JPH06157494A - Alpha-acylaminoketone derivative, its production and its utilization - Google Patents

Abstract

PURPOSE:To obtain a compound useful as a synthetic intermediate for pilocarpine, etc., which is a therapeutic medicine for glaucoma by subjecting a benzyl ester group of a specific benzyl ester derivative to hydrogenolysis and successive decarboxylation. CONSTITUTION:An acid halide of formula I (R<1> is lower alkyl; X is halogen), e.g. homopilopic acid chloride is made to react with a malonic acid derivative of formula II (R<2> is same as R<1>; R<3> is H, lower alkyl, lower alkoxy, nitro, cyano or halogen), e.g. acetamide malonic acid dibenzyl ester to afford a benzyl ester derivative expressed by formula III. The benzyl ester derivative is dissolved in acetic acid and subjected to removal of benzyl group due to hydrogenolysis and successive decarboxylic acid reaction in the presence of 5% palladium-carbon under hydrogen atmosphere at ambient temperature while stirring for 4hr and 50min to provide the objective alpha-acylaminoketone derivative expressed by formula IV and useful as a synthetic intermediate for pilocarpine which a therapeutic medicine for glaucoma and its analogue compounds.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a general formula (I) useful as an intermediate in the synthesis of pilocarpine, a therapeutic agent for glaucoma, and related compounds.

[0002]

[Chemical 6]

(In the formula, R ¹ and R ² each independently represent a hydrogen atom or a lower alkyl group), an α-acyl aminoketone derivative, a method for producing the same and a general formula (III) using the same:

[0004]

[Chemical 7]

The present invention relates to a method for producing an α-aminoketone derivative represented by the formula (wherein R ¹ is as defined above) or an acid adduct thereof.

[0006]

2. Description of the Related Art Documents describing a method for synthesizing an α-aminoketone derivative represented by the general formula (III), which is an intermediate of pilocarpine for treating glaucoma, and an acid adduct thereof are:
Tetrahedron, Vol. 28, page 967 (1972). In this document, homopyropin acid chloride is reacted with acetamide malonic acid di-t-butyl ester to obtain a coupling body, and then HCl is used.
A method for producing aminomethylhomopyropyrketone by treatment or the like is described.

Also, J. Am. Chem. Soc. Vol. 80, No. 6
On page 077 (1958), benzoyl chloride is reacted with acetamide malonic acid di-t-butyl ester to give benzoylacetamidomalonic acid di-t-butyl ester, which is then treated with an acid. A method for synthesizing α-acetamidoacetophenone is described. However, since the flammable gas isobutene is used for the production of acetamidomalonic acid di-t-butyl ester, there is a problem that the risk of ignition is great. Further, there is a problem that it is difficult to synthesize a large amount of acetamidomalonic acid, which is a raw material, because it requires lyophilization after hydrolysis of ethyl ester, which is difficult.

[0008]

DISCLOSURE OF THE INVENTION As a result of intensive studies by the present inventors, the novel α-acylaminoketone derivative described later uses acetamidomalonic acid di-t-butyl ester having the above-mentioned problems. It was found that the desired α-aminoketone derivative and its acid adduct can be produced in a higher yield than the conventional method by using these compounds, and thus completed the present invention.

[0009]

The present invention has the general formula (I):

[0010]

[Chemical 8]

(Wherein R ¹ and R ² each independently represents a hydrogen atom or a lower alkyl group), an α-acyl aminoketone derivative represented by the general formula (II):

[0012]

[Chemical 9]

(Wherein R¹And R²Each independently water
Represents an elementary atom or a lower alkyl group, R ³Is hydrogen atom, low
Class alkyl group, lower alkoxy group, nitro group, cyano group
Alternatively, it represents a halogen atom. ) Benzyl ester
Of benzyl ester group
The above general formula characterized by being removed by subsequent decarboxylation
Production of α-acyl aminoketone derivative represented by (I)
Method, general formula (I):

[0014]

[Chemical 10]

(Wherein R ¹ and R ² each independently represents a hydrogen atom or a lower alkyl group), the α-acyl aminoketone derivative is hydrolyzed under acidic conditions. (III):

[0016]

[Chemical 11]

