JPH11269148A - Production of 3,4-dihydrocarbostyrils - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially safely obtain the subject compound useful as an antithrombotic agent in good operability and good yield by cyclizing a specific compound in the presence of anhydrous aluminum chloride in a specific solvent under heating. SOLUTION: (A) A compound of formula I (R' is H, OH or a 1-4C alkoxy) [e.g. N-(4-hydroxyphenyl)-3-chloropropioneamide] is cyclized under heating in the presence of (B) anhydrous aluminum chloride in (C) a halogenated benzene solvent (e.g. dichlorobenzene) containing a nitrogen-containing organic compound selected from an amine (e.g. trioctylamine), an acid amide (e.g. N,N- dimethylformamide) at 110 deg.C to boiling point of the component C, e.g. about 200 deg.C, preferably 110-160 deg.C to provide the objective unsaturated or 6-hydroxy- substituted 3,4-dihydrocarbostyril of formula II (R is H or OH). An amount of the nitrogen-containing organic compound used is preferably 0.05-10 mol based on 1 mol component A.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an improved method for producing 3,4-dihydrocarbostyrils which are unsubstituted or substituted at the 6-position with a hydroxyl group. The 3,4-dihydrocarbostyrils produced according to the present invention are useful as intermediates for pharmaceuticals such as antithrombotic agents, cerebral circulation improving agents, anti-inflammatory agents, anti-ulcer agents, and anti-asthmatic agents.

[0002]

BACKGROUND OF THE INVENTION Unsubstituted or 6-hydroxy substituted 3,4-
Dihydrocarbostyril (II) is 3-chloropropionanilide or its derivative (I) obtained by acylating aniline or para-substituted aniline with β-chloropropionyl chloride (hereinafter collectively referred to as 3-chloropropionanilide derivative). It has been known that, as a starting material, the compound can be synthesized by a Friedel-Crafts reaction by heating and ring closing in the presence of anhydrous aluminum chloride as shown in the following reaction formula.
(See U.S. Pat. No. 3,819,637). In this reaction, anhydrous aluminum chloride is used in a large amount, which is several times or more the molar ratio of the raw material compound.

[0003]

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In the above formula, R ′ and R are as defined in claim 1. That is, when the R ′ group is an alkoxy group, the above-mentioned reaction converts the alkoxy group into a hydroxyl group.

However, in the method described in the above patent,
Since no solvent is used, stirring cannot be performed until the 3-chloropropionanilide derivative and the anhydrous aluminum chloride, which are the raw materials, are heated and melted, and impurities are easily generated during the stirring. In addition, there is a problem that the contents gradually solidify even during the reaction and stirring becomes impossible, and it is difficult to industrially produce 3,4-dihydrocarbostyrils by this method.

As a remedy, a paraffinic solvent is used, and if necessary, N, N-dimethylformamide,
A reaction method has been proposed in which additives such as N, N-dimethylacetamide and 1,3-dimethyl-2-imidazolidone are added to a reaction system to improve fluidity (JP-A-9-124605).

However, in the present reaction using a large amount of anhydrous aluminum chloride with only a non-polar solvent such as a paraffinic solvent, the solvent and anhydrous aluminum chloride are not compatible at all, so that the starting material, 3-chloropropionanilide derivative, Problems such as adhesion of the complex with anhydrous aluminum chloride to the inner wall of the reaction vessel, the stirring blades, and the like occur, and sufficient stirring cannot be performed. Therefore, additives such as N, N-dimethylformamide are added to the reaction system for the purpose of improving fluidity. As a result, the temperature at which fluidity is maintained until sufficient stirring can be performed, but the operability is not necessarily good because the compatibility with the paraffin-based solvent is not improved. For example, raw materials, solvent, anhydrous aluminum chloride,
When an additive such as N, N-dimethylformamide is charged and heated to a predetermined temperature, while the temperature is lower than 100 ° C., the above problem is not improved, and sufficient stirring cannot be performed.

[0008]

DISCLOSURE OF THE INVENTION The present invention solves the above-mentioned problems, and uses a solvent capable of dissolving anhydrous aluminum chloride to produce a 3-chloropropionanilide derivative as a raw material by a Friedel-Crafts reaction. An object of the present invention is to provide a method capable of producing 3,4-dihydrocarbostyrils with high safety, good operability and high yield.

[0009]

Solvents generally used in the Friedel-Crafts reaction include, for example, nitrobenzene, chlorobenzene, dichlorobenzene, methylene chloride, chloroform and dichloroethane. Since these solvents, especially aromatic solvents, form a complex with anhydrous aluminum chloride and dissolve anhydrous aluminum chloride, they are excellent reaction solvents in terms of safety and operability.

