JPS58190395A - Preparation of optically active cis-imidazolidinedicarboxylic acid derivative - Google Patents
Preparation of optically active cis-imidazolidinedicarboxylic acid derivativeInfo
- Publication number
- JPS58190395A JPS58190395A JP7183482A JP7183482A JPS58190395A JP S58190395 A JPS58190395 A JP S58190395A JP 7183482 A JP7183482 A JP 7183482A JP 7183482 A JP7183482 A JP 7183482A JP S58190395 A JPS58190395 A JP S58190395A
- Authority
- JP
- Japan
- Prior art keywords
- optically active
- cis
- imidazolidinedicarboxylic
- chromobacterium
- bzl
- 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.)
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は一般式(I)
(式中、Rは低級アルキル基を示す。Bzlはベンジル
基を示す。4位、5位の配位は4S、5Rの配位である
6)
で示される光学活性シス゛−イミダゾリジンジカルボン
酸誘導体の製造方法に関するものである。Detailed Description of the Invention The present invention is based on the general formula (I) (wherein R represents a lower alkyl group. Bzl represents a benzyl group. The coordination at the 4th and 5th positions is 4S and 5R coordination. The present invention relates to a method for producing the optically active cis-imidazolidinedicarboxylic acid derivative shown in 6).
すなわち本発明は一般式(3)
(式中、Rは低級アルキル基を示す。Bzlはベンジル
基を示す。)
で示されるシス−イミダゾリジンジカルボン酸ジエステ
ル類(以下ジエステル類と略称する。)ニクロモハクt
’)ラム((3hromobacterium )属に
属するエステラーセ牛産菌またはクロモバクテリウム属
に属するエステラーゼ生産菌由来のエステラーセを接触
せしめることにより、前記一般式〇)で示される光学活
性シス−イミダゾリジンジカルボン酸誘導体(以下、ハ
ーフェステル類と略称するう )を製造する方法を提供
するものである。That is, the present invention relates to cis-imidazolidine dicarboxylic acid diesters (hereinafter abbreviated as diesters) represented by the general formula (3) (wherein R represents a lower alkyl group and Bzl represents a benzyl group). t
') The optically active cis-imidazolidine dicarboxylic acid derivative represented by the above general formula (hereinafter abbreviated as Hafestel).
一般式(1)および(至)において低級アルキル基とは
メチル、エチル、n−プロピル、イソプロピル、n−ブ
チル、t−ブチル、n−ペンチル、n−ヘキシル基等の
01〜6アルキル基を意味する。In general formulas (1) and (to), lower alkyl group means 01-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl group, etc. do.
本発明によって得られる光学活性ハーフェステル類(D
はビオチンおよびその他医薬品の合成中間体として極め
て1要な化合物である。Optically active halfesters (D
is an extremely important compound as a synthetic intermediate for biotin and other pharmaceuticals.
テ
本発明者らは、微生物を用いてジエステル類(6)から
光学活性ハーフニスチル類(1)の製造方法を鋭意検討
した。その結果、クロモバクテリウム(Chromob
acterium )属に属すル:X−7,fラーゼ生
産菌またはクロモバクテリウム属に属するエステラーゼ
生産菌由来のエステラーセを用いた場合、光学活性なハ
ーフェステル類(I)が得られることを見い出し、本発
明方法を完成するに至った。The present inventors have intensively investigated a method for producing optically active half-nystyl compounds (1) from diesters (6) using microorganisms. As a result, Chromobacterium (Chromobacterium
It has been found that optically active halfesters (I) can be obtained when an esterase derived from a Le: I have completed the method.
本発明方法においてはクロモバクテリウム接触せしめる
ことlこより半加水分解する際、反 J応は緩和な条
件下、収率よく進行し、本発明目的化合物ハーフェステ
ル類(I)を得ることかでき、しかも生捕水分解反応は
立体選択的又は特異的に進行する。In the method of the present invention, when the hemihydrolysis is carried out by contacting with Chromobacterium, the reaction proceeds in good yield under mild conditions, and the objective compound of the present invention, Hafesters (I), can be obtained. The raw water decomposition reaction proceeds stereoselectively or specifically.
