JP3007330B2 - Method for producing 3-dichloromethylpyridine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the preparation of 2-alkoxy-5-alkoxymethylpyridine derivatives which are novel intermediates for preparing 2-chloro-5-chloromethyl-pyridine, which is known as an intermediate for insecticides. To a method for producing 3-dichloromethylpyridine, which is a starting material for

2-Chloro-5-chloromethylpyridine converts 2-chloropyridine-5-carboxylic acid to the corresponding acid chloride with thionyl chloride; if necessary, the latter is esterified with butanol and then sodium borate It is known that the compound can be obtained by reducing the compound to a hydroxymethyl compound and finally substituting the hydroxyl group in the side chain with chlorine using thionyl chloride (for example, US Pat. No. 4,576,629). No .: Journal of Heterocyclic Chemistry 16 ,
333-337 [1979]).

[0003] Disadvantages of this process and its potential for large-scale implementation are the starting compound 2-chloro-pyridine-5.
-High price of carboxylic acid and reducing agent borate,
The latter also offers safety issues related to the liberation of hydrogen during the course of the reaction.

Furthermore, it is known that 2-chloro-5-chloromethylpyridine can also be obtained when reacting 2-chloro-5-methylpyridine with elemental chlorine (see, for example, German Patent No. 3). 630,046). However, a disadvantage of this method is that the reaction does not proceed homogeneously, which means that in order to avoid the formation of substantial amounts of polychlorinated by-products, the chlorine is not It is necessary to interrupt the conversion (see also EP 9,212; EP 65,358).

Here, equation (1)

[0006]

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The 2-chloro-5-chloromethyl-pyridine of the general formula (II)

[0008]

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A 2-alkoxy-5-alkoxymethyl-pyridine derivative of the formula wherein R ¹ represents alkyl,
It has been found that it can be obtained by reacting with a chlorinating agent at a temperature of 0 to 200 ° C. in the presence of a diluent if necessary and in the presence of a reaction aid if necessary.

The fact that the reaction of the 2-alkoxy-5-alkoxymethyl-pyridine derivative of the formula (II) with the chlorinating agent according to the process of the invention leads to the exchange of both alkoxy groups for chlorine means that 2-methoxy To convert pyridine to 2-chloropyridine, phosphorus oxychloride does not cause any reaction in the absence of dimethylformamide,
Less suitable for large-scale industrial production, the "Bills-Meier-Hark conditions" (i.e., oxyformation in the presence of large amounts of dimethylformamide, with the formation of large amounts of wastewater during work-up). The use of phosphorus chloride) has been known for some time, and must be considered unexpected. Moreover, with yields of less than 40%, the reaction only gives highly contaminated products which have to be subjected to complicated purifications by chromatography (in this respect, synthesis). 1984 , 743-745).

The advantages of the process according to the invention are that the 2-alkoxy-5-alkoxymethyl-pyridines to be used as starting compounds are readily available, the total number of steps of the synthesis is small and in the preparation of (II), Inexpensive chemical 3-methylpyridine can be used as a basic compound, and an inexpensive chemical can be used for synthesis.

For example, 2-methoxy-5 as starting material
When using -methoxymethylpyridine and phosphorus (V) chloride, the course of the reaction in the process according to the invention can be represented by the following formula:

[0013]

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Formula (II) shows that 2
Gives a general definition of -alkoxy-5-alkoxymethyl-pyridine derivatives. R ¹ in formula (II) preferably represents straight-chain or branched alkyl having 1 to 6, especially 1 to 4, carbon atoms.

Examples which may be mentioned as starting materials of the formula (II) are: 2-methoxy-5-methoxymethyl-pyridine, 2-ethoxy-5-ethoxymethyl-pyridine, 2-propoxy-5 -Propoxymethyl-pyridine, 2-isopropoxy-5-isopropyloxymethyl-pyridine, 2-butoxy-5-butoxymethyl-pyridine, 2-isobutoxy-5-isobutoxymethyl-pyridine, 2-sec-butyl-5- sec-butoxymethyl-pyridine and 2-tert-butoxy-
5-tert-butoxymethyl-pyridine.

