JPS622037B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing cyclic amines.

More specifically, the present invention relates to the general formula [In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a lower alkoxy group, Z represents an anion group, and n represents an integer of 1 to 2. ] A general formula characterized by electrolytic reduction of a compound represented by [In the formula, R ¹ , R ² and n are the same as above. ] The present invention relates to a method for producing cyclic amines and salts thereof.

In this specification, lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl,
Examples include tert-butyl group, and lower alkoxy groups include methoxy, ethoxy, propoxy,
Examples include isopropoxy, butoxy, and tert-butoxy groups. In the above general formula [1], the anion group represented by Z can be any anion group, but particularly preferred examples include halogen ions such as chloride ions, bromide ions, and iodide ions. , lower alkanesulfonates such as methanesulfonate, benzenesulfonate, p
-Arylsulfonate groups such as toluenesulfonate and the like can be mentioned.

In the above electrolytic reduction reaction, the compound of general formula [1] used as a starting material is a new compound, and these can be produced, for example, by the method shown in the following reaction scheme-1.

[In the above formula, R ¹ , R ² , n and Z are the same as above. ] That is, the compound of general formula [1] is obtained by adding formic acid or formic acid amide to the known compound of general formula [3] according to the Taylor method [see J.Chem.Soc., p. 1153 (1951)]. It is easily produced by reacting phosphorus oxychloride, and then reacting the resulting compound of general formula [4] with an excess of the compound of general formula [5] in, for example, tetrahydrofuran at room temperature. The above electrolytic reduction reaction is usually carried out in a suitable solvent by passing a direct current through it. Examples of solvents include water, methanol,
Alcohols such as ethanol, aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, and nitriles such as acetonitrile can be used. Although the reaction proceeds at room temperature, it is of course possible to carry out the reaction at a low temperature below room temperature or under heating, for example, it can be carried out advantageously at -10°C to 100°C, preferably 0°C to room temperature. Typically, it is necessary to add a suitable or supporting electrolyte to pass a direct current through the solvent system in carrying out electrode reduction. In the case of the above method, since the starting material solution already has conductivity, there is no need to add an electrolyte. Alternatively, the reaction may proceed more favorably by coexisting a quaternary ammonium salt. Furthermore, the above method is characterized in that by adding a small amount of metal such as lead, the yield of the target product can be improved and the production of by-products can be reduced.

All commonly used materials can be used as the electrode material, but platinum, mercury, lead, carbon, etc. are particularly effective. It is also optional to use a diaphragm, but when a diaphragm is used, it is a matter of course that the reaction is carried out in the cathode chamber.

The optimal values of the current and terminal voltage vary depending on the equipment used and the scale of the reaction, and the equipment or scale of the reaction used when carrying out the above method is completely arbitrary. . Therefore, the current value and the voltage value between the terminals can also be appropriately determined.
However, controlling the electrode potential of the cathode often provides advantageous results. In this case, the cathode potential is suitably determined by measuring the reduction potential of the compound of general formula [1] (immonium salt), which is the starting material, and setting it at a potential in the vicinity thereof.

In the above method, the target compound of general formula [2] can be obtained from the starting materials without producing complex isomers as by-products, so purification after the reaction is very easy. Through this operation, the desired product can be obtained with extremely high purity and high yield. Furthermore, if necessary, the target product can be easily purified by column chromatography.

The compound of general formula [2] thus obtained can easily form a salt with a commonly used pharmaceutically acceptable acid, and such salts are also included in the compounds of the present invention. Examples of acids that can be used include alkyl halides such as hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, oxalic acid, maleic acid, methyl iodide, methyl chloride, and ethyl iodide.

The compound of general formula [2] and its salts thus produced include known compounds and novel compounds. The compound has a smooth muscle relaxing effect and is useful as a bronchodilator, an antitussive, a cerebral circulation improver, an agent for preventing premature birth, and other pharmaceuticals.

The above method for producing the compound of the present invention has the following advantages: the raw materials are easily available, the target product can be obtained by very simple and safe operations, the reaction steps are short and the target product can be obtained in good yield. It has the characteristics that it can be easily obtained, that it produces very few by-products that are difficult to separate, and that it does not use any special or environmentally friendly chemicals.

Examples of manufacturing the compounds of the present invention are listed below.

Production Example 1 10 mmol of 3,4-dihydro-6,7-dimethoxyisoquinoline was dissolved in 80 ml of dimethylformamide and electrostatic reduction was carried out at -1.8 V in the presence of a small amount of lead. When the current value becomes 10 mA or less, 15 mmol of methanesulfonic acid is added and electrolysis is continued. The amount of current applied was 2.2F/mol. In the above electrolytic reduction, a clay plate is used as a diaphragm, toluenesulfonic acid tetraethylammonium salt is placed in the anode chamber as a solvent and supporting electrolyte, and the above reaction reagent, lead and solvent are placed in the cathode chamber, and a platinum electrode is used as an electrode. I used what I used. The same applies to Production Example 2.

After distilling off dimethylformamide under reduced pressure, the residue was dissolved in methylene chloride and washed once with an aqueous sodium bicarbonate solution. After drying the methylene chloride layer with magnesium sulfate, it was isolated using aluminum column chromatography to obtain syrupy 1,1'-bis(3,4
-dihydro-6,7-dimethoxyisoquinoline)
get.

Yield 45% NMR spectrum (CDCl ₃ ) δ = 2.5-3.2 (ppm) (m, 10H, protons at the 3, 3' 4, 4', 2, 2' positions of the isoquinoline skeleton) = 3.63 and 3.83 (s, 12H, OCH ₃ × 4) = 4.07 (s, 2H, 1, 1′ pronto) = 6.34 and 6.80 (s, 4H, 5, 5′, 8, 8′ pronto) Production example 2 3, 4- 10 mmol of the methiodide salt of dihydro-6,7-dimethoxyisoquinoline was dissolved in 80 ml of dimethylformamide, and the following procedure was repeated in the same manner as in Production Example 2 to prepare syrup-like 1,1'-bis(2-methyl-
3,4-dihydro-6,7-dimethoxyisoquinoline) is obtained. Yield 58% NMR spectrum ( _CDCl3 ) δ = 2.1-3.2 (ppm) (m, 16H) = 3.34, 3.43, 3.44 and 3.55 (s, 12H) = 5.93, 6.05, 6.26 and 6.83 (s, 4H)

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a lower alkoxy group, Z represents an anion group, and n represents an integer of 1 to 2. ] A general formula characterized by electrolytic reduction of a compound represented by [In the formula, R ¹ , R ² and n are the same as above. ] A method for producing cyclic amines and their salts.