JPS61148161A - 1-(2-(4-hydroxyphenylcarbonyl)ethyl)-4-benzylpyridinium salt - Google Patents

Abstract

NEW MATERIAL:A 1-[1-(4-hydroxyphenylcarbonyl)ethyl]-4-benzylpyridinium salt shown by the formula I (X is halogen). EXAMPLE:1-[1-(4-Hydroxyphenylcarbonyl)ethyl]4-benzylpyridinium salt. USE:An intermediate for synthesizing 1-(4-hydroxyphenyl)-2-(4-benzylpiperidino) propane 1-ol shown by the formula II having alpha-receptor blocking action or its acid addition salt. PREPARATION:4-Benzylphyridine is reacted with a p-hydroxy-alpha-halo genopropiophenone in a nonpolar solvent such as benzene, or toluene to give a compound shown by the formula I. A compound shown by the formula II is obtained in high yield by using this novel compound without introducing a protecting group into the compound shown by the formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 1-(4-hydroxyphenyl)-2-( represented by formula (2) % formula %
4-benzylpiperidino)pronognol-1-ol or its acid addition salts (e.g. hydrochloric acid, maleic acid, succinic acid,
The following general formula (1) (where X represents a halodane atom) is useful as an intermediate in the production of salts of tartaric acid and citric acid. (nyl)ethyl-4-benzylpyridinium salt.

Piperidinoalkanol and its salts having the structure of formula (2) have an α-receptor blocking effect, but the conventional method for producing them has been to use 4-penzylbiperidine and formula (3) (wherein X is halodane). , in particular chlorine or bromine, and Y represents a protecting group replaceable by hydrogen, such as a methoxymethyl group or a benzyl group) to give a compound of general formula (4), and then by reduction Simultaneously or sequentially, the group Y is reductively eliminated, and the -C- group is converted into 47-1534
No. 8) is presented.

However, the starting material 4-benzylpiperidine for obtaining the compound of formula (4) is generally not commercially available;
- Benzylpyridine must be reduced before use. In addition, one raw material (3) is synthesized by benzylating p-hydroxypropiophenone to obtain p-pendyloxyglopiophenone, and then halodanizing the α-position of this. -The phenolic OH of hydroxypropiophenone is protected with Y and used.

This group Y needs to be eliminated at the end, regardless of K, which unnecessarily complicates the reaction.

That is, in the past, as shown in the following reaction 2A,...A In order to obtain the compound of formula (1), the initial raw material was reduced with Ushii's home, or after the introduction of a protecting group, it was converted into a compound of formula (1). Since the method involves reacting each other with each other and finally removing the protecting group, the reaction process is complicated, and the process for producing the compound of formula CD has the disadvantage that the operation is carried out on the surface side.

In view of the above circumstances, the present inventors conducted repeated experiments on a method for efficiently producing the compound of formula (2) and its acid addition salt, and found that 4-benzylpyridine and p-hydroxy-α-
By reacting with halo r nogropiophenone,
A novel substance 1-[:1-(4-hydroquinphenylcarbonyl)ethyl]-4-benzylpyridinium salt represented by the following general formula (1) (wherein X represents a halodane atom, preferably a chlorine or bromine atom) By subjecting this new substance to a reduction reaction with an appropriate catalyst, phenolic OH can be obtained as in the conventional method.
1-(4-hydroxyphenyl)-2-(4-benzylpiperidino)fo pan-1= Therefore, it was found that the new substance of formula (1) is very useful as an intermediate for the synthesis of compound 2).

That is, the present inventors have conducted extensive research in order to industrially advantageously synthesize the compound of formula (2).
When synthesizing the compound of formula (1), it was thought that when p-hydroxypropiophenone was directly halogenated, halogenation at the α-position and simultaneous rhodanization [of the phenyl nucleus] occurred. As a raw material for the synthesis of p
-Hydroxypropiophenone is benzylated to synthesize p-penzyloxyglobiophenone, and then α
p-benzyloxy-α-bromozolobiophenone obtained by bromination at the p-hydroxy-
No consideration was given to using α-halognoglopiopheno/ as a raw material for the synthesis of the compound of formula (2).