However, when the above-mentioned ring-closing reaction is carried out with these aromatic solvents, the solidification of the contents is eliminated and the operability is good, but the reaction product of the raw material 3-chloropropionanilide derivative with the solvent is not obtained. It was formed in large amounts as impurities, and the yield of the desired 3,4-dihydrocarbostyrils was extremely low. This is described in Japanese Patent Application Laid-Open No.
It is also described in 124605. Therefore, in the conventional method described in this publication, a high yield is obtained by using a paraffinic solvent as a solvent. However, as described above, a paraffin-based solvent cannot dissolve a large amount of anhydrous aluminum chloride, and thus has a problem of poor operability.

The present inventors have conducted intensive studies on a reaction method capable of achieving both the operability of the reaction and the yield of the desired product. As a result, the halogenated benzene was used as a reaction solvent, and an amine or an acid amide was added to the reaction system. As a result, they have found that the desired 3,4-dihydrocarbostyrils can be synthesized in terms of safety and operability in comparison with the conventional method and with a high yield comparable to the above-mentioned conventional method, and completed the present invention. Was.

The above-mentioned Japanese Patent Application Laid-Open No. 9-124605 describes that a halogenated benzene solvent such as chlorobenzene produces a large amount of impurities as a by-product, resulting in a poor yield. Also,
It is also described that the addition of an acid amide to the reaction system increases the fluidity. However, when an amine or an acid amide coexists in the reaction system when halogenated benzene is used as a solvent, the reaction between the raw material and the solvent is effectively suppressed and impurities
The above publication does not suggest anything that the target product can be produced in high yield while suppressing the yield reduction due to (by-products), and it is based on the unique knowledge of the present invention that cannot be predicted from this publication. is there.

Here, the present invention relates to the following general formula (I)

[0014]

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(Wherein R ′ is hydrogen, a hydroxyl group,
Or a compound having the following general formula (II):

[0016]

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In the process for producing an unsubstituted or 6-hydroxy-substituted 3,4-dihydrocarbostyril represented by the formula (wherein R represents hydrogen or a hydroxyl group), a compound selected from amines and acid amides is used. The method is characterized in that the reaction is carried out in a halogenated benzene solvent containing a nitrogen organic compound.

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION The raw material used in the present invention has a general formula
3-chloropropionanilide or a derivative thereof represented by (I) wherein R ′ is as described above (this is referred to as a 3-chloropropionanilide derivative) as described above. More specifically, it can be named N- (4-unsubstituted or substituted phenyl) -3-chloropropionamide.

Specific examples of the starting compound include 3-chloropropionanilide (R '= H), 3-chloropropionanisidide (R' = methoxy), and 3-chloropropionphenethidide (R '= ethoxy). , N- (4-hydroxyphenyl) -3-chloropropionamide (R '= OH)
And the like.

The starting compound represented by the general formula (I) is
As described in U.S. Pat.No. 3,819,637, aniline or a 4-substituted derivative thereof can be synthesized by acylation with .beta.-chloropropionic acid chloride. Good.

When the 3-chloropropionanilide derivative represented by the general formula (I) is heated and ring-closed in the presence of anhydrous aluminum chloride, the desired 3,4-dihydrocarbostyril is formed. When the R ′ group is an alkoxy group, a change from an alkoxy group to a hydroxyl group occurs at the same time.

In the present invention, this reaction is carried out in a halogenated benzene solvent containing a halogenated benzene as a solvent, an amine and / or an acid amide added to the reaction system, and the reaction system. There is a feature.

Examples of the halogenated benzene as a solvent include chlorobenzene, dichlorobenzene, trichlorobenzene, bromobenzene, dibromobenzene, tribromobenzene, fluorobenzene, difluorobenzene,
Trifluorobenzene and the like can be mentioned, and one or more of these can be used. The solvent is preferably composed only of halogenated benzene,
Other solvents (eg, halogenated aliphatic hydrocarbons, paraffins) may be used together (eg, 30% by weight or less).

The amount of the solvent used is sufficient as long as the contents maintain fluidity. For example, the solvent is used in an amount of at least 1 times the weight of the raw material 3-chloropropionanilide derivative.
When halogenated benzene is used as the solvent, both the anhydrous aluminum chloride and the starting compound are dissolved in the solvent, so that a homogeneous reaction occurs, the fluidity of the contents is maintained, and the operability of the reaction is improved.