即ち、メソ体であるジエステル類(6)を半加水分解す
る際、2ち類の光学対掌体の生成が考えられるが、本発
明方法を用いればそれらの2種類のうちいずれか一方の
対掌体のみが過剰に生成し、さらに場合によっては一方
的に1稲類の対常体のみを生成するといういわゆる不斉
加水分解が生ずるのである。That is, when semi-hydrolyzing diester (6), which is a meso form, it is possible that two types of optical antipodes are produced, but if the method of the present invention is used, one of these two types can be produced. This results in so-called asymmetric hydrolysis, in which only the palmar form is produced in excess, and in some cases only the stereogenic form of one rice species is produced unilaterally.
本発明方法により、選択的に得られるハーフェステル類
(I)は48.5R配位をもつものであり、光学活性な
d−ビオチンに変換することが出来ろ。たとえば、その
1例を示すと反応式(イ)の通りである。The halfesters (I) selectively obtained by the method of the present invention have a 48.5R coordination and can be converted into optically active d-biotin. For example, one example is shown in reaction formula (a).
更応式(4)
%式%()
()
(式中、R,Bzlは前述の通りであり、R1は低級ア
ルキル基を示し、XはC/ 、 Br 、 Iのハロゲ
ン原子を示す。)
すなわち光学活性なハーフェステル類(I)の低級アル
コキシカルボニル基を選択的に還元シ、次いで閉環する
ことにより光学活性なラクトン(ト)を得ることができ
ろ。光学活性なハーフェステル類(I)の低級アルコキ
シカルボニル基を選択的に還元する方法としては一般に
低級アルコキシカルボニル基を選択的に還元する事がで
きる還元剤、例えば水素化ホウ素ナトリウム、水素化ホ
ウ素リチウム、水素化ジイソブチルアルミニウム(DI
BAL−El)、水素化ジエチルアルミニウムナトリウ
ム(OMI−1−1)等を用いろ事により実施する事が
できる。反応溶媒としては反応の進行をさまたげない溶
媒であれば特に制限はないが、好ましい溶媒としてジエ
チルエーテル、テトラヒドロフラン、ジオキサン、エチ
レングリコール、ジメチルエーテル等のエーテル系溶媒
、トルエン、ヘキサン等の炭化水素系還元剤である場合
にはエタノール、イソプロパツール勢のアルコール系溶
媒あるいはこれらと水との混合溶媒を用いることもでき
る。反応温度は室温で良いが、室温より冷却するかある
いは溶媒沸点まで加温しても良い。還元剤がアルミニウ
ム系還元剤である場合には−70〜−20℃に冷却する
事が好ましい。Reaction formula (4) % formula %() () (In the formula, R and Bzl are as described above, R1 represents a lower alkyl group, and X represents a halogen atom of C/, Br, or I.) That is, the optically active lactone (I) can be obtained by selectively reducing the lower alkoxycarbonyl group of the optically active halfester compound (I) and then ring-closing it. As a method for selectively reducing the lower alkoxycarbonyl group of the optically active hafesters (I), a reducing agent capable of selectively reducing the lower alkoxycarbonyl group, such as sodium borohydride, lithium borohydride, Diisobutylaluminum hydride (DI
BAL-El), sodium diethylaluminum hydride (OMI-1-1), and the like. The reaction solvent is not particularly limited as long as it does not hinder the progress of the reaction, but preferred solvents include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol, and dimethyl ether, and hydrocarbon reducing agents such as toluene and hexane. In this case, an alcoholic solvent such as ethanol or isopropanol, or a mixed solvent of these and water may be used. The reaction temperature may be room temperature, but it may be cooled below room temperature or heated to the boiling point of the solvent. When the reducing agent is an aluminum-based reducing agent, it is preferable to cool it to -70 to -20°C.
還元反応終了後、反応液を中性または酸性としたのち、
クロロホルム、酢竪エチル等の有機溶媒で抽出するが、
このとき、閉環し、光学活性なラクトン(至)を得るこ
とができる。After the reduction reaction is completed, the reaction solution is made neutral or acidic, and then
Extract with organic solvents such as chloroform and ethyl acetate,
At this time, the ring is closed and an optically active lactone can be obtained.
光学活性なラクトン(至)を収率良く得るには還元反応
後、反応液を酸性とする事が好ましい。In order to obtain optically active lactones in good yield, it is preferable to make the reaction solution acidic after the reduction reaction.
