JPS632258B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula The present invention relates to a novel method for producing an indole derivative represented by the formula (wherein R represents an alkyl group).

The compounds of the formula and their acid addition salts have β-adrenergic neuroleptic action and are useful in the treatment and prevention of arrhythmia, atrial fibrillation or coronary artery disease, and in particular, the compound in which R is isopropyl is known as pindolol. Widely used.

Conventionally, as a method for producing this type of compound, for example, the following method is known.

(1) A process in which 4-hydroxyindole is reacted in the form of an alkali metal salt with epichlorohydrin in an oxygen-free system and the crude product is then reacted with an alkylamine, or after reacting said product with a benzylalkylamine. , a method of hydrogenolytically removing a benzyl group from a reaction product (see Japanese Patent Publication No. 42-9954), (2) Reacting 4-hydroxyindole with epichlorohydrin in an alkaline medium in an oxygen-free system. The crude product is then reacted with benzylamine, and then the benzyl group is eliminated by hydrogen reduction in the presence of a catalyst (Japanese Patent Publication No. 43-1999).
26621), (3) A method for producing 4-indolyloxy derivatives by reacting 4-hydroxyindole with a 3-azetidinol derivative to open the ring of azetidinol (see Japanese Patent Publication No. 47-19259). , (4) Reacting an alkali metal salt of 4-hydroxyindole with 1-halogeno-2,3-propanediol, and converting the resulting 4-(2,3-dihydroxypropoxy)-indole into phenylsulfonate or alkylsulfonate. and then desulfonation by the action of an alkylamine (see JP-A-48-54058).

However, in these methods, the 4-hydroxyindole used as the raw material is extremely unstable in the air and under light, making it difficult to handle.Especially when implementing these methods on an industrial scale, the raw material There were drawbacks such as contamination of impurities due to self-decomposition and side reactions, complicating purification and lower yields, and further complicating the reaction process due to the introduction and removal of protecting groups.

For this reason, it is desired to develop a production method that does not involve 4-hydroxyindole, and a method has also been reported in which an indole ring is formed after introducing an amino alcohol side chain (JP-A-52-89668 and JP-A No. 55-52).
(Refer to each publication No. 11559). However, this method has drawbacks such as requiring many steps to form an indole ring and requiring a long time for the reaction.

As a result of various researches to solve the drawbacks of these conventional methods, the present inventor found that the general formula (wherein R represents an alkyl group), a compound represented by the general formula (In the formula, X and Y are halogen atoms, and each R ¹ may be the same or different and each represents an alkyl group, an aryl group, or an aralkyl group.) It has been found that by reduction and hydrolysis to , by ring closure and cleavage of the oxazolidinone ring, compounds of the formula can be obtained in high yields by simple and economical means.

The alkyl group for the substituent R in the starting material of the formula and the corresponding target material of the formula is preferably a lower alkyl group, such as a methyl group, ethyl group, n-propyl group, n-butyl group, isobutyl group, Mention may be made of tertiary butyl groups, especially isopropyl groups or secondary butyl groups.

As the halogen atom of the substituents X and Y in the formula, a chlorine atom or a bromine atom is usually used,
The alkyl group for R ¹ is preferably a methyl group, ethyl group, propyl group, or butyl group, the aryl group is preferably a phenyl group or naphthyl group, and the aralkyl group is preferably a benzyl group or a phenethyl group.

Oxazolidinone derivatives of the formula include, for example, 6-
(2-Hydroxy-3-alkylaminopropoxy)-2-nitrotoluene is reacted with carbonate esters or phosgene, or 6-hydroxy-2-nitrotoluene is reacted with 5-halogenmethyl-3
-obtained by reaction with alkoxyoxazolidin-2-one.

A compound of the formula can be obtained by reacting a substituted formamide with a halogenating agent. It is preferable to use the so-called Vilsmeier reagent obtained by reacting dimethylformamide with phosphorus oxychloride or thionyl chloride without isolation.

In carrying out the invention, compounds of the formula and compounds of the formula are reacted, preferably in the presence of a solvent. As the solvent, aprotic solvents such as hydrocarbons, halogenated hydrocarbons, ethers, glycol ethers, dimethyl sulfoxide, and dimethylformamide are used.

This reaction can be carried out under normal pressure, reduced pressure or increased pressure. The reaction temperature is usually below the boiling temperature of the reaction mixture, preferably 50 to 150°C, and the reaction is generally completed in several hours. In order to accelerate the reaction, it is preferred to add an organic base such as triethylamine.

The reaction product of the compound of the formula and the compound of the formula is reduced by a conventional method, preferably a catalytic reduction method using hydrogen in the presence of a catalyst. The base required in this case includes, for example, sodium hydroxide,
A strong inorganic base such as potassium hydroxide is preferred. Examples of catalysts include platinum, palladium, nickel,
A metal such as cobalt or its oxide or hydroxide is used.

The reduction reaction is preferably carried out in a solvent, and in particular in a water-containing solvent, cleavage of the oxazolidinone ring by hydrolysis can also be carried out at the same time. As the solvent, for example, alcohols, glycols, dimethylformamide, etc. are preferable. It is preferable to reduce the amount slowly over time, usually 3 to 20
Adjust the reaction temperature, amount of hydrogen gas introduced, etc. so that the reaction can be completed within a certain time.

