JP2606184B2 - Method for producing novel 2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for producing 2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine.

[0002] 2-hydroxymethyl-4-methoxy-
3,5-Dimethylpyridine has the general formula [A]

[0003]

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(Wherein, R ¹ represents a linear or branched alkyl group having 1 to 8 carbon atoms or a fluoroalkyl group having 2 to 4 carbon atoms which may be substituted with a cyclic alkyl group. This compound is useful as an intermediate for the production of a compound having antiulcer activity described in JP-A-63-146882.

[0005]

2. Description of the Related Art A compound represented by the general formula [A] is represented by the general formula [B]

[0006]

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(Wherein R ¹ has the same meaning as described above).

The compound represented by the general formula [B] has the general formula

[0009]

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(Wherein R ¹ is as defined above) and a compound of the general formula [C]

[0011]

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(Wherein X represents a halogen atom).

The compound represented by the general formula [C] is represented by the formula [D]

[0014]

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It is prepared from 2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine represented by the formula:

The method for producing the compound represented by the formula [D] is described in JP-B-63-53887 and JP-A-2-18086.
No. 8 publication.

The method described in JP-B-63-53887 is a method using (a) 3,5-dimethylpyridine as a starting material and 4-methoxy-3,5-dimethylpyridine-
Method via N-oxide and (b) Starting from 2,3,5-trimethylpyridine, using 4-methoxy-2,
This is a method via 3,5-trimethylpyridine-N-oxide. The method described in JP-A-2-180868 is a method using (c) 3,5-dimethylpyridine as a starting material and passing through 2-aminomethyl-4-methoxy-3,5-dimethylpyridine.

[0018]

The yield of the above method (a) is about 3% in total from 3,5-dimethylpyridine, and the yield of the method (b) is 2,3,5-trimethylpyridine. Is about 50% in total. (C) In the method,
Catalytic reduction of 2-cyano-4-methoxy-3,5-dimethylpyridine to give 2-aminomethyl-4-methoxy-3,
5-dimethylpyridine, which is a compound represented by the formula [D] in two steps via an operationally dangerous diazotization reaction, and the yield is about 40% in total from 3,5-dimethylpyridine is there. Either method cannot be said to have a high yield, and there has been a demand for an industrial production method which has a higher yield than these methods and is safe in operation.

According to Japanese Patent Publication No. 63-53887, an intermediate, 4-methoxy-, which is used for producing compound [D] from 2,3,5-trimethylpyridine as a starting material.
2,3,5-trimethylpyridine-N-oxide [E]
Is described as a production intermediate that can be stored in bulk form. However, in our experiments, 4-
Methoxy-2,3,5-trimethylpyridine-N-oxide had deliquescence as shown in Table 1, and was a compound that was difficult to handle.

[0020]

Means for Solving the Problems The present inventors have made the following reaction pathways.

[0021]

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When 2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine is produced by the above process, the compound can be obtained with high purity, high yield and safely, and the intermediate has no deliquescent property. The present invention has been found to be advantageous in operation and has been completed.

3,5-dimethylpyridine [I] is reacted with aqueous hydrogen peroxide to produce 3,5-dimethylpyridine-N-oxide [II], and [II] is reacted with concentrated sulfuric acid, fuming sulfuric acid and potassium nitrate. To produce 3,5-dimethyl-4-nitropyridine-N-oxide [III], and [III]
Is reacted with dimethyl sulfate and then with sodium cyanide to produce 2-cyano-3,5-dimethyl-4-nitropyridine [IV].

[IV] is reacted with sodium methoxide to produce 2-cyano-4-methoxy-3,5-dimethylpyridine [V], and [V] is catalytically reduced in an acidic solvent in the presence of a catalyst poison. To give 2-hydroxymethyl-4-methoxy-
3,5-dimethylpyridine [D] is produced.

As the hydrogenation catalyst in the catalytic reduction step, a palladium catalyst is preferable, a 2-10% palladium-carbon catalyst, a 2-10% palladium-barium sulfate catalyst,
Particularly preferred is a 10% to 10% palladium-alumina catalyst.

The catalyst poison is preferably an iron salt, specifically, ferric chloride.

The acidic solvent is preferably an inorganic acid, particularly sulfuric acid or hydrochloric acid. The concentration of the acid is preferably 5 to 18 normal for sulfuric acid and 5 to 12 normal for hydrochloric acid. When the concentration of the acid is low, the selectivity of the reaction is reduced and a large amount of by-products are generated, and the progress of the reaction is slow, which is not practical. On the other hand, if the acid concentration is too high, the cyano group is hydrolyzed to a carbamoyl group, resulting in a reduced yield.

A hydrogen pressure of 1 to 10 kg / cm ² is excellent in terms of selectivity of the reaction, and is advantageous in operation.

The reaction temperature is preferably from 10 to 30 ° C. If the temperature is too high, a hydrolysis reaction occurs.

