Process for preparing halogenated pyridine derivatives

Abstract

The present invention relates to a process for preparing halogenated pyridine derivatives of the formula (II) proceeding from compounds of the formula (I) via intermediates of the formula (IIIa) or (IIIb) ##STR00001##
where the radicals Q and W are each independently halogen, R.sup.2 is halogen or O-pivaloyl, and Y is halogen, CO.sub.2R.sup.1 or NO.sub.2, where R.sup.1 is (C.sub.1-C.sub.6)-alkyl or (C.sub.1-C.sub.6)-haloalkyl.

Claims

1. A process for preparing a compound of formula (II) ##STR00020## wherein Q and W are each independently halogen, and Y is halogen, CO.sub.2R.sup.1 or NO.sub.2, where R.sup.1 is (C.sub.1-C.sub.6)-alkyl or (C.sub.1-C.sub.6)-haloalkyl, wherein, in a first process step a), a compound of formula (I) ##STR00021## wherein W and Y each have the definitions given above, is reacted with an organozinc base of structure (NR.sup.3R.sup.4)ZnR.sup.2 or (NR.sup.3R.sup.4).sub.2Zn wherein R.sup.2 is halogen or O-pivaloyl and R.sup.3 and R.sup.4 together form a (CH.sub.2).sub.4, (CH.sub.2).sub.5 or (CH.sub.2).sub.2O(CH.sub.2).sub.2 group, where each of these groups may optionally be substituted by 1, 2, 3 or 4 R.sup.5 radicals and R.sup.5 is selected from the group consisting of methyl, ethyl, n-propyl and i-propyl, to give a compound of formula (IIIa) or formula (IIIb) ##STR00022## wherein W, Y and R.sup.2 each have the definitions given above, wherein the step a) is conducted at a temperature between 30 C. and 80 C., and this compound of formula (IIIa) or (IIIb) is reacted in a second process step b) with a compound of the structure Q-X wherein X is halogen and Q has the abovementioned definition to give the compound of formula (II).

2. The process according to claim 1, wherein Q and X have the same definition and are each iodine or bromine, W is fluorine or chlorine, R.sup.2 is halogen, and Y is chlorine, bromine, CO.sub.2R.sup.1 or NO.sub.2, where R.sup.1 is (C.sub.1-C.sub.4)-alkyl.

3. The process according to claim 1, wherein R.sup.3 and R.sup.4 together form a (CH.sub.2).sub.5 group, where each of these groups may optionally be substituted by 1, 2, 3 or 4 R.sup.5 radicals, and R.sup.5 is selected from the group consisting of methyl and ethyl.

4. The process according to claim 1, wherein Q and X have the same definition and are each iodine, W is fluorine, R.sup.2 is chlorine, and Y is chlorine, bromine, CO.sub.2R.sup.1 or NO.sub.2, where R.sup.1 is methyl.

5. The process according to claim 1, wherein R.sup.3 and R.sup.4 together form a (CH.sub.2).sub.5 group substituted by 4 methyl groups.

6. The process according to claim 1, wherein the organozinc base is a compound of formula (V)
(TMP).sub.xZnCl.sub.2-x,(V) wherein x is the number 1 or 2.

7. The process according to claim 1, wherein the organozinc base is present in conjunction with an alkali metal halide or alkaline earth metal halide.

8. The process according to claim 1, wherein the organozinc base is used in a total amount of 0.5 to 5 equivalents, based on the compound of formula (I).

9. The process according to claim 1, wherein the compound Q-X is an elemental halogen, optionally F.sub.2, Cl.sub.2, Br.sub.2 or I.sub.2.

10. The process according to claim 1, wherein the compound Q-X is used in a total amount of 0.5 to 10.0 equivalents, based on the compound of formula (I).

11. The process according to claim 1, that is conducted in the presence of a solvent selected from the group consisting of tetrahydrofuran (THF), 1,4-dioxane, diethyl ether, diglyme, methyl tert-butyl ether (MTBE), tert-amyl methyl ether (TAME), 2-methyl-THF, toluene, xylenes, mesitylene, ethylene carbonate, propylene carbonate, N,N-dimethylacetamide, N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP), N-butyl-2-pyrrolidone (NBP); N,N-dimethylpropyleneurea (DMPU), halohydrocarbon, aromatic hydrocarbon, chlorohydrocarbon, tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichloroethylene, pentachloroethane, difluorobenzene, 1,2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, 1,2-dichlorobenzene, chlorotoluene, trichlorobenzene; 4-methoxybenzene, fluorinated aliphatic, fluorinated aromatic, trichlorotrifluoroethane, benzotrifluoride and 4-chlorobenzotrifluoride, or a mixture of at least two of these solvents with one another.

