JPS6126785B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing aminocarbostyryl derivatives and salts thereof. The compound obtained in the present invention has the general formula [In the formula, one of R ⁶ and R ⁷ represents a hydroxyl group, and the other represents an amino group. Furthermore, the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton represent a single bond or a double bond. ] Aminocarbostyryl derivatives and salts thereof. All of these compounds are known compounds, and are useful as intermediates for synthesizing the compound of general formula () useful as a β-blocker agent as described later. Conventionally, as a method for producing aminocarbostyryl derivatives represented by the general formula () and their salts, the general formula [In the formula, one of R ¹ and R ² represents a hydroxyl group, and the other represents a hydrogen atom. 3rd and 4th positions of carbostyril skeleton
The carbon-carbon bond at position is the same as above. ] There is a known method for obtaining aminocarbostyryl derivatives of the general formula () and their salts by nitrating a hydroxycarbostyryl derivative represented by the following formula and then reducing the obtained nitrocarbostyryl derivative [JP-A-51-1999] 6971, JP 51-6972, JP 51-52178 and JP 51-52179
See issue]. However, according to such a method, 9~
The desired compound of general formula () was obtained with an extremely low yield of 36%. This is because in nitration of the compound of general formula (), the nitro group is more likely to be introduced at the ortho position than the para position relative to the hydroxyl group of the compound of general formula (), and the nitro group is introduced at the para position. This is based on the fact that the compound cannot be obtained selectively. Therefore, the above conventional method was not an industrially advantageous method. The inventors of the present invention have conducted extensive research in order to solve the drawbacks of such conventional methods. As a result, by coupling the compound of general formula () with the diazonium salt of arylamine and then reducing this, the desired compound of general formula () can be obtained in a high yield, more than twice that of the conventional method. obtained with
It has been found that the intended purpose of the invention can be achieved. The present invention was completed based on this knowledge. That is, the present invention provides a diazonium salt of an arylamine and a compound having the general formula [In the formula, one of R ¹ and R ² represents a hydroxyl group, and the other represents a hydrogen atom. Furthermore, the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton represent a single bond or a double bond. ] The general formula produced by coupling reaction with a hydroxycarbostyryl derivative represented by [In the formula, one of R ³ and R ⁴ represents a hydroxyl group, and the other represents a group -N=N-R ⁵ (R ⁵ is an aryl group). The carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. ] characterized by reducing the diazocarbostyryl derivative represented by [In the formula, one of R ⁶ and R ⁷ represents a hydroxyl group, and the other represents an amino group. 3rd and 4th positions of carbostyril skeleton
The carbon-carbon bond at position is the same as above. ] The present invention relates to a method for producing an aminocarbostyryl derivative represented by the following and its salt. According to the production method of the present invention, in the coupling reaction of the compound of the general formula (), the group -N=N-R ⁵ is selectively introduced at the para position with respect to the hydroxyl group of the compound of the general formula (), Therefore, the target compound of general formula () can be produced in a much higher yield of 70% or more than in conventional methods. Therefore, the production method of the present invention is industrially extremely advantageous. All compounds of general formula () used as starting materials in the present invention are known compounds. Diazonium salts of arylamines are also known compounds. Diazonium salts of arylamines are produced by diazotizing arylamines. Typical examples of the aryl group constituting the arylamine include a naphthyl group, a phenyl group, etc., and such aryl groups include a lower alkoxy group, a lower alkyl group, a halogen atom, a sulfonyl group, a nitro group,
It may be substituted with a cyano group, a carboxy group, etc. A wide variety of known diazotization methods can be applied to diazotize the arylamine. Specifically, the diazotization agent used is an inorganic salt (concentrated hydrochloric acid,
mixtures of concentrated sulfuric acid, etc.) and nitrites (sodium nitrite, potassium nitrite, etc.), mixtures of lower fatty acids (acetic acid, etc.) and nitrites, mixtures of lower fatty acids and nitrosyl sulfuric acid, mixtures of phosphoric acid and nitrosyl sulfuric acid. , a mixture of concentrated sulfuric acid and nitrosyl sulfuric acid, and the like. Inorganic salts (including phosphoric acid) and lower fatty acids are usually used in a large excess amount relative to the arylamine when diazotization is carried out without a solvent, and usually in a large excess amount relative to the arylamine when diazotization is carried out in a solvent such as water. It is preferable to use an excess of 2 times the molar amount, preferably 2.5 to 5 times the molar amount. Further, the nitrite and nitrosyl sulfate are usually used in equimolar to excess amounts, preferably equimolar to twice the molar amount, relative to the arylamine. The reaction is usually carried out at -60 to 0°C, preferably -10 to 0°C, and is usually completed in 30 minutes to 6 hours. The arylamine diazonium salt thus produced is isolated by a conventional method or used as it is for the next reaction without isolation. A wide range of conventional coupling reaction conditions can be applied to the coupling reaction between the arylamine diazonium salt and the compound of general formula ().
