JP3144920B2 - α-Acylaminoketone derivatives, production method thereof and use thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound of the general formula (I) useful as an intermediate in the synthesis of pilocarpine and its analogs for treating glaucoma.

[0002]

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(Wherein R ¹ and R ² each independently represent a hydrogen atom or a lower alkyl group), a process for producing the same, and a general formula (III) using the same.

[0004]

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(Wherein R ¹ is as defined above) or a method for producing an α-aminoketone derivative or an acid adduct thereof.

[0006]

2. Description of the Related Art Documents describing methods for synthesizing α-aminoketone derivatives represented by the general formula (III), which are intermediates of pilocarpine, a therapeutic agent for glaucoma, and acid adducts thereof include:
Tetrahedron, Vol. 28, p. 967 (1972). In this reference, after reacting homopyropine chloride with di-t-butyl acetamidomalonate to obtain a coupling product, HCl was added.
A method for producing aminomethyl homopropyl pyrketone by performing a treatment or the like is described.

[0007] Also, J. Am. Chem. Soc.
On page 077 (1958), benzoyl chloride is reacted with di-t-butyl acetamidomalonate to obtain di-t-butyl benzoylacetamidomalonate, which is then treated with an acid. A method for synthesizing α-acetamidoacetophenone is described. However, the production of di-t-butyl acetamidomalonate has a problem that the risk of ignition is large because isobutene, which is a combustible gas, is used. Furthermore, since the synthesis of acetamidomalonic acid as a raw material requires freeze-drying after hydrolyzing the ethyl ester, there is also a problem that mass synthesis is difficult.

[0008]

As a result of extensive studies by the present inventors, a novel α-acylaminoketone derivative described later uses di-t-butyl acetamidomalonate having the above-mentioned problems. It has been found that the desired α-aminoketone derivative and its acid adduct can be produced with higher yield than the conventional method by using this product, and the present invention has been completed.

[0009]

According to the present invention, there is provided a compound represented by the general formula (I):

[0010]

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(Wherein, R ¹ and R ² each independently represent a hydrogen atom or a lower alkyl group), a general formula (II):

[0012]

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(Wherein R¹And R^TwoAre each independently water
R represents a hydrogen atom or a lower alkyl group; ^ThreeIs a hydrogen atom, low
Lower alkyl group, lower alkoxy group, nitro group, cyano group
Or a halogen atom. Benzyl ester
Hydrogenation of the benzyl ester group of
The general formula characterized by being removed by subsequent decarboxylation
Production of α-acylaminoketone derivative represented by (I)
Method, general formula (I):

[0014]

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(Wherein, R ¹ and R ² each independently represent a hydrogen atom or a lower alkyl group). (III):

[0016]

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(Wherein, R ¹ has the same meaning as described above). In the general formulas (I), (II), and (III), among the groups represented by R ¹ , R ² , and R ³ , a lower alkyl group refers to an alkyl group having 1 to 6 carbon atoms, and a methyl group, Ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, pentyl group, hexyl group can be exemplified, and the lower alkoxy group is an alkoxy having 1 to 6 carbon atoms. A methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, t-butoxy group, pentyloxy group, and hexyloxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The α-acylaminoketone 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. You. The hydrogenolysis reaction of the compound represented by the general formula (II) is performed using various catalysts under a hydrogen atmosphere. As the catalyst to be used, fine powders and oxides of noble metals such as platinum, palladium, rhodium and ruthenium, those supported on various carriers (for example, carbon, alumina, silica gel, diatomaceous earth, etc.), and Raney nickel are used. And preferably palladium supported on carbon.

The reaction is usually performed in the presence of a solvent. Examples of the solvent used include 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 as a mixture. Preferably, acetic acid can be illustrated.