ラクトン体(ト)は公知化合物であり、これを相当する
チオラクトン体(IV)に誘導する。次にグリニヤール
反応により側鎖を導入して得られるアルコール体Mを脱
水、水素添加して化合物(財)を得る。この化合物(V
I)をハロゲン化水素にてチオファニウム塩(■)とし
、マロン酸ジエチルと反応して化合物(■)としたのち
、加水分解、脱炭酸 Nl 、N3−ジベンジル基を除
去する事により光学活性なd−ビオチン(TX)を得る
事ができる。The lactone (I) is a known compound, and is derived into the corresponding thiolactone (IV). Next, the alcohol M obtained by introducing a side chain by Grignard reaction is dehydrated and hydrogenated to obtain a compound (good). This compound (V
I) was converted into a thiophanium salt (■) with hydrogen halide, reacted with diethyl malonate to form a compound (■), and then hydrolyzed and decarboxylated to remove the Nl and N3-dibenzyl groups to form optically active d. -Biotin (TX) can be obtained.
したがって本発明によって得られる光学活性なハーフェ
ステル類α)は特別の光学分割工程を経由する1%なく
、シかも途中でラセミ化する事なく光学活性なd−ビオ
チン(IX)に導くことができ、この事はd−ビオチン
(ff)の極めて有利な工業的製造法を可能とするもの
である。Therefore, the optically active halfesters α) obtained by the present invention can be led to optically active d-biotin (IX) without undergoing any special optical resolution step and without undergoing racemization during the process. This makes possible an extremely advantageous industrial production method for d-biotin (ff).
本発明方法を実施するには、通常行なわれる微生物の培
養に繁用される培地にクロモバクテリウム(Chrom
obactarium ) gll八属るf、 ステラ
ーヤ生産菌を生育せし、め、その生育の肖初からあるい
は後に前記一般式(I])で示されるジエステル類(2
)を加え、培養を継続し、半加水分解を行なう方法が最
も簡便である。この場合、培養温度は菌の増殖か可能で
あれば特に制限はないがii!s ’125〜87℃で
行なうのか好ましく、培養日数は通常半日〜7H間か適
尚であり、基質濃度は0.1〜1096程度が適当であ
る。To carry out the method of the present invention, Chromobacterium (Chromobacterium
(obactarium) gll, and the diesters (2
), continue culturing, and perform semi-hydrolysis. In this case, there is no particular restriction on the culture temperature as long as the growth of bacteria is possible, but ii! It is preferable to carry out the culturing at a temperature of s'125 to 87°C, the number of days of culturing is suitably between half a day and 7 hours, and the substrate concentration is suitably about 0.1 to 1096.
微生物の培養液を遠心分離等の操作により集菌しその微
生物細胞を用いて半加水分解する方法、あるいは微生物
の細胞を超音波処理、リゾチーム処理等により、酵素を
遊離させ、冷却下遠心分離、硫安分画、沈澱透析等によ
り、エステラーゼを得てこれを用いて半加水分解する方
法にても実施出来る。これらの場合には、一般式(2)
で示されるジエステル類を好ましくはpH5〜8に調整
した水溶液又は緩衝溶液に懸濁するか溶解し、ジエステ
ル類■に対して微生物の細胞もしくはエステラーゼを好
ましくはo、oot〜0.1重量比添加し、好ましくは
10〜40℃で攪拌することにより反応が進行し、通常
1時間〜数日間で反応が完了する。A method of collecting microorganism culture fluid by centrifugation or other operations and performing semi-hydrolysis using the microbial cells, or a method of releasing enzymes by subjecting microorganism cells to ultrasonic treatment, lysozyme treatment, etc., followed by centrifugation under cooling, It can also be carried out by obtaining an esterase by ammonium sulfate fractionation, precipitation dialysis, etc. and performing semi-hydrolysis using this. In these cases, general formula (2)
The diesters represented by are suspended or dissolved in an aqueous solution or a buffer solution preferably adjusted to pH 5 to 8, and microbial cells or esterase are added to the diesters at a weight ratio of preferably o, oot to 0.1. The reaction proceeds preferably by stirring at 10 to 40°C, and is usually completed in 1 hour to several days.
上述、水溶液とは硫酸、塩酸、リンheの鉱酸、酢酸、
クエン酸尋の有機酸、水酸化ナトリウム、水酸化カリウ
ム、炭酸ナトリウム等の無機塩基、トリエチルアミン、
ピリジン等の有機塩基、酢酸ナトリウム、塩化ナトリウ
ム等の塩を添加した水溶液を意味する。As mentioned above, the aqueous solution includes sulfuric acid, hydrochloric acid, phosphorous mineral acid, acetic acid,
Organic acids such as citric acid, inorganic bases such as sodium hydroxide, potassium hydroxide, and sodium carbonate, triethylamine,
It refers to an aqueous solution containing an organic base such as pyridine and a salt such as sodium acetate or sodium chloride.