Diazonium salt of arylamine and general formula ()
The proportion of the compound to be used is not particularly limited and may be appropriately selected within a wide range, but it is usually 0.5 to 1.5 mol, preferably equimolar, of the latter to the former. The reaction is usually carried out in a solvent. Examples of solvents include water, lower alcohols such as methanol, ethanol and isopropanol, ethers such as dioxane and tetrahydrofuran,
Dimethyl sulfoxide, dimethyl formamide and the like can be mentioned. If the compound of general formula () is not dissolved in the above solvent, a basic compound such as sodium hydroxide or potassium hydroxide may be added to the reaction system as a solubilizing agent. The amount of the basic compound added is usually from equimolar to 3 times the molar amount of the compound of general formula (), preferably from equimolar to 2 times the molar amount. The reaction is usually carried out at -60 to 50°C, preferably -10°C to room temperature, and is usually completed in about 1 to 6 hours. In this way, a diazocarbostyryl derivative represented by the general formula () is produced. For the reduction of the compound of general formula (), a wide range of known reduction methods can be applied, such as a method using a known reducing agent, a method using electrolytic reduction, and a method using catalytic reduction. Examples of the reducing agent include sulfur compounds such as sodium dithionite, sodium sulfide, sodium disulfide, sodium hydrogen sulfide, and ammonium sulfide, iron-hydrochloric acid, zinc-acetic acid, tin-hydrochloric acid, and stannous chloride-hydrochloric acid. . Among these, stannous chloride-hydrochloric acid is preferred. The amount of such a reducing agent to be used is not particularly limited and may be appropriately selected from a wide range.
It is usually used in an equimolar to excess amount, preferably 2 to 5 times the molar amount of the compound of general formula ().
Furthermore, a wide variety of known hydrogenation catalysts can be used as the hydrogenation catalyst used in the catalytic reduction, and specific examples include palladium on carbon, Raney nickel, and platinum dioxide. The reaction by catalytic reduction proceeds advantageously in a solvent such as water, lower alcohols such as methanol, ethanol, and isopropanol, and acetic acid. The reaction conditions for reduction are not limited in any way and may be appropriately selected depending on the type and amount of the above-mentioned reducing agent or hydrogenation catalyst, but when a reducing agent is used, it is usually 0 to 150°C, preferably The reaction may be carried out at 50 to 100°C, and when a hydrogenation catalyst is used, the reaction may be carried out at normal hydrogen pressure and 0 to 100°C, preferably at room temperature. The aminocarbostyryl derivative represented by the general formula () produced in this way can be easily isolated by conventional separation means such as recrystallization, filtration, distillation, extraction, column chromatography, briparate thin layer chromatography, etc. Refined. The compound of general formula () can easily form an acid addition salt with an inorganic acid such as hydrochloric acid, sulfuric acid, or hydrogen bromide, or an organic acid such as oxalic acid or p-toluenesulfonic acid. The compound of the general formula () obtained in the present invention can be converted into a known β-blocker agent () by the method shown in the following reaction scheme [West German Published Patent Application No.
