JPH06745B2 - Method for producing 2 and / or 6 methylpyridine bases - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Use) In the present invention, a pyridine base having no substituent at the 2-position and / or the 6-position is reacted with a lower aliphatic alcohol to give the 2-position and / or the pyridine nucleus. Alternatively, the present invention relates to a method for producing 2 and / or 6-methylpyridine bases by methylating the 6-position.

These methylated pyridine bases are industrially extremely useful substances as pharmaceuticals and other intermediates.

(Prior art and problems to be solved by the present invention) Various methods have been conventionally proposed as a method for methylating a pyridine base having no substituent at the 2-position and / or the 6-position. For example, (1) a method of contacting carbon monoxide and hydrogen with pyridine in the presence of nickel oxide at a reaction temperature of 150 to 400 ° C. to obtain α-picoline (US Pat.
3354165), (2) in the presence of nickel or nickel oxide,
A method of contacting pyridine and methanol at a reaction temperature of 295 ° C. to obtain α-picoline (US Pat. No. 3428641),
(3) A method for obtaining α-picoline by reacting pyridine with methanol in the presence of Raney nickel at a reaction temperature of 250 ° C. (Pharmaceutical Journal, Vol. 101, No. 1, pp. 20-24, 1981)
Etc. are known. However, the above methods (1) and (2) are industrially disadvantageous because the yield of the target product is as low as about 50%. Further, the method (3) gives a relatively high yield of α-picoline of 72.3%, but the yield is remarkably low in methylation of pyridine bases having a substituent other than pyridine. (See Comparative Example 1 below). Therefore, it has a narrow application range as an industrial production.

(Means for Solving Problems) The present inventors have found that 2 and / or 6-methylpyridine bases can be inexpensively and efficiently prepared from industrially easily available raw materials,
Further, as a result of earnest research on a method of manufacturing with high quality, the present invention has been completed.

That is, in the present invention, in the presence of a cobalt catalyst, pyridine bases having no substituents at the 2-position and / or the 6-position are reacted with an aliphatic alcohol having 1 to 4 carbon atoms at 180 ° C. or higher to form a pyridine nucleus. 2- and / or 6-methylpyridine bases characterized in that the 2- and / or 6-positions are methylated (provided that 2,3,5-collidine, 2,3,5,6
-Excluding tetramethylpyridine).

The pyridine bases having no substituents at the 2- and / or 6-positions, which are the starting materials in the present invention, may be substituted with a lower alkyl group having 1 to 4 carbon atoms at a position other than the 2- and / or 6-positions. , And may not be substituted, specifically, pyridine, α-picoline, β-picoline, γ-picoline, 2,3-lutidine, 2,4-lutidine, 2,5-
Lutidine, 2-ethylpyridine, 4-propylpyridine, 2-propylpyridine, 2-methyl-5-ethylpyridine, 3-methyl-5-ethylpyridine, 3,5-diethylpyridine, 4-butylpyridine, 3-butyl Examples include pyridine.

As the alcohol used in the present invention, methanol,
Examples include ethanol, propanol, butanol and the like. The amount used is sufficient if it is equimolar or more to the pyridine base, but it is preferably in the range of 2 to 5 times by mole.

The target substance of the present invention is a compound in which only the 2-position or the 6-position is methylated by the methylation reaction of the present invention (hereinafter referred to as 2
-Monomethyl form) and a compound in which both the 2-position and the 6-position are simultaneously methylated (hereinafter referred to as 2,6-dimethyl form). Specific examples include α-picoline and 2,6-lutidine. , 2,5-lutidine, 2,4-lutidine, 2,3,6-collidine, 2,4,6-collidine, 2,5,6-trimethylpyridine, 2-ethyl-6
-Methylpyridine, 2-methyl-4-propylpyridine, 2-methyl-6-propylpyridine, 2,6-dimethyl-3-ethylpyridine, 2,3-dimethyl-5-ethylpyridine, 2-methyl-3, 5-diethylpyridine, 2-methyl-4-butylpyridine, 2-methyl-3
-Butyl pyridine and the like. According to the method of the present invention, when the 2-monomethyl compound or the 2,6-dimethyl compound is substantially substantially solely produced by appropriately selecting the reaction conditions, or when the 2-monomethyl compound and the 2,6-dimethyl compound are combined. May give birth.

