JPH05140140A - Production of dihydrofuranone derivative - Google Patents

Production of dihydrofuranone derivative

Info

Publication number
JPH05140140A
JPH05140140A JP3299039A JP29903991A JPH05140140A JP H05140140 A JPH05140140 A JP H05140140A JP 3299039 A JP3299039 A JP 3299039A JP 29903991 A JP29903991 A JP 29903991A JP H05140140 A JPH05140140 A JP H05140140A
Authority
JP
Japan
Prior art keywords
formula
lower alkyl
catalyst
ruthenium
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
JP3299039A
Other languages
Japanese (ja)
Other versions
JP3098825B2 (en
Inventor
Aiichiro Ori
愛一郎 小里
Hiroaki Tan
弘明 丹
Ikuo Tomino
郁夫 富野
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsui Petrochemical Industries Ltd
Original Assignee
Mitsui Petrochemical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mitsui Petrochemical Industries Ltd filed Critical Mitsui Petrochemical Industries Ltd
Priority to JP03299039A priority Critical patent/JP3098825B2/en
Publication of JPH05140140A publication Critical patent/JPH05140140A/en
Application granted granted Critical
Publication of JP3098825B2 publication Critical patent/JP3098825B2/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/52Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts

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

【発明の詳細な説明】Detailed Description of the Invention

【0001】[0001]

【産業上の利用分野】本発明は、緑内障治療薬ピロカル
ピン及びその類縁化合物を合成する際の中間体として有
用な一般式 (II) :
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】[0002]

【化3】 [Chemical 3]

【0003】〔式中、 R1 は低級アルキル基を表し、 R
2 は式: -CH2COOR3 (式中、 R3 は低級アルキル基を表
す。) で示される基を表し、 R1 及び R2 はラクトン環
上でシス配置をもつ。〕で示されるジヒドロフラノン誘
導体の工業的に有利な製法を提供するものである。本発
明によれば、式 (II) の目的化合物は、一般式 (I) :
[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】[0004]

【化4】 [Chemical 4]

【0005】〔式中、 R1 は低級アルキル基を表し、 R
2 は式: -CH2COOR3 (式中、 R3 は低級アルキル基を表
す。) で示される基を表す。〕で示されるフラノン誘導
体をルテニウム触媒の存在下に水素添加させることによ
り高収率、高純度で製造される。
[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】[0006]

【従来の技術】本発明において、出発原料として利用す
るフラノン誘導体(I) 及び目的とするジヒドロフラノ
ン誘導体 (II) の中で R1 がエチル基、 R3 がメチル基
の化合物はテトラヘドロン(Tetrahedron) 第28巻、第96
7頁 (1972年) に記載されている。
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).

【0007】この文献には、フラノン誘導体 (I) をエ
タノール溶媒中5%ロジウム炭素の存在下、水素添加さ
せてジヒドロフラノン誘導体(II) を製造する方法も記
載されている。しかしながら、この方法は高価なロジウ
ム触媒を多量に用い、しかも反応に72時間もの長時間を
必要とすることから工業的生産方法としては問題があっ
た。
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.

【0008】また、特開平3-161481号公報には、 R1
び R3 がエチル基のフラノン誘導体(I) をロジウム又
はパラジウム触媒の存在下、高圧水素雰囲気下で水素添
加し、短時間で目的とするジヒドロフラノン誘導体を製
造する方法が記載されている。しかし、この方法でも依
然として高価なロジウム又はパラジウム触媒を用いると
いう問題点があった。更に、 R1 と R2 がラクトン環上
トランスになる副生物が生成する問題点もあった。
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】[0009]

【発明が解決しようとする課題】本発明は、前述のフラ
ノン誘導体 (I) を水素添加する反応において、安価
で、トランス異性体の副生が少ない触媒を用いることに
より、工業的に有利な方法を確立することを目的とする
ものである。
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】[0010]

