Fluorinated benzaldehydes
View Patent ↗The present invention relates to fluorinated benzaldehydes, to a process for preparing them and also to the use of the fluorinated benzaldehydes for preparing active ingredients, especially in medicaments and agrochemicals.
1. A process for preparing compounds of the formula (I)
where
R 1 is in each case independently C 1 -C 12 -alkyl, chlorine or bromine or a radical of the formulae (IIa) or (IIb)
A-B-D-E (IIa)
A-E (IIb)
where, each independently,
A is absent or is a C 1 -C 8 -alkylene radical and
B is absent or is oxygen, sulphur or NR 2
where R 2 is hydrogen or C 1 -C 8 -alkyl and
D is a carbonyl group and
E is C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, NH(C 1 -C 8 -alkyl) or N(C 1 -C 8 -alkyl) 2 or is a cyclic amino radical having 4 to 12 carbon atoms and
n is an integer of 0 to 3-m and
R F is fluorine, C 1 -C 12 -fluoroalkyl, —O(C 1 -C 12 -fluoroalkyl) or —S(C 1 -C 12 -fluoroalkyl) and
m is an integer of 1 to 3,
comprising
converting a compound of the formula (II)
where R 1 and R F , and also n and m, are as defined above
in the presence of urotropin and
in the presence of acid
to compounds of the formula (I).
2. The process according to claim 1 , wherein R 1 is in each case independently C 1 -C 4 -alkyl or chlorine.
3. The process according to claim 1 , wherein n is 0 or 1.
4. The process according to claim 1 , wherein R F is fluorine, C 1 -C 4 -fluoroalkyl, —O(C 1 -C 4 -fluoroalkyl) or —S(C 1 -C 4 -fluoroalkyl).
5. The process according to claim 1 , wherein the molar ratio of urotropin to compounds of the formula (II) is 1:1 to 10:1.
6. The process according to claim 1 , wherein the molar ratio of acid to compounds of the formula (II) is 1:1 to 100:1.
7. The process according to claim 1 , wherein the acid used is one which, based on an aqueous reference system at 25° C., has a pK value of 3 or less.
8. The process according to claim 1 , wherein the acids used are perfluoroalkylcarboxylic acids, ortho-phosphoric acid and polyphosphoric acids, organic sulphonic acids, hydrochloric, hydrobromic or hydriodic acid optionally dissolved in acetic acid, hydrogen sulphates or sulphuric acid.
9. The process according to claim 1 , wherein the compounds of the formula (II) are prepared by converting compounds of the formula (III)
where
R 1 , R F and m each have the definition specified above and
n is an integer between 0 and 3-m,
a) in the presence of formaldehyde and
in the presence of secondary amines of the formula (IV)
HNR 3 R 4 (IV)
where
R 3 and R 4 are each independently C 1 -C 8 -alkyl or NR 3 R 4 as a whole is a cyclic amino radical having a total of 4 to 12 carbon atoms,
into compounds of the formula (V)
where
R 1 , R 3 , R 4 and R F , and also n and m, each have the definition specified above, and
b) reducing the compounds of the formula (V) to compounds of the formula (II).
10. The process according to claim 9 , wherein the molar ratio in step a) of formaldehyde to compounds of the formula (III) is 0.8 to 10.
11. The process according to claim 9 , wherein the molar ratio in step a) of secondary amines of the formula (IV) to compounds of the formula (III) is 0.8 to 10.
12. The process according to claim 9 , wherein the reduction of step b) is carried out in the presence of hydrogen and hydrogenation catalysts.
13. The process according to claim 12 , wherein the hydrogenation catalyst used is a metal or metal compound selected from the group consisting of a salt or complex of nickel, palladium, platinum, cobalt, rhodium, iridium and ruthenium.
14. The process according to claim 12 , wherein the reduction in step b) is effected at a reaction temperature of 20° C. to 200° C. and a partial hydrogen pressure of 0.1 to 180 bar.