The cobalt catalyst used in the present invention is preferably a Raney cobalt catalyst which is an industrially commercially available Raney cobalt alloy developed with an alkali, but any catalyst containing cobalt metal can be used. Further, the cobalt catalyst may contain other metal such as manganese. The amount of the cobalt catalyst used is not particularly limited, but is preferably in the range of 2 to 80% by weight with respect to the raw material pyridine bases.

In the present invention, the reaction temperature is not particularly limited as long as it is 180 ° C. or higher, but when alcohol is allowed to coexist with pyridine bases in the reaction system from the beginning, it is preferably carried out at 210 ° C. or lower. If the pressure exceeds this value, the decomposition of alcohol will become severe, making it difficult to control the internal pressure. For this reason, when the reaction is carried out at 210 ° C. or higher, it is desirable to continuously or intermittently supply alcohol from the outside of the reactor, and at this time, it is preferable to press-in with a metering pump.

In the present invention, when the 2-monomethyl derivative is efficiently produced, the reaction temperature is not particularly limited, but 190
It is preferable to react in the range of ˜240 ° C. Also 2,6
-For efficient production of the dimethyl compound, the reaction may be carried out for a longer time within the same temperature range, but if desired, the reaction temperature is
It is preferable to react in the range of 0 to 270 ° C., and the reaction time can be shortened. If the reaction temperature is lower than 180 ° C., the reaction rate of any of the above reactions becomes remarkably slow, which is industrially disadvantageous.

In the present invention, the reaction pressure is sufficient if it is equal to or higher than the vapor pressure of the contents at the prescribed temperature, but preferably 10 to
It is in the range of 70 kg / cm ² . Although the reaction pressure rises due to the generated decomposition gas, if the reaction is continued as it is, the reaction pressure increases and the pressure resistance of the reactor is required more than necessary. It is desirable to carry out the reaction while maintaining an appropriate pressure while venting. When removing the decomposition gas, it is usually preferable to use a reflux condenser under a pressurized condition to remove only the non-condensed gas. When the reflux condenser is not used, a part of the raw material and the product is distilled out of the system of the reactor together with the decomposition gas, so that the reaction efficiency is significantly lowered. However, in the present invention, the raw materials and products distilled out of the reactor may be cooled and condensed and recovered and circulated in the reactor, or may be mixed with the raw materials for the next time and the reaction may be performed.

In the present invention, a solvent is not particularly required, but the reaction may be carried out in the presence of an inert solvent such as benzene, toluene and xylene.

The methylated pyridine bases obtained by the above method may be purified by an ordinary method after separating the catalyst from the reaction solution. After briefly undergoing a dehydration step, the reaction solution is easily separated and purified by distillation.

(Effects of the Invention) According to the method of the present invention, 2- and / or 6-methylated pyridine bases can be obtained in high yield with respect to pyridine bases as a raw material, and the reaction is extremely highly selective. Since there are few by-products, it is extremely easy to separate and purify the target product, and high-purity 2 and / or 6-methylated pyridine bases can be obtained, and the present invention is industrially applicable. This is an extremely advantageous method.

(Examples) The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Example 13 In a magnetic stirring autoclave of 3, β-picoline 65
1 g (7 mol), 672 g (21 mol) of methanol and 260 ml of Raney cobalt were charged, and the vessel was replaced with hydrogen.
The internal temperature was kept at 200 ° C. and the reaction was completed in 24 hours. During this period, the internal pressure increased with increasing temperature and reached a maximum of 72 kg / cm ² . After completion of the reaction, the autoclave was cooled to room temperature and the reaction solution was taken out. The catalyst was removed from the reaction solution, and 140 g of caustic soda was added to the solution to obtain 700 g of oil. When the obtained oil was distilled in a 50 cm Dixon packed column, the column top temperature was 66 to 67 ° C / 50 mmHg and the GC purity was 99.1%.
-Picoline 211g and GC at 76-78 ° C / 50mmHg
478 g of 2,5-lutidine having a purity of 99.2% was obtained. The yield of 2,5-lutidine with β-picoline used was 6
At 4.0%, the selectivity was 94.5%.