【課題を解決するための手段】本発明者等は、種々の触
媒について長期に亘り研究を重ねた結果、安価なルテニ
ウム触媒でフラノン誘導体の水素添加反応が行なえ、し
かも、副生する異性体の量が非常に少ないことを見い出
し、本発明を完成するに到った。即ち、本発明は、一般
式 (I) :
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】[0011]

【化5】 [Chemical 5]

【0012】〔式中、 R1 は低級アルキル基を表し、 R
2 は式: -CH2COOR3 (式中、 R3 は低級アルキル基を表
す。) で示される基を表す。〕で示されるフラノン誘導
体をルテニウム触媒の存在下に水素添加させることを特
徴とする一般式 (II) :
[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】[0013]

【化6】 [Chemical 6]

【0014】(式中、 R1 及び R2 は前記と同義であ
り、ラクトン環上でシス配置をもつ。)で示されるジヒ
ドロフラノン誘導体の製造方法に関するものである。前
記式 (I) 及び (II) において、 R1 又は R3 で表され
る低級アルキル基とは、炭素数1〜10のアルキル基をい
い、例えばメチル基、エチル基、プロピル基、イソプロ
ピル基、ブチル基、イソブチル基、sec-ブチル基、 ter
t-ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オ
クチル基、ノニル基が挙げられる。
(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.

【0015】本発明を実施するにあたり、出発原料とし
て利用するフラノン誘導体 (I) は公知物質であり、前
述の文献 (Tetrahedron 第28巻、第967頁 (1972年)) に
記載の方法により製造することができる。本発明に用い
るルテニウム触媒としては、ルテニウムブラック、酸化
ルテニウム、各種担体 (例えば炭素、アルミナ、シリカ
ゲル、シリカ−アルミナ、ケイソウ土、硫酸バリウム、
炭酸カルシウムなど) に担持したルテニウム、好ましく
は炭素又はアルミナに担持したルテニウムを例示するこ
とができる。
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.

【0016】本発明における水素添加反応は無溶媒下で
も、あるいは溶媒中でも行うことができる。溶媒を使用
する場合には、メタノール、エタノール、n−プロパノ
ール、イソプロパノールなどの低級アルコール類;ジエ
チルエーテル、テトラヒドロフラン、ジオキサンなどの
エーテル類;ギ酸、酢酸、プロピオン酸などの低級脂肪
酸類;酢酸メチル、酢酸エチルなどのエステル類;及び
水を単独又は混合して用いることができ、好ましくはメ
タノール、エタノール、n−プロパノール、イソプロパ
ノールなどの低級アルコール類及び水を単独又は任意の
割合に混合して用いる。
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.

【0017】本発明における水素添加反応を行うにあた
り、出発原料のフラノン誘導体 (I) に対し、触媒は金
属ルテニウムとして通常0.0001〜0.9重量倍、好ましく
は0.0005〜0.1重量倍、溶媒は通常0 (無溶媒) 〜 100
重量倍、好ましくは0〜30重量倍使用する。温度は通常
0〜100℃、好ましくは10〜50℃で、水素分圧は通常0.
1〜200気圧、好ましくは1〜60気圧で反応を行う。
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.

【0018】反応終了後、反応混合物を常法に従い処理
することにより、目的とするジヒドロフラノン誘導体
(II) を得ることができる。
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】[0019]

【実施例】以下、実施例及び比較例により本発明を更に
詳細に説明するが、本発明の範囲はこれらの実施例に限
定されるものではない。
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】[0020]

