JPS6317065B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an industrially advantageous method for producing pyridoxine. More specifically, the present invention is based on N
-(1-cyanoethyl)-3- obtained by reacting formamide and fumaronitrile in the presence of an acid
The object of the present invention is to provide a method for producing pyridoxine by reducing amino-4,5-dicyano-2-methylpyridine and subsequently diazotizing and hydrolyzing it.

The present invention can be expressed as follows.

Conventionally, as a method for producing pyridoxine, a method has been known in which oxazole is produced by reacting an ethylene compound. However, in this method, during the production of the raw material oxazole, the reaction mixture forms an extremely hard lump, and its handling and isolation of the product are considered to be the greatest difficulties during industrial production. On the other hand, a method for producing pyridoxine using 3-amino-4,5-dicyano-2-methylpyridine as an intermediate has been known for a long time. However, this method also cannot be used as an industrial production method because the synthesis of 3-amino-4,5-dicyano-2-methylpyridine is extremely complicated and requires multiple steps.

For example, the method of Ichiba et al. (J.Sci.Research Inst.
(Tokyo) 43 , 23-29 (1948)), the synthesis of 3-amino-4,5-dicyano-2-methylpyridine involves condensation ring closure of cyanacetamide and acetylpyruvate amide, dehydration of the amide, and nitrocondensation. The synthesis requires six steps: chlorination, chlorination, reduction of the nitro group, and dechlorination.

Furthermore, the reaction of N-(1-cyanoethyl)-formamide and fumaronitrile in a solvent such as chloroform (Japanese Unexamined Patent Publication No. 1983-32476) is also known;
The yield of amino-4,5-dicyano-2-methylpyridine is as low as about 20%.

The present inventors conducted extensive studies on this reaction, and found that when a large amount of acid is added as a catalyst, the raw material N-(1-cyanoethyl)-formamide decomposes, and for example, N-(1-carbamoylethyl) ) - It was discovered that by-products such as formamide are likely to be produced, and on the other hand, if the acid concentration is too low, the reaction rate becomes low and the reaction yield decreases. Therefore, suppressing the production of by-products, maintaining a constant reaction rate, and preventing a decrease in yield are
It was thought that these propositions were incompatible, but we came up with the idea of extremely reducing the amount of solvent or conducting the reaction without solvent, and based on this idea, we carefully determined the mixing ratio of raw materials and acid catalyst. As a result of investigation, we discovered an industrially extremely advantageous method for producing 3-amino-4,5-dicyano-2-methylpyridine, and completed the present invention. The present invention will be explained in more detail below.

The relationship between the yield of 3-amino-4,5-dicyano-2-methylpyridine (yield considering recovery of unreacted raw materials) and the amount of acid used as a catalyst shows that as the amount of acid increases, the yield of 3-amino-4,5-dicyano-2-methylpyridine -The yield of 4,5-dicyano-2-methylpyridine increases, and the raw material N-
(1-cyanoethyl)-0.05 for formamide
A good yield was ensured at ~0.25 times the mole, but the highest yield was particularly observed at 0.05 times to 0.1 times the mole. Note that, as the acid, halogenated organic acids such as trifluoroacetic acid and trichloroacetic acid, organic acids such as oxalic acid and formic acid, etc. can be used.

Next, regarding the mixing ratio of N-(1-cyanoethyl)-formamide and fumaronitrile, when the molar ratio of N-(1-cyanoethyl)-formamide to 1 fumaronitrile is changed from 0.3 to 5.0, it is 3.
The yield of -amino-4,5-dicyano-2-methylpyridine increases as the molar ratio increases and reaches a maximum at 2.0 to 5.0 times. Here, N-(1-
cyanoethyl)-formamide from the reaction solution.
Amino-4,5-dicyano-2-methylpyridine is easily recovered as crystals from the mother liquor obtained by filtration,
This is a good combination because it can be used as it is as the next raw material.

That is, the molar ratio of N-(1-cyanoethyl)-formamide, fumaronitrile and acid catalyst is 2.0 to 2.0.
When mixed at a ratio of 5.0:1:0.1 to 0.5 and heated to react, 3-amino-4,5-dicyano-2-
Methylpyridine is obtained. After the generated target product is cooled and collected by filtration, 3-amino-4,5-dicyano-2-methylpyridine can be produced more economically by adding new raw materials to the mother liquor containing unreacted raw materials and reacting. can get.

In this way, the yield of 3-amino-4,5-dicyano-2-methylpyridine, which was conventionally about 20%, can be increased to 60-70% at once.

To obtain pyridoxine from 3-amino-4,5-dicyano-2-methylpyridine, 3-amino-4,5-dicyano-2-methylpyridine is first reduced by a commonly used method. That is,
When reduced in the presence of a catalyst such as palladium, platinum, Raney nickel, etc. under normal or increased pressure in a hydrogen stream, 3-amino-4,5-bisaminomethyl-2 is produced.
-Methylpyridine is obtained.

Next, this compound is dissolved in an acidic aqueous solution such as hydrochloric acid or sulfuric acid, and nitrous acid gas or nitrites are added to obtain pyridoxine in the form of an acid salt.

This reaction will be explained below with reference to Examples.

Example 1 N-(1-cyanoethyl)-formamide 2.45
g, fumaronitrile 0.78g, trifluoroacetic acid
0.14 g of the mixture is stirred and reacted at 90-100°C for 18 hours. After the reaction was completed, the reaction product was dissolved in ethyl acetate and treated with a small amount of activated carbon.The ethyl acetate was concentrated under reduced pressure, cooled, and the precipitated crystals were collected by filtration to yield 3-amino-4,5-dicyano-2-methylpyridine. get. The mother liquor was concentrated to remove ethyl acetate, and the residue contained 1.20% of N-(1-cyanoethyl)-formamide.
g, fumaronitrile 0.70g, trifluoroacetic acid
Add 0.13g and stir and react again at 90-100°C for 18 hours. Treat the reaction solution in the same way as the first time, and
Amino-4,5-dicyano-2-methylpyridine is obtained. In this mother liquor, N-(1-cyanoethyl)-
Add 1.20 g of formamide, 0.70 g of fumaronitrile, and 0.13 g of trifluoroacetic acid, and react again at 90 to 100°C. Treat the reaction solution in the same way as the second time,
3-Amino-4,5-dicyano-2-methylpyridine is obtained. When the reaction is repeated four times in this way, N-(1-cyanoethyl)-formamide is finally produced.
4.80g, fumaronitrile 2.88g, trifluoroacetic acid 0.53g to 3-amino-4,5-dicyano-2
-3.80 g of methylpyridine are obtained.

3.80 g of the 3-amino-4,5-dicyano-2-methylpyridine obtained here was mixed with 400 ml of methanol,
Reduction is carried out in a hydrogen stream using 5% palladium on carbon in 16 ml of hydrochloric acid and 8 ml of water as a catalyst. After completion of the reduction, the catalyst is removed by filtration, the filtrate is concentrated, and the residue is recrystallized from ethanol to obtain 5.07 g of 3-amino-4,5-bisaminomethyl-2-methylpyridine trihydrochloride.

4.80 g of 3-amino-4,5-bisaminomethyl-2-methylpyridine trihydrochloride obtained here was
Dissolve in 100 ml of 10% H ₂ SO ₄ , and gradually dropwise add 6.9 g of NaNO ₂ dissolved in water while heating to 80-85°C. After the reaction is complete, barium chloride is added to remove the sulfuric acid, and the filtrate is concentrated to dryness. The residue is extracted with ethanol, the salt is removed, and the ethanol is concentrated to precipitate pyridoxine crystals. When this is filtered, it is 2.30
g of pyridoxine hydrochloride are obtained.

Example 2 N-(1-cyanoethyl)-formamide 2.45
A mixture of 0.78 g of fumaronitrile and 0.22 g of oxalic acid was stirred and reacted at 90 to 100°C for 20 hours. After the reaction is complete,
After dissolving the reaction product in ethyl acetate and treating it with a small amount of activated carbon, the ethyl acetate is concentrated under reduced pressure and the precipitated crystals are collected by filtration to obtain 3-amino-4,5-dicyano-2-methylpyridine. The mother liquor was concentrated to remove ethyl acetate, and the residue contained 1.10 g of N-(1-cyanoethyl)-formamide and 0.70 g of fumaronitrile.
g and 0.20 g of oxalic acid were added thereto, and the mixture was stirred and reacted again at 90-100°C for 20 hours. When the reaction is repeated four times in this way, N-(1-cyanoethyl)-formamide is finally produced.
4.40g, fumaronitrile 2.88g, trifluoroacetic acid 0.82g to 3-amino-4,5-dicyano-2
-3.60 g of methylpyridine are obtained.

Pyridoxine hydrochloride is obtained in the same manner as in Example 1 from 3.60 g of 3-amino-4,5-dicyano-2-methylpyridine thus obtained.

Example 3 N-(1-cyanoethyl)-formamide 4.90
g, fumaronitrile 0.78g, trifluoroacetic acid
0.22 g of the mixture is stirred and reacted at 90-100°C for 18 hours. After the reaction, the reaction product was dissolved in ethyl acetate and treated with a small amount of activated carbon.The ethyl acetate was concentrated under reduced pressure, cooled, and the precipitated crystals were collected by filtration to yield 3-amino-4,5-dicyano-2-methylpyridine. is obtained. Remove ethyl acetate from the mother liquor and add N to the residue.
-(1-cyanoethyl)-formamide 1.20g,
Fumaronitrile 0.70g, trifluoroacetic acid 0.20g
Add and react again with stirring at 90-100°C for 18 hours.
When the reaction is repeated four times in this way, it ends up being N-
4.00 g of 3-amino-4,5-dicyano-2-methylpyridine is obtained from 4.80 g of (1-cyanoethyl)-formamide, 2.88 g of fumaronitrile and 0.80 g of trifluoroacetic acid.

Claims (1)

[Claims] 1 N-(1-cyanoethyl)-formamide, fumaronitrile, and acid in a molar ratio of 2.0 to 5.0:1:0.1
A method for producing pyridoxine or an acid salt thereof, which comprises reducing 3-amino-4,5-dicyano-2-methylpyridine obtained by reaction at a mixing ratio of ~0.5, followed by diazotization and hydrolysis.