Example 2 Into the electromagnetic stirring type autoclave of 1, 65 g of γ-picoline
(0.7 mol), 161 g (3.5 mol) of ethanol and 32 ml of Raney cobalt were charged, the inside of the vessel was replaced with hydrogen, the internal temperature was raised to 200 to 210 ° C., and the reaction was carried out for 16 hours. During this time, the internal pressure rises as the temperature rises, and the maximum pressure is 65 kg /
Reached cm ² . Hereafter, when distilled in the same manner as in Example 1, γ
-Picoline hardly remains and the tower top temperature is 76 to 77 ° C.
2,4-lutidine 6 with GC purity of 99.3% at 50 mmHg
2.8 g was obtained. 2,4-depending on the γ-picoline used
The yield of lutidine was 83.8%.

Example 3 1 γ-picoline 93 in an autoclave (electromagnetic stirring type)
g (1 mol), 96 g (3 mol) of methanol and 37 ml of Raney cobalt were charged, and the inside of the container was replaced with hydrogen.
The reaction was carried out at an internal temperature of 200 ° C for 42 hours. During this time, the maximum internal pressure is 7
It rose to 0 kg / cm ² . Hereafter, when distilled in the same manner as in Example 1, 2,4-lutidine 71.1 having a GC purity of 99.1% was obtained.
g and a column top temperature of 91 to 2 ° C./50 mmHg, and a GC purity of 99.
1.7 g of 4% 2,4,6-collidine were obtained. The yields of 2,4-lutidine and 2,4,6-collidine with γ-picoline were 95.0% and 2.0%, respectively.

Example 4 3 465 g of γ-picoline in an electromagnetic stirring autoclave
(5 mol), 320 g (10 mol) of methanol and 108 ml of Raney cobalt were charged, the inside of the vessel was replaced with hydrogen, the internal temperature was adjusted to 200 to 205 ° C., and the reaction was completed in 8 hours. During this period, the generated decomposition gas was intermittently discharged to the outside of the system while maintaining the internal pressure in the range of 50 to 55 kg / cm ² . The reaction system entrained in the non-condensable gas was condensed and collected outside the autoclave system. The total amount of the reaction liquid and the accompanying liquid was 700 g, and the composition ratio of the mixed liquid by GC analysis was 1.0% methanol, 5% γ-picoline, and 2% water.
0.0%, 2,4-lutidine 65.0%, 2,4,6-
Collidine was 3.0%. Summarizing these, γ−
The yields of 2,4-lutidine and 2,4,6-collidine by picoline were 85.0% and 3.5%, respectively, and the selectivities were 92.0% and 4.1%, respectively.

Comparative Example 1 Raney nickel was used as a catalyst under the same conditions as in Example 4 to carry out a reaction.
The yield of lutidine was 45.0%.

Example 5 In a magnetic stirring type autoclave 1 equipped with a reflux condenser, 321 g of 2,4-lutidine and 64 of Raney cobalt.
g was charged and the inside of the container was replaced with hydrogen. After that, set the internal temperature to 240
The temperature was raised to ° C. Then, using a metering pump, methanol 4
80 g was continuously injected for 8 hours. During this period, the generated decomposition gas was continuously discharged so that the internal pressure was kept in the range of 45 to 55 kg / cm ² . After the reaction, the autoclave was cooled to room temperature and the reaction solution was taken out. Hereafter, when distilled in the same manner as in Example 1, 32.0 g of 2,4-lutidine and 2,4,4
314.0 g of 6-collidine was obtained. The yield of 2,4,6-collidine based on 2,4-lutidine used was 86.0.
%, The selectivity was 96.3%.

Claims (4)

[Claims] 1. At least 180 ° C. in the presence of a cobalt catalyst,
Pyridine bases having no substituents at the 2- and / or 6-positions are reacted with an aliphatic alcohol having 1 to 4 carbon atoms to methylate the 2- and / or 6-positions of the pyridine nucleus. And / or a method for producing 6-methylpyridine bases (excluding 2,3,5-collidine and 2,3,5,6 tetramethylpyridine) 2. The production method according to claim 1, wherein the produced decomposition gas is discharged to the outside of the reaction system and reacted under a predetermined pressure. 3. The method according to claim 1, wherein the cobalt catalyst is Raney cobalt. 4. The method according to claim 1, wherein the reaction is carried out while injecting alcohol into the reactor under pressure and releasing the produced decomposition gas to the outside of the reaction system.