Chem. 1985, 50, 2926-2929, discloses the reaction of anthranilates with
orthoesters, therefore it was expected that enamines, which are structurally comparable to
anthranilates, react with orthoesters as well, and which then would no longer be available for
a reaction with trifluoroacetylacetic acid to trifluoromethylpyridine.
Unexpectedly, in a mixture containing orthoesters, enamines and trifluoroacetylacetic acid,
the formation of trifluoromethylpyridine was observed.
Compared to prior art, the method of the instant invention offers several advantages:
Importantly, no vinyl ethers, trifluoroacetylated enolether intermediates or isolated
trifluoroacetylated enamine intermediates are required, e.g. as is used in form of a 4-ethoxyl,
l,l-trifluorobut-3-en-2-one, named l-ethoxy-3-oxo-4-trifluorobutene, in WO 2004/078729
Al, that is the substance (3) in example P2 of the WO 2004/078729 Al, which is prepared
e.g. according to Moriguchi, J . Org. Chem., 1995, 60, 3523-3528 from vinylether, as cited in
WO 2004/078729 Al on page 16 lines 8-9. Moreover, the method of the present invention
reduces the number of synthetic steps compared to known procedures, what reduces the
overall costs.
In the following text, if not otherwise stated, the following meanings are used:
ambient pressure usually 1 bar, depending on the weather;
alkyl means a linear or branched alkyl, examples of alkyl include methyl, ethyl,
n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and the
like;
cyclic alkyl or cyclo alkyl include cyclo aliphatic, bicyclo aliphatic and tricycle aliphatic
residues; examples of "cycloalkyl" include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and adamantyl;
alkoxy means alkyl-O, i.e. the radical obtained by removal of the oxygen-bound
hydrogen from an aliphatic alcohol;
(alkoxy)alkoxy refers to alkoxy groups, in which the alkyl group is substituted with one
additional alkoxy group; examples of (alkoxy)alkoxy include methoxymethoxy
with formula MeO-CH2-0-, 2-(methoxy)ethoxy with formula
MeO-CH2-CH2-0- and 2-(cyclopropylmethoxy)ethoxy with formula
(C3H5)CH 2-0-CH 2-CH2-0-;
Ac acetyl;
tBu tertiary butyl;
cyanuric acid chloride 2,4,6-trichloro-l,3,5-triazine
DBU 1,8-diazabicyclo[5 .4 .0]undec-7-ene;
DABCO l,4-diazabicyclo[2.2.2]octane;
DMF N,N-dimethylformamide;
DMA N,N-dimethylacetamide;
DMSO dimethylsulfoxide;
dppf 1,1'-bis(diphenylphosphino)ferrocene
halogen means F, CI, Br or J, preferably F, CI or Br;
hemiacetal refers to the adduct of an alcohol, for instance methanol or ethanol, with a
ketone or with an aldehyde; a hemiacetal may also result upon the addition of
water to an enol ether; for instance, the hemiacetal of methanol with
trifluoroacetone is F3C-C(OH)(OCH 3)-CH3;
hexanes mixture of isomeric hexanes;
hydrate refers to the adduct of water with a ketone or with an aldehyde, for instance,
the hydrate of trifluoroacetone is F3C-C(OH)2-CH3;
LDA Lithium diisopropyl amide
NMP N-methyl-2-pyrrolidone;
sulfamic acid HO-S0 2-NH2;
THF tetrahydrofuran;
trifluoroacetone 1,1,1 -trifluoropropan-2-one;
xylene 1,2-dimethylbenzene, 1,3-dimethylbenzene, 1,4-dimethylbenzene or a mixture
thereof.