However, with this solvent alone, as described above, a side reaction between the raw material and the solvent occurs, and the yield is significantly reduced. According to the present invention, by adding one or more nitrogen-containing organic compounds selected from amines and acid amides to the solvent, unexpectedly, this side reaction is effectively suppressed, and high yield is obtained. The desired 3,4-dihydrocarbostyrils can be obtained at a high rate. The suppression of this side reaction
It is speculated that the amine or acid amide may reduce the catalytic activity of anhydrous aluminum chloride.

The amine and acid amide are not particularly limited as long as they are stably present under the reaction conditions. Preferably, the amine is a cyclic or acyclic non-aromatic primary, secondary or tertiary amine. Specific examples of amines that can be used include hexylamine, heptylamine, octylamine, nonylamine, decylamine, undecylamine, dodecylamine (laurylamine), tridecylamine, tetradecylamine, pentadecylamine, cetylamine, and stearylamine. , Ethylhexylamine, 3- (2-ethylhexyloxy) propylamine, 3-methoxypropylamine, 3-ethoxypropylamine, aliphatic amines such as ethanolamine; dipropylamine, dibutylamine, diamylamine, dioctylamine, dioctylamine, Aliphatic secondary amines such as stearylamine and diethylhexylamine; tripropylamine;
Aliphatic tertiary amines such as tributylamine, triamylamine, trioctylamine, triethylhexylamine, dimethyloctylamine, dimethyllaurylamine, dimethylstearylamine, dilaurylmonomethylamine; tetramethylethylenediamine, 3- (dibutylamino) propyl Diamines such as amine, 3- (methylamino) propylamine and 3- (dimethylamino) propylamine; alicyclic amines such as cyclohexylamine; heterocyclic amines such as piperidine, piperazine and pyrrolidine. .

Examples of the acid amide include N, N-dimethylformamide, N, N-dimethylacetamide, 2-pyrrolidone, N-methyl-2-pyrrolidone, hydantoins and the like. Among these, aliphatic tertiary amines and
N, N-dimerformamide is particularly preferred.

The amount of the nitrogen-containing organic compound selected from amines and acid amides is 0.05 to 10 times, preferably 0.05 to 10 times the molar ratio of the starting material to the 3-chloropropionanilide derivative.
It is 0.1 to 5 times, more preferably 0.2 to 2 times. When the amount is small, the activity of the anhydrous aluminum chloride is not sufficiently reduced, the reaction product of the 3-chloropropionanilide derivative and the solvent increases, and the yield of the target 3,4-dihydrocarbostyril decreases. Conversely, if too large, the activity of the anhydrous aluminum chloride is too low, the reaction rate is low,
Not preferred.

The amount of anhydrous aluminum chloride used in the reaction must be at least 3 mol times the starting material 3-chloropropionanilide derivative, and is usually 3 to 10 times, preferably 4 times, the molar ratio to the starting material. Use up to 6 times as much.

The reaction temperature is usually from 110 ° C. to the boiling point of the solvent,
For example, it is carried out at about 200 ° C., preferably at 110 to 160 ° C. The reaction may be carried out at normal pressure, increased pressure or reduced pressure without any particular problem. The reaction time varies depending on the reaction temperature, the amount of the nitrogen-containing organic compound added, and the like, but is usually about 1 to 24 hours.

There is no particular limitation on the reaction system. A solvent, a nitrogen-containing organic compound, a 3-chloropropionanilide derivative, and anhydrous aluminum chloride are charged into a reaction vessel, and the reaction is carried out by raising the temperature to a predetermined temperature. Then, a 3-chloropropionanilide derivative or anhydrous aluminum chloride as a raw material may be added and reacted.

After completion of the reaction, the product may be recovered from the reaction solution by a conventional method. For example, after cooling the reaction solution,
It is poured into water to deactivate the anhydrous aluminum chloride, and the precipitated crystals are recovered by means such as filtration. In some cases, a solvent such as toluene or xylene may be added to dissolve the nitrogen-containing organic compound. Also, the crystals can be washed with a suitable solvent. When it is desired to increase the purity of the crude crystals obtained by the reaction, recrystallization may be performed with a suitable solvent.

[0033]

The present invention will be described below in detail with reference to examples. In the examples,% for purity is% by weight, and% for yield is% by mol.

Example 1 In a 100 ml glass flask equipped with a stirrer, thermometer and reflux condenser, 25 g of o-dichlorobenzene and 5 g of N- (4-hydroxyphenyl) -3-chloropropionamide (95.9% , 0.024 mol), 8.84 g (0.025 mol) of trioctylamine and 16.7 g (0.125 mol) of anhydrous aluminum chloride.
Heated to ° C. During this heating, the raw material compound, anhydrous aluminum chloride and the amine were completely dissolved in the solvent, and a uniform reaction liquid having high fluidity was obtained, and the stirring was easy. The reaction was continued with stirring at 130 ° C. for 15 hours.