A method for producing an α-aminoketone derivative represented by the formula (wherein R ¹ has the same meaning as defined above) or an acid adduct thereof. In the general formulas (I), (II) and (III), the lower alkyl group among the groups represented by R ¹ , R ² and R ³ means an alkyl group having 1 to 6 carbon atoms, such as a methyl group, An ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, a pentyl group, and a hexyl group can be exemplified. The lower alkoxy group is an alkoxy group having 1 to 6 carbon atoms. A methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a t-butoxy group, a pentyloxy group and a hexyloxy group can be exemplified. Moreover, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The α-acyl aminoketone derivative represented by the general formula (I) is produced by removing the benzyl ester group of the benzyl ester derivative represented by the general formula (II) by hydrogenolysis and subsequent decarboxylation. It The hydrogenolysis reaction of the compound represented by the general formula (II) is carried out in a hydrogen atmosphere using various catalysts. Examples of the catalyst used include fine powders of platinum, palladium, rhodium, ruthenium, and other noble metals, oxides, those supporting them on various carriers (for example, carbon, alumina, silica gel, diatomaceous earth, etc.), or Raney nickel. Preferable examples are palladium supported on carbon.

The reaction is usually carried out in the presence of a solvent. As the solvent to be used, lower alcohols such as methanol, ethanol, n-propanol and isopropanol, ethers such as tetrahydrofuran and dioxane, lower fatty acids such as formic acid, acetic acid and propionic acid, esters such as methyl acetate and ethyl acetate. , Water, and dilute hydrochloric acid. These may be used alone or in combination. Preferable is acetic acid.

In carrying out the hydrocracking reaction, when a noble metal catalyst is used as the catalyst, the compound represented by the general formula (II) is usually 0.0001 to 1 times by weight, preferably 0.0005 to 0 times as a metal. 0.1 times by weight, when Raney nickel is used, it is generally 0.01 to 10 times by weight, preferably 0.05 to 1 times by weight, and the solvent is usually 0.1 to 100 times by weight, preferably 1 to 30 times by weight.

The temperature is usually 0 to + 100 ° C., preferably +
The reaction is carried out at 10 to + 80 ° C. and the hydrogen partial pressure is usually 0.1 to 200 atm, preferably 1 to 60 atm. For the decarboxylation reaction, after completion of the hydrogenolysis reaction, when an acidic solvent such as acetic acid or dilute hydrochloric acid is used as the solvent for the hydrogenolysis reaction, the reaction is carried out as it is.
The reaction is carried out at-+ 150 ° C, preferably + 10- + 100 ° C for usually 1 minute to 100 hours, preferably 10 minutes to 20 hours. However, decarboxylation may proceed simultaneously with the hydrocracking reaction, and in such a case, it is not necessary to take time for the decarboxylation reaction.

The produced α-acyl aminoketone derivative represented by the general formula (I) can be isolated by a conventional method. Here, a method for producing the benzyl ester derivative represented by the general formula (II) used as a raw material will be described. The benzyl ester derivative represented by the general formula (II) has the following general formula (IV):

[0023]

[Chemical 12]

(Wherein, X represents a halogen atom and R ¹ has the same meaning as described above), and an acid halide represented by the following general formula (V):

[0025]

[Chemical 13]

(In the formula, R ² and R ³ have the same meanings as described above.) The compound can be produced by reacting the malonic acid derivative represented by the alkali metal or alkaline earth metal salt. Here, the compound represented by the general formula (IV) is, for example, tetrahedron (Tetrahedron) Vol. 28, 967
Page (1972), the following general formula:

[0027]

[Chemical 14]

It can be obtained by reacting a compound represented by the formula (wherein R ¹ is as defined above) with thionyl chloride. Examples of the alkali metal or alkaline earth metal salt of the malonic acid derivative represented by the general formula (V) include
Examples thereof include lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt and the like. These salts include compounds represented by the general formula (V) and hydrides or alkoxides of the aforementioned alkali metals or alkaline earth metals, such as methoxide, ethoxide, n-propoxide, isopropoxide, n-butoxide, isobutoxide. , Sec-butoxide, t-butoxide and the like can be easily prepared.

