JPS582938B2 - Method for producing hydroxycarbostyryl derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel method for producing hydroxylupostyryl derivatives, more specifically, a method for producing hydroxylupostyryl derivatives, more specifically using the general formula [where n represents 1 or 2].

This invention relates to a new method for producing a hydroxylupostyryl derivative represented by the following formula.

The compound of general formula [1] obtained in the present invention is useful as a synthetic intermediate for pharmaceuticals such as β-adrenergic nerve stimulants, β-adrenergic nerve blockers, and platelet aggregation inhibitors.

Conventionally, the method for producing the compound of the above general formula [1] is (a)
Journal of Organic Chemistry 196
8, Vol. 33, p. 1089 (George R. Pettit, Wayne C.
Fleming and Kenneth D. Pau
ll, J. Org. Chem. ,33,1089(19
68)], (b) the method by George R. Pett et al., described in Journal of Organic Chemistry, Vol. 36, p. 3490, 1971.
it, Wayne C. Fleming and K.
enneth D. Pau-11, J. Org.
Chem. , 36, 3490 (1971)] and (c) a method of applying the method described in JP-A-52-3077.

(In the above formula, Ac represents CH3CO and X represents a halogen atom.

) That is, method (a) is a method in which hydroxyquinoline is N-oxidized with a peracid, rearranged with acetic anhydride to give acetyloxycarpostyryl, and then hydrolyzed to obtain hydroxycarpostyryl; method (b) Method (c) is a method to obtain hydroxycarbostyryl by alkali melting of oxyquinoline, and method (c) is a method in which anisidine is reacted with β-chloropropionic acid halide to obtain an N-acyl compound, which is subjected to Friedel-Crafts cyclization to obtain hydroxycarbostyryl. 3,4-
This is a method of obtaining dihydrocarpostyril, then acylating the obtained compound, oxidizing it with a halogen-based oxidizing agent, and further hydrolyzing to obtain hydroxycarpostyril.

However, each of these methods has drawbacks.

That is, methods (a) and (b) involve various adverse conditions, such as difficulty in obtaining oxyquinoline as a raw material, the risk of using peracid, and the risk of melting the raw material with alkali, and are difficult to use on an industrial scale. If the reaction is carried out, there is great danger, and decomposition reactions occur, making it possible to obtain the desired product only with low purity and low yield.

In addition, method (c) requires a long reaction process and requires a large amount of cost for industrialization, which is extremely disadvantageous economically.

In addition, in any of these methods, if two hydroxyl groups are to be introduced into the benzene ring, the compound obtained above must be subjected to more complicated treatments, which further reduces the yield of the target compound.

The present invention provides a new production method that completely eliminates such drawbacks, and in which R1 has or does not have a hydrogen atom, a lower alkyl group, or a substituent, in the presence of aluminum chloride. represents an aralkyl group; R2 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a nitro group; n represents 1 or 2;

The present invention relates to a method for producing a hydroxycarpostyryl derivative, which is characterized by subjecting an anilide derivative represented by the following formula to a ring-closing reaction to obtain a hydroxycarpostyryl derivative represented by the general formula [where n is the same as above].

The compound of general formula (II) used as a starting material in the present invention is a new compound, for example, an aniline derivative represented by a known general formula [wherein R and n are the same as above] and a known general formula [ In the formula, X represents a halogen atom.

R2 is the same as above.

It is easily produced by reacting with an acid halide compound represented by the following formula.

The reaction between the compound of general formula [III] and the compound of general formula [IV] can be carried out using the known Schotten-Baumann reaction.

For example, a compound of general formula [III] and a compound of general formula [IV] may be reacted in an inert solvent in the presence of a basic compound.

The ratio of the compound of the general formula [III] and the compound of the general formula [IV] is not particularly limited and may be appropriately selected from a wide range, but usually the latter is used by equimolar to 5 times the molar ratio of the former. It is preferable to use equimolar to twice the molar amount.