After the completion of the reaction, the cooled reaction solution was poured into 100 g of water, and the precipitated crystals were collected by filtration, dried and dried.
2.65 g of crude crystals were obtained. When the crude crystals were analyzed by liquid chromatography, the purity of 6-hydroxy-3,4-dihydrocarbostyril was 91.6% and the yield was 62.0%. Further, 6-hydroxy-3,4-dihydrocarbostyril in the filtrate was 16.0% in yield, and the total yield was 78.0%.

Example 2 In a 100 ml glass flask equipped with a stirrer, thermometer and reflux condenser, 5 g of o-dichlorobenzene and 5 g of N- (4-hydroxyphenyl) -3-chloropropionamide (95.9% , 0.024 mol), 4.42 g (0.012 mol) of trioctylamine and 16.7 g (0.125 mol) of anhydrous aluminum chloride.
C., and reacted by stirring at the same temperature for 6 hours.

After completion of the reaction, the cooled reaction solution was poured into 100 g of water, and the precipitated crystals were collected by filtration, dried and dried.
3.93 g of crude crystals were obtained. When the crude crystals were analyzed by liquid chromatography, the purity of 6-hydroxy-3,4-dihydrocarbostyril was 72.2% and the yield was 72.6%. 6-Hydroxy-3,4-dihydrocarbostyril in the filtrate was 12.1% in yield, and the total yield was 84.7%.

Examples 3 to 9 The reaction and subsequent treatment of the reaction solution were carried out in the same manner as in Example 2 except that dioctylamine was changed to another amine or acid amide shown in Table 1. The reaction results are as shown in Table 1.

Example 10 5 g of o-dichlorobenzene and 5 g of N- (4-hydroxyphenyl) -3-chloropropionamide (95.9%) were placed in a 100 ml glass flask equipped with a stirrer, a thermometer and a reflux condenser. , 0.024 mol), 4.42 g (0.012 mol) of triethylhexylamine and 16.7 g (0.125 mol) of anhydrous aluminum chloride were heated to 150 ° C. with stirring, and reacted at the same temperature with stirring for 2 hours.

After completion of the reaction, the cooled reaction solution was poured into 100 g of water, and the precipitated crystals were collected by filtration, dried and dried.
3.63 g of crude crystals were obtained. When the crude crystals were analyzed by liquid chromatography, the purity of 6-hydroxy-3,4-dihydrocarbostyril was 85.4%, and the yield was 7%.
9.1%. Also, 6-hydroxy-3,
4-Dihydrocarbostyril was 3.4% in yield, and the total yield was 82.7%.

Example 11 In a 100 ml glass flask equipped with a stirrer, thermometer and reflux condenser, 5 g of o-dichlorobenzene and 5 g of N- (4-hydroxyphenyl) -3-chloropropionamide (95.9% , 0.024 mol), 4.42 g (0.012 mol) of triethylhexylamine and 16.7 g (0.125 mol) of anhydrous aluminum chloride were heated to 100 ° C. with stirring, and reacted at the same temperature for 24 hours with stirring.

After completion of the reaction, the cooled reaction solution was poured into 100 g of water, and the precipitated crystals were collected by filtration, dried and dried.
2.82 g of crude crystals were obtained. When the crude crystals were analyzed by liquid chromatography, the purity of 6-hydroxy-3,4-dihydrocarbostyril was 83.7% and the yield was 60.2%. Further, 6-hydroxy-3,4-dihydrocarbostyril in the filtrate was 15.3% in yield, and the total yield was 75.5%.

The results of the above examples are summarized in Table 1.

[0044]

[Table 1]

Example 12 5 g of o-dichlorobenzene and 5 g of 3-chloropropionanisidide were placed in a 100 ml glass flask equipped with a stirrer, thermometer and reflux condenser.
(98.5%, 0.023 mol), trioctylamine 4.42 g (0.01
2 mol) and anhydrous aluminum chloride 16.7 g (0.125 mol)
And heated to 130 ° C with stirring.
The mixture was stirred for an hour to react.