The compound represented by the general formula (V) is
For example, the general formula:

[0030]

[Chemical 15]

(Wherein R ² has the same meaning as defined above) and the general formula:

[0032]

[Chemical 16]

(In the formula, R ³ has the same meaning as described above.) It can be easily synthesized by a transesterification method with a compound represented by the formula. The reaction between the compound represented by the general formula (IV) and the alkali metal or alkaline earth metal salt of the malonic acid derivative represented by the general formula (V) is usually carried out in the presence of a solvent. Any solvent can be used as long as it is inert to the reaction, and commonly used solvents include ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-diethoxyethane, and 1,2-dimethoxyethane. Aromatic hydrocarbons such as benzene, toluene and xylene, amides such as formamide, N, N-dimethylformamide, N-methylpyrrolidone and the like, preferably tetrahydrofuran, toluene and N, N-dimethylformamide can be exemplified.

In carrying out this reaction, the alkali metal salt of the malonic acid derivative represented by the general formula (V) is usually 0.1 to 5 times, preferably the molar amount of the acid halide represented by the general formula (IV). Is 0.5 to 1.5 times mol, and the solvent is usually 2
It is used in an amount of ˜100 times by weight, preferably 5 to 30 times by weight. The reaction is usually −78 ° C. to + 150 ° C., preferably −
It is carried out at 20 ° C to + 80 ° C for usually 1 minute to 10 hours, preferably 10 minutes to 5 hours. After completion of the reaction, the reaction mixture is treated according to a conventional method to obtain the compound represented by the general formula (II).

The α-acyl aminoketone derivative represented by the general formula (I) is converted to the α-amino ketone derivative represented by the general formula (III) or an acid adduct thereof by hydrolysis under acidic conditions. You can This hydrolysis reaction is usually performed in the presence of a solvent. Examples of the solvent used include lower alcohols such as methanol, ethanol and isopropanol, lower fatty acids such as formic acid and acetic acid, and water alone or in combination, preferably water.

Examples of the acid used in the reaction include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. When carrying out the reaction, the acid is usually 0.01 to 100 times mol, preferably 0.5 to 10 times mol, and the solvent is usually 0.5 to the α-acylaminoketone derivative represented by the general formula (I). It is used in an amount of ˜100 times by weight, preferably 2 to 30 times by weight.

The reaction is usually 0 to + 150 ° C., preferably +
It is carried out at 50 to + 120 ° C. for usually 1 minute to 100 hours, preferably 0.5 to 10 hours. The produced α-aminoketone derivative represented by the general formula (III) or its acid addition product can be separated and purified according to a conventional method.

[0038]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. Example 1 (+)-Homopyropinic acid 7.13 g (4
1.22 mmol) was dissolved in 20 ml of toluene, 10 ml of thionyl chloride was added, and the mixture was heated at 70 ° C. for 1 hour. After cooling, the reaction solution was concentrated to give homopyropin acid chloride (general formula (IV), R
¹ = C ₂ H ₅ , X = Cl) was prepared.

Dibenzyl acetamidomalonate (general formula (V), R ² = CH ₃ , R ³ = H) 14.86 g (4
3.49 mmol) was suspended in 90 ml of toluene and heated to 50 ° C. To this, 7.19 g (43.49 mmol) of 58.1% sodium t-butoxide was added and stirred for 1 hour. The reaction solution was ice-cooled and the above acid chloride was added with 20 ml of toluene.
The solution dissolved in was added dropwise over 10 minutes. After the dropping, the mixture was stirred under ice cooling for 1 hour, and 50 ml of ice water was added. After stirring for 10 minutes, the layers were separated, and the organic layer was concentrated under reduced pressure to obtain 22.5 g of a crude product of a benzyl ester derivative having the structure below.

