Process for the preparation of 2-chloro-5-chloromethylpyridine, and new intermediates

A process for the preparation of a 2-chloro-5-chloromethyl-pyridine, of the formula (I) ##STR1## comprising reacting a 2-alkoxy-5-alkoxymethylpyridine derivative of the formula (II) ##STR2## in which R.sup.1 represents alkyl, with a chlorinating agent, is appropriate, in the presence of a diluent and if appropriate, in the presence of a reaction auxiliary, at a temperature between 0.degree. C. and 200.degree. C.

The invention relates to a new process for the preparation of 
2-chloro-5-chloromethyl-pyridine, which is known as an intermediate for 
insecticides, to new intermediates for this process, and to a process for 
their preparation. 
It is known that 2-chloro-5-chloromethylpyridine is obtained in a 
complicated multi-step process when 2-chloropyridine-5-carboxylic acid is 
converted with thionyl chloride into the corresponding acid chloride; if 
appropriate, the latter is esterified with ethanol, then reduced with 
sodium boranate to give the hydroxymethyl compound, and the hydroxyl group 
in the side chain is finally substituted by chlorine using thionyl 
chloride (cf., for example, U.S. Pat. No. 4,576,629; J. Heterocycl. Chem. 
16, 333-337 [1979]). 
The disadvantage of this process, and what is prohibitive with regard to 
large-scale feasibility, is the high price of the starting compound 
2-chloropyridine-5carboxylic acid and of the reducing agent sodium 
boranate, which, furthermore, also presents a safety problem with respect 
to the liberation of hydrogen during the course of the reaction. 
Furthermore, it is known that 2-chloro-5-chloromethylpyridine is obtained 
when 2-chloro-5-methylpyridine is reacted with elemental chlorine (cf., 
for example, DE-A 3,630,046). However, the disadvantage in this process is 
that the reaction does not proceed uniformly, which makes it necessary to 
interrupt the chlorination at an early stage, before the reaction could 
have proceeded to completion, in order to avoid the formation of 
substantial amounts of polychlorinated by-products (cf. also EP-A 9,212; 
EP-A 65,358). The resulting mixtures can only be separated with difficulty 
and give products whose purity is unsatisfactory. 
It has now been found that 2-chloro-5-chloromethyl-pyridine, of the formula 
(I), 
##STR3## 
is obtained when 2-alkoxy-5-alkoxymethyl-pyridine derivatives of the 
general formula (II) 
##STR4## 
in which R.sup.1 represents alkyl, are reacted with a chlorinating agent, 
if appropriate in the presence of a diluent and if appropriate in the 
presence of a reaction auxiliary, at temperatures between 0.degree. C. and 
200.degree. C. 
It is surprising that the reaction of 2-alkoxy-5-alkoxymethyl-pyridine 
derivatives of the formula (II) with chlorinating agents according to the 
process according to the invention leads to an exchange of both alkoxy 
groups against chlorine, since it was known from the prior art that 
"Vilsmeier-Haack conditions" (that is to say phosphorus oxychloride in the 
presence of large amounts of dimethylformamide, with considerable amounts 
of waste water being produced during working-up), which are not very 
suitable for large-scale industrial production, would be required for 
converting 2-methoxypyridine into 2-chloropyridine, phosphorus oxychloride 
in the absence of dimethylformamide not effecting any kind of reaction. 
Furthermore, with less than 40% yield, this reaction gives only a highly 
contaminated product which must be subjected to complicated purification 
by chromatography (cf. in this context, Synthesis 1984, 743-745). 
Advantages of the process according to the invention are that the 
2-alkoxy-5-alkoxymethyl-pyridine derivatives (II) which are used as 
starting compounds are readily accessible, that the total number of 
synthesis steps is low, and that inexpensive chemicals for synthesis are 
employed in the preparation of (II), it being possible for the inexpensive 
chemical 3-methylpyridine to be employed as the basic compound. 
If, for example, 2-methoxy-5-methoxymethylpyridine and phosphorus(V) 
chloride are used as the starting substances, the course of the reaction 
in the process according to the invention can be outlined by the following 
equation: 
##STR5## 
Formula (II) provides a general definition of the 
2-alkoxy-5-alkoxymethyl-pyridine derivatives to be used as starting 
substances. R.sup.1 in formula (II) represents straight-chain or branched 
alkyl, preferably having 1 to 6, in particular having 1 to 4, carbon 
atoms. 
Examples which may be mentioned of the starting substances of the formula 
(II) are: 
2-methoxy-5-methoxymethyl-pyridine, 2-ethoxy-5-ethoxymethyl-pyridine, 
2-propoxy-5-propoxymethyl-pyridine,2-isopropoxy-5-isopropoxymethyl-pyridin 
e,2-butoxy5-butoxymethyl-pyridine, 2-isobutoxy-5-isobutoxymethylpyridine, 
2-sec-butoxy-5-sec-butoxymethyl-pyridine and 
2-tert-butoxy-5-tert-butoxymethyl-pyridine. 