However, according to the results of separate studies conducted by the present inventors, it was found that p-hydroxy-α-halodanoyl was produced from p-hydroxypropiophenone in good yield without the side reactions that were conventionally thought. It was discovered that it is possible to synthesize globiophenone, and 1 this p-hydroxy-α
- It has been discovered that the compound of formula (1), which is a new substance, can be obtained in high yield by reacting halognoglopiopheno/ with 4-benzylpyridine. By reducing the new substance 1-(1-(4-hydroquinphenylcarbonyl)ethyl]-4-penzylpyridinicum salt, the formula (
1) can be obtained, p-hydroxy-α-halo-r-noglobiophenone can be effectively used as a raw material for the synthesis of the compound of formula (2), and moreover, it can be used as a novel substance of formula (1). By using p
-Hydroxy-α-halo-r-nopropiophenone or the phenolic OH of the compound of formula (1) does not need to be protected by a protecting group, and the new substance of formula (1) can be simply reduced to the desired formula. The compound (2) can be obtained, therefore there is no need to remove the protecting group at the end as in the conventional method, and the reaction product is not contaminated with by-products due to removal of the protecting group, so it is purified. The present inventors have discovered that the process is advantageous from the above point of view, that the process for producing the compound of formula (2) is simplified, and that the reaction proceeds advantageously, leading to the present invention.

The novel substance (1) of the present invention comprises 4-benzylpyridine and p
-Hydroxy-α-nolognozolopiophenone. In this case, this reaction is preferably carried out in a nonpolar solvent such as benzene or toluene by a method of refluxing for 4 to 10 hours, preferably 6 to 8 hours, and the new substance of formula (1) is refluxed in a nonpolar solvent such as benzene or toluene. Since it is insoluble, it forms as a precipitate in highly pure form. The yield is usually 90-99%, which is almost quantitative.

The novel substance (1) of the present invention is useful as a synthetic intermediate for the compound of formula (2), and when producing the metal compound of formula (2) from this new substance (1), the compound of formula (1) is It is subjected to reduction all at once or stepwise to change the -C- group to -CHOH and the pyridine ring to a piperidine ring, respectively.
In this case, the suitable solvent is a mixed solvent of water and a lower alcohol (for example, methanol, ethanol, inglono-9ol) or water; in the case of a water-alcohol mixed solvent, the alcohol content is advantageously 60-09b. Note that this reduction reaction is carried out in the presence of a suitable catalyst, such as platinum oxide or Raney nickel. Here, when Raney nickel is used, it is used in an amount of 4 to 8% based on the weight of the compound of formula (1), and when platinum oxide is used, it is used in an amount of 2 to 4% based on the weight of the compound of formula (1). is preferable. When platinum oxide is used, the yield from the compound of formula (1) to the compound of formula (3) is astoundingly high at 89 to 96 cm, and even when Raney nickel is used, the yield is 89 to 96 cm.
Yields range from 2 to 90%. In this case, when platinum oxide is used as a catalyst, the reaction can be carried out under normal pressure, and the reaction temperature can also be set at room temperature.

Note that the acid addition salts of the compound of formula (2) produced by the above method, such as salts of hydrochloric acid, maleic acid, succinic acid, -soap, and citric acid, can be obtained from the compound of formula (2) by a conventional method. I can do it.

In this way, the novel substance (1) of the present invention is effectively used as an intermediate for obtaining the compound of formula (2), but the compound of formula (2) using the novel substance (1) of the present invention is The method for producing the compound has the following advantages when compared with conventional methods.

1. Commercially available 4-benzylpyridine can be used as is.

2 In the conventional method, after protecting the 7 enolic OH of p-hydroxygropiophenone, it is halogenated to form the formula (3
) is produced and used in the reaction, and in this way it is necessary to log the 7-enolic OH with the protecting group Y, and finally, from the compound of formula (4) Although it is necessary to remove or release the group, in the present invention, there is no need to introduce such a protecting group, and therefore no extra reaction is required.

