JPS5830306B2 - Amino alcohol usage information - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for synthesizing aminoalcohol derivatives.

More specifically, the present invention relates to a method for synthesizing aminoalcohol derivatives by reacting a pyridinium compound with a reducing agent, and the resulting compound is - where R1 is 1 halogen atom (fluoro, chlorobrome or iodo). R2 represents a hydrogen atom or a lower alkyl group], each of which is a new compound that has not been described in any literature, and is noticeable in the nervous system. It has a pharmacological effect,
It is an extremely useful substance as an antispasmodic, analgesic, antitussive, and antihypertensive.

The present inventors continued their research in search of an economically advantageous method for synthesizing aminoalcohol derivatives, and found that they were able to synthesize many derivatives that could not be obtained by conventional methods using simple steps and in good yields. He succeeded in doing so.

That is, conventional methods for synthesizing amino alcohol derivatives include:
Two methods are known: one in which halohydrin is reacted with an amino derivative, and the other in which nitroalcohol derivatives or aminoketone derivatives are reduced, but these methods require multiple reaction steps and are very complicated, and the yield is also very low. It has drawbacks and cannot be said to be an economically advantageous synthesis method.

The present inventors improved the shortcomings of these conventional methods of synthesizing amino alcohol derivatives and researched an economically advantageous synthetic method, and found that when the pyridinium salt was reduced using an appropriate reducing agent, - They discovered that amino alcohol derivatives could be obtained and completed the present invention.

The present invention is based on the general formula (I) (where R1 represents a monohalo-substituted phenyl group or phenyl, furyl, pyridyl, or indolyl group, and R2 represents a hydrogen atom or a lower alkyl group).

In addition, the pyridinium salt compound represented by the formula (X represents a halogen atom) is reduced using a reducing agent to form the general formula
) 2 (Here, R1 and R2 represent the same thing as above), and optionally, by converting all these derivatives into acid addition salts, the aminoalcohol derivative is synthesized. It's a method.

The pyridinium salt compound, which is the starting compound of the present invention, can be obtained by reacting iodine and a pyridine derivative with a methyl ketone derivative represented by R1COCH3(III) (where R1 represents the same as above). L, C.

KingyJ, Am, Chem, Soc, 66 y 8
94 (1944)).

The pyridinium salt compound of the general formula (I) obtained here is dissolved in a suitable solvent, especially ethanol, methanol, or water, and a suitable reducing agent, such as sodium borohydride, is added under stirring, and the mixture is heated at 20°C. 〜100℃、0.5〜10
By reducing the reaction mixture over time, the amino alcohol derivative of general illusion ① can be obtained in high yield.

The present invention also includes converting the compound thus obtained into an addition salt with an inorganic acid or an organic acid by a conventional pharmaceutically acceptable technique.

For example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, citric acid, maleic acid, anthranilic acid, fumaric acid, etc. are common.

These salts can be used to improve the solubility and stability of the compound obtained in the present invention.

The purpose of this invention is to obtain a novel compound with an extremely strong pharmacological effect that has not been previously known, and at the same time, the purpose is to provide a new and excellent method for producing amino alcohol derivatives. That is.

Therefore, in the method of the present invention, by appropriately selecting and using the substituents R1 and R2 of the pyridinium compound as a raw material, a very wide range of corresponding amino alcohol derivatives can be obtained. This method itself has a great feature as a method for producing amino alcohol derivatives in that it can advantageously produce conventionally known amino alcohol derivatives.

This method, which can be used to produce a wide variety of amino alcohol derivatives, will be described in detail below.

Examples of the pyridinium compound represented by the general formula (I) as a raw material include the following.

That is, examples of substituents for the monohalo-substituted phenyl group of R1 are:
Halogen atoms such as chlorine, bromine, iodine, and fluorine are used.

In addition to the above, as R1, thienyl, furyl, indolyl, and pyridyl groups are used.

R2 represents a hydrogen atom or a lower alkyl group.

As the lower alkyl group, an acyclic saturated or unsaturated alkyl group is used, which may be linear or branched, examples of which include methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, 5ec-butyl,
tert-butyl, pentyl groups, or vinyl,
Examples include allyl, -propenyl, 2-furnyl, 1,3-pentenyl, and 2-pentenyl.

As X-, halogen, A-, Br or ■
- is used.

The raw material compound represented by the general formula (1) obtained in this way is reacted with a reducing agent in the presence of a solvent to produce the target substance, an amino alcohol derivative represented by the general formula (II). However, commonly known reducing agents are used, especially borohydride sl-IJ.
Good results can be obtained using um.

The solvent used is preferably water or a suitable inert organic solvent such as methanol, ethanol, inpropatol, ethanol/ether, and the like.

As detailed above, according to the present invention, the general formula (
In I[), it is possible to easily synthesize a large number of compounds by selecting the side chains of R1 and R2.

The compounds obtained in the present invention are shown in Table I.

Next, examples of the present invention will be shown, but these examples are not intended to limit the present invention.