The starting substances of the formula (II) were hitherto unknown. The new 
2-alkoxy-5-alkoxymethyl-pyridine derivatives of the formula (II) are 
obtained when 3-dichloromethyl-pyridine, of the formula (III), 
##STR6## 
is reacted with an alcohol of the formula (IV) 
EQU R.sup.1 OH (IV) 
where R.sup.1 has the abovementioned meaning, and with alkali metal salts 
of alcohols of the formula (IV) 
at temperatures between 0.degree. C. and 150.degree. C., preferably between 
20.degree. C. and 100.degree. C., and the product is worked up by 
customary methods. For example, the reaction mixture is concentrated after 
the reaction; after cooling, the concentrate is stirred with organic 
solvents (e.g., ether), salts are separated by filtration with suction, 
and the filtrate is concentrated. The residue is then purified by 
customary methods, for example, by chromatography. 
No model is known from the field of pyridine derivative chemistry for the 
above-described route for the preparation of the new 
2-alkoxy-5-alkoxymethyl-pyridine derivatives. It is therefore surprising 
that 2-alkoxy-5-alkoxymethyl-pyridines can be prepared from 
3-dichloromethyl-pyridine and alkoxides. 
3-Dichloromethylpyridine, which has the formula (III) and is required as an 
intermediate, is already known (cf. EP-A 9,212 and EP-A 65,358), but it is 
generally obtained as a by-product in the chlorination of 
3-methylpyridine. 
Moreover, it has been found that 3-dichloromethylpyridine, of the formula 
(III), is obtained in good yields as the main product when 
3-methylpyridine, of the formula (V), 
##STR7## 
is reacted with elemental chlorine in the presence of an organic acid, 
such as, for example, acetic acid, propionic acid, chloroacetic acid, 
dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, 
methanesulphonic acid and/or trifluoromethanesulphonic acid (preferably 
acetic acid) and if appropriate additionally in the presence of an 
inorganic acid, such as, for example, hydrogen chloride, hydrogen bromide 
or sulphuric acid (preferably sulphuric acid), and also in the presence of 
a free-radical initiator, such as, for example, azo-bisisobutyronitrile, 
benzoyl peroxide or tert-butyl perbenisobutyro zoate, at temperatures 
between -20.degree. C. and +150.degree. C., preferably between 0.degree. 
C. and 100.degree. C., and the reaction product is worked up by customary 
methods, for example by taking it up in a suitable organic solvent, such 
as, for example, ethyl acetate, neutralizing the solution with an alkali 
(for example NaOH), separating off the organic phase, drying the organic 
phase and distilling off the solvent. 
With a view to the prior art (where compound (III) is obtained only as a 
by-product), the selective course of the process described above is 
considered as extremely surprising. 
Formula (IV) provides a general definition of the alcohols furthermore 
required as starting substances. R.sup.1 in formula (IV) represents a 
straight-chain or branched alkyl, preferably having 1 to 6, in particular 
having 1 to 4, carbon atoms. 
In the preparation of compounds of the formula (II), it is preferred to 
employ the lithium, sodium or potassium salts, in particular the sodium 
salts, of these alcohols. 
Examples which may be mentioned are: methanol, ethanol, propanol, 
isopropanol, butanol, isobutanol, secbutanol and tert-butanol, and also 
the sodium salts of these alcohols. 
Chlorinating agents which are preferably suitable for the preparation of 
2-chloro-5-chloromethyl-pyridine, of the formula (I), from 
2-alkoxy-5-alkoxymethyl-pyridine derivatives of the formula (II) by the 
process according to the invention are inorganic or organic acid 
chlorides, such as, for example, phosphorus(V) chloride, phosphorus(III) 
chloride, phosphoryl chloride (phosphorus oxychloride), thionyl chloride, 
phosgene, acetyl chloride or benzotrichloride, in particular mixtures of 
phosphorus(V) chloride and phosphoryl chloride. 
The process according to the invention can be carried out either without 
the addition of a diluent, in substance, or in the presence of a suitable 
diluent. These include, in particular, aliphatic, alicyclic or aromatic, 
optionally halogenated hydrocarbons, such as, for example, benzene, 
toluene, xylenes, chlorobenzene, dichlorobenzenes, petroleum ether, 
hexane, cyclohexane, methylcyclohexane, dichloromethane, chloroform or 
tetrachloromethane. 
If appropriate, the process according to the invention can be carried out 
in the presence of a suitable reaction auxiliary. Possible reaction 
auxiliaries are tertiary amines, such as triethylamine, 
N,N-dimethylaniline, pyridine or 4-dimethylamino-pyridine, and furthermore 
also catalytic amounts of formamides, such as N,N-dimethyl-formamide or 
N,N-dibutylformamide, or metal halides, such as magnesium chloride or 
lithium chloride. 
