JPS60152469A - Preparation of cis-diester derivative - Google Patents
Preparation of cis-diester derivativeInfo
- Publication number
- JPS60152469A JPS60152469A JP915984A JP915984A JPS60152469A JP S60152469 A JPS60152469 A JP S60152469A JP 915984 A JP915984 A JP 915984A JP 915984 A JP915984 A JP 915984A JP S60152469 A JPS60152469 A JP S60152469A
- Authority
- JP
- Japan
- Prior art keywords
- cis
- dicarboxylic acid
- reaction
- acid
- aqueous solution
- 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
Links
Abstract
Description
【発明の詳細な説明】
本発明は式［Ｉ］
〔式中、几はメチル、エチル等の０１−４低級アルキル
基を意味する。〕
で示されるシス−ジエステル体の新規かつ工業的製造方
法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of the formula [I] [wherein 几 means a 01-4 lower alkyl group such as methyl or ethyl. ] It is related with the novel and industrial manufacturing method of the cis-diester body shown by these.
更に詳しくは式［■コ
で示されるシス−ジカルボン酸を水溶液中ジアルキル硫
酸と反応させることにより式［Ｉ］で示されるシス−ジ
エステル体を製造する方法に関する。More specifically, the present invention relates to a method for producing a cis-diester represented by formula [I] by reacting a cis-dicarboxylic acid represented by formula [■] with dialkyl sulfuric acid in an aqueous solution.
本発明方法にて得ることができるシス−ジエステル体［
Ｉ］はビオチン等医薬品の合成中間体として有用なもの
である（特開昭５８−１２８８７６号公報、同５８−１
９０８９５号公報）。Cis-diester compound obtainable by the method of the present invention [
I] is useful as a synthetic intermediate for pharmaceuticals such as biotin (Japanese Patent Application Laid-open No. 128876/1987, 58-1
90895).
従来シス−ジエステル体（Ｉ）の製造方法としては単離
すれたシス−ジカルボン酸体［１［］をルイス酸の存在
下メタノールと反応させて得るという方法が知られティ
た［ Ｊ、 Ａｍｅｒ、Ｃｈｅｍ、、 Ｓｏｃ、。Conventionally, as a method for producing cis-diester compound (I), a method has been known in which the isolated cis-dicarboxylic acid compound [1] is reacted with methanol in the presence of a Lewis acid [J, Amer, Chem,, Soc,.
１００（５）１５５８−１５６８（１９７８）］本発明
者らは上記エステル化反応では高価なルイス酸を使用す
るということから、別途エステル化反応を鋭意検討し、
ルイス酸に代えて、硫酸を用いると無水のシス−ジカル
ボン酸〔■〕からシス−ジエステル体［Ｄが収率よく得
られるということを見出し、本発明を完成した。100 (5) 1558-1568 (1978)] Since the above esterification reaction uses an expensive Lewis acid, the present inventors separately investigated the esterification reaction, and
The present invention was completed based on the discovery that cis-diester [D] can be obtained in good yield from cis-dicarboxylic anhydride [■] by using sulfuric acid instead of Lewis acid.
以下に本発明方法を具体的に説明する。The method of the present invention will be specifically explained below.
シス−ジカルボン酸（Ｉ［）を１〜２０％含む水溶液に
、必要に応じ塩酸、硫酸、リン酸等の鉱酸、あるいは炭
酸ガス、又は水酸化ナトリウム、水酸化カリウム、炭酸
水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、
炭酸カリウム等の無機塩基を加え、水溶液のｐＨを６〜
１０に調製した後、シス−ジカルボン酸に対し２〜２０
よりシス−ジエステル体（Ｉ）を得ることかできる。Add mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, carbon dioxide gas, or sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, hydrogen carbonate to an aqueous solution containing 1 to 20% of cis-dicarboxylic acid (I[) as necessary. potassium, sodium carbonate,
Add an inorganic base such as potassium carbonate to adjust the pH of the aqueous solution to 6-6.
10, then 2 to 20 for cis-dicarboxylic acid.
The cis-diester form (I) can also be obtained.
