JPS5953256B2 - α↑1-tert. -Production method of butylaminomethyl-4-hydroxy-m-xylene-α↑1,α↑3-diol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention describes the therapeutically valuable α1-tert-butylaminomethyl-4-hydroxy-m-xylene-α11α3-
This invention relates to a new method for producing diols and acid addition salts thereof.

This compound is known for its pharmacological properties and is widely used in the treatment of short-term breath conditions and other severe bronchospasm conditions.

The preparation of α1-tert-butylaminomethyl-4-hydroxy-m-xylene-α11α3-diol is described, for example, in British Patents Nos. 1,200,886 and 1,247,370.
listed in the number.

The method of GB 1200886 includes several intermediate steps. In addition, the reduction of ester groups has been carried out using lithium aluminum hydride in diethyl ether or tetrahydrofuran, which is an expensive process and cannot be carried out on an industrial scale due to the risk of ignition of the solvent. It is a danger. GB 1247370 likewise consists of several steps and its intermediate parts are produced in very low yields. That is, this method uses 5-acetyl- or 5-bromoacetyl-salicylic acid ester for seo
2 to give 5-glyoxysalcylic acid ester, which is condensed with an amine compound to give the corresponding azomethine derivative, and the resulting azomethine compound is reduced with sodium borohydride and lithium aluminum hydride to obtain the desired product. We are getting a compound. Due to the solubility of the intermediate product in this process, it is extremely difficult to extract and separate the product from the reaction medium in the subsequent reduction step, and the yield of the product in the entire process is, for example, 12 It was found that the rate was low, less than %. Therefore, α1−T
ert. -butylaminomethyl-4-hydroxy-m-
Knowing the solubility characteristics of xylene-α1,αS-diol, it can be said that this method can only be realized on a laboratory scale. (In this connection, see the reaction scheme below) The present invention overcomes the disadvantages of the above-mentioned process, the key point of which is to protect the phenolic hydroxyl group of the starting compound by an arylmethyl group. .

That is, an object of the present invention is to provide an industrial production method for producing α1-Tert/-butylaminomethyl-4-hydroxy-m-xylene-α1,α3-diol easily and in good yield. .

This method involves the simultaneous hydrogenation of imine derivatives having the formula ~11-1 (wherein R represents a lower straight-chain or branched hydrocarbon group containing 1 to 6 carbon atoms and Ar represents an aryl group). and reduction to a compound having the formula, from which the arylmethyl protecting group is removed by catalytic hydrogenation.

The process starts from a benzoic acid derivative having the formula (wherein R is a lower straight-chain or branched hydrocarbon group containing 1 to 6 carbon atoms and Ar is an aryl group) and produces an intermediate product. It can be advantageously carried out in a continuous production method using one substrate without isolating it.

Oxidation of benzoic acid derivatives with, for example, selenium dioxide in dioxane gives the formula ~. 111 , which gives the corresponding glyoxal derivative with Te
rt. -butylamine H,NC(CH,), to obtain an imine derivative having the formula.

The compound is then combined with a suitable alkali metal aluminum hydride derivative, such as the formula NaAIj(0CH,CH20CH
, )2H2 with sodium bis(2-methoxyethoxy)aluminum hydride or with formula NaAIj(
C, H, ), H, is converted by simultaneous zero hydrogenation and reduction with sodium diethylaluminium hydride to give a compound having the formula, from which the arylmethino I group is subsequently removed by catalytic hydrogenation. .

The advantage of this process lies in the continuity of the process, which is achieved by protecting the phenolic hydroxyl group in the benzokanazane derivative by an arylmethyl group. In this way, losses in isolation and purification of intermediates are avoided and the final product is obtained in a highly pure and easily isolated form. In this process, the ester derivative is first oxidized, for example with selenium in dioxane, preferably at the boiling point of the solvent, to give the corresponding glyoxa-M derivative 1.

In the sequel, the reaction mixture can be used after removing the precipitated Tt selenium in the reaction. T to PWL
Once ert-butylamine is added, standing at room temperature for 3 hours is sufficient to form the desired imine derivative.

