JP2876668B2 - Industrial production of 2-methoxy-6-methylaminopyridine - Google Patents

Description

The present invention relates to a method for producing 2-methoxy-6-methylaminopyridine. 2-Methoxy-6-methylaminopyridine is very useful as a synthetic intermediate for pharmaceuticals and agricultural chemicals.

<Prior Art> As a conventional production method, a reaction solution with 2-halo-6-methylaminopyridine, methanol and an alkali metal hydroxide is used to prepare 0.5 to 0.5 to 2-halo-6-methylaminopyridine. A method of extracting with a halogenated hydrocarbon in the presence of 1.0 times by weight of methanol and then distilling (Japanese Patent Application Laid-Open No.
163817), a method of reacting 2-halo-6-methylaminopyridine with methanol in the presence of an alkali metal hydroxide in an aromatic hydrocarbon solvent (JP-A-63-154999, etc.), and 2-Chloro-6-methylaminopyridine is reacted with methanol in the presence of an alkali metal hydroxide, and the reaction solution is treated with 1.5 to 10.0 times the amount of water based on the weight of the generated 2-methoxy-6-methylaminopyridine. The methanol is recovered by adding and heating, followed by filtration,
A separation method (Japanese Patent Application Laid-Open No. Sho 62-311107) is known. <Problems of the prior art> The halogenated hydrocarbon solvents used in the method described in JP-A-61-163817 have recently been pointed out as having environmental pollution, safety problems, etc. is there.

In the method described in JP-A-63-154999, separation of an aromatic hydrocarbon solvent used as a solvent from 2-methoxy-6-methylaminopyridine is relatively difficult in distillation, and The distillation yield of the product may be reduced. In addition, halogenated hydrocarbons,
When an aromatic hydrocarbon is used as an extraction solvent for a target product, a large amount of by-products is extracted, thereby lowering the distillation yield and the purity of the target product, and further, generating a large amount of residue in the distillation step. .

Further, the method described in JP-A-62-311107 does not include an extraction operation, and the yield of 2-methoxy-6-methylaminopyridine, which is a target product, is relatively high in water because it has a relatively high solubility in water. May occur.

<Means for Solving the Problems> The present inventors have conducted intensive studies on a more industrial production method of 2-methoxy-6-methylaminopyridine. High solubility in aliphatic hydrocarbon solvents and 2
When methanol is recovered after the reaction of -halo-6-methylaminopyridine with an alkali metal hydroxide, and 2-methoxy-6-methylaminopyridine is extracted with an aliphatic hydrocarbon solvent from a liquid separated and filtered. It has been found that, compared to halogenated hydrocarbon solvents and aromatic hydrocarbon agents, it is possible to extract selectively and efficiently, and to obtain the target product having a low purity and a high purity after distillation. Further, when an aliphatic hydrocarbon solvent is used, distillation separation is facilitated as compared with halogenated hydrocarbon solvents and aromatic hydrocarbon solvents, and the distillation yield of the target product is improved. It was found that 6-methylaminopyridine was obtained, and the present invention was completed. That is, the present invention
(1) Water is added to a reaction solution obtained by reacting 2-halo-6-methylaminopyridine with methanol in the presence of an alkali metal hydroxide, and methanol is distilled off.
Further, an industrial process for producing high-purity 2-methoxy-6-methylaminopyridine, comprising extracting with an aliphatic hydrocarbon solvent and then distilling.

(2) The method according to claim (1), wherein the boiling point of the aliphatic hydrocarbon solvent is in the range of 35 to 100 ° C.

<Operation> Hereinafter, the present invention will be described in detail.

According to the method of the present invention, 2-halo-6 is added to a high-pressure reactor.
-Methylaminopyridine, methanol and an alkali metal hydroxide are charged, the inside of the vessel is sufficiently purged with nitrogen, and the reaction is carried out by heating and stirring.

The 2-halo-6-methylaminopyridine applicable to the present invention includes 2-chloro-6-methylaminopyridine, 2-bromo-6-methylaminopyridine, 2-iodo-6-methylaminopyridine and 2-fluoro -6
Methylaminopyridine is 2-chloro-6-methylaminopyridine and 2-bromo-6-methylaminopyridine from the industrial viewpoint of economic efficiency.

The amount of methanol used in this reaction is 2-halo-
Equimolar to 6-methylaminopyridine is theoretically sufficient, but an equimolar reaction rate is slow, and a large excess does not bring any benefit. Therefore, the molar ratio is in the range of 3.0 to 11.0 times, and more preferably in the range of 4.2 to 7.2 times.

Examples of the alkali metal hydroxide used in the present invention include lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, and the addition amount is 2 to 4 times that of 2-halo-6-methylaminopyridine. A molar range is preferred.

The reaction temperature is usually 100 to 200 ° C., preferably 140
~ 190 ° C. At 140 ° C. or lower, the reaction rate decreases, and a large amount of 2-halo-6-methylaminopyridine as a raw material may remain. At 190 ° C. or higher, a large amount of by-products are generated, and the separation property at the time of extraction is reduced. Degradation may occur.