12. The process according to claim 11, wherein the solvent is THF or N,N-dimethylformamide (DMF).

13. The process according to claim 1, wherein step b) is conducted at a temperature between 0 C. and 80 C.

14. A compound of formula (IIIa) ##STR00023## wherein W is fluorine, Y is halogen, C(O).sub.2R.sup.1 or N(O).sub.2, where R.sup.1 is (C.sub.1-C.sub.6)-alkyl or (C.sub.1-C.sub.6)-haloalkyl, and R.sup.2 is halogen or O-pivaloyl.

15. A compound of formula (IIIb) ##STR00024## wherein W is fluorine, and Y is halogen, CO.sub.2R.sup.1 or NO.sub.2, where R.sup.1 is (C.sub.1-C.sub.6)-alkyl or (C.sub.1-C.sub.6)-haloalkyl.

16. A compound of formula (II) ##STR00025## wherein Q is iodine, W is fluorine, and Y is Br, C(O).sub.2R.sup.1 or N(O).sub.2, where R.sup.1 is (C.sub.1-C.sub.6)-alkyl or (C.sub.1-C.sub.6)-haloalkyl.

17. The process according to claim 2, wherein R.sup.2 is chlorine, bromine or iodine.

18. The process according to claim 7, wherein the organozinc base is present in conjunction with lithium chloride or magnesium chloride.

19. The process according to claim 4, wherein Y is bromine.

Description

EXAMPLE 1

Synthesis of 6-chloro-3-fluoro-2-iodopyridine

(1) ##STR00019##

(2) To 2-chloro-5-fluoropyridine (132 mg, 1.0 mmol), dissolved in THF (2 ml), is added TMPZnCl.LiCl (1.31M in THF, 0.84 ml, 1.1 mmol) at 60 C. under argon; this reaction solution is stirred for 30 min. Subsequently, iodine (355 mg in 4 ml of THF) is added at 25 C. and the solution is stirred for a further 30 min. After customary workup by addition of saturated ammonium chloride and sodium thiosulphate solutions, the reaction mixture is extracted with ethyl acetate, and the combined organic phases are dried over Na.sub.2SO.sub.4 and concentrated in the membrane pump vacuum. After purification by column chromatography (ethyl acetate/cyclohexane), 6-chloro-3-fluoro-2-iodopyridine (158 mg, 62%) is obtained as a yellow solid. HPLC-MS: log P=2.53; mass (m/z): no ionization; 1H-NMR (D6-DMSO): 7.80 (m, 1H), 7.61 (m, 1H).

EXAMPLE 2

Synthesis of methyl 5-fluoro-6-iodopyridine-2-carboxylate

(3) To methyl 5-fluoropyridine-2-carboxylate (155 mg, 1.0 mmol), dissolved in THF (2 ml), is added TMPZnCl.LiCl (1.31M in THF, 0.84 ml, 1.1 mmol) at 60 C. under argon; this reaction solution is stirred for 30 min. Subsequently, iodine (355 mg in 4 ml of THF) is added at 25 C. and the solution is stirred for a further 30 min. After customary workup and purification by column chromatography (ethyl acetate/cyclohexane), methyl 5-fluoro-6-iodopyridine-2-carboxylate (197 mg, 70%) is obtained as a yellow solid. HPLC-MS: log P=1.85; mass (m/z): 281.9; 1H-NMR (D6-DMSO): 8.10 (m, 1H), 7.86 (m, 1H), 3.89 (s, 3H).

EXAMPLE 3

Synthesis of 6-bromo-3-fluoro-2-iodopyridine

(4) To 2-bromo-5-fluoropyridine (880 mg, 5.0 mmol), dissolved in THF (5 ml), is added TMPZnCl.LiCl (1.31M in THF, 4.2 ml, 5.5 mmol) at 60 C. under argon; this reaction solution is stirred for 30 min. Subsequently, iodine (1.78 g in 4 ml of THF) is added at 25 C. and the solution is stirred for a further 30 min. After customary workup by addition of saturated ammonium chloride and sodium thiosulphate solutions, the reaction mixture is extracted with ethyl acetate, and the combined organic phases are dried over Na.sub.2SO.sub.4 and concentrated in the membrane pump vacuum. After purification by column chromatography (ethyl acetate/cyclohexane), 6-bromo-3-fluoro-2-iodopyridine (1.31 g, 87%) is obtained as a yellow solid. HPLC-MS: log P=2.67; mass (m/z): no ionization; 1H-NMR (D6-DMSO): 7.72 (m, 2H).