The starting materials of the formula (III) have hitherto not been known. Novel 2-alkoxy-5- of formula (II)
The alkoxymethyl-pyridine derivative has the formula (III)

[0017]

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3-dichloromethyl-pyridine of formula (IV) R ¹ OH (IV) wherein R ¹ has the meaning given above and an alkali metal salt of an alcohol of formula (IV), 150
C., preferably at a temperature of from 20 to 100.degree. C., and can be obtained by post-treating the product by a conventional method. For example, after the reaction, the reaction mixture is concentrated and cooled, then the concentrate is stirred with an organic solvent (eg, ether), the salts are separated by suction filtration, and the filtrate is concentrated. The residue is then removed in a customary manner.
For example, by chromatography.

No model from the field of pyridine derivative chemistry is known for the above process for the preparation of the new 2-alkoxy-5-alkoxymethyl-pyridines. Therefore, it is unexpected that 2-alkoxymethyl-pyridine can be produced from 3-dichloromethyl-pyridine and alkoxide. 3-Dichloromethylpyridines having the formula (III) and required as intermediates are already known (EP 9,
212 and 65,358) but are generally obtained as a by-product in the chlorination of 3-methylpyridine.

Furthermore, the 3-dichloropyridine of the formula (III) is

[0021]

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The 3-methylpyridine of acetic acid, propionic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid and / or
Or trifluoromethanesulfonic acid (preferably acetic acid)
And optionally additionally in the presence of an inorganic acid such as, for example, hydrogen chloride, hydrogen bromide or sulfuric acid (preferably sulfuric acid) and also, for example, azo-bis-iso In the presence of butyronitrile, benzoyl peroxide or tert-butyl benzoate, -20C to + 150C, preferably 0 to 100C.
At a temperature of elemental chlorine, the reaction product is dissolved in a customary manner, for example in a suitable solvent such as, for example, ethyl acetate, and the solution is treated with an alkali (eg NaOH). It has been found that after neutralization, separation of the organic phase and drying of the organic phase, the solvent can be distilled off and worked up to obtain the main product in good yield.

From the prior knowledge (compound (III) can only be obtained as a by-product), the selective course of the above-mentioned method must be regarded as quite unexpected.

Formula (IV) provides a general definition of alcohols further required as starting materials. Formula (IV)
R ¹² therein preferably represents straight-chain or branched alkyl having 1 to 6, especially 1 to 4, carbon atoms.

In the preparation of the compounds of the formula (II) it is preferred to use the lithium, sodium or potassium salts, especially the sodium salts, of these alcohols.

Examples which may be mentioned are:
Methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol and tert-butanol, and also the sodium salts of these alcohols.

Chlorinating agents suitable for the preparation of 2-chloro-5-chloromethyl-pyridines of the formula (I) from 2-alkoxy-5-alkoxymethyl-pyridines of the formula (II) according to the process of the invention Are chlorides of inorganic or organic acids, such as, for example, phosphorus (V) chloride, phosphorus (III) chloride, phosphoryl chloride (phosphorous oxychloride), thionyl chloride, phosgene, acetyl chloride or benzotrichloride, in particular phosphorus chloride. It is a mixture of (V) and phosphoryl chloride.

The process of the present invention can be carried out substantially without the addition of a diluent or in the presence of a suitable diluent. Diluents include, for example, benzene, toluene, xylene, chlorobenzene, dichlorobenzene,
Aliphatic, cycloaliphatic or aromatic, such as petroleum ether, hexane, cyclohexane, methylcyclohexane, dichloromethane, chloroform or tetrachloromethane;
It optionally includes halogenated hydrocarbons.

If necessary, the process according to the invention can be carried out in the presence of a suitable reaction aid. Possible reaction auxiliaries are tertiary amines, such as, for example, triethylamine, N, N-dimethylaniline, pyridine or 4-dimethylamino-pyridine, and also catalytic amounts of, for example, N, N-dimethyl-formamide. Or formamide, such as N, N-dibutylformamide, or a metal halide, such as, for example, magnesium chloride or lithium chloride.

When carrying out the process according to the invention, the reaction temperatures can be varied within a wide range. In general, the process according to the invention is carried out at a temperature between 0 and 200C, preferably between 10 and 120C.

To perform the method of the present invention, generally,
1 to 10 molar equivalents per mole of 2-alkoxy-5-alkoxymethylpyridine of formula (II), preferably 1 to
5 molar equivalents of chlorinating agent are used.

In general, the reaction components are mixed with gentle stirring, generally with a slight increase in temperature, and stirring is continued until the reaction is complete. The reaction product is prepared in the usual manner (see Production Examples)
Post-processing.

It has the formula (I) and can be obtained by the method according to the invention. 2-Chloro-5-chloromethyl-pyridine can be used as an intermediate in the production of pesticides (see EP 163,855 and EP 192,060).