See Publication No. 2711719]. (In the above, R ⁸ represents an alkylcarbonylalkyl group, and R ⁹ represents a β-3,4-dimethoxyphenethyl group.) The production example of a diazonium salt of an arylamine is listed as a reference example, and the following examples are shown below. The following description will further clarify the present invention. Reference example: Synthesis of benzenediazonium chloride Add aniline to a solution of 600 ml of concentrated hydrochloric acid and 2,250 g of ice.
Add 192g of sodium nitrite and then add sodium nitrite while stirring.
A solution containing 150 g in 300 ml of water is added dropwise over a period of 40 minutes. After the dropwise addition is completed, stirring is continued for 30 minutes to obtain a solution of benzenediazonium chloride. Example 1 (a) 340 g of 5-hydroxy-3,4-dihydrocarbostyryl is dissolved in 1350 ml of 10% aqueous sodium hydroxide solution, and 3 kg of ice is added thereto. Then, while stirring vigorously, the entire benzenediazonium chloride solution obtained in the above reference example was added dropwise over a period of 1 hour. After the addition, the mixture was further stirred for 2 hours. The precipitated crystals were collected, thoroughly washed with water, and dried to give reddish brown needle-like crystals of 5-hydroxy-8-phenylazo.
518 g of 3,4-dihydrocarbostyryl are obtained. Yield 93% Melting point 239-242℃ (decomposition) Elemental analysis (as C ₁₅ H ₁₃ N ₃ O ₂ ) C (%) H (%) N (%) Theoretical value 67.40 4.90 15.72 Actual value 67.75 5.31 15.89 (b ) 5-hydroxy-8-phenylazo-3,4
- Dihydrocarbostyril 267g in concentrated hydrochloric acid 700ml
Then, 451 g of stannous chloride dihydrate was added and stirred at 70 to 80°C for 1 hour. After the reaction is completed, cool on ice, collect precipitated crystals, thoroughly wash with acetone, and dry. The obtained crude crystals were recrystallized from water to give white needle-like crystals of 8-amino-5-hydroxy-3,4-dihydrocarbostyryl hydrochloride 197
get g. Yield: 92% Melting point: 300℃ or higher The obtained compound has an infrared absorption spectrum (KBr
3360cm ^-1 , 2600cm ^-1 , 2640cm ^-1 ,
Characteristic absorptions of amine hydrochloride were shown at 1570 cm ^-1 and 1505 cm ^-1 . The infrared absorption spectrum of this compound matched that of a separately synthesized standard compound (described in JP-A No. 51-6972), and also showed no drop in melting point in the mixing test. The compound thus obtained is 8-amino-5-hydroxy-
It was confirmed to be 3,4-dihydrocarbostyryl hydrochloride. Example 2 (a) 340 g of 8-hydroxy-3,4-dihydrocarbostyryl is dissolved in 1300 ml of 10% aqueous sodium hydroxide solution, and 3 kg of ice is added thereto. Then, while stirring vigorously, the entire benzenediazonium chloride solution obtained in the above reference example was added dropwise over a period of 1 hour. After the addition, the mixture was further stirred for 2 hours. The precipitated crystals were collected, thoroughly washed with water, and dried to give reddish brown needle-like crystals of 8-hydroxy-5-phenylazo.
501 g of 3,4-dihydrocarbostyryl are obtained. Yield 90% Melting point 234-236℃ (decomposition) Elemental analysis value (as C ₁₅ H ₁₃ N ₃ O ₂ ) C (%) H (%) N (%) Theoretical value 67.40 4.90 15.72 Actual value 67.71 5.72 15.98 (b ) 8-Hydroxy-5-phenylazo-3,4
- Dihydrocarbostyril 267g in concentrated hydrochloric acid 700ml
Then, 451 g of stannous chloride dihydrate was added and stirred at 70-80°C for 1 hour. After the reaction is completed, cool on ice, collect precipitated crystals, thoroughly wash with acetone, and dry. The obtained crude crystals were recrystallized from dilute hydrochloric acid to obtain white needle-like crystals of 5-amino-8-hydroxy-3,4-dihydrocarbostyryl hydrochloride.