【実施例1】4−カルボエトキシメチル−3−エチル−
2 (5H)−フラノン4.00g、5%ルテニウム炭素(エ
ヌ・イー ケムキャット(株)製) 0.4g、50%含水エ
タノール20mlをステンレス製オートクレーブに入れ、水
素圧50kg/cm2 で水素添加反応を行った。6時間攪拌
後、触媒をろ過した。ろ液からエタノールを留去し、ト
ルエン20mlで2回抽出した。抽出液を濃縮すると、還元
生成物4.00g (収率99%) が得られた。得られた生成物
をガスクロマトグラフィー (以下「GC」という) で分
析したところ、副生したトランス異性体の含有量は0.8
%であった。 GC分析条件 カ ラ ム:5%シリコンOV−17 (Chromosorb W AW-
DMCS. 60/80mesh) 、ID 5mmφ×1m カラム温度:初期温度 100℃ (2分保持) 、最終温度 1
60℃ (20分保持) 、昇温速度 5℃/分 キャリアーガス:N2 , 50ml/分
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】[0021]

【実施例2】溶媒として50%含水メタノールを用い、23
時間攪拌を行った以外は実施例1と同様に実験を行い還
元生成物3.95g (収率97%) を得た。 トランス異性体含有量 0.7% (GC)
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】[0022]

【実施例3】水素圧9kg/cm2 で9時間攪拌を行った以
外は実施例1と同様に実験を行い還元生成物3.88g (収
率96%) を得た。 トランス異性体含有量 0.7% (GC)
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】[0023]

【実施例4】無溶媒で10時間攪拌を行った以外は実施例
1と同様に実験を行い還元生成物3.96g (収率98%) を
得た。 トランス異性体含有量 0.6% (GC) 〔比較例1〕4−カルボエトキシメチル−3−エチル−
2 (5H)−フラノン 60.0g、5%ロジウム炭素(エヌ
イー ケムキャット(株)製) 3.0g、エタノール 2
40mlをステンレス製オートクレーブに入れ、水素圧50kg
/cm2 で水素添加反応を行った。5時間攪拌後、触媒を
ろ過し、ろ液を濃縮すると還元生成物59.4g (収率98
%) が得られた。
[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.

【0024】トランス異性体含有量 4.4% (GC) 〔比較例2〕触媒として5%パラジウム炭素(エヌ イ
ー ケムキャット(株)製)を用い、比較例1と同様に
反応を行ったところ、トランス異性体の含有量は20%で
あった。
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】[0025]

【発明の効果】本発明によれば、ジヒドロフラノン誘導
体 (II) を安価に、しかも高純度で製造することができ
る。
According to the present invention, the dihydrofuranone derivative (II) can be produced at low cost and with high purity.

Claims (1)

【特許請求の範囲】[Claims] 【請求項1】 一般式 (I) : 【化1】 〔式中、 R1 は低級アルキル基を表し、 R2 は式: -CH
2COOR3 (式中、 R3 は低級アルキル基を表す。) で示さ
れる基を表す。〕で示されるフラノン誘導体をルテニウ
ム触媒の存在下に水素添加させることを特徴とする一般
式 (II) : 【化2】 (式中、 R1 及び R2 は前記と同義であり、ラクトン環
上でシス配置をもつ。)で示されるジヒドロフラノン誘
導体の製造方法。
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.
JP03299039A 1991-11-14 1991-11-14 Method for producing dihydrofuranone derivative Expired - Fee Related JP3098825B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP03299039A JP3098825B2 (en) 1991-11-14 1991-11-14 Method for producing dihydrofuranone derivative

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP03299039A JP3098825B2 (en) 1991-11-14 1991-11-14 Method for producing dihydrofuranone derivative

Publications (2)

Publication Number Publication Date
JPH05140140A true JPH05140140A (en) 1993-06-08
JP3098825B2 JP3098825B2 (en) 2000-10-16

Family

ID=17867426

Family Applications (1)

Application Number Title Priority Date Filing Date
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Country Status (1)

Country Link
JP (1) JP3098825B2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100832565B1 (en) * 2006-12-27 2008-05-26 재단법인서울대학교산학협력재단 Antibacterial furanone derivative and method of preventing a biofilm formation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100832565B1 (en) * 2006-12-27 2008-05-26 재단법인서울대학교산학협력재단 Antibacterial furanone derivative and method of preventing a biofilm formation

Also Published As

Publication number Publication date
JP3098825B2 (en) 2000-10-16

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