& New substance 1-(1-(4-hydroxyphenylcarbonyl)ethyl)-4-indylpyridinium salt obtained by reacting 4-benzylpyridine and p-hydroxy-α-halognopropiophenone The target substance can be obtained by simply reducing it, and there is no need to remove the protecting group as mentioned above, so there is no generation of by-products due to the removal of the protecting group, and the production and purification processes are easy. is simplified.

4. The reaction to obtain formula (1) is quantitative, and the subsequent reduction reaction to obtain the target substance of formula (2) also has a very high yield, so the yield throughout the entire process is high.゜Production examples of the novel substance of the present invention will be shown below.

[Production Example 1] p-hydroxy-α-noromuglopiophenone 2 Z
91 (0.1 mol) and 4-benzylpyridine 17
, 811 (0,105 moj) was added to 300111 benzene and refluxed for 7 hours, then after cooling, the precipitate was collected by filtration to obtain 1-(1-(4-hydroxyphenylcarbonyl)ethyl)- 37.4 g of 4-penzylhyricinium bromide was obtained (yield: 94 g).The physical properties of this pyridinium bromide are as follows.

Melting point: 212°C Infrared absorption spectrum (KBr): Fig. 1 Nuclear magnetic resonance spectrum C (CD3) 280): Fig. 2 Elemental analysis: Actual value 3.32 6L 17% 5.12% [Production example 2 ] p-hydroxy-α-chloropropiophenone 1 g,
5. p (0,1mat) and 4-benzylpyridine 1
7,81 (0,105 moj) was added to 3001 Ll of benzene and refluxed for 7 hours, then after cooling, it was filtered to collect the precipitate. ) Ethyl-4-penzylhylisonium chloride 326I was obtained (yield 92%).

Next, a method for producing the compound of formula (2) from the novel substance of the present invention will be specifically explained using the following reference examples.

[Reference Example 1] Pyridinium bromide-19,9Ji obtained in Production Example 1
' (0.05 mol) in 50% aqueous ethanol 10
Catalytic reduction is carried out at normal pressure using 0.8 g of 0+mi/4C dissolved platinum oxide.

After absorbing the theoretical amount of hydrogen, the catalyst is removed and the solvent is distilled off. Note that the reaction temperature was about 18°C and the reaction time was 8 hours.

The obtained product is dissolved in water, treated with activated carbon, an equivalent amount of aqueous sodium carbonate is added, the precipitate is poured into F water, and dried to obtain the desired 1-(4-hydroxyphenyl)-2-( 15.6 g of 4-benzylpiperidino) 4-benzylpiperidino) are obtained. Yield 96%,
The melting point is 108-109℃, and if necessary, ethanol/
Recrystallize from a mixed solvent of water.

This is treated with tartaric acid in a conventional manner to obtain tartrate.

Melting point: 150-153°C [Reference Example 2] Pyridinium bromide 19.9.9 (
0.05 mod) was dissolved in 160 g of 50 g of aqueous ethanol and heated at 260°C using a Raneyi Kel 2I.

Catalytic reduction is carried out at 100 atm.

After the reaction, the reaction mixture was treated in the same manner as in Reference Example 1 to obtain 1-(4-hydroxyphenyl)-2-(4-benzylpiperidino)propan-1-ol 1&8I. Yield: 85 cm.

[Reference Example 3] □ Pyridinium chloride obtained in Production Example 2 17.71 (
0,05moj) in the same manner as in Example 1 to obtain 1-(
14.8 g of 4-hydroxyphenyl)-2-(4-benzylpiperidino)propan-1-ol are obtained. Yield: 91 cm.

[Brief explanation of the drawing]

Figure i11 is an infrared absorption spectrum of 1-(:1-(4-hydroxyphenylcarbonyl)ethyl]-4-penzylpyridinium bromide, and Figure 2 is a nuclear magnetic resonance spectrum of the same compound.

Claims (1)

[Claims] 1 1-[1-(4- hydroxyphenylcarbonyl)ethyl]-4-benzylpyridinium salt.