The direct raw material of the present invention, 2-cyano-4
-Methoxy-3,5-dimethylpyridine is a very stable crystalline substance, has no deliquescence, is easy to handle, and has an operational advantage as an industrial production method.

[0031]

EXAMPLES Reference Example 1 (3,5-dimethylpyridine-
N-oxide) 203.0 g of 3,5-dimethylpyridine was added to acetic acid 1000
Then, 200 ml of 30% hydrogen peroxide solution was added to the solution at 35 ° C., and the mixture was stirred at 75 ° C. for 3 hours. The reaction solution was cooled to 40 ° C., 140 ml of 30% aqueous hydrogen peroxide was added, and the mixture was stirred at 75 to 83 ° C. for 8 hours, and then allowed to stand at room temperature overnight. This solution was concentrated under reduced pressure to about 300 ml, and the remaining solution was added with 40% sodium hydroxide at 0 to 5 ° C to adjust the pH to 13 ml.
And extracted with chloroform.
233 g of dimethylpyridine-N-oxide were obtained (the yield was quantitative).

Reference Example 2 (3,5-dimethyl-4-nitropyridine-N-oxide) 200 g of 3,5-dimethylpyridine-N-oxide, 580 ml of concentrated sulfuric acid, 290 ml of 30% fuming sulfuric acid and 444.0 g of potassium nitrate The mixture was stirred in a boiling water bath for 7 hours, cooled to 20 ° C., and then stirred under ice-cooling with 3 kg of ice and water 1
000 ml.

The solution was adjusted to pH 7 with 40% sodium hydroxide at 30 ° C., extracted with chloroform, and the solvent was distilled off.
The obtained yellow solid was recrystallized with a mixed solution of chloroform and hexane to obtain 206.4 (75.6% yield) of 3,5-dimethyl-4-nitropyridine-N-oxide.

Reference Example 3 (2-cyano-3,5-dimethyl-4-nitropyridine) A mixture of 200.0 g of 3,5-dimethyl-4-nitropyridine-N-oxide and 338.0 ml of dimethyl sulfate. The liquid was stirred at 60-70 ° C for 5 hours. The solution was cooled to 5 ° C., 450 ml of water was added while maintaining the temperature, and the mixture was extracted three times with ethyl ether to remove excess dimethyl sulfate.

550 ml of water was added to the aqueous solution after the removal, and a solution of 122.0 g of sodium cyanide dissolved in 990 ml of water was added to this solution at -3 to 0 ° C. under a nitrogen stream over 3 hours, and added for 4 hours The temperature was raised to 7 ° C., and the precipitated pale yellow crystals were collected by filtration, washed with water and dried to give 2-cyano-3,5.
-Dimethyl-4-nitropyridine 210.5 g (quantitative yield) was obtained.

Reference Example 4 (2-cyano-4-methoxy-3,5-dimethylpyridine) 2-cyano-3,5-dimethyl-4-nitropyridine 2
A mixture of 00.0 g and 1130 ml of methanol was cooled to 3 ° C, and 306.6 ml of a 28% sodium methoxide / methanol solution was added dropwise at 3 to 6 ° C. The mixture was stirred at 40 to 50 ° C. for 30 minutes, and then heated to reflux for 40 minutes and cooled to 3 ° C.

This reaction solution was added to 3700 ml of water at a temperature of 8 ° C. or lower and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and then dried over silica gel (BW-2).
00, manufactured by Fuji Devison Chemical Co., Ltd.) and stirred to decolorize. The desiccant and silica gel were removed by filtration, and the filtrate was evaporated under reduced pressure to give 2-cyano-4-methoxy-3,5-dimethylpyridine 172.6 as pale yellow crystals.
g (94.3% yield). The melting point is 59.0-60.
It was 0 ° C.

Example 1 A 5% palladium-carbon catalyst was added to a mixture of 200.0 g of 2-cyano-4-methoxy-3,5-dimethylpyridine, 2000 ml of 9N sulfuric acid and 2.0 g of ferric chloride. 0
g, and the mixture was subjected to catalytic reduction at a hydrogen pressure of 3 kg / cm ² and a reaction temperature of 20 to 25 ° C. for 2 hours. Remove the catalyst from the reaction mixture, 40%
After adjusting the pH to 8 with sodium hydroxide and saturated sodium bicarbonate, the mixture was extracted with chloroform. After the chloroform layer was dried over anhydrous sodium sulfate, it was purified by silica gel column chromatography (silica gel; BW-200, manufactured by Fuji Devison Chemical Co., Ltd., developing solvent; ethyl acetate: ethanol) to give a light yellow solid 2- Hydroxymethyl-4-methoxy-3,5-dimethylpyridine 190.1
g (92.2% yield).

The product was analyzed by thin layer chromatography and NM
It was identified by the R spectrum and confirmed to be a single substance.