15. A compound of the formula (I)
where
R 1 is in each case independently C 1 -C 12 -alkyl, chlorine or bromine or a radical of the formulae (IIa) or (IIb)
A-B-D-E (IIa)
A-E (IIb)
where, each independently,
A is absent or is a C 1 -C 8 -alkylene radical and
B is absent or is oxygen, sulphur or NR 2
where R 2 is hydrogen or C 1 -C 8 -alkyl and
D is a carbonyl group and
E is C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, NH(C 1 -C 8 -alkyl) or N(C 1 -C 8 -alkyl) 2 or is a cyclic amino radical having 4 to 12 carbon atoms and
n is an integer of 0 to 3-m and
R F is fluorine, C 1 -C 12 -fluoroalkyl, —O(C 1 -C 12 -fluoroalkyl) or —S(C 1 -C 12 -fluoroalkyl) and
m is an integer of 1 to 3.
16. The compound of formula (I) according to claim 15 selected from the group consisting of 5-fluoro-2-hydroxy-3-methylbenzaldehyde, 5,6-difluoro-2-hydroxy-3-methylbenzaldehyde and 2-hydroxy-3-methyl-5-(trifluoromethoxy)benzaldehyde.
17. A compound of the formula (II)
where
R 1 is in each case independently C 1 -C 12 -alkyl, chlorine or bromine or a radical of the formulae (IIa) or (IIb)
A-B-D-E (IIa)
A-E (IIb)
where, each independently,
A is absent or is a C 1 -C 8 -alkylene radical and
B is absent or is oxygen, sulphur or NR 2
where R 2 is hydrogen or C 1 -C 8 -alkyl and
D is a carbonyl group and
E is C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, NH(C 1 -C 8 -alkyl) or N(C 1 -C 8 -alkyl) 2 or is a cyclic amino radical having 4 to 12 carbon atoms and
n is an integer of 0 to 3-m and
R F is fluorine, C 1 -C 12 -fluoroalkyl, —O(C 1 -C 12 -fluoroalkyl) or —S(C 1 -C 12 -fluoroalkyl) and
m is an integer of 1 to 3,
with the exception of 4-fluoro-2-methylphenol.
18. The compound of formula (II) according to claim 17 selected from the group consisting of 4-fluoro-2-methylphenol, 4,5-difluoro-2-methylphenol and 2- methyl-4-(trifluoromethoxy)phenol.
19. A compounds of the formula (V)
where
R 1 is in each case independently C 1 -C 12 -alkyl, chlorine or bromine or a radical of the formulae (IIa) or (IIb)
A-B-D-E (IIa)
A-E (IIb)
where, each independently,
A is absent or is a C 1 -C 8 -alkylene radical and
B is absent or is oxygen, sulphur or NR 2 where R 2 is hydrogen or C 1 -C 8 -alkyl and
D is a carbonyl group and
E is C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, NH(C 1 -C 8 -alkyl) or N(C 1 -C 8 -alkyl) 2 or is a cyclic amino radical having 4 to 12 carbon atoms and
n is an integer of 0 to 3-m and
R F is fluorine, C 1 -C 12 -fluoroalkyl, —O(C 1 -C 12 -fluoroalkyl) or —S(C 1 -C 12 -fluoroalkyl) and
m is an integer of 1 to 3 and
R 3 and R 4 are each independently C 1 -C 8 -alkyl or NR 3 R 4 as a whole is a cyclic amino radical having a total of 4 to 12 carbon atoms,
with the exception of 5-fluoro-2-hydroxy-N,N-dimethylbenzylamine.
20. The compounds of formula (V) according to claim 19 selected from the group consisting of 4,5-difluoro-2-hydroxy-N,N-dimethyl-benzylamine, 2-hydroxy-5-(trifluoromethoxy)-N,N-dimethyl-benzylamine, 6-hydroxy-2,3,4-trifluoro-N, N-dimethylbenzylamine and 2-hydroxy-4-(trifluoromethyl)-N,N-dimethylbenzylamine.
21. A process for treating cardiovascular disorders and diseases comprising administering medicaments containing active ingredients based on compounds of claim 15 to subjects in need thereof.