反応温度としては−２０°〜８０°Ｃ１好ましくは一１
０〜３０°Ｃにて実施することができ、反応中の反応液
のｐＨは６〜１０に保つことが好ましい。The reaction temperature is -20° to 80°C, preferably -11
The reaction can be carried out at 0 to 30°C, and the pH of the reaction solution during the reaction is preferably maintained at 6 to 10.
反応液にトルエン、１，２−ジクロロエタン、ジクロル
メタン、アセトン、テトラヒドロフラン等の有機溶媒を
加えて同様の反応を行っても良い。A similar reaction may be carried out by adding an organic solvent such as toluene, 1,2-dichloroethane, dichloromethane, acetone, or tetrahydrofuran to the reaction solution.
反応終了後、析出物を戸別することにより、シス−ジエ
ステル体（Ｉ）を得ることかでき、又、通常の抽出操作
を行うことによってもシス−ジエステル体（Ｉ）を得る
こともできる。After completion of the reaction, the cis-diester form (I) can be obtained by separating the precipitate from house to house, or the cis-diester form (I) can also be obtained by carrying out an ordinary extraction operation.
必要に応じ、上記方法で得られるシス−ジエステル体（
Ｉ）をメタノール、エタノール、アセトン等及びそれら
の含水溶媒を用い精製すること、及び／あるいは細かな
結晶を得ることができる。If necessary, the cis-diester form obtained by the above method (
I) can be purified using methanol, ethanol, acetone, etc. and their water-containing solvents, and/or fine crystals can be obtained.
本発明方法の原料であるシス−ジカルボン酸ＣＩ］は工
業的には、たとえば式〔■〕で示されるジカルボン酸を
水溶液中アルカリ性条件下ホスゲン（Ｕ８Ｆ ２，４８
９，２８２ （１９４９））。The raw material for the method of the present invention, cis-dicarboxylic acid CI], is industrially produced by, for example, dicarboxylic acid represented by the formula [■] under alkaline conditions in an aqueous solution with phosgene (U8F 2,48
9, 282 (1949)).
あるいはクロル炭酸アルキル（特１ｔｔ［５１−８２７
０号公報）を用いて反応することにより得られる。Or alkyl chlorocarbonate (special 1tt [51-827
No. 0).
本発明本方法に従かえば、式［１ｍ〕で示されるジカル
ボン酸から得られるシス−ジカルボン酸（ｎ）を含む水
溶液を原料として、そのまま用いジアルキル硫酸と反応
させシス−ジエステル体（１）を収率良く得ることがで
き、必ずしもシス−ジカルボン酸を単離して用いる必要
はない。あるいは単離した場合に於ても乾燥が必要でな
い。この点、本発明方法は工業上の製造における価値の
大きな方法である。According to the method of the present invention, an aqueous solution containing a cis-dicarboxylic acid (n) obtained from a dicarboxylic acid represented by formula [1m] is used as a raw material and reacted with dialkyl sulfuric acid to obtain a cis-diester (1). It can be obtained in good yield, and it is not necessary to isolate and use the cis-dicarboxylic acid. Alternatively, even when isolated, drying is not necessary. In this respect, the method of the present invention is of great value in industrial production.
（参考例）
■ シス−ジベンジルアミノコノ１り酸１６．２９に１
０％ＫＯＨ水６１ｇ、トルエン１０５９を加え溶解した
。この溶液に２５〜８０°Ｃにて３５％、ＫＯＨ水でｐ
Ｈを１０〜１１に調整しながらホスゲン１７．１ ’ｌ
を導入し１こ。反応液を分液し、シス−１，３−ジベン
ジル−２−オキソイミダゾリジン−４，５−ジカルボン
酸を含む水溶液２４５ｙを得た。この水溶液は下記条件
下高速液体クロマトグラフィーで分析し、シス−１，３
−ジベンジル−２−オキソイミダゾリジン−４，５−ジ
カルボン酸１６．６＠を含有するものであった。(Reference example) ■ Cis-dibenzylaminoconolylic acid 1 in 16.29
61 g of 0% KOH water and 1059 g of toluene were added and dissolved. Add 35% KOH to this solution at 25-80°C.