SUMMARY OF THE INVENTION
Subject of the invention is a method for preparation of compound of formula (I);
the method comprises a step (StepSl);
step (StepSl) comprises a reaction (ReacSl);
reaction (ReacSl) is a reaction of a compound of formula (II) with a compound of formula
(III) and a compound of formula (IV);
compound of formula (II) is selected from the group consisting of compound of
formula (II- 1), compound of formula (P-2), compound of formula (Ila), and mixtures
thereof;
Rl is selected from the group consisting of C1-10 alkyl, C3_ cycloalkyl, C(0)-0-Ci_ 4 alkyl,
CH=CH 2, benzyl, phenyl and naphthyl;
the Ci_io alkyl of Rl is unsubstituted or substituted with 1, 2, 3, 4 or 5 identical or
different substituents selected from the group consisting of halogen, OH,
0-C(0)-Ci_ 5 alkyl, O-C O alkyl, S-C 0 alkyl, S(O)-C 0 alkyl, S(O2)-Ci_i 0 alkyl,
0-Ci_6 alkylen-0-Ci_6 alkyl, C3_ cycloalkyl and 1,2,4-triazolyl;
the benzyl, the phenyl and the naphthyl of R l are independently from each other
unsubstituted or substituted with 1, 2, 3, 4 or 5 identical or different substituents
selected from the group consisting of halogen, Ci_4 alkoxy, N0 2 and CN;
Y is selected from the group consisting of Ci_ alkoxy, 0-Ci_ alkylen-0-Ci_ alkyl, NH2,
NHR4 and N(R4)R5;
R4 and R5 are identical or different and independently from each other Ci_6 alkyl, or
represent together a tetramethylene or a pentamethylene chain;
RIO is selected from the group consisting of Ci_s alkyl, C3-10 cycloalkyl and phenyl,
said phenyl is unsubstituted or substituted with 1 or 2 identical or different substituents
independently from each other selected from the group consisting of halogen,
cyano, nitro, Ci_ alkyl and phenyl;
R20 is selected from the group consisting of Ci_6 alkyl, 0(CO)CH 3, 0(CO)CF 3, and OS0 3H.
DETAILED DESCRIPTION OF THE INVENTION
Compound of formula (II), compound of formula (III) and compound of formula (IV) are
simultaneously present in step (StepSl) and in reaction (ReacSl), therefore reaction
(ReacSl) is preferably done in one pot, i.e. reaction (ReacSl) is a one pot reaction.
Preferably, R l is selected from the group consisting of Ci_ alkyl, C3_ cycloalkyl,
C(0)-0-Ci_4 alkyl, CH=CH 2, benzyl and phenyl;
said Ci_5 alkyl of R l is unsubstituted or substituted with 1, 2, 3, 4 or 5 identical of different
substituents selected from the group consisting of halogen, OH, 0-C(0)-CH 3,
0-Ci_5 alkyl, S-Ci_5 alkyl, S(0)-Ci_ 5 alkyl, S(0 2)-Ci_5 alkyl, 0-Ci_ 4 alkylen-0-Ci_ 4 alkyl,
C3 _6 cycloalkyl and 1,2,4-triazolyl;
said benzyl and said phenyl of R l are independently from each other unsubstituted or
substituted with 1, 2, 3, 4 or 5 identical of different substituents selected from the group
consisting of halogen, Ci_2 alkoxy, N0 2 and CN;
more preferably, R l is selected from the group consisting of methyl, ethyl, isopropyl,
tert-butyl, cyclopropyl, trifluoromethyl, difluoromethyl, chloromethyl, bromomethyl,
C(0)-0-CH 3, C(0)-0-C 2H5, CH2-0-C(0)-CH 3, CH2- 0-CH 3, CH2-S-CH 3,
CH2-S(0 2)-CH 3, CH2-CH 2- 0-CH 3, CH2-0-CH 2-CH 2-0-CH 3,
CH2-0-CH 2-CH 2-0-CH 2-CH 3, CH=CH 2 and phenyl
even more preferably, R l is selected from the group consisting of methyl, ethyl,
chloromethyl, bromomethyl, CH2-0-C(0)-CH 3, and CH2-0-CH 2-CH 2-0-CH 3
especially, Rl is selected from the group consisting of methyl, chloromethyl, and
Preferably, Y is selected from the group consisting of Ci_ alkoxy, NHR4 and N(R4)R5;
R4 and R5 are identical or different and independently from each other Ci_ alkyl, or
represent together a tetramethylene or a pentamethylene chain;
more preferably, Y is selected from the group consisting of methoxy and ethoxy.