緩%溶液とはリン酸二水章カリウムー水酸化ナトリウム
、リン酸二水素カリウム−リン酸二水素ナトリウム、フ
タル酸水素カリウム−塩酸、グリシン−塩化ナトリウム
−水酸化ナトリウム郷の一般的緩衝溶液を意味し、反応
を防げるものり外は特に制限はない。Slow percent solution means common buffer solutions of potassium dihydrogen phosphate-sodium hydroxide, potassium dihydrogen phosphate-sodium dihydrogen phosphate, potassium hydrogen phthalate-hydrochloric acid, glycine-sodium chloride-sodium hydroxide. However, there are no particular restrictions other than those that can prevent reactions.
又、本発明を実施する場合、必要に応じメタノール、エ
タノール、n−プロパツール、イソプロパツール、n−
ブタノール、t−ブタノールの如きアルコール系溶媒、
エーテル、テトラヒドロフラン、ジオキ廿ンの如きエー
テル系溶媒、ベンゼン、トルエン等の芳香族炭化水素系
溶媒、アセトン、メチルエチルケトン、ジエチルケトン
等のケトン系溶媒、トリエチルアミン、ピリジン等のア
ミン系溶媒、ジメチルホルム7ミド、ジメチルスルホキ
シド吟の極性溶媒、又、ソルビタンモノパルミテート、
ソルビタンモノラウレート等の如き界面活性剤を添加す
る事も出来る。Furthermore, when carrying out the present invention, methanol, ethanol, n-propertool, isopropertool, n-
Alcohol solvents such as butanol and t-butanol,
Ether solvents such as ether, tetrahydrofuran and dioxychloride; aromatic hydrocarbon solvents such as benzene and toluene; ketone solvents such as acetone, methyl ethyl ketone and diethyl ketone; amine solvents such as triethylamine and pyridine; and dimethylformamide. , dimethyl sulfoxide, a polar solvent, and sorbitan monopalmitate,
Surfactants such as sorbitan monolaurate and the like can also be added.
1.8−ジベンジル2−オキソイミダゾリジン−4t5
−ジカルボン酸とメタノール、エタノール、n−プロパ
ツール、イソプロパツール、n −フタノール、t−ブ
タノール、n−ペンタノール、あるいはn−ヘキサノー
ルを硫酸の存在下に脱水反応を行なう事によって対応す
るジエステル類(至)として合成することができる。1.8-Dibenzyl 2-oxoimidazolidine-4t5
- Diesters obtained by dehydrating dicarboxylic acids and methanol, ethanol, n-propanol, isopropanol, n-phthanol, t-butanol, n-pentanol, or n-hexanol in the presence of sulfuric acid. It can be synthesized as (to).
以下に実権例をもって本発明をさらに詳細に説明するが
、本発明はこれらにより限定されない事は勿論のことで
ある。The present invention will be explained in more detail below using practical examples, but it goes without saying that the present invention is not limited thereto.
参考例1
シス−1,8−ジベンジル−2−オキソイミダゾリジン
−4,5−ジカルボン酸ジエチルエステルの製造法
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985.41、ベンゼン500
−199.596エタノール4fi清/、濃EN酸5.
0りからなる反応液を10時間還流後、冷却し反応液を
水、5%NaOH水、水の順で洗浄した。Reference Example 1 Production method of cis-1,8-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid diethyl ester Cis-1,8,-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid 985. 41, Benzene 500
-199.596 ethanol 4fi clear/concentrated EN acid 5.
After refluxing the reaction solution for 10 hours, the reaction solution was cooled, and the reaction solution was washed with water, 5% NaOH water, and water in this order.
その後減圧濃縮し、得られた残渣を95%エタノールで
再結晶し7た。Thereafter, it was concentrated under reduced pressure, and the resulting residue was recrystallized from 95% ethanol.
m−P 74〜76℃ノizX 1.8 ’)ヘ
ンシル−2−オキソイミダゾリジン−4,5−ジカルボ
ン酸ジエチルエステルを得た。m-P 74-76°C NoizX 1.8') Hensyl-2-oxoimidazolidine-4,5-dicarboxylic acid diethyl ester was obtained.