Production Example Reference Example 1

[0035]

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For 5.1 g (33.3 mol) of phosphorus oxychloride, first 14 g (66.6 mol) of phosphorus (V) chloride and then 5.1 g of phosphorus oxychloride while cooling in an ice bath.
(33.3 mol) of 2-methoxy-5-methoxymethyl-pyridine are added in one portion. The reaction mixture is refluxed for 3 hours and then concentrated under reduced pressure. Dilute the residue with ice water,
The mixture is neutralized with 2N-sodium hydroxide solution and shaken with ethyl acetate. The organic phase is separated off, dried over sodium sulfate and filtered. The filtrate is freed of the solvent by distillation under reduced pressure of a water pump. This gives 2.4 g (45% of theory) of 2 as a residue (yellow liquid).
To give -chloro-5-chloromethyl-pyridine.

Reference Example of Starting Material of Formula (II) II-1

[0038]

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35.8 g (purity 73%; 0.161 mol) of 3-dichloromethyl-pyridine in 50 ml of methanol were combined with 29.5 g (0.55 mol) of methanol in 90 ml of methanol.
Mol) in a refluxing solution of sodium methoxide. The reaction mixture is refluxed for 4 hours and then concentrated.

The residue is stirred with diethyl ether,
The sodium chloride remaining undissolved is separated by suction filtration and the filtrate is concentrated. The residue is purified by chromatography on silica gel (eluent: petroleum ether / ethyl acetate, 5: 1 by volume).

This is 12.3 g (50% of theory) of 2-
This gives methoxy-5-methoxymethyl-pyridine. ¹
1 H NMR (CDCl ₃ , δ, ppm): 2.8; 3.9;
4.4.

In the same manner, the following compound is obtained: Reference Example (II-2) From 3-dichloromethylpyridine using sodium ethoxide and ethanol, compound:

[0043]

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¹ H NMR (CDCl ₃ , δ, ppm):
3.5; 4.3; 4.4.

REFERENCE EXAMPLE (II-3) Compound from 3-dichloromethylpyridine using sodium isoproxide and isopropanol:

[0046]

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¹ H NMR (CDCl ₃ , δ, ppm):
4.4.

Reference Example (II-4) Compounds of 3-dichloromethylpyridine were prepared by using sodium isobutoxide and isobutanol.

[0049]

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¹ H NMR (CDCl ₃ , δ, ppm):
3.2; 4.05; 4.4.

Example of starting material of formula (III) (III-1)

[0052]

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23.3 g (0.25 mol) of 3-methylpyridine were mixed with 25 g (0.255 mol) of concentrated sulfuric acid and 150 m
One drop of acetic acid is added dropwise with stirring to a mixture cooled in an ice bath. The reaction mixture is heated to 75 ° C. and a solution of 4.0 g of azo-bisisobutyronitrile in 30 ml of glacial acetic acid is added dropwise over a period of 8 hours while passing a vigorous stream of chlorine. After concentration of the mixture, the residue is dissolved in ethyl acetate and neutralized with 2N sodium hydroxide solution. The organic phase is filtered off with suction, dried over sodium sulphate and then filtered. The solvent is removed from the filtrate by distillation under reduced pressure of a water pump. This gives 41 g (73% of theory, purity 79%) of 3-dichloromethyl-pyridine as residue (yellow liquid).

The main features and embodiments of the present invention are as follows.

1. Expression (V)

[0056]

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The 3-methylpyridine in the presence of an organic acid, and optionally additionally in the presence of an inorganic acid and also in the presence of a free radical initiator,
Reacting with elemental chlorine at a temperature of up to + 150 ° C.

[0058]

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Method for producing 3-dichloromethylpyridine.

2. 2. A process as claimed in claim 1 wherein the free radical initiator is a compound of the series consisting of azo-bis-isobutyronitrile, benzoyl peroxide and tert-butyl perbenzoate and the reaction is carried out at a temperature of from 0 to 100.degree.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-58-29765 (JP, A) JP-A-3-135956 (JP, A) JP-A-55-43017 (JP, A) JP-A-54-1979 115381 (JP, A) (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 213/26 CA (STN)

Claims (1)

(57) [Claims] (1) Formula (V) In the presence of an organic acid and optionally additionally of an inorganic acid and also in the presence of a free radical initiator at -20 to + 150 ° C.
Reacting with elemental chlorine at a temperature of the formula (III): Production method of 3-dichloromethylpyridine.