The target substance can be isolated and purified by conventional methods, and depending on the operating conditions, a compound of the formula can be obtained in the form of a free base or an acid addition salt. Examples of acids for forming acid addition salts include hydrochloric acid, hydrobromic acid,
Inorganic acids such as sulfuric acid and phosphoric acid as well as organic acids such as acetic acid, propionic acid, oxalic acid, maleic acid, succinic acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid are used. It will be done.

Example of preparing a compound of the formula -(2-hydroxy-3-isopropylaminopropoxy)-2-nitrotoluene (13.4 g) was dissolved in 350 ml of dimethylformamide, diethyl carbonate
Add 30.7 g and 25 g of potassium carbonate, and reflux with stirring for about 7 hours. After the reaction is completed, potassium carbonate is removed and the solvent is distilled off from the liquid under reduced pressure. The resulting brown residue is dispersed in a large amount of ice water and extracted in several portions with 200 ml of chloroform. After drying the extract with 23 g of sodium sulfate and filtering it,
When chloroform is removed by vacuum distillation and the obtained yellow crystals are recrystallized from dichloromethane-n-hexane, the following formula with a melting point of 108-110℃ is obtained. 13.46 g of pale yellow crystals of 5-(2-methyl-3-nitrophenoxymethyl)-3-isopropyl-oxazolidin-2-one (yield: 91.56)
%) is obtained.

Elemental analysis value C ₁₄ H ₁₈ N ₂ O ₅ as C H N Calculated value (%) 57.14 6.12 9.52 Actual value (%) 57.03 6.07 9.49 Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3440, 2965, 2915, 2865, 1720 , 1604,
1528, 1450, 1438, 1355, 1265, 1205,
1052, 831, 795, 770, 748 Example 1 While cooling 8.0 g of anhydrous dimethylformamide, 13 g of thionyl chloride is added dropwise over about 20 minutes. During this time, the temperature of the reaction solution is maintained at 10-20°C. After the dropwise addition, stir at the same temperature for about 15 minutes, then add 5-(2-
Methyl-3-nitrophenyl)-oxymethyl-
3-isopropyloxazolidin-2-one 29.4
Dissolve g in 250 ml of dichloroethane and add dropwise.
Stir for about 1 hour at a temperature around 20°C and then heat under reflux for 6 hours. As the reaction progresses, the reaction solution turns red to deep red. After the reaction, dichloroethane was distilled off under vacuum, and the remaining dark red oil was dissolved in 500 ml of a 3N sodium hydroxide-ethanol aqueous solution (2 ethanol: 1 water).
Add 9.0 g of % palladium hydroxide-carbon and heat to about 60°C while gradually introducing hydrogen. As hydrogen is consumed, the reaction solution changes from reddish brown to yellow to pale yellow, and then gradually becomes colorless. When it becomes colorless, hydrogen consumption stops and the reduction ends in about 10 hours. The completion of the reaction is confirmed by plotting the reaction solution on a thin silica gel plate and developing it using isopropyl alcohol-10% aqueous ammonia (10:1) as a developing solvent, and then checking the position of a purple spot developed with Ehrlich's reagent.

The reaction solution was filtered, ethanol was distilled off from the solution under vacuum, an appropriate amount of water was added, the mixture was left overnight, and the precipitated crystals were recrystallized from ethanol, resulting in a melting point of 169.
15.6 g (yield: about 62.9%) of 4-(2-hydroxy-3-isopropylaminopropoxy)-indole represented by the following formula are obtained as colorless needle crystals at a temperature of -171 DEG C.

Elemental analysis value C ₁₄ H ₂₀ N ₂ O ₂ as C H N Calculated value (%) 67.74 8.06 11.29 Actual value (%) 67.63 8.02 11.31 Ultraviolet absorption spectrum (methanol 16 ppm solution) 264-266 nm, 276-278.5 nm and 288 nm maximum absorption.

Minimal absorption at 236-238nm and 284.5-286.5nm.

Ultraviolet extinction coefficient value (C = 6.5 × 10 ^-5 mol / ethanol for spectrum) λ _nax : 265 nm (ε = 7.37 × 10 ³ ) 278 nm (Shoulder ε = 5.08 × 10 ³ ) 288 nm (ε = 4.30 × 10 ³ ) λ _nio : 237 nm (ε=2.61×10 ³ ) 285.3 nm (ε=3.07×10 ³ ) Example 2 168 ml of anhydrous dimethylformamide is cooled, 13 g of thionyl chloride is added dropwise, and the reaction is carried out in the same manner as in Example 1. 5-(2-Methyl-3-nitrophenyl)-oxymethyl-3-sec-butyloxazolidine-2 was added to the reaction solution after the Vilsmeier reagent was produced.
Dissolve 31 g of -one in 300 ml of dichloromethane and add dropwise. Following treatment in the same manner as in Example 1, the melting point
15.6 g (yield: about 59.5%) of 4-(2-hydroxy-3-sec-butylaminopropoxy)-indole of the following formula is obtained at 153 DEG -155 DEG C.

Claims (1)

[Claims] 1. General formula (wherein R represents an alkyl group), a compound represented by the general formula (In the formula, X and Y are halogen atoms, and each R ¹ may be the same or different and each represents an alkyl group, an aryl group, or an aralkyl group.) A general formula characterized by ring closure and cleavage of the oxazolidinone ring by reduction and hydrolysis to A method for producing an indole derivative represented by the formula (wherein R has the above-mentioned meaning).