JPS6121950B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a novel 4-halogenomethylisoquinolone derivative useful as an intermediate for pharmaceuticals or veterinary drugs. More specifically, the present invention relates to the general formula () [In formula (), Y represents a substituted or unsubstituted benzelsulfonyl group, and R ₁ , R ₂ , R ₃ and R ₄ each represent a hydrogen atom, a hydroxyl group, or a hydroxyl group with a protective group. ] A halogenating agent is applied to the compound represented by the general formula (). [In formula (), X is a halogen atom, Y, R ₁ ,
R ₂ , R ₃ and R ₄ have the same meanings as in the above general formula (). ] It is related with the manufacturing method of the novel 4-halogenomethyl isoquinolone derivative shown by these. The compound group represented by the general formula () has an isoquinolone structure as its basic skeleton, and has 1-2
- It can be obtained by a known method from ketol esters via isocoumarin derivatives. This process was first described in a publication published in Berlin in 1896 (Fortschritte der
Theerfarbenfabrikatio und verwandter
Industriezweige, 1896, Berlin, p969-971), and a relatively new one is March 1969.
Related descriptions can be found in "Chemical Dictionary 1" published by Tsukikyoritsu Shuppan Co., Ltd., page 597 left column "α-isoquinolone" and page 594 left column "isocarbostyril". The hydroxyl group with a protecting group in the general formula () includes a lower alkoxy group, an acyloxy group, a benzoyloxy group, a benzenesulfonyloxy group, or a p-toluenesulfonyl group. It is attached to a hydroxyl group. An object of the present invention is to selectively halogenate the methyl group at the 4-position of an isoquinolone derivative having a methyl group at the 4-position. In this case, if the nitrogen atom at position 2 is not protected with an appropriate protecting group, 4
Although it is not possible to selectively halogenate the methyl group at position 2 with good yield, as shown in the general formula (),
In compounds in which the nitrogen atom at the 2-position is a benzenesulfonyl group or a protecting group having a substituent such as a methyl group, a halogen atom, or a nitro group on the benzene ring of this group, when a halogenating agent is applied, the desired general formula A compound represented by () can be obtained. In addition, if the compound of general formula () has a large number of hydroxyl groups, the yield will drop significantly during halogenation, or many by-products will be produced, making it difficult to separate the target product. Must be protected with a protecting group. The method of the present invention is generally performed under heating or at room temperature, and in some cases under cooling.
A compound represented by is reacted with an equimolar or excess amount of a halogenating agent under conditions that generate radicals,
The desired compound represented by the general formula () is obtained in good yield. The halogenating agent used in the present invention includes chlorine,
Examples include bromine, N-bromophthalimide, and N-bromosuccinimide, but in order to generate radicals, it is necessary to expose them to light, add peroxides such as benzoyl peroxide, or heat them at high temperatures. It is necessary to carry out the reaction. When reacting the compound represented by the general formula () with a halogenating agent, an appropriate solvent is usually used depending on the properties of both raw materials, but a solvent that is not halogenated is preferred. Specific examples of the solvent used include methylene chloride, chloroform, carbon tetrachloride, benzene, monochlorobenzene, and mixtures thereof. Generally, the product can be purified by recrystallization or column chromatography using an appropriate solvent, but in many cases it can be used as a raw material for other reactions without purification. The compounds represented by the general formula () obtained in this way are all new compounds that have not been described in literature, and they easily react with alcohols, amines, organic acids, salts, etc., and have useful effects as pharmaceuticals or veterinary drugs. It is an important intermediate for producing compounds with For example, 2-benzenesulfonyl-4-
4-[N・N
-Bis-(β-hydroxyethyl)]aminomethyl-5,6,7-trimethoxyisocoumarin has a hypolipidemic effect. That is, this compound has a phosphodiesterase inhibitory effect and an effect of lowering blood lipids in mammals, and is useful as an agent for preventing arteriosclerosis. The present invention will be specifically explained below by giving examples and reference examples of the present invention. The specific preparation method of the compound used in each example among the compound group represented by the general formula () is shown after Example 4 as Synthesis Example 1 and Synthesis Example 2. Example 1 2-benzenesulfonyl-4-bromomethyl-
Process for producing 5,6,7-trimethoxyisoquinolone 5,6,7-trimethoxy-4-methylisoquinolone 3.0g, benzenesulfonyl chloride,
3.3g and 4.6g of triethylamine in toluene
The mixture was dissolved in 50 ml and heated under reflux for 3 hours. After cooling, it was washed with water, an oil layer was taken, and it was dehydrated with anhydrous sodium sulfate. The dehydrated oil layer is evaporated to dryness,
The residue was recrystallized from n-hexane-benzene.
3.5 g of 2-benzenesulfonyl-5,6,7-trimethoxy-4-methylisoquinolone having a melting point of 120-122 DEG C. was obtained. 2-benzenesulfonyl- thus obtained
3.4 g of 5,6,7-trimethoxy-4-methylisoquinolone was dissolved in 50 ml of benzene and heated to reflux. To this, 1.6 g of N-bromosuccinimide
and 0.1 g of benzoyl peroxide were gradually added. After further heating under reflux for 10 minutes, the mixture was cooled to 10° C., and the precipitated crystals were removed by filtration. The filtrate was evaporated and the residue was crystallized by adding n-hexane and filtered. 2-benzenesulfonyl-4-brumomethyl-5,6, having a melting point of 76-79°C
3.6 g of crude crystals of 7-trimethoxyisoquinolone were obtained. Elemental analysis gave the following results as C ₁₉ H ₁₈ BrNSO ₆ .