実施例1
グルコース1.0 ? 、酵母エキス(極東製薬工業)
0.5F、ペプトン(ミクニ化学産業)1.0P、
リン酸水素二カリウム0. FI F、蒸留水100−
からなる溶液を希塩酸にてpH7,0に調整した。この
液体培養液を120’Cにて20分間蒸気滅菌した後、
Chromobacter iumChooolatu
m (I Fθ3758)を接種シ、26℃で48時間
振盪培養した。Example 1 Glucose 1.0? , yeast extract (Kyokuto Pharmaceutical Industries)
0.5F, Peptone (Mikuni Chemical Industry) 1.0P,
Dipotassium hydrogen phosphate 0. FI F, distilled water 100-
The pH of the solution was adjusted to 7.0 with dilute hydrochloric acid. After steam sterilizing this liquid culture solution at 120'C for 20 minutes,
Chromobacterium Chooolatu
m (IFθ3758) was inoculated and cultured with shaking at 26°C for 48 hours.
これにシス−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エステル400
〜を添加したのち、さらに26℃で72時間振盪反応さ
せた。To this, cis-1,8-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid dimethyl ester 400
After adding ~, the reaction was further carried out with shaking at 26°C for 72 hours.
この反応液に酢酸エチル100−を加え、希塩酸ζごて
酸性としたのち、セライトを遇した。After adding 100% of ethyl acetate to this reaction solution and making it acidic with diluted hydrochloric acid zeta, it was poured onto celite.
を液を分液し、有機層を水にて洗浄後、無水硫酸マグネ
シウムにて乾燥し、減圧濃縮した。The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
残渣に5 * 1ill水20−を加え、溶解後エーテ
ル20mにて洗浄し、分液した。5*1ill 20ml of water was added to the residue, and after dissolution, it was washed with 20ml of ether and separated.
水滴を希硫酸にてpH2とし、析出した白色結晶を沖過
し、水にて洗浄後乾燥した。The water droplets were adjusted to pH 2 with dilute sulfuric acid, and the precipitated white crystals were filtered off, washed with water, and then dried.
(48,5K) −1、8−’)ヘンリに−5−メトキ
シカルボニル−2−オキソイミダゾリジン−4−カルボ
ン酸84011Fが得られた。(48,5K) -1,8-') Henry's -5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid 84011F was obtained.
融点 149〜151℃
〔a〕ass −28,0° (C=1.DMF)
であった。Melting point 149-151°C [a] ass -28,0° (C=1.DMF)
Met.
参考例2
水素化ホウ票リチウム4819とテトラヒドロフラン8
−の混合液に実施例1で得られた(4B、5R)−1,
8−ジベンジル−5−メトキシカルボニル−2−オキソ
イミダゾリジン4−カルボン酸240wqとテトラヒド
ロフラン4wdからなる溶液を室温にて滴下した。Reference example 2 Lithium hydride 4819 and tetrahydrofuran 8
-(4B,5R)-1 obtained in Example 1,
A solution consisting of 240 wq of 8-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine 4-carboxylic acid and 4 wd of tetrahydrofuran was added dropwise at room temperature.
次にこの反応液を2時間還流したのち、テトラヒドロフ
ランを留去した。残漬に冷却下メタノール4−を徐々に
加え、次に濃塩酸0.5iを加えた。この混合物を1時
間還流したのち減圧濃縮した。残漬をシリカゲルカラム
クロマト精製し、(4aS、5aR)−t 、 8−ジ
ベンジルへキサヒドロ−IH−フロ(8,4−d〕イミ
ダゾール−2,4−ジオンを得た。Next, this reaction solution was refluxed for 2 hours, and then tetrahydrofuran was distilled off. While cooling, 4-4 methanol was gradually added to the residue, and then 0.5 i of concentrated hydrochloric acid was added. This mixture was refluxed for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (4aS, 5aR)-t, 8-dibenzylhexahydro-IH-furo(8,4-d]imidazole-2,4-dione.