In carrying out the hydrogenolysis reaction, when a noble metal catalyst is used as the catalyst for the compound represented by the general formula (II), the metal is usually 0.0001 to 1 times by weight, preferably 0.0005 to 0 times by weight. 0.1 times by weight, when Raney nickel is used, usually 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 a hydrogen partial pressure of usually 0.1 to 200 atm, preferably 1 to 60 atm. In the decarboxylation reaction, after the completion of the hydrogenolysis reaction, if an acidic solvent such as acetic acid or dilute hydrochloric acid is used as a solvent for the hydrogenolysis reaction, acetic acid, hydrochloric acid or the like is added to the reaction system as it is.
The reaction is carried out at a temperature of from + 150 ° C, preferably from +10 to + 100 ° C, usually for 1 minute to 100 hours, preferably for 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 resulting α-acylaminoketone 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]

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(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]

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(Wherein R ² and R ³ have the same meanings as described above), and can be produced by reacting a malonic acid derivative represented by the following formula with an alkali metal or alkaline earth metal salt. Here, the compound represented by the general formula (IV) is described, for example, in Tetrahedron, Vol. 28, No. 967
(1972), ie the following general formula:

[0027]

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(Wherein R ¹ has the same meaning as described above), and can be obtained by reacting thionyl chloride with the compound represented by the formula: As the alkali metal or alkaline earth metal salt of the malonic acid derivative represented by the general formula (V),
Examples thereof include a lithium salt, a sodium salt, a potassium salt, a magnesium salt, and a calcium salt. These salts include a compound represented by the general formula (V) and a hydride or alkoxide of the aforementioned alkali metal or alkaline earth metal, for example, methoxide, ethoxide, n-propoxide, isopropoxide, n-butoxide, isobutoxide. , Sec-butoxide, t-butoxide and the like.

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

[0030]

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

[0032]

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(Wherein R ³ has the same meaning as described above), and 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 performed in the presence of a solvent. Any solvent can be used as long as it is inert to the reaction.Examples of 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 and N-methylpyrrolidone; and preferably tetrahydrofuran, toluene and N, N-dimethylformamide.

In carrying out this reaction, the amount of the alkali metal salt of the malonic acid derivative represented by the general formula (V) is usually 0.1 to 5 times, preferably 1 to 5 times 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 up to 100 times by weight, preferably 5 to 30 times by weight. The reaction is usually carried out at -78 ° C to + 150 ° C, preferably-
The reaction is carried out at 20 ° C. to + 80 ° C., usually for 1 minute to 10 hours, preferably for 10 minutes to 5 hours. After completion of the reaction, the reaction mixture is treated according to a conventional method to obtain a compound represented by the general formula (II).

The α-acylaminoketone derivative represented by the general formula (I) can be converted into the α-aminoketone derivative represented by the general formula (III) or an acid adduct thereof by hydrolysis under acidic conditions. Can be. 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 as a mixture, 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. In conducting the reaction, the acid is usually 0.01 to 100-fold mol, preferably 0.5 to 10-fold mol, and the solvent is usually 0.5 to 100 mol of the α-acylaminoketone derivative represented by the general formula (I). It is used in an amount of up to 100 times by weight, preferably 2 to 30 times by weight.

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

[0038]

EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples. (Example 1) 7.13 g of (+)-homopyropic acid (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 mixture was concentrated and homopyropine chloride (general formula (IV), R
^{_{1 = C 2 H 5, X}} = Cl) was prepared.

14.86 g of dibenzyl acetamidomalonate (general formula (V), R ² = CH ₃ , R ³ = H)
(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-butoxy was added and stirred for 1 hour. The reaction solution was cooled on ice, and the above-mentioned acid chloride was dissolved in 20 ml of toluene.
Was added dropwise over 10 minutes. After the dropwise addition, the mixture was stirred for 1 hour under ice cooling, 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 benzyl ester derivative having the following structure.

[0040]

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(Physical Properties 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 = 9.7 Hz, 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 to 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 give 5
% Palladium-carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (hydrogen partial pressure: 1 atm) for 4 hours and 50 minutes. During this time,
In order to remove generated carbon dioxide, the pressure was reduced every 20 minutes and replaced with hydrogen. After completion of the reaction, the catalyst was filtered and concentrated under reduced pressure to obtain 12.1 g of a crude α-acylaminoketone derivative having the following structure.