Preferably, RIO is selected from the group consisting of Ci_s alkyl, C 3-10 cycloalkyl and
phenyl,
said phenyl being unsubstituted or substituted with 1 or 2 identical or different
substituents independently from each other selected from the group consisting of
halogen, cyano, nitro, and Ci_ alkyl;
more preferably, RIO is selected from the group consisting of Ci_s alkyl, C 3-10 cycloalkyl and
phenyl,
said phenyl being unsubstituted or substituted with 1 or 2 identical or different
substituents independently from each other selected from the group consisting of
halogen and Ci_ alkyl;
even more preferably, RIO is selected from the group consisting of Ci_ alkyl, C3-6 cycloalkyl
and phenyl;
especially, R10 is selected from the group consisting of Ci_4 alkyl;
more especially, R10 is methyl or ethyl.
Preferably, R20 is selected from the group consisting of Ci_4 alkyl, 0(CO)CH 3, 0(CO)CF 3,
and OSO 3H;
more preferably R20 is selected from the group consisting of methyl, ethyl, 0(CO)CH 3,
0(CO)CF 3, and OSO 3H;
even more preferably R2 is methyl or ethyl.
Preferably, compound of formula (II) is selected from the group consisting of compound of
formula (II- 1), compound of formula (P-2), and mixtures thereof.
Preferably, the molar ratio [compound of formula (II) : compound of formula (III)] is from
[ 1 : 0.9] to [ 1 : 100], more preferably from [ 1 : 0.9] to [ 1 : 10], even more preferably from
[ 1 : 0.9] to [ 1 : 5], especially from [ 1 : 0.9] to [ 1 : 2.5].
Preferably, the molar ratio [compound of formula (II) : compound of formula (IV)] is from
[20 : 1] to [ 1 : 20], more preferably from [10 : 1] to [ 1 : 10], even more preferably from
[10 : 1] to [ 1 : 5], especially from [10 : 1] to [ 1 : 3].
Reaction (ReacSl) can be done in a solvent;
preferably, the solvent is a solvent (SolvSl) and solvent (SolvSl) is preferably selected from
the group consisting of ethyl acetate, butyl acetate, dichloromethane, chloroform,
acetonitrile, propionitrile, DMF, DMA, DMSO, sulfolane, THF, 2-methyl-THF,
3-methyl-THF, dioxane, 1,2-dimethoxyethane, toluene, benzene, chlorobenzene,
nitrobenzene, and mixtures thereof;
more preferably, solvent (SolvSl) is selected from the group consisting of ethyl acetate, butyl
acetate, dichloromethane, acetonitrile, propionitrile, DMF, DMA, sulfolane, THF,
2-methyl-THF, 3-methyl-THF, dioxane, 1,2-dimethoxyethane, toluene, benzene,
chlorobenzene, and mixtures thereof;
even more preferably, solvent (SolvSl) is selected from the group consisting of ethyl acetate,
butyl acetate, dichloromethane, acetonitrile, DMF, DMA, dioxane, 1,2-dimethoxyethane,
toluene, chlorobenzene, and mixtures thereof.
Preferably, the weight of solvent (SolvSl) is from 0.1 to 100 times, more preferably from 1 to
50 times, even more preferably from 1 to 25 times, of the weight of compound of formula
(II).
Reaction (ReacSl) can be done in the presence of an acid,
preferably the acid is a compound (AddSl);
compound (AddSl) is selected from the group consisting of acetic acid, propionic acid,
trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, sulfuric acid, hydrochloric
acid, acetic acid anhydride, acetyl chloride, toluenesulfonic acid, camphorsulfonic acid,
methanesulfonic acid, and mixtures thereof;
preferably, compound (AddSl) is selected from the group consisting of acetic acid, propionic
acid, trifluoroacetic acid, trichloroacetic acid, sulfuric acid, hydrochloric acid, acetic acid
anhydride, toluenesulfonic acid, methanesulfonic acid, and mixtures thereof;
more preferably, compound (AddSl) is selected from the group consisting of acetic acid,
trifluoroacetic acid, trichloroacetic acid, sulfuric acid, hydrochloric acid, acetic acid
anhydride, methanesulfonic acid, and mixtures thereof;
even more preferably, compound (AddSl) is selected from the group consisting of acetic acid,
trifluoroacetic acid, trichloroacetic acid, sulfuric acid, and mixtures thereof.