Phosgene 17.1'l while adjusting H to 10-11
Introduced 1. The reaction solution was separated to obtain an aqueous solution 245y containing cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid. This aqueous solution was analyzed by high performance liquid chromatography under the following conditions.
-Dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid 16.6@.
■ 参考例■で得た水溶液１００′ｌ（シス−１゜３−
ジベンジル−２−オキソイミダゾリジン−４，５−ジカ
ルボン酸６．７８１を含む）に水５５−１■、２−ジク
ロルエタン４０−を加えたのち、濃塩酸を滴下し、ｐＨ
１とした。■ 100'l of the aqueous solution obtained in Reference Example ■ (cis-1゜3-
(containing 6.781 dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid), added 55-1 cm of water and 40-ml of 2-dichloroethane, and then added concentrated hydrochloric acid dropwise to
It was set to 1.
これを２０〜２５℃で６時間攪拌した。析出結晶を反応
液から戸別し、１，２−ジクロルエタン１００ｍＺ、水
５０ゴで洗浄後、乾燥し、結晶トしてシス−１，３−ジ
ベンジル−２−オキソイミダゾリジン−４，５−ジカル
ボン酸６．４４１を得た。ｍ、ｐ、１７Ｂ−１７５°Ｃ
■ 参考例■で得たシス−１，３−ジベンジル−２−オ
キソイミダゾリジン−４，５−ジカルボン酸６．４４１
にメタノール８９ゴ、濃硫酸８．２’Ｍ’を加え、６時
間還流した。この反応液を、重炭酸カリウム１０．０１
１、水３９ゴの溶液中に滴下し、滴下後２０〜２５°Ｃ
で１時間攪拌した。This was stirred at 20-25°C for 6 hours. The precipitated crystals were separated from the reaction solution, washed with 100 mZ of 1,2-dichloroethane and 50 mZ of water, dried, and crystallized to give cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid. 6.441 was obtained. m, p, 17B-175°C
■ Cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid obtained in Reference Example ■6.441
89 g of methanol and 8.2 M' of concentrated sulfuric acid were added to the mixture, and the mixture was refluxed for 6 hours. This reaction solution was mixed with 10.01 g of potassium bicarbonate.
1. Drop into a solution of 39 grams of water and heat to 20-25°C after dropping.
The mixture was stirred for 1 hour.
析出した白色結晶を濾過、水洗浄後乾燥し、シス−１，
８−ジベンジル−２−オキソイミダゾリジン−４，５−
ジカルボン酸ジメチルｍ、Ｐ、１０８−１０９°Ｃ
（実施例１）
参考例■で得たシス−１，３−ジベンジル−２−オキソ
イミダゾリジン−４，５−ジカルボン酸８．５４９に２
％ＫＯｆＩ水５８ｆを加え溶解した。この溶液を濃塩酸
にてｐ ｆｉ ９．０に調整し、これにジメチル硫酸２
０．２ ｆを加え１５％ＮａＯＨ水でｐＨを８．０〜９
．０に調整しながら２５〜３０°Ｃで４時間攪拌した。The precipitated white crystals were filtered, washed with water, and dried to give cis-1,
8-dibenzyl-2-oxoimidazolidine-4,5-
Dimethyl dicarboxylate m, P, 108-109°C (Example 1) 2 to 8.549 cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid obtained in Reference Example ■
58 f of %KOfI water was added and dissolved. This solution was adjusted to p fi 9.0 with concentrated hydrochloric acid, and dimethyl sulfate 2
Add 0.2 f and adjust the pH to 8.0-9 with 15% NaOH water.
．． The mixture was stirred at 25 to 30°C for 4 hours while adjusting the temperature to 0.
