The present invention relates to a process for the synthesis of haloalkyl
5 substituted pyridine compounds, a process for manufacturing a pharmaceutically
or agriculturally active compound, preferably a herbicidal compound, and a
haloalkyl substituted pyridine compound.
Certain haloalkyl substituted pyridine compounds are useful for example
as intermediates for the preparation of various agriculturally active substances.
10 JP2017025054 discloses, for example, the use oftrifluoromethyl substituted
nicotinic acid derivatives for the synthesis of heterocycle amide compounds.
R.W. Lang et al, Helv. Chim. Acta, Vol 71 (1988) p. 596-601 discloses
antihypertensives based on certain 6-(trifluoromethyl)-substituted 2(1H)pyridinones.
JP2019182864 discloses a manufacturing method for pyridine
15 compounds that necessitates the use of a variety of sol vents and multiple
extraction steps, leading to a high amount of waste of contaminated solvents and
aqueous waste contaminated with organics.
It is an object of the present invention to provide an efficient process for
manufacturing of certain haloalkyl substituted pyridine compounds which allows
20 for good yields and product purities, starting from readily available starting
materials, avoiding waste and multiple steps for purification.
25
The invention thus concerns a process for the manufacture of a compound
offormula (IV), which comprises a step (a) of reacting a compound offormula
(I) and a compound of formula (II) to form the intermediary product (III)
0
R'o1 ~2OH I
~ R3
+
(I) (II) (Ill)
wherein R1 is selected from the group ofC1- C4 alkyl groups
30 wherein step (a) is performed in the presence of a base and in the absence
of a solvent,
wo 2021/152055 PCT/EP2021/052048
5
10
15
- 2-
which further comprises a step (b) wherein the intermediary product (III) is
cyclized into the compound of formula (IV) by addition of an acid.
0 0
RCO~R' OH ~o-R'
~R3 (b) R31LN~O
(Ill) (IV)
Another object of the present invention is a process for the purification of a
compound of formula (IV), wherein the process comprises a step (c) wherein the
compound of formula (IV) comprising impurities is reacted with a basic metal
salt to form the product of formula (V)
0
~0~R1
R31LN~O
(IV)
(c)
a step (d) wherein the compound of formula (V) is isolated as a solid
compound and
a step (e) wherein the compound of formula (V) is contacted with an acid
20 to obtain a purified compound of formula (IV).
The invention further concerns the compound of formula (V).
The residues R1 to R4 will be defined below.
In the context of the present invention, the singular form is intended also to
include the plural. All aspects and embodiments of the present invention are
25 combinable. In the context of the present invention, the term "comprising" is
intended to include the meaning of"consisting of' and "consisting essentially
of'. Endpoints of ranges are also included in the disclosure, e.g. a temperature
range of 20°C to 50°C includes the values 20°C and 50°C. When a double bond
is depicted in a particular E/Z geometry, this is intended to also denote the other
30 geometric form as well as mixtures thereof Compounds bearing one or more
stereocenters are intended to include all mixtures of the stereoisomers, including
stereochemically pure isomers. It should be noted that the compound of formula
(IV) can also be depicted in its enol form as shown below. When the keto form is
depicted, this includes the enol form.
35 0
c{o-R'
R3 N 0
(IV) keto
-
0
_cCo-R'
R3 N OH
(IV) enol
wo 2021/152055 PCT/EP2021/052048
- 3 -
The compound of formula (III) likewise, when drawn in its enol form,
5 includes the keto form.
10
In a first aspect, the invention concerns a process for the manufacture of a
compound offormula (IV), which comprises a step (a) of reacting a compound
of formula (I) and a compound of formula (II) to form the intermediary product
(III)
0
R'o1 ~2OH I
~ R3
+
(I) (II) (Ill)
wherein R1 is selected from the group ofC1- C4 alkyl groups
15 wherein step (a) is performed in the presence of a base and in the absence
20
25
of a solvent,
which further comprises a step (b) wherein the intermediary product (III) is
cyclized into the compound of formula (IV) by addition of an acid.
0 0
RCO~R' OH ~o-R'
~R3 (b) R31LN~O
(Ill) (IV)
R1 is selected from the group of C1 - C4 alkyl groups, including all isomers
of propyl and butyl. Preferably, R1 is methyl or ethyl, and most preferably, R1 is
ethyl.
R2 is -CN or -C(O)NH2, wherein -CN is preferred.
R3 is selected from the group consisting ofCFH2, CC1F2, CF2H, CF3 and
CChF. R3 preferably is CF3.
30 R4 is selected from the group of C1 - C4 alkyl groups, including all isomers
of propyl and butyl. Preferably, R 4 is methyl, ethyl or n-butyl, and most
preferably, R4 is ethyl.
In a most preferred aspect of the process comprising step (a) and (b), R1
and R4 are ethyl, R3 is CF3 and R2 is -CN.
35 Step (a) is performed in the presence of a base. The nature of the base is
not particularly limited and can be, for example, selected from the group
wo 2021/152055 PCT/EP2021/052048
- 4-
consisting of sodium hydroxide, potassium hydroxide, sodium methoxide,
sodium hydride, sodium hydrogen carbonate, sodium carbonate, potassium
carbonate, ammonia, triethylamine, diisopropylethylamine, pyridine and 4-
( dimethylamino )pyridine. The more preferred bases are triethylamine and
5 diisopropylethylamine. Diisopropylethylamine is more easily recycled. The
amount ofbase in step (a) generally is from 0.7 to 2 molar equivalents relative to
the compound of formula (II), preferably from 0.9 to 1.2 molar equivalents, and
most preferably from 1 to 1.05 molar equivalents. It is defined that the base is
not a solvent in the sense of the present invention.