[0040]

[Chemical 17]

(Physical property data) ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89
(3H, t, J = 7.2 Hz), 1.0 to 1.8 (2
H, m), 1.10 (3H, s), 2.3 to 3.1 (4
H), 3.84 (1H, dd, J1 = 9.7Hz, J2
= 3.6 Hz), 4.18 (1H, dd, J1 = 9.7)
Hz, J2 = 5.0 Hz), 5.21 (2H, s),
6.85 (1H, s), 7.1-7.5 (10H) mass spectrometry (field desorption (FD) method):
m / e = 495 (see FIG. 1) 22.5 g of the obtained crude product was dissolved in 100 ml of acetic acid to obtain 5
% Palladium-carbon (1 g) was added, and the mixture was stirred at room temperature for 4 hours and 50 minutes under a hydrogen atmosphere (hydrogen partial pressure: 1 atm). During this time,
In order to remove the generated carbon dioxide, the pressure was reduced and replaced with hydrogen every 20 minutes. After the completion of the reaction, the catalyst was filtered and concentrated under reduced pressure to obtain 12.1 g of a crude product of the α-acylaminoketone derivative having the following structure.

[0042]

[Chemical 18]

(Physical property data) ¹ H-NMR δ (ppm): 1.04 (3 H, t, J =
7.2 Hz), 1.2 to 1.9 (2H, m), 2.06
(3H, s), 2.4 to 2.7 (3H), 2.9 to 3.
3 (1H, m), 3.97 (1H, dd, J1 = 9.4)
Hz, J2 = 3.2 Hz), 4.14 (2H, d, J =
5 Hz), 4.35 (1 H, dd, J1 = 9.4 Hz,
J2 = 5.8 Hz), 6.0-6.2 (1H) mass spectrometry (FD method): m / e = 227 (see FIG. 2) 12.2 g of the obtained crude α-acyl aminoketone derivative was distilled water. It was dissolved in 95 ml, concentrated hydrochloric acid (8.63 ml) was added, and the mixture was heated under reflux for 5 hours. After cooling, a part of the reaction solution was sampled and concentrated to dryness. The amino group was trifluoroacetylated with trifluoroacetic anhydride and subjected to gas chromatographic analysis under the conditions shown below. As a result, α-aminoketone derivative (general formula (III), R ¹ = C ₂ H ₅ ) of The yield was found to be 89.5% from homopyropic acid.

Analytical conditions Column: 5% silicon SE-52 (Uniport HP 6
0-80mesh) 5φ x 1 m Column temperature: 140 ° C (holding for 4 minutes) -Raising temperature 5 ° C / minute-
200 ° C. Carrier gas: N ₂ , 50 ml / min Internal standard: phthalic acid di-n-butyl ester Retention time: Internal standard 7.5 min, trifluoroacetyl derivative 10 min (Example 2) The amount of acetic acid used was 50 ml. An experiment was carried out in the same manner as in Example 1 except that the yield of the α-aminoketone derivative was 88.7%.

(Example 3) Dropping of the acid chloride was carried out at 23 to 36.
The experiment was conducted in the same manner as in Example 1 except that the reaction was carried out at 0 ° C. and the amount of acetic acid used was 50 ml, and the yield of the α-aminoketone derivative was 83.0%. (Example 4) The amount of acetic acid used was 50 ml, and
Adjust the amount of distilled water that dissolves the α-acyl aminoketone derivative to 4
When an experiment was conducted in the same manner as in Example 1 except that the amount was 3 ml, the yield of the α-aminoketone derivative was 88.7%.

Example 5 1.45 g (8.79 mmol) of 58.1% sodium t-butoxy was added to 25 parts of toluene.
It was suspended in ml and heated to 40 ° C. To this, 3.00 g (8.79 mmol) of dibenzyl acetamidomalonate was added, and the mixture was stirred at 40 ° C. for 1 hour and then at 50 ° C. for 1 hour. The reaction solution was ice-cooled, and a solution of homopyrropic acid (1.44 g, 8.37 mmol) prepared by the same method as in Example 1 in 5 ml of toluene was added dropwise over 3 minutes. After dropping, the mixture was stirred under ice cooling for 1 hour, 15 ml of ice water was added, and the formed precipitate was filtered and separated. The organic layer was concentrated under reduced pressure to obtain 4.27 g of an oily residue containing the benzyl ester derivative (II).