融点 117〜118°C
[a]n +62.5° (C,=t、(l[[/
3 )実施例2
グルコース8.OF、酵母エキス(極東製薬工業) 1
.5 F、ペプトン(ミクニ化学産業)8.0?、リン
酸水素二カリウム1.5F、蒸留水800mgからなる
溶液を希塩酸にてpH47,0にp4整した。この培養
液を120℃暑ごて20分間蒸気滅龜したのちChro
mobacter iumChocolatum (I
FO8758)を接種し、26℃で72時間振盪培養
した。Melting point 117-118°C [a]n +62.5° (C,=t, (l[[/
3) Example 2 Glucose8. OF, yeast extract (Kyokuto Pharmaceutical Industries) 1
.. 5 F, Peptone (Mikuni Chemical Industry) 8.0? A solution consisting of 1.5 F dipotassium hydrogen phosphate and 800 mg of distilled water was adjusted to pH 47.0 with dilute hydrochloric acid. After sterilizing this culture solution with steam for 20 minutes in a hot iron at 120°C,
mobacterium Chocolatum (I
FO8758) and cultured with shaking at 26°C for 72 hours.
培養液を5,000rpm25分間、冷却子で遠心分離
して集菌した。菌体を0.8611食塩水100mにて
8回洗浄(遠心分離にて)し、集菌した。菌体に0.1
M−リン酸緩衝溶液(PE[7,0) 50m、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エステル1.50 Pを加
え、1規定水炉化ナトリウム溶液にてpH7付近に調整
しながら室温にて70時間攪拌した。The culture solution was centrifuged at 5,000 rpm for 25 minutes using a cooler to collect bacteria. The bacterial cells were washed 8 times with 100 m of 0.8611 saline (by centrifugation) and collected. 0.1 for bacterial cells
M-phosphate buffer solution (PE[7,0) 50m, cis-1,8-dibenzyl-2-oxoimidazolidine-4
, 5-dicarboxylic acid dimethyl ester (1.50 P) was added thereto, and the mixture was stirred at room temperature for 70 hours while adjusting the pH to around 7 with a 1N water furnace sodium solution.
この反応液を遠心分離し、菌体と上ずみ液とに分離した
(M体は回収)。上ずみ液を希硫酸にてPH2とし析出
した白色結晶を沖過し、水にて洗浄後乾燥した。This reaction solution was centrifuged and separated into bacterial cells and supernatant (M cells were collected). The supernatant liquid was adjusted to pH 2 with dilute sulfuric acid, and the precipitated white crystals were filtered, washed with water, and then dried.
(4s、5fL)−1+ 8−ジベンジル−5−メトキ
シカルボニル−2−オキソイミダゾリジン−◆−カルボ
ン酸L40Fが得られた。(4s, 5fL)-1+ 8-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-♦-carboxylic acid L40F was obtained.
融点 145〜147℃
〔α〕ars 25.0° (C=1.DMF
)参考例8
水素化ホウ素ナトリウム820〜とイソプロピルアルコ
ール85−の混合液に実施例2で得られた(4B、5R
)−1,8−ジベンジル−5−メトキシカルボニル−2
−オキソイミダゾリジン−4−カルボン酸1.20Pと
テトラヒドロフラン15mからなる溶液を室温にて滴下
した。次にこの反応液を60〜70℃にて7時間攪拌し
た。この反応液を冷却し、W#塩酸2.51を加え減圧
にて反応液を濃縮した。残渣に水250iを加え、クロ
ロホルム100m/にて2回抽出した。クロロホルム層
を水にて洗浄し、無水硅酸マグネシウムにて乾燥後減圧
濃縮し、残渣1.08Fを得た。Melting point 145-147°C [α]ars 25.0° (C=1.DMF
) Reference Example 8 A mixture of sodium borohydride 820~ and isopropyl alcohol 85~ obtained in Example 2 (4B, 5R
)-1,8-dibenzyl-5-methoxycarbonyl-2
A solution consisting of 1.20 P of -oxoimidazolidine-4-carboxylic acid and 15 m of tetrahydrofuran was added dropwise at room temperature. Next, this reaction solution was stirred at 60 to 70°C for 7 hours. The reaction solution was cooled, 2.51% of W# hydrochloric acid was added, and the reaction solution was concentrated under reduced pressure. 250 μl of water was added to the residue, and the mixture was extracted twice with 100 μl of chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium silicate, and concentrated under reduced pressure to obtain a residue of 1.08F.
残渣をシリカゲルカラムクロマトfPIaし、(4m8
.6aK ) −1、8−ジベンジルへキサヒドロ−I
H−フロ[B、4−d〕イミダゾール−2,4−ジオン
を得た。The residue was subjected to silica gel column chromatography fPIa (4 m8
.. 6aK) -1,8-dibenzylhexahydro-I
H-furo[B,4-d]imidazole-2,4-dione was obtained.