[0040]

(Equation 1)

Example 2 A mixture of 200.0 g of 2-cyano-4-methoxy-3,5-dimethylpyridine, 200 ml of 9 N sulfuric acid and 2.0 g of ferric chloride was treated with 5% palladium-carbon catalyst. 0
g, and the mixture was subjected to catalytic reduction at a hydrogen pressure of 3 kg / cm 2 and a reaction temperature of 20 to 25 ° C for 2 hours. Remove the catalyst from the reaction mixture, 40%
After adjusting the pH to 8 with sodium hydroxide and saturated sodium bicarbonate, the mixture was extracted with chloroform. After drying the chloroform layer with anhydrous sodium sulfate, silica gel (silica gel; BW-200, manufactured by Fuji Devison Chemical Co., Ltd.) 2
Then, the mixture was stirred for 10 minutes. The impurities were removed by filtration, and the filtrate was concentrated to give 2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine as a pale yellow solid.
2 g (90.8% yield) was obtained. The product was identified by thin layer chromatography and NMR spectrum and confirmed to be a single product.

Example 3 A mixture of 200.0 g of 2-cyano-4-methoxy-3,5-dimethylpyridine, 500 ml of 12N sulfuric acid and 2.0 g of ferric chloride was treated with 5% palladium-barium sulfate catalyst 30. 0.0g, hydrogen pressure 1kg / cm2, reaction temperature 30 ° C
For catalytic reduction. The same post-processing as in Example 1 was performed,
188.8 g (yield 91.6%) of 2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine was obtained.
The product was identified by thin layer chromatography and NMR spectrum and confirmed to be a single product.

Example 4 A mixture of 200.0 g of 2-cyano-4-methoxy-3,5-dimethylpyridine, 2000 ml of 5N hydrochloric acid and 2.0 g of ferric chloride was treated with 5% palladium-alumina catalyst 3.
0.0 g was added, and the mixture was subjected to catalytic reduction at a hydrogen pressure of 4 kg / cm 2 and a reaction temperature of 30 ° C. The same post-processing as in Example 1 was performed, and
189.2 g (yield 91.8%) of -hydroxymethyl-4-methoxy-3,5-dimethylpyridine was obtained. The product was identified by thin layer chromatography and NMR spectrum and confirmed to be a single product.

Example 5 Hygroscopic Test of Compound [V] The moisture absorption of the compound [V] was determined by the following method.

[0045]

(Equation 2)

A test compound (10.0 g) was allowed to stand in a beaker at a temperature of 25 ° C. and a relative humidity of 68%, and the weight change was measured over time to determine the moisture absorption of the test compound at each time. Was.

In addition, 4-methoxy-2,3,5-trimethylpyridine-N-oxide [E] was similarly tested and compared. The results are shown in Table 1.

[0048]

[Table 1]

The compound [V] showed no moisture absorption after 60 minutes, and no change in the shape. On the other hand, the compound [E] began to oil immediately after the start of the test, and showed a moisture absorption of 5% after 3 minutes and 23% after 60 minutes.

[0050]

The catalytic reduction of 2-cyano-4-methoxy-3,5-dimethylpyridine in an acidic solvent in the presence of a catalyst poison with a hydrogenation catalyst provides high purity, high yield and safety. -Hydroxymethyl-4-methoxy-3,5-
Dimethylpyridine can be obtained. In addition, the present method uses the direct raw material 2-cyano-4-methoxy-3,5
-Dimethylpyridine is a very stable crystalline substance and has no deliquescence, so it is easy to handle and advantageous in operation.

Claims (6)

(57) [Claims] 1. A method of catalytically reducing 2-cyano-4-methoxy-3,5-dimethylpyridine in an acidic solvent in the presence of a catalyst poison with a hydrogenation catalyst. A method for producing methoxy-3,5-dimethylpyridine. 2. The hydrogenation catalyst is a palladium catalyst in which palladium is supported on a carrier at a ratio of 2 to 10%.
The described 2-hydroxymethyl-4-methoxy-3,5-
A method for producing dimethylpyridine. 3. The method for producing 2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine according to claim 1, wherein the catalyst poison is an iron salt. 4. The 2-hydroxymethyl-4 according to claim 1, wherein the acidic solvent is sulfuric acid or hydrochloric acid, and the concentration of the acid is 5 to 18 normal for sulfuric acid and 5 to 12 normal for hydrochloric acid. A method for producing -methoxy-3,5-dimethylpyridine. 5. The 2-hydroxymethyl-4-methoxy- according to claim 1, wherein the hydrogen pressure is 1 to 10 kg / cm ^2.
A method for producing 3,5-dimethylpyridine. 6. The method according to claim 1, wherein the reaction temperature is 10 to 30 ° C.
Or 2-hydroxymethyl-4-methoxy- according to 2
A method for producing 3,5-dimethylpyridine.