This was dissolved in 20 ml of acetic acid, 0.043 g of 5% palladium-carbon was added, and the mixture was added under a hydrogen atmosphere (hydrogen partial pressure:
(1 atm) and stirred at room temperature. After 4 hours, 0.017 g of 5% palladium-carbon was added, and the reaction was performed for a total of 9 hours.
After completion of the reaction, the catalyst was filtered and concentrated under reduced pressure. To the resulting residue was added 10 ml of water and 4 with 20 ml of 1,2-dichloroethane.
3 g of sodium chloride was added and dissolved, and the mixture was extracted 3 times with 20 ml of ethyl acetate. The organic layers were combined, and anhydrous sodium sulfate and anhydrous magnesium sulfate were sequentially added and dried. When the desiccant is filtered and the filtrate is concentrated under reduced pressure, the α-acyl aminoketone derivative 1.
77 g was obtained (yield 93.2%).

(Comparative Example)

[0049]

[Chemical 19]

8.52 g of sodium t-butoxy (5
(1.5 mmol) was dissolved in 50 ml of toluene by heating at about 45 ° C. To this, a solution of 14.08 g (51.5 mmol) of di-t-butyl acetamidomalonate in 80 ml of toluene was added dropwise over 30 minutes. After dropping, 4
The mixture was stirred at 5 ° C for 30 minutes and at 50 ° C for 1 hour and cooled. The acid chloride prepared from 8.45 g (49.08 mmol) of (+)-homopyropic acid was added dropwise to the reaction solution under ice cooling in the same manner as in Example 1 over 5 minutes. After completion of dropping, the mixture was stirred for 1 hour and 50 ml of ice water was added. After liquid separation, the toluene layer was concentrated under reduced pressure to obtain 24.01 g of a crude product. The crude product was analyzed by high performance liquid chromatography (HPLC) and found to contain 17.79 g of compound 2 (yield 84.8%).

HPLC analysis conditions Column: R-SIL-5-06, 250 mm × 4.6 φ
(YMC) Eluent: Hexane / isopropanol = 9/1, 1 ml
/ Min Internal standard: 1-Acetylaminoadamantane Detection: UV 220nm

[0052]

[Chemical 20]

24.01 g of the obtained crude product (containing 17.79 g (41.6 mmol) of the compound of 2 ) was mixed with water, and 10.8 ml (130 mmol) of concentrated hydrochloric acid was added thereto. The temperature was raised from room temperature to the reflux temperature over 4 hours.
During this period, the low boiling point organic matter generated was distilled off. Then, the mixture was refluxed for 4 hours and cooled. When the obtained reaction liquid was analyzed under the same conditions as in Example 1, the yield of α-aminoketone 3 was 83.0% (from homopyropic acid: 70.4%).

[0054]

INDUSTRIAL APPLICABILITY According to the present invention, a novel compound useful as an intermediate in synthesizing pilocarpine for treating glaucoma and its related compounds is provided. The compound of the present invention can be synthesized without using acetamide malonic acid di-t-butyl ester, which is difficult to synthesize in a large amount, and has the general formula
It is useful as a synthetic intermediate for obtaining the α-aminoketone derivative represented by (III) in high yield.

[Brief description of drawings]

1 is a chart of mass spectrometry of the benzyl ester derivative obtained in Example 1. FIG.

2 is a chart of mass spectrometry of the α-acyl aminoketone derivative obtained in Example 1. FIG.

Claims (3)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ and R ² each independently represent a hydrogen atom or a lower alkyl group.) An α-acyl aminoketone derivative. 2. General formula (II):(In the formula, R¹And R²Are independently hydrogen atom or low
Represents a primary alkyl group, R ³Is a hydrogen atom, lower alkyl
Group, lower alkoxy group, nitro group, cyano group or halogen
Represents an atom. ) Of the benzyl ester derivative
Hydrogenolysis of the benzyl ester group and subsequent dehydrogenation
General formula (I) characterized by being removed by carbonic acid:(In the formula, R¹And R²Is as defined above. ) Indicated by
A method for producing an α-acyl aminoketone derivative. 3. General formula (I): (In the formula, R ¹ and R ² each independently represent a hydrogen atom or a lower alkyl group.) The α-acyl aminoketone derivative represented by the formula (III) is hydrolyzed under acidic conditions. : [Chemical 5] (In the formula, R ¹ has the same meaning as above.) A method for producing an α-aminoketone derivative or an acid adduct thereof.