After the completion of the reaction, the cooled reaction solution was poured into 100 g of water, and the precipitated crystals were collected by filtration, dried and dried.
3.36 g of crude crystals were obtained. When the crude crystals were analyzed by liquid chromatography, the purity of 6-hydroxy-3,4-dihydrocarbostyril was 78.8% and the yield was 70.0%. Further, 6-hydroxy-3,4-dihydrocarbostyril in the filtrate was 19.2% in yield, and the total yield was 89.2%.

Comparative Example 1 In a 100 ml glass flask equipped with a stirrer, thermometer and reflux condenser, 25 g of o-dichlorobenzene and 5 g of N- (4-hydroxyphenyl) -3-chloropropionamide (95.9% , 0.024 mol) and 16.7 g (0.125 mol) of anhydrous aluminum chloride were heated to 130 ° C. with stirring, and reacted at the same temperature with stirring for 6 hours. The reaction solution was a homogeneous solution, and the operability such as stirring was good.

After completion of the reaction, the cooled reaction solution was poured into 100 g of water, but no crystals were precipitated. Then, the mixture was extracted with ethyl acetate, and the extract was concentrated to obtain 24.0 g of an oily substance. The oil was analyzed by liquid chromatography,
The 6-hydroxy-3,4-dihydrocarbostyril concentration is
The yield was 7.5%, and the yield was 46.0%. The yield of 6-hydroxy-3,4-dihydrocarbostyril in the aqueous layer was 0.3%, and the total yield was 46.3%.

Comparative Example 2 25 g of o-dichlorobenzene and 5 g of 3-chloropropionanisidide were placed in a 100 ml glass flask equipped with a stirrer, thermometer and reflux condenser.
8.5%, 0.023 mol) and 16.7 g of anhydrous aluminum chloride
(0.125 mol) and heated to 140 ° C with stirring.
The mixture was reacted by stirring at the same temperature for 5 hours.

After completion of the reaction, the cooled reaction solution was poured into 100 g of water, but no crystals were precipitated. Then, extraction was performed with ethyl acetate, and the extract was concentrated to obtain 23.9 g of an oily substance. The oil was analyzed by liquid chromatography and found to be 6
-Hydroxy-3,4-dihydrocarbostyril concentration is 7.
8% and the yield was 49.3%. In addition, 6
-Hydroxy-3,4-dihydrocarbostyril was 0.2% in a yield, and the total yield was 49.5%.

Comparative Example 3 Chlorobenzene was placed in a 100 ml glass flask equipped with a stirrer, thermometer and reflux condenser.
25 g, 3-chloropropionanisidide 5 g (98.5%,
0.023 mol) and 16.7 g of anhydrous aluminum chloride (0.125 m
ol), heated to 140 ° C. while stirring, and reacted by stirring at the same temperature for 3 hours.

After completion of the reaction, the cooled reaction solution was poured into 100 g of water, but no crystals were precipitated. Then, the mixture was extracted with ethyl acetate, and the extract was concentrated to obtain 8.5 g of an oily substance. The oil was analyzed by liquid chromatography and found to be 6
-Hydroxy-3,4-dihydrocarbostyril concentration is 2.
The yield was 4%, and the yield was 5.4%. In addition, 6
-Hydroxy-3,4-dihydrocarbostyril was 0.1% in yield, for a total yield of 5.5%.

As can be seen from the results of the comparative examples, when the reaction for cyclizing the 3-chloropropionanilide derivative in the presence of anhydrous aluminum chloride is carried out in a halogenated benzene solvent, the operability of the reaction is good. The essential yield is as low as 5.5 to 49.5%, indicating that considerable side reaction between the solvent and the starting compounds has occurred.

On the other hand, according to the present invention, when an amine or an acid amide is present in a reaction system using the above solvent,
While maintaining good operability, as shown in each example,
The desired 3,4-dihydrocarbostyrils could be obtained in a high yield of 75 to 96.5%.

[0055]

According to the present invention, a homogeneous reaction is carried out by using a solvent capable of dissolving anhydrous aluminum chloride used in a large amount in the reaction, thereby ensuring high operability of the reaction and high yield. To produce 3,4-dihydrocarbostyrils.

Claims (1)

[Claims] (1) The following general formula (I): (Wherein, R ′ represents hydrogen, a hydroxyl group, or an alkoxy group having 1 to 4 carbon atoms) by heating and ring-closing in the presence of anhydrous aluminum chloride to obtain a compound represented by the following general formula (II) Embedded image (Wherein, R represents hydrogen or a hydroxyl group)
Wherein the reaction is carried out in a halogenated benzene solvent containing a nitrogen-containing organic compound selected from an amine and an acid amide, in the method for producing an unsubstituted or 6-hydroxy-substituted 3,4-dihydrocarbostyril represented by And how.