METHOD FOR PREPARATION OF 4-ALKOXY-l,l,l-TRIFLUOROBUT-3-EN-2-
ONES FROM 1,1,1-TRIFLUOROACETONE
The invention discloses a method for the preparation of 4-alkoxy- 1,1,1 -trifluorobut-3-en-2-
ones from 1,1,1 -trifluoroacetone .
BACKGROUND OF THE INVENTION
4-Alkoxy and 4-aryloxy-l,l,l-trifluorobut-3-en-2-ones of formula (I) are important synthetic
intermediates for the preparation of fluorinated heterocycles.
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.
WO 2005/026149 A, DE 24 29 674 A and EP 5 1 209 A disclose certain precursors used in
instant invention.
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:
O
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.
US 20130079377 describes the use and preparation from vinyl ethers of 4-alkoxy- 1,1,1-
trifluorobut-3-en-2-ones for the synthesis of novel vanilloid receptor ligands.
US 20120101305 discloses the preparation of 4-alkoxy- l,l,l-trifluorobut-3-en-2-ones from
vinyl ethers and trifluoroacetyl chloride.
US 20140051892 Al discloses a method for the preparation of 4-ethoxy- 1,1,1 -trifluorobut-3-
en-2-one by reacting trifluoroacetyl chloride with ethyl vinyl ether, followed by thermolysis
of the resulting chlorinated intermediate. A disadvantage of this method is the formation of
hydrogen chloride, which is corrosive and could lead to a product of low storability .
WO 2004/078729 Al discloses the preparation of compound of formula (Xa) from inter alia
4-alkoxy- 1,1,1 -trifluorobut-3-en-2-ones;
and discloses on page 18 in example P2 the use of 4-ethoxy- l,l,l-trifluorobut-3-en-2-one for
the preparation of compound of formula (X-1).
Compound of formula (Xa) and compound of formula (X-l) are intermediates for the
preparation of herbicides.
All known routes to 4-alkoxy- 1,1,1 -trifluorobut-3 -en-2-ones are based on the reaction of vinyl
ethers with trifluoroacetyl chloride or trifluoroacetic anhydride, whereupon one equivalent of
HCl or trifluoroacetic acid are formed as byproducts, that must usually be trapped by addition
of a base to prevent the acid-mediated degradation of the product. A further disadvantage of
this synthetic strategy for the large scale production of 4-alkoxy- 1,1,1 -trifluorobut-3 -en-2-
ones is the high flammability and mutagenicity of vinyl ethers.
There was a need for an improved method for the preparation of 4-alkoxy- 1,1,1 -trifluorobut-
3-en-2-ones. The method should not require the use of the problematic trifluoroacetyl chloride
and ethylvinylether. This need was met by the method of instant invention as outlined below.
Compared to prior art, the method of the instant invention offers several advantages: It gives
access to 4-alkoxy- 1,1,1 -trifluorobut-3 -en-2-ones without the formation of hydrogen chloride.
Only acetic acid, ethyl acetate, and ethyl formate are formed as byproducts, allowing the use
of non-HCl-resistant reactors. Importantly, no problematic vinyl ethers are required.
Moreover, the method of the present invention only comprises one synthetic step, and is
therefore less costly than the two-step procedure disclosed in US 20140051892 Al.
In the following text, if not otherwise stated,
ambient pressure usually 1 bar, depending on the weather;
halogen means F, CI, Br or I, preferably CI, Br or I;
alkyl means a linear or branched alkyl, examples of alkyl include methyl, ethyl, npropyl,
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;
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 1,1,1-
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 1,1,1-trifluoroacetone is F3C-C(OH) 2-CH3;
LDA Lithium diisopropyl amide
NMP N-methyl-2-pyrrolidone;
sulfamic acid HO-S0 2-NH2;
Temp Temperature;
TriFA 1,1,1-trifluoroacetone;
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 the preparation of compound of formula (I);
o
F,C OR1 (I)
the method comprises step StepSl; step StepSl comprises a reaction ReacSl;
reaction ReacSl is a reaction of a compound of formula (II) with 1,1,1-trifluoroacetone in the
presence of compound of formula (IV);
wherein
Rl is Ci_4 alkyl;
R4 and R5 are identical or different and independently from each other selected from the
group consisting of H and C alkyl.
DETAILED DESCRIPTION OF THE INVENTION
Compound of formula (II), 1,1,1 -trifluoroacetone and compound of formula (IV) can be
mixed for the reaction ReacS 1 in any order.
Preferably, Rl, is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and
n-butyl;
more preferably, Rl is selected from the group consisting of methyl, ethyl and n-propyl;
even more preferably, Rl is methyl or ethyl;
especially, Rl is ethyl.
Preferably, R4 and R5 are identical or different and independently from each other selected
from the group consisting of hydrogen and Ci_2 alkyl;
more preferably, R4 and R5 are identical or different and independently from each other
selected from the group consisting of hydrogen and methyl;
even more preferably, R4 and R5 are identical or different and independently from each other
hydrogen or methyl;
especially, R4 and R5 are methyl.
Preferably, the molar amount of compound (II) is from 1 to 20 times, more preferably from 1
to 10 times, and even more preferably from 1 to 6 times, based on the molar amount of
1,1,1 -trifluoroacetone.
Preferably, the molar amount of compound (IV) is from 2 to 60 times, more preferably from 2
to 20 times, and even more preferably from 2 to 10 times, based on the molar amount of
1,1,1 -trifluoroacetone.