Example 1 Preparation of 1-parafluorophenyl-2-(1,2,5°6-tetrahydro-1-pyridinyl)-1-ethanol Parafluorophenacylpyridinium iodide2.
Dissolve 0g in a mixed solvent of 100rrLl of water and 100wLl of methanol to obtain 1.33g of sodium boron hydride.
Add while stirring at room temperature.

Stir as it is at room temperature for 2 hours, then put on a hot water bath for 50 to 60 minutes.
Stir and heat the reaction at 0°C for 2 hours.

After the reaction is completed, about twice as much water is added, the reaction solution is made completely alkaline with a 10% aqueous solution of caustic soda, and extracted with chloroform.

The chloroform extract was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to obtain a solid residue, which was reconsolidated from petroleum ether to obtain the target product 1-parafluorophenyl-2.
-(1,2,5,6-tetrahydro-1-pyridinyl)
-1-ethanol (1-p-furuoropheny)
l -2-(1, 2, 5+6- tetrahydr
o-1-pyridinyl) -1-e thano
1.13 g of 1) was obtained as colorless prism crystals in a yield of 83%.

The melting point and elemental analysis values of this substance were as follows.

Melting point 68-70°G Elemental analysis value C13H16FNO Theoretical value C near 0.56 H near, 29 N: 6.33 Actual value C near 0.74 H near, 16 N: 6.47 Obtained by this example 1-parafluorophenyl-2-
(1,2,5,6-tetrahydro-1-pyridinyl)-
1 - Convert ethanol to the corresponding hydrochloride salt using the calculated amount of hydrochloric acid.

The hydrochloride obtained can be recrystallized from acetone-petroleum ether.

Hydrochloride is a colorless prismatic crystal with a melting point of 170-173℃
Met.

Example 2 Method for producing 2-(2-pyridyl)-2-(1,2,5,6-tetrahydro-1-pyridinyl)-1-ethanol 1-(2-pyridoylmethyl)pyridinium iodide 20g was added to methanol 500ml is dissolved in 50 ml of water, and 12.79 g of the reducing agent, sodium borohydride, is added thereto with stirring at room temperature.

Stir as it is for 2 hours at room temperature, then further stir at 50-60℃ for 2 hours.
Heat reaction on a hot water bath for an hour.

Post-treatment was carried out according to Example 1 to obtain a residue, which was recrystallized from petroleum benzene (yield 72%), target product 1 (2
-pyridyl) -2-(1,2,5,6-tetrahydro-1-pyridinyl)-1-ethanol(1(2-pyridyl)
idyl) -2-(1, 2, 5.

6-tetrahydro-1-pyridinyl
)-1ethanol) 9.2g of colorless prism crystals
get.

The melting point and elemental analysis values of this substance were as follows.

Melting point 61-62°G Elemental analysis value Cl2H16N20 Theoretical value C near 0.56 N near, 90 N: 13.71
Actual value C near 0.85 N near, 91 N: 13.62
The obtained 1-(2-pyridyl)-2-(1,2°5.6
-tetrahydro-1-pyridinyl)-1ethanol,
The hydrochloride was obtained in the same manner as in Example 1.

Hydrochloride is a colorless prismatic crystal with a melting point of 164-16
It showed 6°C.

Example 3 Preparation of l-(2-furyl)2-(1,2,5,6tetrahydro-1-pyridinyl)-1-ethanol 1-(2-furoylmethyl)pyridinium iodide 6.3g was added to 100ml of water and 150ml of methanol. While stirring at room temperature, 4.45 g of sodium borohydride was added and reacted in the same manner as in Example 1. The same post-treatment was performed to obtain the target compound 1-(2-furyl)-2. -(1, 2, 5.

6-tetrahydro-1-pyridinyl)-1-ethanol, (1-(2-furyl)-2-(1,2.

5,6-tetrahydro-1-pyrid
1nyl)-1-ethanol) is obtained as crystals.

The crude crystals thus obtained were recrystallized from petroleum ether,
2.8 g of colorless prism crystals are obtained (yield 76%).

The melting point and elemental analysis values of this substance were as follows.

Melting point 53-54°C Elemental analysis value C11HI3 NO2 Theoretical value C: 68.37 N near, 82 N near, 25 Actual value C: 68.65 N near, 85 N near, 05 1 obtained in this way -(2-frill)-2(1,2,5
,6-tetrahydro-1-pyridinyl)-1-ethanol was treated in the same manner as in Example 1 to obtain the hydrochloride.

This hydrochloride is a colorless prismatic crystal with a melting point of 152-15
It was 4°C.

Claims (1)

[Scope of Claims] (In the formula, R1 represents phenyl substituted with one halogen, or each group of chenyl, furyl, pyridyl, or indolyl, R2 represents a hydrogen atom or a lower alkyl group, and X represents , representing a halogen atom) and a reducing agent, and optionally converting the obtained base into its salt. (In the formula, R1 and R2 represent the same meanings as above)
A method for producing an amino alcohol derivative and a salt thereof.