Preferably, the molar ratio [compound of formula (II) : compound (AddSl)] is from
[ 1 : 0.001] to [ 1 : 100], more preferably from [ 1 : 0.01] to [ 1 : 10], even more preferably
from [ 1 : 0.05] to [ 1 : 5], especialy [ 1 : 0.05] to [ 1 : 2], more especially [ 1 : 0.05] to
[ 1 : 1], even more especially [ 1 : 0.05] to [ 1 : 0.5].
Preferably, the reaction temperature of reaction (ReacSl) is from -50 to 250°C, more
preferably from -20 to 180°C, even more preferably from 0 to 150°C, especially from 10
to 150°C, more especially from 50 to 120°C.
Preferably, reaction (ReacSl) is done at a pressure of from ambient pressure to 20 bar, more
preferably of from ambient pressure to 15 bar, even more preferably of from ambient
pressure to 10 bar.
Preferably, the reaction time of reaction (ReacSl) is from 30 min to 96 h, more preferably
from 45 min to 48 h, even more preferably from 45 min to 36 h, especially from 45 min
to 24 h, more especially from 1 h to 24 h.
After reaction (ReacSl), compound of formula (I) can be isolated by any conventional
method.
Preferably, compound of formula (I) is isolated after reaction (ReacSl) by hydrolysis and
acidification of the reaction mixture resulting from reaction (ReacSl).
Hydrolysis and acidification is preferably done by addition of a compound (InAcSl),
compound (InAcSl) is an aqueous inorganic acid, preferably compound (InAcSl) is
selected from the group consisting of aqueous hydrochloric acid and aqueous sulfuric
acid.
After hydrolysis and acidification, any solvent (SolvSl) is preferably removed by distillation;
compound of formula (I) is preferably extracted by extraction with a solvent
(SolvExtrSl), solvent (SolvExtrSl) is preferably selected from the group consisting of
ethyl acetate, isopropyl acetate, butyl acetate, toluene, chlorobenzene, dichloromethane,
chloroform and mixtures thereof; the extraction is preferably followed by removal of
solvent (SolvExtrSl) by distillation.
Also possible is the purification of compound of formula (I) by saponification by treatment of
the reaction mixture resulting from reaction (ReacSl) or by treatment of the crude
product of formula (I) with an aqueous or methanolic solution of NaOH or KOH,
followed by acidification and extraction with solvent (SolvExtrS 1), preferably followed
by removal of solvent (SolvExtrS 1) by distillation, to yield compound of formula (I) with
Y = OH.
Compounds of formula (II) are known compounds and can be prepared by or in analogy of
known methods.
For instance compound of formula (P-2) can be prepared by saponification of ethyl
trifluoroacetoacetate as taught by F. Swarts, Bulletin de la Classe des Sciences, Academie
Royale de Belgique, 1926, 12, 721-725.
Compound of formula (III) is commercially available or can be prepared by in analogy of
known methods.
Compounds of formula (IV) are known compounds and can be prepared by or in analogy of
known methods, for instance as described in WO 2004/078729 Al.
Further subject of the invention is the use of compound of formula (I) for the preparation of
pharmaceutical, chemical or agro-chemical products,
with compound of formula (I) as defined above, also with all their preferred embodiments,
wherein compound of formula (I) has been prepared according to the method as described
above, also with all their preferred respective embodiments.
Examples
Example 1: Reaction (ReacSl)
A mixture of compound of formula (P-2) (0.10 g, 0.64 mmol), DMF (0.5 ml), compound of
formula (IV-1) (74 mg, 0.64 mmol), compound of formula (III- 1) (0.16 ml, 0.96 mmol),
(TII-1) (IV-1)
and sulfuric acid (0.007 ml, 0.13 mmol) was stirred at 80 °C for 3 h. A sample of the reaction
mixture was diluted with brine (3 ml) and aqueous hydrochloric acid ( 1 N, 2 ml), and
extracted with ethyl acetate (3 ml). After concentration under reduced pressure of the extract
the analysis by 1H NMR showed compound of formula (1-1).