In this way, by appropriate selection of solvent and sorbent,
Reaction of the second reactive keto group in the glyoxal derivative VK with tert-butylamine is prevented. Furthermore, an unexpected feature of the present invention is the simultaneous hydrogenation and reduction of the carbon-nitrogen double bonds of the imine derivatives, as well as of the keto and ester groups, by the use of suitable alkali metal aluminum hydride derivatives. .

This type of reaction has never been described in the literature. When the reducing agent used is sodium bis(2-methoxyethoxy)aluminum hydride or sodium diethylaluminum hydride, the solvent is usually benzene or toluene, both of which can be used in the process of the invention. However, it has now been unexpectedly discovered that better results can be obtained if the reaction is carried out in dioxane. That is, the reaction mixture used for producing the imine derivative can be used as it is. To save reducing agent, excess t-butylamine is shown to be evaporated under reduced pressure. This simultaneous hydrogenation and reduction of imine derivatives is only possible by protecting the phenolic hydroxyl group on the benzene ring. If protection is not applied,
The product must be extracted from the aqueous solution, α1-
Tert. -butylaminomethyl-4-hydroxy-m
Given the known solubility properties of -xylene-α1,α3-diols, this is impossible to attempt on an industrial scale and moreover leaves considerable amounts of undesired X. A product is produced. Arylmethyl protecting groups in compounds can be removed by catalytic hydrogenation, for which a suitable catalyst is, for example, palladium on charcoal, and a suitable solvent is, for example, an alcohol.

The invention also relates to the intermediate compounds produced by the process.

These compounds are new compounds, and their preparation and properties have never been described in the literature. Incidentally, the reaction process diagrams of the above-mentioned British Patent No. 1247370 method and the method of the present invention are shown below for reference.

In this figure, the yield obtained by each method is indicated by the symbol S. This allows the process of the invention to obtain higher yields compared to the process of GB 1,247,370, and that the processes of the invention can be carried out sequentially in one and the same medium (e.g. dioxane). will be easily understood. That is, the present invention avoids extraction of intermediate products, thereby increasing the overall yield of the process. It will be clear that if each extraction step is added, the yield will be reduced. The continuity of the entire process is based on the fact that the imine derivative (formula) as defined herein is hydrogenated and simultaneously reduced by a suitable hydride derivative. In contrast, in the cited method, the corresponding reaction is carried out in two separate steps. The method of the invention is illustrated by the following example.

Example 1 α1-Tert. 0.35 kg of water was added to 59 kg of -butylaminomethyl-4-benzyloxy-m-xylene-α1,α3-dionoledioxane, and the mixture was mixed with 70-
Heat to 80°C.

Add 4.39 kg of selenium dioxide.

After dissolving the selenium dioxide, 11.8 kg of ethyl ester of 5-aceto-2-benzyloxybenzoic acid dissolved in 35.5 kg of dioxane are added. During this addition, the reaction mixture is further heated until it boils (approximately 10'C). Continue boiling under reflux for 6 hours. During this boiling, the color of the reaction mixture changes to black due to the precipitated selenium. After boiling, the mixture is allowed to cool to room temperature. Separate selenium. (If it is desired to isolate the glyoxal derivative, it is done by evaporating the dioxane. The glyoxal derivative made in this way is thereby obtained as a viscous oil.) Add 5.9 kg of the glyoxal derivative to the f-liquid at room temperature. Tert. - Add butylamine and stir at room temperature for 4 hours.

Evaporate excess tert-butylamine under reduced pressure. The reaction mixture was dissolved in a 70% benzene solution of sodium bis(2-methoxyethoxy)aluminum hydride under nitrogen atmosphere.
Pour into kg.

This addition takes place at approximately 60°C. After addition, boil under reflux for 1 hour. The complex compound with the reducing agent and other products is decomposed with water and hydrochloric acid in a conventional manner. The oil layer of the product is separated, dissolved in chloroform, dried over sodium sulfate and treated with activated charcoal. Evaporate the chloroform under reduced pressure. From the evaporation residue,
If necessary, the product is recrystallized from ethanol. Yield 8
．． 8-9.0 kg (65-70% of theoretical value), melting point approximately 1
35° C. Example 2 Starting as in Example 1, but after preparing the imine derivative, the solvent is evaporated.