A wide variety of known basic compounds can be used as the basic compound used in the reaction, such as alkali metal or alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, etc. , alkali metal carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, metal alcoholates such as sodium methoxide and potassium ethoxide, quaternary amines such as pyridine, quinoline, triethylamine, trimethylamine, and N,N-dimethylaniline. be able to.

The amount of the basic compound to be used is not particularly limited and may be appropriately selected from a wide range.
It is preferable to use an equimolar to 5-fold molar amount, preferably an equimolar to 2-fold molar amount of the compound (II).

The inert solvent used in the reaction is not particularly limited, and a wide range of solvents that are not directly involved in the reaction can be used. Specifically, water, methanol, ethanol, isopropanol, t
Lower alcohols such as ert-butanol, ether,
Ethers such as dioxane and tetrahydrofuran, halogenated hydrocarbons such as chloroform, 1,2-dichloroethane and methylene chloride, aromatic hydrocarbons such as benzene, toluene and xylene, ketones such as acetone and methyl ethyl ketone, ethyl acetate, Examples include esters such as methyl acetate and ethyl propionate, quaternary amines such as pyridine, quinoline, and triethylamine, dimethyl sulfoxide, dimethyl formamide, and mixed solvents thereof.

The reaction temperature of the reaction is usually about 0 to 100°C, preferably room temperature to about 60°C, and the reaction time is usually about 1 to 15 hours.

In this way, the compound of general formula (II), which is the starting material of the present invention, is produced.

Examples of the aralkyl group represented by R1 in the general formula [■] include an aralkyl group in which a linear or branched alkylene group having 1 to 4 carbon atoms and a phenyl group are bonded, Specifically, benzyl, β-phenethyl, 1
-Methyl-2-phenylethyl, 4-phenylbutyl groups, etc. can be exemplified.

The phenyl group constituting the aralkyl group may be substituted with a lower alkyl group, lower alkoxy group, halogen atom, nitro group, etc. as a substituent.

Aluminum chloride is used in the closure reaction of the compound of general formula [■].

The reaction may be carried out without a solvent or in a solvent.

As the solvent used, a wide range of solvents commonly used in Friedel-Crafts reactions can be used, and specifically, nitrobenzene, chlorobenzene, 2,4-dichlorobenzene,
Examples include aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane and tetrachloroethane, and carbon disulfide.

When the reaction is carried out without a solvent, an inorganic base such as common salt or potassium chloride, which does not participate in the reaction, may be added to lower the melting point of the Lewis acid.

The reaction temperature for such reaction is not particularly limited and may be appropriately selected from a wide range, but it is usually 40 to 200°C, preferably 50 to 150°C.

The reaction time is usually about 1 to 15 hours.

According to the method of the present invention, the reaction can be carried out under mild reaction conditions without using dangerous reagents, and side reactions and decomposition reactions can be reduced.

In addition, general formula [III] and general formula [IV] are used as starting materials.
] Even if the compound is used, it takes only two steps to reach the target compound (general formula [I]), and the target compound can be obtained in high yield.

In addition, to obtain the target compound in which the benzene ring is substituted with two hydroxyl groups, the problem can be solved all at once by using a suitable compound of the general formula [III].

Furthermore, the general formula [III] and general formula [IV] of the starting material
This compound is easily available and inexpensive, and is far more economically advantageous than conventional methods.

Reference examples and examples are listed below to further clarify the present invention.

Reference Example 1 12.3 g of p-anisidine was added to 50 ml of acetone, and while the internal temperature was maintained at 40 to 50°C, K2CO316.
A solution of 6 g in 50 ml of water and cinnamoyl chloride 2
A solution of 0.0 g in 50 ml of acetone was simultaneously added dropwise over 1 hour.