[0042]

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(Physical property data) ¹ H-NMR δ (ppm): 1.04 (3H, 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 (1H, dd, J1 = 9.4 Hz,
J2 = 5.8 Hz), 6.0-6.2 (1H) Mass spectrometry (FD method): m / e = 227 (see FIG. 2) 12.1 g of the obtained crude α-acylaminoketone derivative was distilled water. The mixture was dissolved in 95 ml, concentrated hydrochloric acid (8.63 ml) was added, and the mixture was refluxed 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, the α-aminoketone derivative (general formula (III), R ¹ = C ₂ H ₅ ) was obtained. 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 1m Column temperature: 140 ° C (hold for 4 minutes)-Temperature rise 5 ° C / min-
200 ° C. Carrier gas: N ₂ , 50 ml / min Internal standard: phthalic acid di-n-butyl ester Retention time: 7.5 minutes for internal standard, 10 minutes for trifluoroacetyl derivative (Example 2) Reduce the amount of acetic acid used to 50 ml An experiment was conducted in the same manner as in Example 1 except that the yield was 88.7%.

Example 3 Drops of acid chloride were added at 23 to 36.
When the experiment was carried out in the same manner as in Example 1 except that the reaction was carried out at 50 ° C. and the amount of acetic acid used was changed to 50 ml, the yield of α-aminoketone derivative was 83.0%. (Example 4) The amount of acetic acid used was 50 ml, and
The amount of distilled water for dissolving the α-acylaminoketone derivative is 4
An experiment was conducted in the same manner as in Example 1 except that the amount was changed to 3 ml. As a result, the yield of the α-aminoketone derivative was 88.7%.

Example 5 1.45 g (8.79 mmol) of 58.1% sodium t-butoxide was dissolved in toluene 25
The suspension was 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 prepared by dissolving an acid chloride prepared from 1.44 g (8.37 mmol) of homopyropic acid in the same manner as in Example 1 in 5 ml of toluene was added dropwise over 3 minutes. After the dropwise addition, the mixture was stirred for 1 hour under ice cooling, 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 acetic acid (20 ml), 5% palladium-carbon (0.043 g) was added, and the mixture was added under a hydrogen atmosphere (hydrogen partial pressure:
(1 atm) and stirred at room temperature. Four hours later, 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 obtained residue, 10 ml of water was added, and 4 ml of 1,2-dichloroethane was added.
3 g of sodium chloride was added and dissolved, and the mixture was extracted three 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. The drying agent is filtered, and the filtrate is concentrated under reduced pressure.
77 g were obtained (93.2% yield).

(Comparative Example)

[0049]

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8.52 g of sodium t-butoxide (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 dripping, 4
The mixture was stirred at 5 ° C for 30 minutes and at 50 ° C for 1 hour and cooled. An acid chloride prepared from 8.45 g (49.08 mmol) of (+)-homopyropinic acid in the same manner as in Example 1 was added dropwise to the reaction solution over 5 minutes. After completion of the dropwise addition, 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. When the crude product was analyzed by high performance liquid chromatography (HPLC), it was found that 17.79 g of Compound 2 was contained (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 220 nm

[0052]

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

[0054]

According to the present invention, there is provided a novel compound useful as an intermediate in synthesizing pilocarpine for treating glaucoma and its analogous compounds. The compound of the present invention can be synthesized without using acetamidomalonic acid di-t-butyl ester, which is difficult to synthesize in large quantities, 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 the drawings]

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

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

──────────────────────────────────────────────────続 き Continued on front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 307/33 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A compound of the general formula (I): (In the formula, R ¹ and R ² each independently represent a hydrogen atom or a lower alkyl group.) 2. A compound of the general formula (II):(Where R¹And R^TwoAre each independently a hydrogen atom or low
Represents a lower alkyl group; ^ThreeIs hydrogen atom, lower alkyl
Group, lower alkoxy group, nitro group, cyano group or halogen
Represents an atom. )) Of the benzyl ester derivative
Hydrogenolysis and subsequent removal of the benzyl ester group
General formula (I) characterized by being removed by carbonic acid:(Where R¹And R^TwoIs as defined above. )
For producing α-acylaminoketone derivatives. 3. A compound of the general formula (I): (Wherein, R ¹ and R ² each independently represent a hydrogen atom or a lower alkyl group), wherein the α-acylaminoketone derivative represented by the general formula (III) is hydrolyzed under acidic conditions. : (Wherein, R ¹ has the same meaning as described above), or a method for producing an α-aminoketone derivative or an acid adduct thereof.