JP2002138085A - Manufacturing method of alkyloxyaminofuranone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an efficient route for manufacturing an oxyaminofuranone derivative on an industrial scale. SOLUTION: The alkyloxyaminofuranone derivative represented by formula (2) [wherein, R1 and R3 are each as defined in formula (1)] is manufactured by reacting a β-amino acid ester represented by formula (1) [wherein, R1 and R2 are independently each an alkyl group which may be substituted; R3 is an alkyl or an aryl group both of which may be substituted] or its acid addition salt with a phosphoric compound selected from the group consisting of phosphoric acid, phosphorous acid, phosphinic acid and a condensed phosphoric compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing an alkyloxyaminofuranone derivative required for synthesizing an inhibitor of an interleukin-1-beta converting enzyme. The optically active alkyloxyaminofuranone derivative is, for example, a compound useful as a raw material for synthesizing an inhibitor of interleukin-1-beta converting enzyme described in WO99 / 03852, and the above-mentioned interleukin-1-beta An inhibitor of the converting enzyme is expected to be effective as a rheumatoid arthritis agent.

[0002]

2. Description of the Related Art As a method for obtaining the above-mentioned alkyloxyaminofuranone derivative, WO 99/03852 describes a method for starting from ethoxyfuranone.

[0003]

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[0004] J. J. Heterocyclic C
hem. , 27,815 (1990) describes a method for producing a 5-methoxyfuranone derivative by cyclizing a 4,4-dimethoxybutanoate derivative in a dioxane solution containing 2N hydrochloric acid.

[0005]

The above-mentioned WO 99/038
In the production method described in Japanese Patent Publication No. 52, a raw material is ethoxyfuranone, which is used to produce an optically active alkyloxyaminofuranone derivative by three synthesis steps of 1) Michael addition, 2) separation of diastereomers, and 3) epimerization. However, since the raw material ethoxyfuranone is synthesized from furfural by a photoreaction, it is not only expensive and difficult to produce industrially, but also a single diastereomer contained in a diastereomer mixture. Has a problem such as a low yield of 27% when it is isolated as an acid addition salt. Therefore, there is a problem as a production route for industrially producing a target optically active alkyloxyaminofuranone derivative.

On the other hand, the present inventors have proposed an efficient production route for industrially producing the following optically active alkyloxyaminofuranone derivatives.

[0007]

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The method of cyclizing a 4,4-dimethoxybutanoic acid ester derivative with hydrochloric acid is described as (3S) -4,4-diethoxy-3-[(1R) -1-].
When applied to ethyl phenylethyl] amino] butanoate, it was found that the desired cyclized product could not be obtained, probably because the compound had an amino group.

[0009]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems. The present inventors have found that an oxyaminofuranone derivative can be produced, and have completed the present invention. Thereby, in producing the desired alkyloxyaminofuranone derivative, the above WO99 /
It has become possible to manufacture by an industrially efficient manufacturing route other than the manufacturing route described in Japanese Patent No. 03852.

That is, the gist of the present invention is the following general formula (1)

[0011]

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(Wherein, R ¹ and R ² each independently represent an optionally substituted alkyl group, and R ³ represents an optionally substituted alkyl group or an aryl group). reacting a β-amino acid ester or an acid addition salt thereof in the presence of a phosphoric acid compound selected from the group consisting of phosphoric acid, phosphorous acid, hypophosphorous acid and a condensed phosphoric acid compound; 2)

[0013]

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(Wherein R ¹ and R ³ have the same meanings as in the general formula (A)).

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The β-amino acid ester used as a raw material of the method of the present invention may be synthesized by a known method, for example, the following general formula (3)

[0016]

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(Wherein R ¹ , R ² and R ³ represent the general formula (1)
And CH ₃ COOR ² are condensed to obtain a compound represented by the following general formula (4)

[0018]

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After obtaining the compound represented by the formula, R ³ N
The following general formula (5) obtained by dehydrating and condensing an amine represented by H ₂

[0020]

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(Wherein R ¹ , R ² and R ³ have the same meaning as in the general formula (1)). Here, in the above formula, R ¹ and R ²
May be the same or different, and each represents a linear, branched or cyclic alkyl group which may be substituted with a substituent inert to a reaction such as a halogen atom, an alkoxy group, and an aryl group; Is preferably 1 to 10. Specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, a benzyl group, and a phenylethyl group. Of these, a methyl group and an ethyl group are preferred.

R ³ is a linear, branched or cyclic alkyl or aryl group which may be substituted with a substituent which is inert to the reaction, such as a halogen atom, an alkoxy group and an aryl group. Examples thereof include a methyl group, an ethyl group, a propyl group, a butyl group, a benzyl group, a phenethyl group and the like. The acid addition salt of β-amino acid ester is not particularly limited, but hydrogen halides such as hydrochloric acid, hydrobromic acid and hydroiodic acid; sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, propane Sulfonic acids such as sulfonic acid, butanesulfonic acid, pentanesulfonic acid, hexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid and 2-naphthalenesulfonic acid; phosphoric acids such as phosphoric acid and polyphosphoric acid Carboxylic acid salts such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, and benzoic acid.

The β-amino acid ester or an acid addition salt thereof used as a raw material may be obtained by column chromatography,
The product purified by distillation or the like may be used or the crude product may be used as it is, and the mixing ratio of diastereomers may be arbitrary. The method of the present invention is performed using a phosphoric acid compound selected from the group consisting of phosphoric acid, phosphorous acid, hypophosphorous acid and a condensed phosphoric acid compound,
The condensed phosphoric acid compound can be easily prepared by a known method using 85% phosphoric acid and phosphorus pentoxide.
Of these, those having a phosphoric acid compound concentration of 80% by weight or less in terms of P ₂ O ₅ are preferred, and more preferably 50 to 75% by weight.
%, Particularly preferably 65 to 73% by weight.