When carrying out the process according to the invention, the reaction 
temperatures can be varied within a substantial range. In general, the 
process is carried out at temperatures between 0.degree. C. and 
200.degree. C., preferably between 10.degree. C. and 120.degree. C. 
For carrying out the process according to the invention, between 1 and 10 
mole equivalents, preferably between 1 and 5 mole equivalents, of the 
chlorinating agent are generally employed per mole of 
2-alkoxy-5-alkoxymethyl-pyridine derivative of the formula (II). 
In general, the reactants are combined with gentle cooling and then stirred 
until the reaction is complete, in general at a slightly elevated 
temperature. The reaction product is worked up by customary methods (cf. 
Preparation Examples). 
2-Chloro-5-chloromethyl-pyridine, which has the formula (I) and can be 
obtained by the process according to the invention, can be used as an 
intermediate in the preparation of insecticides, (cf. EP-A 163,855 and 
EP-A 192,060).

PREATION EXAMPLES 
Example 1 
##STR8## 
To 5.1 g (33.3 mmol) of phosphorus oxychloride there are first added 14 g 
(66.6 mmol) of phosphorus(V) chloride and then, with cooling in an 
ice-bath, 5.1 g (33.3 mmol) of 2-methoxy-5-methoxymethyl-pyridine in 
portions. The reaction mixture is refluxed for 3 hours and then 
concentrated in vacuo. The residue is diluted with ice-water, the mixture 
is rendered neutral with 2N sodium hydroxide solution, and shaken with 
ethyl acetate. The organic phase is separated off, dried with sodium 
sulphate and filtered. The solvent is removed from the filtrate by 
distillation under a waterpump vacuum. This gives 2.4 g (45% of theory) of 
2-chloro-5-chloromethylpyridine as the residue (yellow liquid). 
STARTING SUBSTANCES OF THE FORMULA (II) 
Example (II-1) 
##STR9## 
A solution of 35.8 g (73% pure; 0.161 mol) of 3-dichloromethyl-pyridine in 
50 ml of methanol is added dropwise to a refluxed solution of 29.5 g (0.55 
mol) of sodium methoxide in 90 ml of methanol. The reaction mixture is 
refluxed for 4 more hours and then concentrated. 
The residue is stirred with diethyl ether, sodium chloride which has 
remained undissolved is separated off by filtration with suction, and the 
filtrate is concentrated. The residue is purified by chromatography on 
silica gel (eluent: petroleum ether/ethyl acetate, 5:1 by volume). 
This gives 12.3 g (50% of theory) of 2-methoxy-5-methoxymethyl-pyridine. 
.sup.1 H-NMR (CDCl.sub.3, .delta., ppm): 2.8; 3.9; 4.4. 
The following are obtained analogously: 
Example (II-2) 
The compound 
##STR10## 
from 3-dichloromethylpyridine with sodium ethoxide and ethanol 
.sup.1 H-NMR (CDCl.sub.3, .delta., ppm): 3.5; 4.3; 4.4. 
Example (II-31) 
The compound 
##STR11## 
from 3-dichloromethylpyridine with sodium isopropoxide and isopropanol 
.sup.1 H-NMR (CDCl.sub.3, .delta., ppm): 4.4. 
Example (II-4) 
The compound 
##STR12## 
from 3-dichloromethylpyridine with sodium isobutoxide and isobutanol 
.sup.1 H-NMR (CDCl.sub.3), .delta., ppm): 3.2; 4.05; 4.4. 
STARTING COMPOUND OF THE FORMULATE (III) 
Example (III-1) 
##STR13## 
23.3 g (0.25 mol) of 3-methylpyridine are added dropwise with stirring to a 
mixture, cooled in an icebath, of 25 g (0.255 mol) of concentrated 
sulphuric acid and 150 ml of acetic acid. The reaction mixture is heated 
to 75.degree. C., and a solution of 4.0 g of azo-bisisobutyronitrile in 30 
ml of glacial acetic acid is added dropwise in the course of 8 hours, with 
a vigorous stream of chlorine being passed through. After the mixture has 
been concentrated, the residue is taken up in ethyl acetate and rendered 
neutral using 2N sodium hydroxide solution. The organic phase is filtered 
off with suction, dried with sodium sulphate and filtered. The solvent is 
removed from the filtrate by distillation under a waterpump vacuum. This 
gives 41 g (73% of theory, 79% pure) of 3-dichloromethyl-pyridine as the 
residue (yellow liquid). 
It will be appreciated that the instant specification is set forth by way 
of illustration and not limitation, and that various modifications and 
changes may be made without departing from the spirit and scope of the 
present invention.