[Table] Example 2 2-benzenesulfonyl-4-bromomethyl-
Production method of 5,7-dimethoxyisoquinolone 5,7-dimethoxy-4-methylisoquinolone
4.6 g of benzenesulfonyl chloride and 3.5 g of triethylamine were mixed in 50 ml of toluene and heated under reflux for 3 hours. After cooling, 100 ml of benzene was added thereto, and the mixture was washed with water. The oil layer was collected, dehydrated with anhydrous sodium sulfate, and then concentrated to dryness. The residue was recrystallized from benzene to give a melting point of 139-140.
5.1 g of crystals of 2-benzenesulfonyl-5,7-dimethoxy-4-methylisoquinolone with ℃
I got it. 2-benzenesulfonyl- thus obtained
5,7-dimethoxy-4-methylisoquinolone
2.0g was dissolved in 50ml of benzene and heated to reflux. To this was gradually added a mixture of 1.0 g of N-bromosuccinimide and 0.1 g of benzoyl peroxide. After further heating under reflux for 15 minutes, the mixture was cooled to 10° C., and the precipitated crystals were removed by filtration. The filtrate was evaporated to dryness, and the resulting crystals were washed with n-hexane to obtain 2.5 g of crude crystals of 2-benzenesulfonyl-4-bromomethyl-5,7-dimethoxyisoquinolone having a melting point of 113-117°C. I got it. Elemental analysis gave the following results as C ₁₈ H ₁₆ BrNSO ₅ .

[Table] Example 3 2-benzenesulfonyl-5,7-dibenzenesulfonyloxy-4-bromomethylisoquinolone production method 5,7-dihydroxy-4-methylisoquinolone 4.0g, benzenesulfonyl chloride 13.4g
and 9.5 g of triethylamine were dissolved in 50 ml of toluene and 20 ml of acetone and heated under reflux for 3 hours. After cooling, 100 ml of benzene was added thereto, washed with water to obtain an oil layer, and this was dehydrated with anhydrous sodium sulfate. After dehydration, it was concentrated and dried, and the residue was recrystallized from benzene. 2 with a melting point of 195-197℃
-Crystals of benzenesulfonyl-5,7-dibenzenesulfonyloxy-4-methylisoquinolone
5.5g was obtained. 2-benzenesulfonyl- thus obtained
3.5 g of 5,7-dibenzenesulfonyloxy-4-methylisoquinolone, 1.3 g of N-bromosuccinimide and 0.2 g of benzoyl peroxide were added to benzene.
50 ml and heated under reflux for 10 hours. After cooling and filtering, the filtrate was evaporated to dryness to give 2-benzenesulfonyl-5,7-dibenzenesulfonyloxy-4.
- Crude crystals of bromomethylisoquinolone were obtained. Since this compound is easily decomposed, it was immediately used as a raw material for other reactions. A reaction example using the compound obtained in Example 3 as a raw material is shown below as a reference example. Reference Example 1 Method for producing 5,7-dihydroxy-4-(N-methylpiperazinyl)methylisoquinolone 2-benzenesulfonyl-5 obtained in Example 3
The entire amount of crude crystals of 7-dibenzenesulfonyloxy-4-bromomethylisoquinolone was dissolved in 50 ml of benzene, 1.4 g of N-methylpiperazine was added thereto, and the mixture was reacted at room temperature for 3 hours. Insoluble materials were removed by filtration and the filtrate was evaporated. Add the residue to acetone.
Purification by silica gel chromatography using methanol (4:1) as solvent gave 1.0 g of 2-benzenesulfonyl-5,7-dimethoxy-4-(N-methylpiperazinyl)methylisoquinolone as an oil. This oil was further dissolved in 50 ml of methanol, and 1 ml of an aqueous solution containing 0.3 g of caustic soda was added.
Heated under reflux for 1 hour. After the solvent was evaporated, the filtrate was made acidic with dilute sulfuric acid, then made alkaline with an aqueous sodium bicarbonate solution, and the filtrate was evaporated. The residue was purified by silica gel chromatography using a methanol solvent to obtain 0.2 g of crystals of 5,7-dihydroxy-4-(N-methylpiperazinyl)methylisoquinolone having a melting point of 163°C. Elemental analysis gave the following results as C ₁₅ H ₁₉ N ₃ O ₃ . C H N Calculated value (%) 62.27 6.62 14.53 Experimental value (%) 62.50 6.38 14.62 In addition, the main infrared absorption spectrum (ν ^KBr cm ₋₁ )
obtained the following results. 1610, 1460, 1350, 1290, 1140, 1000, 810 Example 4 Process for producing 4-bromomethyl-5,6,7-trimethoxy-2-p-toluenesulfonylisoquinolone 6.0 g of 5,6,7-trimethoxy-4-methylisoquinolone, 7.1 g of p-toluenesulfonyl chloride and 9.2 g of triethylamine were added to toluene.
50 ml and heated under reflux for 3 hours. The reaction solution was cooled and washed with water, and the toluene layer was dehydrated with anhydrous sodium sulfate. This liquid was evaporated to dryness, and benzene-n
- Recrystallization from hexane gave 5.7 g of white crystals of 5,6,7-trimethoxy-4-methyl-2-p-toluenesulfonylisoquinolone. Dissolve 3.0 g of this crystal in 50 ml of toluene, heat until reflux, and add 1.4 g of N-bromosuccinimide to this solution.
A mixture of g and 0.1 g of benzoyl peroxide was slowly added and heated under reflux for a further 10 minutes. After cooling the reaction solution, the precipitated crystals were removed by filtration, and the filtrate was evaporated to dryness. The residue was separated by silica gel chromatography using a benzene-ethyl acetate solvent system (benzene:ethyl acetate = 30:1 ^VOl ratio) to obtain 4-bromomethyl-, which has a melting point of 102-105°C.
1.3 g of white crystals of 5,6,7-trimethoxy-2-p-toluenesulfonylisoquinolone were obtained. Elemental analysis gave the following results as C ₂₀ H ₂₀ BrNO ₆ S.