1H NMR (400 MHz, de-DMSO): delta 2.78 (s, 3H), 3.91 (s, 3H), 7.89 (d, J = 8 Hz, 1H), 8.44
(d, J = 8 Hz, 1H).
Example 2 : Reaction (ReacSl)
A mixture of compound of formula (P-2) (0.12 g, 0.77 mmol), toluene (0.5 ml), compound of
formula (IV-1) ( 113 mg, 0.98 mmol), compound of formula (III- 1) (0.16 ml, 0.96 mmol), and
trifluoroacetic acid (0.01 ml, 0.13 mmol) was stirred at 80 °C for 17 h. A sample of the
reaction mixture was diluted with brine (3 ml) and aqueous hydrochloric acid ( 1 N, 2 ml), and
extracted with ethyl acetate (3 ml). After concentration of the extract under reduced pressure
the analysis by 1H NMR showed compound of formula (1-1), 1H NMR data was as shown in
example 1.
Example 3 : Reaction (ReacSl)
A mixture of compound of formula (P-2) (0.169 g, 1.08 mmol), toluene (0.52 ml), compound
of formula (IV-2) (0.26 mmol, prepared in analogy to example P2 of WO 2004/078729 Al,
wherein the reaction mixture, which is obtained after cooling and which contains
3-amino-4-methoxyethoxy-but-2-enoic acid ethyl ester, which is compound of formula
(IV-2), is taken and concentrated under reduced pressure, the thus obtained residue was used
in instant example, the content of compound of formula (IV-2) in this residue is determined
by 1H-NMR against a standard),
(IV-2)
compound of formula (III- 1) (0.40 ml, 2.4 mmol), and trifluoroacetic acid (0.01 ml, 0.13
mmol) was stirred at 80 °C for 18 h. The mixture was diluted with aqueous hydrochloric acid
( 1 N, 10 ml), extracted with ethyl acetate ( 1 time with 5 ml, 2 times with 2.5 ml), the
combined extracts were washed with brine (5 ml), dried (MgS0 4), and concentrated under
reduced pressure, to yield the compound of formula (1-2) as an oil ( 114 mg).
Quantification by 1H NMR with an internal standard (4-nitrobenzaldehyde) indicated, that the
yield with respect to compound of formula (IV) was 54%.
1H NMR (400 MHz, CDC13) : delta 1.42 (t, J = 7 Hz, 3H), 3.36 (s, 3H), 3.57 (m, 2H), 3.71 (m,
2H), 4.43 (q, J = 7 Hz, 2H), 5.02 (s, 2H), 7.68 (d, J = 8 Hz, 1H), 8.26 (d, J = 8 Hz, 1H).

Claims
1. Method for preparation of compound of formula (I);
the method comprises a step (StepSl);
step (StepSl) comprises a reaction (ReacSl);
reaction (ReacSl) is a reaction of a compound of formula (II) with a compound of formula
(III) and a compound of formula (IV);
compound of formula (II) is selected from the group consisting of compound of
formula (II- 1), compound of formula (P-2), compound of formula (Ila), and mixtures
thereof;
(III)
Rl is selected from the group consisting of Ci_io alkyl, C 3- cycloalkyl, C(0)-0-Ci_ 4 alkyl,
CH=CH 2, benzyl, phenyl and naphthyl;
the Ci_io alkyl of Rl is unsubstituted or substituted with 1, 2, 3, 4 or 5 identical or
different substituents selected from the group consisting of halogen, OH,
0-C(0)-Ci_5 alkyl, O-C Oalkyl, S-C Oalkyl, S(O)-Ci_i0 alkyl, S(O2)-Ci_i 0 alkyl,
0-Ci_ alkylen-0-Ci_ alkyl, C3_ cycloalkyl and 1,2,4-triazolyl;
the benzyl, the phenyl and the naphthyl of R l are independently from each other
unsubstituted or substituted with 1, 2, 3, 4 or 5 identical or different substituents
selected from the group consisting of halogen, Ci_4 alkoxy, N0 2 and CN;
Y is selected from the group consisting of Ci_ alkoxy, 0-Ci_ alkylen-0-Ci_ alkyl, NH2,
NHR4 and N(R4)R5;
R4 and R5 are identical or different and independently from each other Ci_ alkyl, or
represent together a tetramethylene or a pentamethylene chain;
RIO is selected from the group consisting of Ci_s alkyl, C3-10 cycloalkyl and phenyl,
said phenyl is unsubstituted or substituted with 1 or 2 identical or different substituents
independently from each other selected from the group consisting of halogen,
cyano, nitro, Ci_ alkyl and phenyl;
R20 is selected from the group consisting of Ci_6 alkyl, 0(CO)CH 3, 0(CO)CF 3, and OS0 3H.
