Process for preparing 2-haloalkylnicotinic acids

Details Process for preparing 2-haloalkylnicotinic acids Process for preparing 2-haloalkylnicotinic acids

2003-02-24

2004-08-17

Morris, Patricia L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06777556

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for preparing 2-haloalkylnicotinic acids and derivatives thereof and also to intermediates.
2. Brief Description of the Prior Art
2-Haloalkylnicotinic acids and their derivatives, particularly 2-trifluoromethylnicotinic acid, are valuable intermediates, for example for preparing active pharmaceutical ingredients and agrochemicals.
Tetrahedron Lett. 1998, 39, 7965 and J. Heterocycl. Chem. 1995, 32, 543 disclose that 2-halomethyl-5-cyanopyridines can be prepared from halomethyl-substituted enones and enaminonitriles. These may be converted in a manner known per se, for example by hydrolysis, to the corresponding nicotinic acids. A disadvantage of industrial application of this process is that the preparation of the corresponding enaminonitriles is costly and inconvenient. Hence the resulting products are expensive.
According to Heterocycles 1997, 46, 129, 2-trifluoromethylnicotinic acids may be prepared from &bgr;-trifluoroacetylvinylamine and substituted 1,3-diketones. However, it is generally only possible by this process to obtain nicotinic acids substituted in the 6-position., From this, it is possible to obtain compounds unsubstituted in the 6-position, for example by reductive dehalogenation of the 6-halo compounds. Owing to the high number of reaction steps, this process is also uneconomic.
Alternatively, according to WO 00/39094, substituted &bgr;-acetylvinylamines and &bgr;-ketoesters can be converted to the corresponding nicotinic esters. Owing to the costly and inconvenient preparation of the isolated &bgr;-acetylvinylamines, this process is also unsuitable for industrial application.
There was therefore a need to develop a process which, starting from readily available reactants, makes it possible to prepare the 2-haloalkylnicotinic acids in few steps.
SUMMARY OF THE INVENTION
A process has now been found for preparing 2-haloalkylnicotinic acids and 2-haloalkyl acid derivatives, which is characterized in that
a) compounds of the general formula (I)
in which
R
1
is C
1
-C
12
-haloalkyl and
R
2
is C
1
-C
12
-alkyl
are reacted with compounds of the general formula (II)
in which
R
3
, R
4
and R
5
are each independently C
1
-C
12
-alkyl
to give compounds of the general formula (III)
in which
R
3
, R
4
, R
5
and R
5
are each as defined above, and
b) the compounds of the general formula (III) are reacted with ammonia or ammonium salts to give compounds of the general formula (IV)
in which
R
1
and R
5
are as defined above, and
c) optionally, the compounds of the general formula (IV) are hydrolysed
to give compounds of the general formula (V)
in which
R
1
is C
1
-C
12
-haloalkyl and
R
6
is M or hydrogen, where M is one equivalent of an alkali metal or half an equivalent of alkaline earth metal.
The scope of the invention also encompasses the compounds of the general formulae (III) and (IV) themselves.
DETAILED DESCRIPTION OF THE INVENTION
The invention is described more fully hereunder with particular reference to its preferred embodiments. For the purposes of the invention, alkyl is a straight-chain or cyclic, branched or unbranched alkyl radical. For example and with preference, C
1
-C
12
-alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, cyclohexyl, n-hexyl, n-octyl, isooctyl, n-decyl and n-dodecyl.
For the purposes of the invention, haloalkyl means a straight-chain or cyclic, branched or unbranched alkyl radical which is substituted once or more than once overall in the &agr;-position at least singly by halogen atoms which may each be selected independently from the group of fluorine, chlorine and bromine.
For example and with preference, C
1
-C
12
-haloalkyl is fluoromethyl, difluoromethyl, trifluoromethyl, tribromomethyl, dibromofluoromethyl, bromodifluoromethyl, trichloromethyl, dichlorofluoromethyl, chlorodifluoromethyl, trifluoromethyl, tribromomethyl, dibromofluoromethyl, pentafluoroethyl and n-nonafluorobutyl.
It is pointed out that any desired combinations of preferred compounds are encompassed by the scope of the invention.