[Table] Also, main infrared absorption spectra (ν ^KBr cm ₋₁ )
obtained the following results. 1640, 1590, 1490, 1470, 1390, 1165, 1085. Synthesis Example 1 Synthesis of 5,7-dihydroxy-4-methylisoquinolone or 5,7-dimethoxy-4-methylisoquinolone 77 g of 3,5-dihydroxybenzoic acid, 200 ml of water
Mix 34g of anhydrous potassium carbonate and water at 80℃.
Add a solution consisting of 500 ml. After stirring at 100°C for 30 minutes, the mixture was cooled to 80°C and 46.2 g of monochloroacetone was added. After refluxing for 6 hours, the precipitated crystals were collected by filtration after being left overnight, dried, and recrystallized from hot water.
73 g of acetone dihydroxybenzoate was obtained. (Yield 69.5%) Next, the entire amount of this product was added to 800 ml of 85% sulfuric acid under ice-cooling, and the reaction was carried out at below 5°C for 24 hours. The reactant was discharged into ice water, and the precipitated crystals were collected and recrystallized from acetone. 64 g of 5,7-dihydroxy-4-methylisocoumarin having a melting point of 248-250°C was obtained. (yield
95.7%) When this product is methylated with methyl iodide in dimethoxyethane in the presence of anhydrous potassium carbonate, 5,7-dimethoxy-4 exhibits a melting point of 174-175°C.
-Methylisocoumarin was obtained. Here, the previously obtained 5,7-dihydroxy-
5g of 4-methylisocoumarin and 50ml of dioxane
and 60 ml of 28% ammonia water at 120°C in a sealed tube.
The mixture was allowed to react for 6 hours. After the reaction was completed, the solvent was removed under reduced pressure, the residue was washed with dilute sulfuric acid, and then recrystallized from a water-acetone mixture to give 5,7-dihydroxy-4-methylisoquinolone 4.4, which had a melting point of 250°C or higher. I got g. (Yield 88.5%) In addition, instead of the above 5,7-dihydroxy-4-methylisocoumarin, 5,7-dimethoxy-4-methylisocoumarin was similarly reacted with aqueous ammonia at 120°C in a sealed tube. As a result, 5,7-dimethoxy-4-methylisoquinolone having a melting point of 247-248°C was obtained. (Yield 82.2%) Synthesis Example 2 Synthesis of 5,6,7-trimethoxy-4-methylisoquinone Gallic acid acetone (melting point 152
-154°C), which was cyclized in 85% sulfuric acid to obtain 5,6,7-trihydroxy-4-methylisocoumarin (melting point 260°C or higher). (yield
78.3%) The 5,6,7-trihydroxy-4-methylisocoumarin thus obtained was methylated with methyl iodide in the presence of anhydrous potassium carbonate in methyl ethyl ketone to give 5,6,7-trimethoxy-4-methylisocoumarin. 5.
6,7-trimethoxy-4-methylisoquinolone (melting point 202°C) was obtained.

Claims (1)

[Claims] 1 General formula () [In formula (), Y represents a substituted or unsubstituted benzenesulfonyl group, and R ₁ , R ₂ , R ₃ and R ₄ each represent a hydrogen atom, a hydroxyl group, or a hydroxyl group with a protective group. ] The general formula () is characterized by causing a halogenating agent to act on the compound represented by [In formula (), X is a halogen atom, Y, R ₁ ,
R ₂ , R ₃ and R ₄ have the same meanings as in the above general formula (). A method for producing a 4-halogenomethylisoquinolone derivative represented by