2. Method according to claim 1, wherein
reaction (ReacSl) is done in one pot.
3. Method according to claim 1 or 2, wherein
R l is selected from the group consisting of Ci_ alkyl, C3_ cycloalkyl, C(0)-0-Ci_ 4 alkyl,
CH=CH 2, benzyl and phenyl;
said Ci_5 alkyl of R l is unsubstituted or substituted with 1, 2, 3, 4 or 5 identical of different
substituents selected from the group consisting of halogen, OH, 0-C(0)-CH 3,
0-Ci_5 alkyl, S-Ci_5 alkyl, S(0)-Ci_ 5 alkyl, S(0 2)- _5 alkyl, 0-Ci_ 4 alkylen-0-Ci_ 4 alkyl,
C3 _6 cycloalkyl and 1,2,4-triazolyl;
said benzyl and said phenyl of R l are independently from each other unsubstituted or
substituted with 1, 2, 3, 4 or 5 identical of different substituents selected from the group
consisting of halogen, Ci_2 alkoxy, N0 2 and CN.
4. Method according to one or more of claims 1 to 3, wherein
Y is selected from the group consisting of Ci_ alkoxy, NHR4 and N(R4)R5;
R4 and R5 are identical or different and independently from each other Ci_6 alkyl, or
represent together a tetramethylene or a pentamethylene chain.
5. Method according to one or more of claims 1 to 4, wherein
RIO is selected from the group consisting of Ci_s alkyl, C3-10 cycloalkyl and phenyl,
said phenyl being unsubstituted or substituted with 1 or 2 identical or different
substituents independently from each other selected from the group consisting of
halogen, cyano, nitro, and Ci_ alkyl.
6. Method according to one or more of claims 1 to 5, wherein
R20 is selected from the group consisting of Ci_4 alkyl, 0(CO)CH 3, 0(CO)CF 3, and OS0 3H.
7. Method according to one or more of claims 1 to 6, wherein
compound of formula (II) is selected from the group consisting of compound of formula
(II- 1), compound of formula (P-2), and mixtures thereof.
8. Method according to one or more of claims 1 to 7, wherein
reaction (ReacSl) is done in a solvent;
the solvent is a solvent (SolvSl) and solvent (SolvSl) is selected from the group consisting of
ethyl acetate, butyl acetate, dichloromethane, chloroform, acetonitrile, propionitrile,
DMF, DMA, DMSO, sulfolane, THF, 2-methyl-THF, 3-methyl-THF, dioxane, 1,2-
dimethoxyethane, toluene, benzene, chlorobenzene, nitrobenzene, and mixtures thereof.
9. Method according to one or more of claims 1 to 8, wherein
reaction (ReacSl) is done in the presence of an acid, the acid is a compound (AddSl);
compound (AddSl) is selected from the group consisting of acetic acid, propionic acid,
trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, sulfuric acid, hydrochloric
acid, acetic acid anhydride, acetyl chloride, toluenesulfonic acid, camphorsulfonic acid,
methanesulfonic acid, and mixtures thereof.