By this method, imine derivatives are obtained as viscous oils. This is 801Cf! dissolves in benzene. 40% benzene solution of 70% sodium bis(2-methoxyethoxy)aluminum hydride in nitrogen atmosphere.
Pour into kg. Continue the operation as in Example 1. Yield 7
．． 5-8.0 kg (58-62% of theoretical value), melting point approximately 1
35℃. Example 3 Similar to Examples 1 and 2, but instead of the ethyl ester of 5-aceto-2-benzyloxybenzoic acid, an equivalent amount of methyl ester is used.

Example 4 To 66 kg of dioxane add 0.4 kg of water and heat the mixture to 70-80<0>C.

Add 4.92 kg of selenium dioxide. After dissolving selenium dioxide, 5-aceto-2- dissolved in 40 kg of dioxane
Ethyl ester of benzyloxybenzoic acid 13.2 kg
Add. Continue heating until the reaction mixture boils (approximately 10'C) and then boil at reflux for 6 hours. During this boiling, the reaction mixture turns black due to precipitated selenium. The reaction mixture is cooled to room temperature and the precipitated selenium is separated off. F at room temperature
6.6 kg of Tert. - Add butylamine and stir at room temperature for 4 hours. Excess Tert. - Butylamine is evaporated under reduced pressure. The dioxane solution at room temperature was diluted with sodium diethylaluminium dihydride in a nitrogen atmosphere.
85.5 kg of 5% toluene solution are added at such a rate that the temperature of the reaction mixture does not exceed 25°C. After this addition, stirring is continued for 1 hour at 25°C. The complex compound of the product and the reducing agent thus formed is decomposed in a conventional manner by adding water and an alkaline solution. This addition must be done gradually due to foaming caused by liberated ethane. Separate the organic phase and concentrate. From this evaporation residue, the product can be recrystallized from ethanol if necessary. Yield 9.5-10
．． 3 kg (65-70% of theory), melting point approximately 135°C.
Example 5 Same as Example 4, but the solvent is evaporated after preparation of the imine derivative.

The imine derivative is thus obtained as a viscous oil, which is dissolved in 90 kg of toluene. This toluene solution is used in the next step. Proceed as in Example 4. Yield 8.5-9.1 kg (58-62% of theory), melting point approximately 135°C. Example 6 Similar to Examples 4 and 5, but instead of the ethyl ester of 5-aceto-2-benzyloxybenzoic acid, an equivalent amount of methyl ester is used.

Example 7α1-Tert-butylaminomethyl-4-
Hydroxy-m-xylene-α1,α5-diol α1
-Tert. 10 kg of -butylaminomethyl-4-benzyloxy-1m-xylene-α1,αS-diol,
Add to 135 kg of 95% ethanol.

Add 0.3 kg of palladium charcoal and hydrogenate at normal pressure until hydrogen consumption stops. After removal of the catalyst, the solvent is evaporated. The product is crystallized from the evaporation residue using a methanol-ethanol mixture. Yield 6.5 kg (90% of theory), melting point 157-158°C. The invention, as claimed, includes the following embodiments.

(1) Simultaneous hydrogenation and reduction of imine derivatives with the formula Na
Al(0CH,CH,0CH,), H2 hydrogenation pis(
2-Methoxyethoxy) sodium aluminum.

(2) Simultaneous hydrogenation and reduction of imine derivatives with the formula Na
A process as claimed in the claims, carried out using sodium diethylaluminium dihydride of Al(C2H,)2H.

(3) A process as claimed in the claims, in which the simultaneous hydrogenation and reduction of the imine derivative is carried out in dioxane, benzene or toluene.

Claims (1)

[Claims] 1 Formula ▲ Numerical formula, chemical formula, table, etc. ▼II (Here, R represents a lower straight chain or branched hydrocarbon group containing 1 to 6 carbon atoms, and Ar represents an aryl group. ) is converted into a compound having the formula ▲mathematical formula, chemical formula, table, etc. ▼III by simultaneous hydrogenation and reduction, and the arylmethyl protecting group is removed from this compound by catalytic hydrogenation. The formula ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ Therapeutically valuable α^1-tert. -butylaminomethyl-4-hydroxy-n-xylene-α^1,α
A method for producing ^3-diol and its acid addition salt.