融点 115〜118℃
〔“)D+59.5°(C== 1 、 C:HCl5
)実施例8
’46例2で回収しt二菌体に0.1 M −IJン酸
緩衝耐欣(PH’i’、o ) 50ynt、シス−1
,8−ジペンジル−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1.50?を加え、実
施例2と同様に処理し、(48,5R)−1,3−ジベ
ンジル−5−メトキシカルボニル−2−オキソイミダゾ
リジン−4−カルボン酸184Fが得られた。Melting point 115-118°C [“)D+59.5° (C==1, C:HCl5
) Example 8 '46 Two bacterial cells collected in Example 2 were treated with 0.1 M-IJ acid buffer resistance (PH'i', o) 50 ynt, cis-1
,8-dipenzyl-2-oxoimidazolidine-4,5
-dicarboxylic acid dimethyl ester 1.50? was added and treated in the same manner as in Example 2 to obtain (48,5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid 184F.
融点 146〜148℃Melting point: 146-148℃
Claims (1)
基を示す。) ・ニ で示されるシスーイミダゾリジンカルボン酸ジエステル
類に、クロモバクテリウム (Chromobacterium ) 属に属するエ
ステラーゼ生産菌またはクロモバクテリウム属に属する
エステラーゼ生産菌出来のエステラーゼを接触せしめる
ことを特徴とする一般式 (式中、Rは低級アルキル基を示す。Bzlはベンジル
基を示す。4位、5位の配位は48.5Rの配位である
。) で示される光学活性なシス−イミダゾリジンジカルボン
酸誘導体の製造方法[Claims] General formula (in the formula, R represents a lower alkyl group. Bzl represents a benzyl group) - To the cis-imidazolidine carboxylic acid diesters represented by D, to the genus Chromobacterium The general formula (wherein R represents a lower alkyl group. Bzl represents a benzyl group. The method for producing an optically active cis-imidazolidinedicarboxylic acid derivative represented by
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7183482A JPS58190395A (en) | 1982-04-28 | 1982-04-28 | Preparation of optically active cis-imidazolidinedicarboxylic acid derivative |
US06/460,797 US4496739A (en) | 1982-01-27 | 1983-01-25 | Intermediates to optically active cis-1,3-dibenzyl-hexahydro-1H-furo[3,4-d]imidazole-2,4-dione |
EP83100767A EP0084892B2 (en) | 1982-01-27 | 1983-01-27 | Preparation of optically active cis-1,3-dibenzyl-hexahydro-1H-furo(3,4-d)imidazole-2,4-dione and its intermediates |
DE8383100767T DE3375025D1 (en) | 1982-01-27 | 1983-01-27 | Preparation of optically active cis-1,3-dibenzyl-hexahydro-1h-furo(3,4-d)imidazole-2,4-dione and its intermediates |
US06/579,602 US4544635A (en) | 1982-01-27 | 1984-02-13 | Preparation of optically active cis-1,3-dibenzyl-hexahydro-1H-furo[3,4-d]imidazole-2,4-dione and its intermediates |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7183482A JPS58190395A (en) | 1982-04-28 | 1982-04-28 | Preparation of optically active cis-imidazolidinedicarboxylic acid derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS58190395A true JPS58190395A (en) | 1983-11-07 |
JPH059064B2 JPH059064B2 (en) | 1993-02-03 |
Family
ID=13471964
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP7183482A Granted JPS58190395A (en) | 1982-01-27 | 1982-04-28 | Preparation of optically active cis-imidazolidinedicarboxylic acid derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS58190395A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100715929B1 (en) * | 2000-02-09 | 2007-05-08 | 스미또모 가가꾸 가부시끼가이샤 | Process for producing optically active hemiesters |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200300676A (en) | 2001-12-04 | 2003-06-16 | Tanabe Seiyaku Co | Biotin intermediate and its production |
-
1982
- 1982-04-28 JP JP7183482A patent/JPS58190395A/en active Granted
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100715929B1 (en) * | 2000-02-09 | 2007-05-08 | 스미또모 가가꾸 가부시끼가이샤 | Process for producing optically active hemiesters |
Also Published As
Publication number | Publication date |
---|---|
JPH059064B2 (en) | 1993-02-03 |
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