After the addition was completed, the reaction mixture was further stirred at the same temperature, poured into 2 liters of ice-water, and left to stand. The precipitated crystals were filtered off. The crude crystals were dissolved in chloroform, and the organic layer was mixed with 1N hydrochloric acid, 1N sodium hydroxide, and water. The solvent was distilled off after drying with Na2SO4, and the resulting residue was recrystallized from methanol-water to obtain prismatic N-cinnamoyl-p-anisidine 23.
Obtain 1g.

Melting point: 155.6-156.4°C Reference Example 2 12.3 g of o-anisidine was added to 100 ml of pyridine, and while stirring at room temperature, 20.0 g of cinnamoyl chloride was added to pyridine 1.
The solution added to 00ml was added dropwise over 1 hour.

After the dropwise addition was completed, the reaction solution was stirred at room temperature overnight, and then mixed with 3 liters of ice-water.
After pouring into water and leaving to stand, remove the crystals that precipitate.

The crude crystals are washed successively with 1N hydrochloric acid, saturated deuterated water, and water, and the obtained crude crystals are recrystallized from methanol-water to obtain 23.8 g of prismatic N-cinnamoyl-o-anisidine.

Melting point: 137.5-138.5°C Reference Example 3 15.3 g of 2,5-dimethoxyaniline was added to 50 ml of dimethyl sulfoxide, and 6.0 g of NaOH was added to 50 ml of water with stirring while keeping the internal temperature at 50-60°C. 31.7 g of cinnamoyl dimethyl sulfoxide and 50 g of dimethyl sulfoxide
ml solution was added dropwise at the same time over 1 hour.

After the dropwise addition was completed, the reaction solution was stirred at the same temperature for 3 hours, and then placed on ice.
Pour into 3 liters of water and leave to stand, then collect a lot of precipitated crystals.

After thoroughly washing the crude crystals in the order of 1N hydrochloric acid, saturated deuterated water, and water, the obtained crude crystals were recrystallized from isopropanol to obtain prismatic N-cinnamoyl-2,5-dimethoxy-aniline 26. Obtain 7g.

Melting point 116.5-118°C Example I 10 g of N-cinnamoyl-p-anisidine and AlCl,
Add 50g to 100ml of chlorobenzene and add 100~1
Stir at 10°C for 2 hours.

After the reaction solution was cooled, it was poured into 1.5 liters of ice-water and allowed to stand, and the precipitated crystals were taken off and washed with water.

The obtained crude crystals are recrystallized from methanol to obtain 5.7 g of 6-hydroxycarbostyryl in the form of colorless needles.

Melting point 313-316.5°C Example 2 N-cinnamoyl p-penzyloxyaniline 32.
9g and 391g of AlCl in 300m of tetrachloroethane
After cooling the reaction solution, it was poured into 3 liters of ice-water and allowed to stand. The precipitated crystals were collected by filtration and washed with water.

The obtained crude crystals were dissolved in a 2N aqueous sodium hydroxide solution (400 g).
ml and remove insoluble matter.

After the P solution was adjusted to pH≈2 with hydrochloric acid, the precipitated crystals were collected by filtration, washed with water, and then the crude crystals were recrystallized from methanol to obtain 14.5 g of 6-hydroxycarpostyryl in the form of colorless needles.

Melting point 313-316.5°C Example 3 N-(p-chlorocinnamoyl)-p-anisidine 14
．． 4g and 353.2g of AlCl to 150g of chlorobenzene
ml and stirred at 100-110°C for 5 hours.

After the reaction solution was cooled, it was poured into 2 liters of ice-water and allowed to stand. The precipitated crystals were collected by filtration and washed with water.

The obtained crude crystals were dissolved in a 2N aqueous sodium hydroxide solution (300 g).
ml and remove insoluble matter.

After adjusting the pH of the P solution to 2 with hydrochloric acid, the precipitated crystals were collected by filtration, washed with water, and then the crude crystals were recrystallized from methanol to obtain 6.8 g of 6-hydroxycarbostyryl in the form of colorless needles.