Reaction ReacS 1 can be done in the presence of a catalyst CatS 1;
catalyst CatSl is selected from the group consisting of trifluoroacetic acid, sulfuric acid,
ZnCl2, ZnBr2, Znl2, BF3, BF3OEt2, BBr3, BC13, MgCl2, and CaCl2;
preferably, catalyst CatS 1 is selected from the group consisting of trifluoroacetic acid, sulfuric
acid, ZnCl2, ZnBr2, Znl2, BF3OEt2, BC13, MgCl2, and CaCl2;
more preferably, catalyst CatS 1 is selected from the group consisting of trifluoroacetic acid,
sulfuric acid, ZnCl2, BF3OEt2, MgCl2, and CaCl2;
even more preferably, catalyst CatS 1 is selected from the group consisting of trifluoroacetic
acid, ZnCl2, BF3OEt2, and MgCl2;
Preferably, the molar amount of catalyst CatSl is from 0.001 to 2 times, more preferably from
0.005 to 1 times, and even more preferably from 0.01 to 0.5 times, based on the molar
amount of 1,1,1-trifluoroacetone.
Preferably, reaction ReacS 1 is done at a temperature of from 0 °C to 250 °C, more preferably
from 20 °C to 200 °C, even more preferably from 60 °C to 150 °C.
Preferably, reaction ReacS 1 is done at a pressure of from ambient pressure to 150 bar, more
preferably from ambient pressure to 100 bar, even more preferably from ambient pressure
to 70 bar.
Preferably, the reaction time of reaction ReacS 1 is from 10 min to 72 h, more preferably from
1 h to 48 h, even more preferably from 2 h to 24 h.
Reaction (ReacSl) can be done in a solvent;
preferably, the solvent is a solvent (SolvSl) and solvent (SolvSl) is selected from the group
consisting of ethyl acetate, butyl acetate, dichloromethane, 1,2-dichloroethane,
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, 1,2-dichloroethane, acetonitrile, propionitrile, DMF, DMA,
DMSO, 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, 1,2-dichloroethane, acetonitrile, DMF, DMA, sulfolane,
dioxane, 1,2-dimethoxyethane, toluene, chlorobenzene, and mixtures thereof;
especially, solvent (SolvSl) is selected from the group consisting of ethyl acetate, butyl
acetate, dichloromethane, 1,2-dichloroethane, 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
1,1,1 -trifluoroacetone.
After reaction ReacSl, any catalyst CatSl can be removed by filtration.
Compound of formula (I) can be isolated after the reaction ReacS 1 by any conventional
method, for instance by distillation under reduced pressure or by crystallization. Preferably,
any volatile byproduct is distilled off, and the residue is purified or used without further
purification.
Examples
Example 1
A mixture of 1,1,1 -trifluoroacetone (0.80 ml, 8.93 mmol), triethylorthoformate (2.23 ml, 13.0
mmol) and acetic anhydride (2.53 ml, 27.0 mmol) was stirred in a closed vial at 140 °C for 16
h.
Analysis of a sample by 1H NMR (CDC13) indicated formation of compound of formula (1) in
65% yield with respect to 1,1,1 -trifluoroacetone used.
Examples 2 to 5
Examples 2 to 5 were done in the same way as example 1, with any differences as given
Table 1.
Example 6
A mixture of 1,1,1 -trifluoroacetone (0.20 ml, 2.2 mmol), trimethylorthoformate (1.0 ml, 9.1
mmol), and acetic anhydride (1.6 ml, 16.9 mmol) was stirred in a closed vial at 140 °C for 16
h. Analysis of a sample by 1H NMR (CDCI3) indicated formation of compound of formula (2)
in 78% yield with respect to trifluoroacetone used.
(2)
1H NMR (CDCI3, 400 MHz) delta = 3.88 (s, 3H), 5.87 (d, J = 12 Hz, 1H), 7.94 (d, J = 12 Hz,
1H).
F NMR (CDCI3) delta = 78.08 ppm.
Claims
1. Method for the preparation of compound of formula (I);
the method comprises step StepSl; step StepSl comprises a reaction ReacSl;
reaction ReacSl is a reaction of a compound of formula (II) with 1,1,1-trifluoroacetone in the
presence of compound of formula (IV);
( ) (IV)
wherein
Rl is Ci_4 alkyl;
R4 and R5 are identical or different and independently from each other selected from the
group consisting of H and C alkyl.
2. Method according to claim 1, wherein
Rl, is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and n-butyl.
3. Method according to claim 1 or 2, wherein
R4 and R5 are identical or different and independently from each other selected from the
group consisting of hydrogen and Ci_2 alkyl.
4. Method according to one or more of claims 1 to 3, wherein
the molar amount of compound (II) is from 1 to 20 times based on the molar amount of
1,1,1 -trifluoroacetone.
5. Method according to one or more of claims 1 to 4, wherein
the molar amount of compound (IV) is from 2 to 60 times based on the molar amount of
1,1,1 -trifluoroacetone.
6. Method according to one or more of claims 1 to 5, wherein
reaction ReacSl is done in the presence of a catalyst CatSl;
catalyst CatSl is selected from the group consisting of trifluoroacetic acid, sulfuric acid,
ZnCl2, ZnBr2, Znl2, BF3, BF3OEt2, BBr3, BC13, MgCl2, and CaCl2.
7. Method according to one or more of claims 1 to 6, wherein
the molar amount of catalyst CatSl is from 0.001 to 2 times based on the molar amount of
1,1,1 -trifluoroacetone.
8. Method according to one or more of claims 1 to 7, wherein
reaction ReacSl is done at a temperature of from 0 °C to 250 °C.
9. Method according to one or more of claims 1 to 8, wherein
the reaction time of reaction ReacSl is from 10 min to 72 h.