Obtain 190g. Yield: 89% Melting point: 300℃ or higher The obtained compound has an infrared absorption spectrum (KBr
3280cm ^-1 , 2600cm ^-1 , 1590cm ^-1 and
It showed the characteristic absorption of amino hydrochloride at 1500 cm ^-1 .
This compound is a separately synthesized standard compound (JP-A-Sho).
The infrared absorption spectrum matched that of the compound (described in Japanese Patent Publication No. 51-52179), and the melting point did not decrease in the mixing test. Therefore, the obtained compound was confirmed to be 5-amino-8-hydroxy-3,4-dihydrocarbostyryl hydrochloride. Example 3 (a) 322g of 8-hydroxycarbostyryl at 10%
Dissolve in 1300ml of caustic soda aqueous solution and add 3 ice cubes to this.
Add Kg. Then, with vigorous stirring, the entire p-methoxybenzenediazonium chloride solution obtained in the same manner as in the above reference example was added dropwise over a period of 1 hour. After the addition, the mixture was further stirred for 2 hours. The precipitated crystals were taken, thoroughly washed with water, and then dried to obtain 537 g of dark red crystals of 8-hydroxy-5-(p-methoxyphenylazo)carbostyryl. Yield 91% Elemental analysis (as C ₁₆ H ₁₃ N ₃ O ₃ ) C (%) H (%) N (%) Theoretical value 65.08 4.44 14.23 Actual value 65.37 4.71 14.42 (b) 8-Hydroxy-5-( Add 295 g of p-methoxyphenylazo) carbostyryl to 700 ml of concentrated hydrochloric acid, then add 451 g of stannous chloride dihydrate.
Stir for 1 hour at 70-80°C. After the reaction is completed, cool on ice, collect precipitated crystals, thoroughly wash with acetone, and dry. The resulting crude crystals were recrystallized from water to obtain 193 g of 5-amino-8-hydroxycarbostyril hydrochloride in the form of white powder. Yield: 91% Melting point: 300℃ or higher The obtained compound has an infrared absorption spectrum (KBr
Tablets) exhibited characteristic absorptions of amine hydrochloride at 3000 cm ^-1 , 2440 cm ^-1 , 1600 cm ^-1 and 1490 cm ^-1 . The infrared absorption spectrum of this compound matched that of a separately synthesized standard compound (described in JP-A-51-52179), and it did not show any drop in melting point in the mixing test. Therefore, the obtained compound was confirmed to be 5-amino-8-hydroxycarbostyryl hydrochloride. Examples 4 to 8 Compounds shown in Table 1 below are obtained in the same manner as in Examples 1 to 3 above. The infrared absorption spectrum of this compound matched that of a separately synthesized standard compound (described in JP-A-51-6972), and it did not show any drop in melting point in the mixing test. The yields in Table 1 are the yields from the compound of general formula (). 【table】

Claims (1)

[Claims] 1 Diazonium salt of arylamine and general formula [In the formula, one of R ¹ and R ² represents a hydroxyl group, and the other represents a hydrogen atom. Furthermore, the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton represent a single bond or a double bond. ] The general formula produced by coupling reaction with the hydroxycarbostyryl derivative represented by [In the formula, one of R ³ and R ⁴ represents a hydroxyl group, and the other represents a group -N=N-R ⁵ (R ⁵ is an aryl group). The carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. ] characterized by reducing the diazocarbostyryl derivative represented by [In the formula, one of R ⁶ and R ⁷ represents a hydroxyl group, and the other represents an amino group. 3rd and 4th positions of carbostyril skeleton
The carbon-carbon bond at position is the same as above. ] A method for producing an aminocarbostyryl derivative represented by and a salt thereof.