The reaction time may be changed depending on the reaction temperature, the amount of the alkali metal hydroxide used, and other conditions.

After completion of the reaction, a predetermined amount of water is added to the reaction solution, and methanol is recovered by distillation under normal pressure.

As the amount of water to be added, 2-methoxy-6 produced
The amount is preferably 1.5 to 10 times the weight of methylaminopyridine, and if the weight is 1.5 times or less, a large amount of solids may precipitate during the recovery of methanol, and it may be difficult to recover methanol. If the weight is more than 10 times, the size of the reactor is increased, and no benefit is brought. Methanol can be recovered by heating the reaction solution to 77 to 120 ° C under normal pressure.

Water may be further added to the methanol recovery residue after recovery to improve operability.

The mixed liquid containing the target substance after the recovery of methanol is filtered to remove insoluble organic substances, and then extracted with an aliphatic hydrocarbon solvent. As the aliphatic hydrocarbon solvent used for the extraction, the boiling point is 35 ° C. or higher, 100 ° C. or less, for example,
Linear aliphatic hydrocarbons such as pentane, hexane and heptane, and cycloaliphatic hydrocarbons such as dimethylbutane, methylpentane, dimethylpentane, cyclohexane and methylcyclopentane, and mixtures thereof include petroleum ether and petroleum benzine. Preferably, pentane, hexane, octane, cyclohexane, petroleum ether and petroleum benzine are industrially available. In addition, when an aliphatic hydrocarbon solvent having a boiling point of 100 ° C. or higher is used, distillation separation from 2-methoxy-6-methylaminopyridine, which is the target substance, is difficult, and the yield decreases.

The amount of the aliphatic hydrocarbon solvent used for the extraction was determined based on the amount of the produced 2-methoxy-6-methylaminopyridine.
A weight of 0.5 to 100 times is preferable, and if it is 0.5 times or less, extraction may be insufficient and the yield may be reduced. Even if it is used at a weight of 100 times or more, not only no remarkable effect is seen but it is not economical. Although the extraction is sufficient even once, it does not matter if the extraction is performed several times.

The obtained extract is subjected to simple distillation or a distillation apparatus equipped with a short packed tower, at normal pressure, at 70 to 140 ° C. to distill off the solvent, and then, under reduced pressure, to remove 2-methoxy-6-methylaminopyridine. Distill. The distillation temperature of 2-methoxy-6-methylaminopyridine can be carried out without any problem as long as it is in the range of 70 to 170 ° C.
The distillation yield may decrease. At 70 ° C or lower,
High vacuum is required, which is not preferable. The degree of decompression during the distillation of 2-methoxy-6-methylaminopyridine may be a degree of decompression at which the target substance is distilled off in the above temperature range.

<Effect of the Invention> According to the present invention, an industrial method for producing high-purity 2-methoxy-6-methylaminopyridine has been established.

<Examples> Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.

Example 1 In a 5 l autoclave equipped with an electric stirrer, 449 g of sodium hydroxide, 800 g of 2-chloro-6-methylaminopyridine,
After 880 g of methanol was charged and the inside of the system was replaced with nitrogen, the temperature was increased while stirring, and the reaction was carried out at 150 ° C. for 4 hours.

After the completion of the reaction, cool to room temperature, add 1100 g of water,
651 g of methanol by heating again to 77-120 ° C
Collected.

Subsequently, 1500 g of water was added to sufficiently dissolve the inorganic substance, and then the reaction solution was taken out of the reaction vessel, and insoluble components were removed by suction filtration.
Further, the aqueous layer and the organic layer of the filtrate were separated, and the aqueous layer was extracted five times with 100 g of cyclohexane, and then mixed with the previous organic layer. As a result of gas chromatography analysis, the target product, 2-methoxy-
1258 g of a cyclohexane solution containing 732.1 g of 6-methylaminopyridine was obtained.

The distillation apparatus used a single distillation apparatus, and 485 g of cyclohexane was recovered from the extract at normal pressure and at an internal temperature of 80 to 120 ° C., and the recovery was 97.0%. Then, the mixture was further heated under a reduced pressure of 22 mmHg to obtain 732.6 g of 2-methoxy-6-methylaminopyridine at a distillation temperature of 123 ° C. As a result of analysis by gas chromatography, the yield was 94.0%, the purity was 99.4%, and the remaining amount in the distillation still was 16 g.

 The results are shown in Table 1.

Examples 2-3 The reaction was carried out in the same reactor as in Example 1 under the conditions shown in Table 1.

 The results are shown in Table 1.

Comparative Examples 1 to 3 The reaction was carried out in the same reactor as in Example 1 under the conditions shown in Table 1.

 The results are shown in Table 1.

Continuation of the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C07D 213/74 CA (STN)

Claims (1)

(57) [Claims] (1) 2-halo- in the presence of an alkali metal hydroxide;
Water is added to a reaction solution obtained by reacting 6-methylaminopyridine and methanol, and methanol is distilled off.
An industrial process for producing high-purity 2-methoxy-6-methylaminopyridine, comprising separating, further extracting with an aliphatic hydrocarbon solvent having a boiling point in the range of 35 to 100 ° C, and then distilling.