10 Step (a) generally is performed at a temperature of from ooc to 90°C, more
preferably of from 1 0°C to 80°C and most preferably at a temperature of from
20°C to 70°C.
The addition time in step (a), calculated from the start of the addition of the
last starting material/reagent, generally is from 5 minutes to 5 hours, more
15 preferably from 10 minutes to 2 hours, and more preferably from 30 to 60
minutes. The reaction time in step (a), calculated from the end of the addition of
the last starting material/reagent, generally is from 5 minutes to 5 hours, more
preferably from 10 minutes to 2 hours, and more preferably from 30 to 60
minutes.
20 The order in which the starting materials and reactants are added to step (a)
is not particularly limited. It is, though, preferred to admix the base and the
compound of formula (I), and then to add the compound of formula (II) to the
mixture ofbase and compound of formula (I). This addition order can have an
advantageous impact on the yield of the reaction and the impurity profile of the
25 intermediate product mixture, and thus, also the end product.
Step (a) is performed in the absence of a solvent. "Absence of a solvent" is
intended to denote that no solvent is added to step (a), this excludes the active
addition of a solvent to step (a). The compounds of formula (I) and (II), as well
as the base, do not constitute a "solvent" in the sense of the present invention. It
30 is acknowledged that in step (a), R40H is liberated. The liberation ofR40H does
not contradict the term "absence of a solvent". The inventors have noted that the
absence of a solvent in step (a) generally improves the reaction of step (a) in the
sense that the reaction runs with less side products and a higher turnover of
starting materials. Additional solvents in step (a), such aromatic or aliphatic
35 hydrocarbons, dimethylformamide, acetonitrile or others, would also lead to
disadvantageous mixtures of solvents in workup and waste treatment.
wo 2021/152055 PCT/EP2021/052048
- 5 -
The step (a) generally yields a compound of formula (III)
0
R~O~R20H
~R3
5 (Ill)
10
15
20
which, as described above, can also be represented by its keto form:
0
R'01 ~20
~ R3
(Ill) keto form
It should be noted that the compound of formula (III) may also be
represented in its salt form (Ilia), which is formed when the compound of
formula (I) is deprotonated, adds to the double bond of (II) and nominally
forms (III) or (Ilia):
Formally, (Ilia) also comprises the cation B+, such as Et3NH+, which stems
from the base used in step (a). The above representations of the compound of
25 formula (III) are interchangeable and are encompassed whenever one formula
relating to (III) is depicted.

CLAIMS
1. Process for the manufacture of a compound of formula (IV), which
comprises a step (a) of reacting a compound of formula (I) and a compound of
formula (II) to form the intermediary product (III)
+
(I) (II)
wherein R1 is selected from the group of C1 - C4 alkyl groups
R2 is -CN or -C(O)NH2
10 R3 is selected from the group consisting ofCFH2, CC1F2, CF2H, CF3 and
CChF
R4 is selected from the group of C1 - C4 alkyl groups
wherein step (a) is performed in the presence of a base and in the absence
of a solvent,
15 which further comprises a step (b) wherein the intermediary product (III) is
20
cyclized into the compound of formula (IV) by addition of an acid.
(b)
2. The process according to claim 1 wherein to the reaction mixture
obtained by step (a) is added a solvent of formula R40H before addition of the
acid in step (b).
3. The process according to claim 1 or 2, wherein R1 is methyl or ethyl,
25 preferably ethyl.
wo 2021/152055 PCT/EP2021/052048
- 17-
4. The process according to anyone of claims 1 to 3, wherein R2 is -CN.
5. The process according to anyone of claims 1 to 4, wherein R3 is CF3.
6. The process according to anyone of claims 1 to 5, wherein R4 is
methyl, ethyl or n-butyl, wherein ethyl is preferred.
5 7. A process for the purification of a compound of formula (IV), wherein
10
the process comprises a step (c) wherein the compound of formula (IV)
comprising impurities is reacted with a basic metal salt to form the product of
formula (V)
(c)
wherein R1 is selected from the group of C1 - C4 alkyl groups
R3 is selected from the group consisting ofCFH2, CC1F2, CF2H, CF3 and
CChF
15 M is a cation of the alkali or earth alkali group;
a step (d) wherein the compound of formula (V) is isolated as a solid
compound and
a step (e) wherein the compound of formula (V) is contacted with an acid
to obtain a purified compound of formula (IV).
20 8. The process according to claim 7, wherein R3 is CF3.
9. The process according to claim 7 or 8, wherein R1 is methyl or ethyl,
preferably ethyl.
10. The process according to anyone of claims 7 to 9, wherein M is Na+ or
wo 2021/152055 PCT/EP2021/052048
- 18-
11. The process according to anyone of claims 7 to 10, wherein step (c) is
performed at a temperature of from -1 ooc to 80°C, preferably at a temperature of
from 20°C to 50°C.
12. The process according to anyone of claims 1 to 6 which further
5 comprises the process according to anyone of claims 7 to 11.
13. A compound of formula (V)
10 wherein R1
, R3 and Mare defined as in anyone of claims 7 to 10.
14. A compound according to claim 11, isolated as a solid.
15. A process for manufacturing a pharmaceutically or agriculturally
active compound, preferably a herbicidal compound, which comprises the
processes according to anyone of claim 1 to 12.