In the compounds of the general formula (I), R
1
is more preferably C
1
-C
4
-haloalkyl, even more preferably trifluoromethyl, trichloromethyl, dichlorofluoromethyl and pentafluoroethyl, trifluoromethyl being still further preferred.
In the compounds of the general formula (I), R
2
is more preferably C
1
-C
4
-alkyl, even more preferably ethyl or methyl, ethyl being still further preferred.
Special mentioned is made of the following compounds of the general formula (I): 1,1,1-trifluoro-2-oxo-4-ethoxybut-3-ene, 1-bromo-1,1-difluoro-2-oxo-4-ethoxybut-3-ene, 1-chloro-1,1-difluoro-2-oxo-4-ethoxybut-3-ene and 1,1,1-trichloro-2-oxo-4-ethoxybut-3-ene.
In the compounds of the general formula (II), R
3
and R
4
are more preferably identical and are each C
1
-C
4
-alkyl, even more preferably identical and are each methyl or ethyl, methyl being still further preferred.
In the compounds of the general formula (II), R
5
is more preferably C
1
-C
4
-alkyl, even more preferably ethyl or methyl.
The following are illustrative examples of the compounds of the general formula (II): methyl 3-N,N-dimethylaminoacrylate, ethyl 3-N,N-diethylaminoacrylate, ethyl 3-N,N-dimethylaminoacrylate and methyl 3-N,N-diethylaminoacrylate.
The compounds of the general formula (I) are commercially available or can be synthesized by methods known from the literature or analogous thereto.
The compounds of the general formula (II) are likewise commercially available and can be synthesized by methods known from the literature (see, for example, WO 00/000460 or DE-OS (German published specification) 44 18 155) or analogous thereto.
Preference is given to carrying out the reaction of step a) in the presence of solvent. Examples of useful solvents include dipolar, aprotic solvents and mixtures which comprise dipolar, aprotic solvents. Examples of useful dipolar, aprotic solvents include nitrites such as acetonitrile, propionitrile, n- and i-butyronitrile, benzyl nitrile and benzonitrile, amides such as formamide, N-methylformamide, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, esters such as methyl acetate, ethyl acetate or butyl acetate, sulphoxides such as dimethyl sulphoxide and sulphones such as sulpholane or mixtures thereof. The dipolar, aprotic solvents may also be used in mixtures, for example, with aliphatic and/or aromatic hydrocarbons and/or ethers. Particularly preferred dipolar, aprotic solvents are N,N-dimethylformamide and N,N-dimethylacetamide. Very particular preference is given to N,N-dimethylformamide. The amount of solvent used is not critical, and preference is given to using from 250 to 500 ml per mole of the particular compound of the general formula (I).
To carry out step a), for example, the particular compound of the general formula (I) and the particular compound of the general formula (II) may be used in a molar ratio of, for example, 0.3:1 to 5:1, preferably 0.5:1 to 2:1, more preferably 0.9 to 1.1 and most preferably in equimolar amounts.
The reaction temperature in step a) may be, for example, 0 to 100° C., preferably 20 to 80° C. and more preferably 30 to 50° C.
The reaction time for step a) may be, for example, 5 min to 48 h, and preference is given to 4 to 12 h.
Step a) of the process according to the invention may be carried out, for example, at a pressure of 0.5 to 100 bar, and preference is given to ambient pressure.
In this way, compounds of the general formula (III) are obtained
in which the R
1
, R
3
, R
4
and R
5
radicals have the same meanings and preferred ranges as specified under the general formulae (I) and (II). The following are illustrative examples of the compounds: ethyl 2-dimethylaminomethylene-6,6,6-trifluoro-5-oxo-3-hexenoate, ethyl 2-dimethylaminomethylene-6-bromo-6,6-difluoro-5-oxo-3-hexenoate, ethyl 2-dimethylaminomethylene-6-chloro-6,6-difluoro-5-oxo-3-hexenoate, ethyl 2-dimethylaminomethylene-6,6,6-trichloro-5-oxo-3-hexenoate.
The compounds of the general formul

Affiliated with

Also associated with

Rating

Process for preparing 2-haloalkylnicotinic acids does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for preparing 2-haloalkylnicotinic acids, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparing 2-haloalkylnicotinic acids will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3340506