The amount of the phosphoric acid compound to be used is usually 0.5 to 100 times by weight, preferably 2 to 10 times by weight, based on the β-amino acid ester. The reaction of the present invention is usually carried out without a solvent, but a solvent may be used. When a solvent is used, an aprotic solvent is usually used. Specific examples of such a solvent include benzene, toluene, xylene, chlorobenzene, 1,2
-Aromatic hydrocarbons such as dichlorobenzene; hexane;
Aliphatic hydrocarbons such as heptane and octane; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; diethyl ether, di-n-propyl ether, diisopropyl ether, di-n-butyl ether and tert-butyl Methyl ether, THF,
Ethers such as 1,4-dioxane; ketones such as acetone, ethyl methyl ketone and isobutyl methyl ketone;
Esters such as ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate; and nitriles such as acetonitrile. These solvents may be used as a mixture of two or more.

The amount of the solvent used is usually 1 to 10 with respect to the β-amino acid ester (1) or an acid addition salt thereof.
0 times by weight, preferably 2 to 30 times by weight. The reaction temperature is usually 0 ° C or higher, preferably 0 to 50 ° C.
° C, and the reaction time varies depending on the type of the β-amino acid ester (1) and the solvent, but is usually between 10 minutes and 12 hours. The reaction pressure is usually normal pressure, but may be under normal pressure or reduced pressure as required. The reaction may be performed in air or in an inert gas such as nitrogen.

The alkyloxyaminofuranone derivative formed by the reaction can be easily obtained simply by dissolving the reaction solution in water, neutralizing with an alkali, extracting with an organic solvent, and concentrating and removing the organic solvent from the extract. Can be released. Further, an acid can be added to the extract to take out as an acid addition salt.

[0027]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to the examples unless it exceeds the gist thereof. Example 1 After charging 9 g of a 70% condensed phosphoric acid compound (6.3 g in terms of P ₂ O ₅ ) into a reactor, the mixture was allowed to stand at room temperature (3S).
Ethyl-4,4-diethoxy-3-[(1R) -1-phenylethyl] aminobutanoate / p-toluenesulfonic acid salt 3.0 g (5.94 mmol, chemical purity 98%, optical purity 98% de) .) Was added. The reaction was continued for 3 hours to complete the reaction. The reaction solution was dissolved in 40 ml of water, and 20 ml of toluene was added.
H was extracted to 6.0 and extracted. The aqueous phase was separated and removed, and the organic phase was washed with saturated saline and dried over anhydrous magnesium sulfate. As a result of analyzing the organic phase by liquid chromatography,
5-ethoxy-4-[(1R) -1-phenylethyl]
1.07 g of amino-dihydro-furan-2-one
(4.29 mmol, yield 72%), (4S, 5R):
(4S: 5S) = 92: 8 was found to be generated. (Example 2) Example 1, except for using 65% condensed phosphoric acid compound (5.85 g in terms _of P ₂ O ₅₎ were reacted in the same manner as in Example 1. The yield of the desired product was 49%. (Example 3) Example 1, except for using 75% condensed phosphoric acid compound (6.75 g in terms _of P ₂ O ₅₎ were reacted in the same manner as in Example 1. The yield of the desired product was 10%. (Example 4) In Example 1, 85% phosphoric acid (P ₂ O ₅
The reaction was carried out in the same manner as in Example 1, except that 5.54 g in terms of conversion was used. The yield of the desired product was 38%. (Comparative Example 1) A solution of 0.4 ml (0.8 mmol) of 2N hydrochloric acid in 40 ml of a dioxane solution was added at room temperature (3
S) -4,4-Diethoxy-3-[(1R) -phenyl-ethylamino] butanoic acid ethyl (3.0 g, 9.28 mmol) was added, and the reaction was continued for 18 hours. As a result of analyzing the reaction solution by liquid chromatography, 5-ethoxy-4-[(1R) -1-phenyl-ethylamino] -dihydro-furan-2-one was not detected.

[0028]

According to the production method of the present invention, an alkyloxyaminofuranone derivative useful as a pharmaceutical intermediate can be produced industrially advantageously.

Claims (6)

[Claims] [Claim 1] The following general formula (1) (Wherein, R ¹ and R ² each independently represent an optionally substituted alkyl group, and R ³ represents an optionally substituted alkyl group or an aryl group.)
-An amino acid ester or an acid addition salt thereof, phosphoric acid,
Reacting in the presence of a phosphoric acid compound selected from the group consisting of phosphorous acid, hypophosphorous acid, and condensed phosphoric acid compound, wherein the reaction is carried out in the following general formula (2): (Wherein, R ¹ and R ³ have the same meanings as in the general formula (A)). 2. The concentration of P ₂ O ₅ in the phosphate compound is 5
2. The method according to claim 1, wherein the amount is 0 to 75% by weight. 3. A compound represented by the general formula (1):
The production method according to claim 1, wherein the production method is an acid addition salt of toluenesulfonic acid. 4. The compound represented by the general formula (2) is a compound represented by the following general formula (2 ′): (Wherein R ¹ and R ³ have the same meanings as in the general formula (1)). 5. The method according to claim 1, wherein the reaction temperature is 0 to 50 ° C. 6. The use amount of a phosphoric acid compound selected from the group consisting of phosphoric acid, phosphorous acid, hypophosphorous acid and condensed phosphoric acid compound is 2 to 10 times by weight of compound (1). The method according to any one of claims 1 to 5, characterized in that: