JPH05140140A - Production of dihydrofuranone derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as a synthetic intermediate for pilocarpines which are a therapeutic agent for glaucoma in high purity and yield at a low cost by hydrogenating a furanone derivative in the presence of a ruthenium catalyst. CONSTITUTION:A compound expressed by formula I [R<1> is lower alkyl; R<2> is CH2COOR<3> (R<3> is lower alkyl)] is made to react in the presence of a ruthenium catalyst supported on carbon or alumina in a solvent such as methanol at 0-100 deg.C under 0.1-200 atm hydrogen pressure to afford a compound expressed by formula II (R<1> and R<2> are in the cis configuration on the lactone ring). The catalyst is used in an amount of 0.0001-0.9 expressed in terms of metallic ruthenium based on the weight of the compound expressed by formula I and the solvent is used in an amount of 0-100 times based on the weight of the compound expressed by the formula I. The ruthenium catalyst is inexpensive and the trans-isomer is hardly formed as a by-product.

Description

Detailed Description of the Invention

[0001]

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

[0002]

[Chemical 3]

[In the formula, R ¹ represents a lower alkyl group;
² represents a group represented by the formula: —CH ₂ COOR ³ (wherein R ³ represents a lower alkyl group), and R ¹ and R ² have a cis configuration on the lactone ring. ] The industrially advantageous manufacturing method of the dihydrofuranone derivative shown by these is provided. According to the present invention, the target compound of formula (II) has the general formula (I):

[0004]

[Chemical 4]

[In the formula, R ¹ represents a lower alkyl group,
² represents a group represented by the formula: —CH ₂ COOR ³ (wherein R ³ represents a lower alkyl group). ] The hydrogenated furanone derivative represented by the formula [1] is produced in high yield and high purity.

[0006]

2. Description of the Related Art In the present invention, a compound of the furanone derivative (I) used as a starting material and the desired dihydrofuranone derivative (II) in which R ¹ is an ethyl group and R ³ is a methyl group is tetrahedron (Tetrahedron). ) Volume 28, 96
It is described on page 7 (1972).

This document also describes a method for producing a dihydrofuranone derivative (II) by hydrogenating a furanone derivative (I) in an ethanol solvent in the presence of 5% rhodium carbon. However, this method has a problem as an industrial production method since it uses a large amount of expensive rhodium catalyst and requires a long time of 72 hours for the reaction.

Further, in Japanese Patent Laid-Open No. 3-116481, hydrogenated furanone derivative (I) in which R ¹ and R ³ are ethyl groups in the presence of a rhodium or palladium catalyst in a high-pressure hydrogen atmosphere is used for a short time. A method for producing the desired dihydrofuranone derivative is described. However, this method still has a problem that an expensive rhodium or palladium catalyst is used. Furthermore, there is a problem that a by-product in which R ¹ and R ² are trans on the lactone ring is generated.

[0009]

DISCLOSURE OF THE INVENTION The present invention is an industrially advantageous method in the reaction for hydrogenating the above-mentioned furanone derivative (I) by using a catalyst which is inexpensive and produces little trans isomer by-product. The purpose is to establish.

[0010]

Means for Solving the Problems As a result of long-term research on various catalysts, the present inventors have found that the hydrogenation reaction of the furanone derivative can be carried out with an inexpensive ruthenium catalyst, and the isomers of by-products They found that the amount was very small, and completed the present invention. That is, the present invention has the general formula (I):

[0011]

[Chemical 5]

[In the formula, R ¹ represents a lower alkyl group;
² represents a group represented by the formula: —CH ₂ COOR ³ (wherein R ³ represents a lower alkyl group). ] The general formula (II) characterized by hydrogenating a furanone derivative represented by the following in the presence of a ruthenium catalyst:

[0013]

[Chemical 6]

(Wherein R ¹ and R ² have the same meanings as described above and have a cis configuration on the lactone ring) and to a process for producing the dihydrofuranone derivative. In the above formulas (I) and (II), the lower alkyl group represented by R ¹ or R ³ means an alkyl group having 1 to 10 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, Butyl group, isobutyl group, sec-butyl group, ter
Examples thereof include t-butyl group, pentyl group, hexyl group, heptyl group, octyl group and nonyl group.

In carrying out the present invention, the furanone derivative (I) used as a starting material is a known substance, and is produced by the method described in the above-mentioned document (Tetrahedron Vol. 28, page 967 (1972)). be able to. The ruthenium catalyst used in the present invention, ruthenium black, ruthenium oxide, various carriers (for example, carbon, alumina, silica gel, silica-alumina, diatomaceous earth, barium sulfate,
Examples thereof include ruthenium supported on (such as calcium carbonate), preferably ruthenium supported on carbon or alumina.

The hydrogenation reaction in the present invention can be carried out without solvent or in a solvent. When a solvent is used, lower alcohols such as methanol, ethanol, n-propanol and isopropanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; lower fatty acids such as formic acid, acetic acid and propionic acid; methyl acetate and acetic acid. Esters such as ethyl; and water can be used alone or as a mixture, and preferably lower alcohols such as methanol, ethanol, n-propanol and isopropanol and water are used alone or as a mixture in an arbitrary ratio.

In carrying out the hydrogenation reaction in the present invention, the catalyst is usually 0.0001 to 0.9 times by weight, preferably 0.0005 to 0.1 times by weight, as metal ruthenium, with respect to the furanone derivative (I) as a starting material, and the solvent is Usually 0 (no solvent) to 100
It is used in a weight ratio, preferably 0 to 30 times. The temperature is usually 0 to 100 ° C, preferably 10 to 50 ° C, and the hydrogen partial pressure is usually 0.
The reaction is carried out at 1 to 200 atm, preferably 1 to 60 atm.

After completion of the reaction, the reaction mixture is treated according to a conventional method to give the desired dihydrofuranone derivative.
(II) can be obtained.

[0019]

EXAMPLES The present invention will be described in more detail with reference to Examples and Comparative Examples, but the scope of the present invention is not limited to these Examples.

[0020]

Example 1 4-Carboethoxymethyl-3-ethyl-
2 (5H) -furanone 4.00 g, 5% ruthenium carbon (manufactured by NE Chemcat Co., Ltd.) 0.4 g, and 50% water-containing ethanol 20 ml were put into a stainless steel autoclave, and hydrogenation reaction was carried out at a hydrogen pressure of 50 kg / cm ^2. It was After stirring for 6 hours, the catalyst was filtered. Ethanol was distilled off from the filtrate, and the mixture was extracted twice with 20 ml of toluene. The extract was concentrated to give 4.00 g of a reduction product (yield 99%). When the obtained product was analyzed by gas chromatography (hereinafter referred to as “GC”), the content of trans isomer as a byproduct was 0.8.
%Met. GC analysis condition column: 5% silicon OV-17 (Chromosorb W AW-
DMCS. 60 / 80mesh), ID 5mmφ × 1m Column temperature: initial temperature 100 ℃ (hold for 2 minutes), final temperature 1
60 ℃ (hold for 20 minutes), heating rate 5 ℃ / minute Carrier gas: N ₂ , 50ml / minute

[0021]

Example 2 Using 50% hydrous methanol as a solvent,
An experiment was performed in the same manner as in Example 1 except that stirring was carried out for a period of time to obtain 3.95 g (yield 97%) of a reduced product. Trans isomer content 0.7% (GC)

[0022]

Example 3 The same experiment as in Example 1 was carried out except that stirring was carried out at a hydrogen pressure of 9 kg / cm ² for 9 hours to obtain 3.88 g (yield 96%) of a reduced product. Trans isomer content 0.7% (GC)

[0023]

[Example 4] The same experiment as in Example 1 was carried out except that stirring was carried out for 10 hours without using a solvent, to obtain 3.96 g (yield 98%) of a reduced product. Trans isomer content 0.6% (GC) [Comparative Example 1] 4-carbethoxymethyl-3-ethyl-
2 (5H) -furanone 60.0 g, 5% rhodium carbon (manufactured by NE Chemcat Corporation) 3.0 g, ethanol 2
Put 40 ml in stainless steel autoclave, hydrogen pressure 50 kg
The hydrogenation reaction was performed at / cm ² . After stirring for 5 hours, the catalyst was filtered off and the filtrate was concentrated to give 59.4 g of reduced product (yield 98
%) was gotten.

Trans isomer content 4.4% (GC) [Comparative Example 2] The reaction was carried out in the same manner as in Comparative Example 1 using 5% palladium carbon (manufactured by NE Chemcat Corporation) as a catalyst. Body content was 20%.

[0025]

According to the present invention, the dihydrofuranone derivative (II) can be produced at low cost and with high purity.

Claims (1)

[Claims] 1. A compound represented by the general formula (I): [In the formula, R ¹ represents a lower alkyl group, and R ² represents a formula: —CH
₂ COOR ³ (in the formula, R ³ represents a lower alkyl group). ] The furanone derivative represented by the formula [II] is hydrogenated in the presence of a ruthenium catalyst. (In the formula, R ¹ and R ² have the same meanings as described above and have a cis configuration on the lactone ring.) A method for producing a dihydrofuranone derivative.