JPS6320429B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula (In the formula, R represents hydrogen, a lower alkyl group, or an acyl group.) A novel compound 3-amino-4-aminomethyl-2-methylpyridine derivative (hereinafter referred to as "compound") that has not been described in any literature. or its salts and their production methods, and the compounds are useful as pharmaceuticals, particularly as intermediates for the production of vitamin _B6 .

A variety of important intermediates have been known in the production of vitamin _B6 . For example, 3-amino-
The 5-aminomethyl-2-methylpyridine derivative is a compound similar to the compound of the present invention, but obtaining this compound requires a stepwise synthesis method, requiring multiple steps and requiring no practical intermediate steps. It cannot be called a body. In addition, the intermediate 3-amino-4,5-diaminomethyl-2 in another vitamin _B6 synthesis method
-Methylpyridine is also similar to the compound, but this compound can be obtained by reducing 3-amino-4,5-dicyano-2-methylpyridine. However, during this reduction reaction, the target product 3-amino-4,5-diaminomethyl-2
- Some of the methylpyridine is further deammoniated, resulting in a low yield, and a large amount of reduction catalyst is also required.

In addition to the above-mentioned important synthetic intermediates for vitamin _B6 , there are pyridinol derivatives. That is, a method for producing vitamin _B6 via a 3-pyridinol derivative synthesized by a reaction between an oxazole derivative and a dienophile is known as the so-called oxazole method.

However, in this method, oxazole, which is an essential raw material, must be synthesized by a solid-liquid mixing reaction, and in this point, a major problem remains as an industrial production method. Furthermore, oxazole
Although it is relatively unstable, its reactivity is not very high, so it has the fateful disadvantage that side reactions are likely to occur if the reaction conditions are strengthened.
In addition, in order to avoid side reactions, the calculated amount of dienophile is
A method of using a large excess of 10 times the mole or more has been considered, but this increases the reaction capacity and is not actually a good idea.

Therefore, the present inventors have conducted intensive studies on an advantageous method for producing vitamin B ₆ as an alternative to these known methods, and have discovered that the above compound () is useful as an intermediate for producing vitamin B ₆ . Completed the invention.

In more detail, the general formula () used as a raw material The compound represented by (in the formula, R is the same as above) is a new compound, and can be obtained, for example, by the reaction of N-formylamino-propionitrile and γ-substituted crotonitrile, and further leads to its salts. You can also do that.

The compound () of the present invention is the above-mentioned compound ()
It can be obtained by subjecting it to a reduction reaction. The reduction reaction is generally carried out using a suitable reducing agent or in the presence of a catalyst. As the catalyst, any catalyst generally used for hydrogenation can be used, such as a nickel-based catalyst such as Raney nickel or Urushibara nickel, or a palladium-based catalyst. Also, for example, lithium-aluminum-
Reducing agents such as metal hydrogen complex compounds such as hydrides can also be used.

The reaction is carried out using an appropriate solvent, such as alcohols such as ethanol and methanol, hexane, benzene,
The reaction is carried out in a solvent such as hydrocarbons such as toluene, ethers such as diethyl ether and dioxane, esters, or water, and the reaction proceeds easily at room temperature and pressure, but if desired, the reaction can be carried out with appropriate heating and pressure. It can also be promoted.

Furthermore, in the case of nitrile ring elements by catalytic reduction, ammonia or a small amount of alkali hydroxide or alkali metal salts are generally added, and in the present invention, advantageous results can be obtained by using these means in some cases. It will be done.

The novel compound () or its salts thus obtained can be easily converted into vitamin B ₆ in high yield by known methods such as hydrolysis and diazotization reaction, if desired.

The present invention will be explained below with reference to Examples and Reference Examples.

Example 1 3.0 g of 5-acetoxymethyl-3-amino-4-cyano-2-methylpyridine was added to 120 ml of methanol.
Add 2 ml of water and 3 ml of concentrated hydrochloric acid, and shake in a hydrogen stream with 0.4 g of palladium-activated carbon (5%) to absorb 680 ml of hydrogen in about 1 hour.
The reaction solution was filtered to remove the catalyst, concentrated under reduced pressure, and then diluted with water at 70%
ml and 2 ml of concentrated hydrochloric acid, and heat and stir at 90°C for 40 minutes. Then, after concentration under reduced pressure, crystallization from ethanol yields 3-amino-4-aminomethyl-5-
Crude crystals of hydroxymethyl-2-methylpyridine dihydrochloride are obtained. Yield: 3.2g. Purification from ethanol-water yields crystals with a melting point of 257-263°C (decomposition).

Elemental analysis value C ₈ H ₁₅ Cl ₂ N ₃ O Calculated value C40.01, H6.30, N17.50, Cl29.53 Actual value C39.81, H6.06, N17.10, Cl29.47 Example 2 5 -acetoxymethyl-3-amino-4-cyano-2-methylpyridine 0.6g in methanol 50ml
Add 1 ml of concentrated hydrochloric acid, shake with 0.2 g of palladium-activated carbon (5%) in a hydrogen stream,
Once the calculated amount of hydrogen has been absorbed, the reaction solution is filtered to remove the catalyst. After concentrating under reduced pressure at below 20℃,
Ethanol was added, the precipitated crystals were collected by filtration, and 5-acetoxymethyl-3-amino-4-aminomethyl-
2-Methylpyridine. Crude crystals of dihydrochloride are obtained. Ethanol - melting point 214 ~ when recrystallized from water
Crystals at 2220℃ (decomposition) are obtained.

IR (KBr) 1745cm ^-1 NMR (δ) Measurement in heavy water (internal standard
C ₆ H ₁₅ NaO ₃ SSi) 2.24 (3H, s) 2.72 (3H, s) 4.54 (2H, s) 5.42 (2H, s) 8.15 (1H, s) When this product is hydrolyzed in dilute hydrochloric acid, Example 1
3-amino-4-aminomethyl-5-hydroxymethyl-2-methylpyridine dihydrochloride shown in is obtained.

Example 3 0.4 g of 5-acetoxymethyl-3-amino-4-cyano-2-methylpyridine was added to Raney Nickel.
Shake in ethanol with 0.9 ml and 0.25 g of sodium carbonate at room temperature under a hydrogen stream. 1 hour later
The reaction solution is filtered, made acidic by adding concentrated hydrochloric acid, and concentrated under reduced pressure. The precipitated crystals were filtered off, washed well with ethanol, and the filtrate and washings were combined and concentrated to yield 3-amino-4-aminomethyl-5-hydroxymethyl-2.
- Obtain crude crystals of methylpyridine dihydrochloride.

Example 4 Dissolve 0.1 g of 3-amino-4-cyano-5-methoxymethyl-2-methylpyridine in 20 ml of methanol, add 0.5 ml of water and 0.5 ml of concentrated hydrochloric acid, and add 0.1 g of palladium-activated carbon (5%). , shake for 30 minutes at room temperature in a stream of hydrogen. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and ethanol was added to crystallize it.
-Amino-4-aminomethyl-5-methoxymethyl-2-methylpyridine dihydrochloride is obtained. melting point
245-255℃ (decomposition).

Reference Example 1 Dissolve 1.0 g of 3-amino-4-aminomethyl-5-hydroxymethyl-2-methylpyridine dihydrochloride in 40 ml of dilute sulfuric acid and prepare an aqueous solution containing 1.15 g of sodium nitrite while heating to 88-92°C and stirring. Drop 10ml. After the addition was completed, the mixture was stirred for an additional 2 hours at the same temperature. Barium chloride is added, the precipitated crystals are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is washed with warm ethanol and the washings are concentrated to obtain 0.7 g of crude crystals of 4,5-dihydroxymethyl-3-hydroxy-2-methylpyridine hydrochloride having a melting point of 203-208°C.

Reference example 2 6.25g of γ-acetoxycrotonitrile and N-
9.8 g of formalylaminopropionitrile and 0.45 g of oxalic acid are heated and stirred at 100 to 110° C. for 48 hours. After the reaction, chloroform and 5% sodium bicarbonate solution were added for extraction, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 7.0 g of a crude product. Purification by silica gel column chromatography and recrystallization yields 5-acetoxymethyl-3-amino-4-cyano-2-methylpyridine. Melting point 110-112℃.

IR (KBr) 3450, 3360, 3250, 2220, 1725
(cm ^-1 ) NMR (δ) Measured in deuterated chloroform 2.14 (3H, s) 2.47 (3H, s) 4.5-4.9 (2H) 5.12 (2H, s) 7.93 (1H, s) Elemental analysis value C ₁₀ H ₁₁ N ₃ O ₂ Calculated value C58.53, H5.40, N20.48 Actual value C58.29, H5.42, N20.37 Reference example 3 Prepare γ-methoxycrotonitrile and N-fluor in the same manner as in Reference example 2. 3-Amino-4-cyano-5-methoxymethyl-2-pyridine is obtained from mylaminopropionitrile. Melting point 86-87℃.

IR (KBr) 3450, 3360, 3240, 2220 (cm ^-1 ) NMR (δ) Measured in deuterated chloroform 2.46 (3H, s) 3.43 (3H, s) 4.3-4.8 (2H) 4.48 (2H, s) 7.93 ( 1H, s)

Claims (1)

[Claims] 1. General formula A 3-amino-4-aminomethyl-2-methylpyridine derivative or a salt thereof, represented by the formula (wherein R represents hydrogen, a lower alkyl group, or an acyl group). 2 General formula A general formula characterized by reducing a 3-amino-4-cyano-2-methylpyridine derivative or a salt thereof represented by (wherein R represents hydrogen, a lower alkyl group, or an acyl group) A method for producing a 3-amino-4-aminomethyl-2-methylpyridine derivative or a salt thereof represented by the formula (wherein R is the same as above).