Melting point 313-316.5°C Example 4 N-cinnamoyl-2,5-dimethoxyaniline 28.
3 g and 391 g of AlCl were added to 300 ml of chlorobenzene and stirred for 3 hours under a N2 stream.

After the reaction solution was cooled, it was poured into 3 liters of ice-water, and after standing, the precipitated crystals were collected and washed with water.

The obtained crude crystals were dissolved in a 2N aqueous sodium hydroxide solution (400 g).
ml and insoluble matters are removed by filtration, the filtrate is adjusted to pH≒2 with hydrochloric acid, and the precipitated crystals are collected by filtration and washed with water.

The crude crystals are repeatedly recrystallized from water to obtain light brown amorphous crystals of 5,8-dihydroxycarpostyril.

Melting point 300°C (decomposition) Example 5 25.3 g of N-cinnamoyl-o-anisidine and AlC
Add 1366.7g to 250ml of chlorobenzene,
Stir at 100-110°C for 2.5 hours.

After the reaction solution was cooled, it was poured into 3 liters of ice-water, and after standing, the precipitated crystals were taken out and washed with water.

The obtained crude crystals were recrystallized from methanol-water to obtain 14.8 g of 8-hydroxycarbostyryl in the form of colorless flakes.
get.

Melting point 299-312°C Example 6 N-(p-methylcinnamoyl)-o-anisidine 26
．． 7 g (0.10 mol) of AlCl (391 g) is added to 250 ml of chlorobenzene and stirred at 100-110° C. for 4 hours.

After the reaction solution was cooled, it was poured into 3 liters of ice-water, and after standing, the precipitated crystals were collected by filtration and washed with water.

The obtained crude crystals were dissolved in a 2N aqueous sodium hydroxide solution (400 g).
ml and insoluble matters are removed by filtration.

After adjusting the pH of the filtrate to 2, the precipitated crystals were collected by filtration, washed with water, and the crude crystals were recrystallized from methanol-water to yield 13.7 g of 8-hydroxycarbostyryl in the form of colorless flakes.
get.

Melting point 299-302°C Example 7 N-(p-nitrocinnamoyl)-p-anisidine 29
．． 8g and 391g of AlCl to 300m of chlorobenzene
1 and stirred at 100-110°C for 4 hours.

After the reaction solution was cooled, it was poured into 3 liters of ice-water, and after standing, the precipitated crystals were collected by filtration and washed with water.

The obtained crude crystals are recrystallized from methanol to obtain 13.2 g of 6-hydroxycarbostyryl in the form of colorless needles.

Melting point 313-316.5°C Example 8 25.3 g of N-cinnamoyl-m-anisidine and AlC
Add 1391g to 250ml of chlorobenzene and make 85~
Stir at 95°C for 2.5 hours.

After the reaction solution was cooled, it was poured into 3 liters of ice-water, and after standing, the precipitated crystals were collected in a furnace and washed with water.

The obtained crude crystals were dissolved in a 2N aqueous sodium hydroxide solution (200 g).
ml and insoluble matters are removed by filtration.

After adjusting the filtrate to pH≒2 with hydrochloric acid, the precipitated crystals were collected by filtration.
Wash with water.

The obtained crude crystals were recrystallized several times from methanol-water to obtain colorless and amorphous 7-hydroxycarpostyryl 8.
．． Obtain 7g.

Melting point 303.5-305.5℃

Claims (1)

[Claims] 1. In the presence of aluminum chloride, the general formula [wherein R1 represents a hydrogen atom, a lower alkyl group, or an aralkyl group with or without a substituent, and R2 represents a hydrogen atom, a halogen atom, a lower It represents an alkyl group, a lower alkoxy group or a ditro group, and n represents 1 or 2. A method for producing a hydroxylupostyryl derivative, which comprises subjecting an anilide derivative represented by the following formula to a ring-closing reaction to obtain a hydroxylupostyryl derivative represented by the general formula [where n is the same as above].