反応液を酢酸エチル１００−で抽出し、有機層を水洗浄
後減圧ｍ縮し、シス−１，３−ジベンジル−２−オキソ
イミダゾリジン−４，５−ジカルボン酸ジメチルエステ
ル３．６８ｙ（収率９５％）を得た。 ｍ、ｐ、１０７
−１０９°Ｃ（実施例２）
参考例■で得た水溶液１００Ｆ（シス−１゜３−ジベン
ジル−２−オキソイミダゾリジン−４，５−ジカルボン
酸６．７８１を含む）に濃塩酸を滴下し、ｐｆＩ ９．
５に調整した。The reaction solution was extracted with 100% ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure to give cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid dimethyl ester 3.68y (yield: 95%). m, p, 107
-109°C (Example 2) Concentrated hydrochloric acid was added dropwise to the 100F aqueous solution (containing 6.781 cis-1°3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid) obtained in Reference Example ①. , pfI 9.
Adjusted to 5.
この反応液にジメチル硫酸８Ｂ、’ｌｆを加え、１５％
ＮａＯＨ水テｐＨを８．０〜９．０に調整しながら２５
〜３０°Ｃで４時間攪拌した。反応液を酢酸エチル１５
０ｍ１にて抽出し、有機層を水洗浄後、減圧濃縮した。Dimethyl sulfate 8B,'lf was added to this reaction solution, and 15%
While adjusting the pH of NaOH water to 8.0 to 9.0,
Stirred at ~30°C for 4 hours. The reaction solution was diluted with 15% ethyl acetate.
The organic layer was washed with water and then concentrated under reduced pressure.
残渣をメタノール７０ｍ７！にて再結晶し、シス−１，
３−ジベンジル−２−オキソイミダゾリジン−４，５−
ジカルボン酸ジメチルエステル６．７５１を得た。 ｍ
、ｐ、１０９〜１１１℃70m7 of methanol for the residue! Recrystallized at cis-1,
3-Dibenzyl-2-oxoimidazolidine-4,5-
6.751 dicarboxylic acid dimethyl ester was obtained. m
, p, 109-111℃
Claims (1)
硫酸反応させることを特徴とする〔式中、几は低級アル
キル基を意味する。〕で示されるシス−ジエステル体の
製造方法。[Claims] The invention is characterized by reacting a cis-dicarboxylic acid represented by the formula 0 with radialkyl sulfuric acid in water [wherein, 几 means a lower alkyl group]. ] A method for producing a cis-diester body.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP915984A JPS60152469A (en) | 1984-01-21 | 1984-01-21 | Preparation of cis-diester derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP915984A JPS60152469A (en) | 1984-01-21 | 1984-01-21 | Preparation of cis-diester derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60152469A true JPS60152469A (en) | 1985-08-10 |
| JPH0452265B2 JPH0452265B2 (en) | 1992-08-21 |
Family
ID=11712835
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP915984A Granted JPS60152469A (en) | 1984-01-21 | 1984-01-21 | Preparation of cis-diester derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60152469A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006232743A (en) * | 2005-02-25 | 2006-09-07 | Sumitomo Chemical Co Ltd | Method for producing dimethyl-1, 3-dibenzyl-2-oxo- imidazolidine-4, 5-dicarboxylate |
| CN105399677A (en) * | 2015-11-17 | 2016-03-16 | 蚌埠丰原医药科技发展有限公司 | Preparation method of trans-naphthenic acid |
| CN106905239A (en) * | 2017-03-15 | 2017-06-30 | 安徽泰格维生素实业有限公司 | A kind of pair of process for purification of benzyl dicarboxylic acids |
-
1984
- 1984-01-21 JP JP915984A patent/JPS60152469A/en active Granted
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006232743A (en) * | 2005-02-25 | 2006-09-07 | Sumitomo Chemical Co Ltd | Method for producing dimethyl-1, 3-dibenzyl-2-oxo- imidazolidine-4, 5-dicarboxylate |
| CN105399677A (en) * | 2015-11-17 | 2016-03-16 | 蚌埠丰原医药科技发展有限公司 | Preparation method of trans-naphthenic acid |
| CN106905239A (en) * | 2017-03-15 | 2017-06-30 | 安徽泰格维生素实业有限公司 | A kind of pair of process for purification of benzyl dicarboxylic acids |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0452265B2 (en) | 1992-08-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |