JPS60204754A - Manufacture of gamma-glutamyltaurine - Google Patents
Manufacture of gamma-glutamyltaurineInfo
- Publication number
- JPS60204754A JPS60204754A JP59059656A JP5965684A JPS60204754A JP S60204754 A JPS60204754 A JP S60204754A JP 59059656 A JP59059656 A JP 59059656A JP 5965684 A JP5965684 A JP 5965684A JP S60204754 A JPS60204754 A JP S60204754A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- gamma
- taurine
- glutamyltaurine
- glutamyl
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
-
- Y—GENERAL 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
(57)【要約】本公報は電子出願前の出願データであるた
め要約のデータは記録されません。(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】
本発明は２式（１）
％式％
の生物学的に活性なガンマ−Ｌ−グルタミルタウリン、
そのエナンチオマー、すなわち式（１）のガンマ−Ｄ−
グルタミルタウリン、両者のラセミ混合物、すなわち式
（Ｉ）のガンマ−ＤＬ−グルタミルタウリンおよびそれ
らの薬理学的に使用可能な塩を製造する新規方法に関す
る。本新規合成法は、公知法に比べよ如簡単でかつよシ
効果的である。DETAILED DESCRIPTION OF THE INVENTION The present invention provides biologically active gamma-L-glutamyl taurine of formula (1)
Its enantiomer, i.e. gamma-D- of formula (1)
The present invention relates to a novel process for producing glutamyl taurine, a racemic mixture of both, ie gamma-DL-glutamyl taurine of formula (I) and their pharmacologically usable salts. The new synthetic method is simpler and more effective than known methods.
キノイン社の特開昭５１−４１２１号公報ならびにこれ
に対するハンガリー特許明細書第１７４，１１４号およ
び西ドイツ特許公開公報第２．５１８．１６０．０号に
は、ガンマ−グルタミルタウリンを製造する多くの方法
が記載されている。ｔｊべてこれらの方法では、タウリ
ンをアシル化する化合物は、活性誘導体たとえば活性エ
ステル誘導体にしたものである。この化合物は、グルタ
ミン酸のアミン基上忙保護基を有するグルタミン酸のα
−半エステル訪導体、たとえばはンジルオキシヵルボニ
ルーグルタミン酸のα−ベンジルエステルである〇本発
明の目的は、ガンマ−グルタミルタウリンを、公知の方
法に比べ、より簡単に、より短かい反応時間で、より少
い化学薬品使用量で、しかもよ如すぐれた収率でもって
製造できる合成法を提供するにある。Kinoin's JP-A-51-4121 and its corresponding Hungarian Patent Specification No. 174,114 and German Patent Application No. 2.518.160.0 describe a number of methods for producing gamma-glutamyl taurine. is listed. In all of these methods, the compound that acylates taurine is an active derivative, such as an active ester derivative. This compound is a glutamic acid α-protecting group on the amine group of glutamic acid.
- A half-ester visiting conductor, for example the α-benzyl ester of dinzyloxycarbonyl-glutamic acid.The object of the present invention is to prepare gamma-glutamyl taurine more easily and in a shorter reaction time than known methods. Therefore, it is an object of the present invention to provide a synthetic method that can be produced with a lower amount of chemicals and a better yield.
不法によれば９式（１１） ％式％（） のタウリンを式（至） のフタリルグルタミン酸無水物でアシル化する。According to illegality, type 9 (11) %formula%() Expression of taurine (to) Acylation with phthalylglutamic anhydride.
得られた弐■
のフタリル−ガンマ−グルタミルタウリンからその保護
基を除去して９式（Ｉ）の所望の化合物を得るのである
。The protecting group is removed from the obtained phthalyl-gamma-glutamyltaurine (2) to obtain the desired compound of formula (9) (I).
実施にあたっては１式（２）のフタリルグルタミン酸無
水物（Ｆ ＊ Ｅ ＋ Ｋｌｎｇおよびり、 Ａ 、
Ａ、 Ｋｌｄｏｌ 。In implementation, phthalylglutamic anhydride (F * E + Klng and A,
A. Kldol.
Ｊ、Ｃｈｅｍ、８ｏｃ、１９４９，３５１５）を溶液中
で式（…）のタウリンと反応させるのがよい。溶媒とし
ては有機溶媒の使用が好ましい。生成した式叡）の７タ
リルーガンマーグルタξルタウリンを７タリル基離脱に
適した薬剤、望ましくけ水利ヒドラジン（Ｃｈｅｍ、Ｂ
ｅｒ、８３，２４６）と反応させて９式（Ｉ）のグルタ
ミルタウリンを得る。生成物を、再結晶および／または
イオン交換クロマトグラフィ技法によシ精製し、そして
所望なら塩に変える。J, Chem, 8oc, 1949, 3515) is preferably reacted with taurine of formula (...) in solution. As the solvent, it is preferable to use an organic solvent. The generated 7-taryl gamma gluta
er, 83,246) to obtain glutamyl taurine of formula (I). The product is purified by recrystallization and/or ion exchange chromatography techniques and, if desired, converted into a salt.
本発明方法は、公知方法に比べ９次のような利点を有す
る。The method of the present invention has the following nine advantages over known methods.
グルタミン酸から、４工程でガンマ−グルタミルタウリ
ンを得ることができる。これに対し、 、従来法は、６
エ程またはそれ以上の工程の合成法であった。Gamma-glutamyl taurine can be obtained from glutamic acid in four steps. On the other hand, the conventional method is 6
It was a synthetic method that required one step or more.
最も簡単な従来法と比べても、所要操作が約半分であり
、かつ所要時間も約半分である。Compared to the simplest conventional method, the required operations are about half, and the time required is also about half.
最も経済的な従来法よシも所要化学薬剤量が少い。The most economical conventional method also requires low amounts of chemicals.
グルタミン酸から、６２％の全収率でもって。From glutamic acid, with an overall yield of 62%.
ガンマ−グルタミルタウリンを得ることができる。Gamma-glutamyl taurine can be obtained.
この収率け、従来法のグルタミン酸に基づく収率よシも
はるかに高い。This yield is also much higher than the yield based on glutamic acid in the conventional method.
不法のその他の特徴は１次の実施例から理解できるであ
ろうが、これらの実施例は本発明の技術的範囲を限定す
るものではない。Other features of the law can be understood from the first embodiment, but these embodiments are not intended to limit the scope of the invention.
実施例１
フタリル−Ｌ−グルタミン酸無水物３．０５ｇ（１１ミ
リモル）に、水を含まないアセトニトリル１５ｙＬ／を
加える。生成した懸濁液を０℃に冷却し、かきまぜなが
らこれに、タウリン１．２５９（１０ミリモル）をテト
ラメチルグアニジン２．５６ＴＬｌ（２０ミリモル）唇
よびアセトニトリル５ｄ中に溶かした溶液を滴下する。Example 1 To 3.05 g (11 mmol) of phthalyl-L-glutamic anhydride is added 15 yL of water-free acetonitrile. The resulting suspension is cooled to 0° C. and a solution of 1.259 (10 mmol) of taurine dissolved in 2.56 TL of tetramethylguanidine (20 mmol) and 5 d of acetonitrile is added dropwise to it while stirring.
０℃で３０分間、そしてさらに２０℃で６０分間攪拌す
る。攪拌終了後は、懸濁液が澄明になる。その反応混合
物に。Stir for 30 minutes at 0°C and an additional 60 minutes at 20°C. After the stirring is complete, the suspension becomes clear. into the reaction mixture.
７０チの水和ヒドラジン１．４ｍＪ（２０ミリモル）お
よびエタノール１０＋＋＋Ａ！を加える。溶液を室温で
一晩放置した後、減圧下で濃縮する。残渣を水５０ゴに
溶かし、氷酢酸１．２虹を加える。分離したフタリルヒ
ドラジンを炉弾または遠心分離によシ除去する。残った
液相の声を、蟻酸の添加により。1.4 mJ (20 mmol) of hydrated hydrazine and 10+++A of ethanol! Add. The solution is left at room temperature overnight and then concentrated under reduced pressure. Dissolve the residue in 50 g of water and add 1.2 g of glacial acetic acid. The separated phthalylhydrazine is removed by bombardment or centrifugation. The voice of the remaining liquid phase is removed by adding formic acid.
２．５に調節する。Ｄｏｗｅｘ ５０ Ｗ Ｘ ２樹脂
（１００〜２００メツシユ）を充填した２、２ｘ４ｏｃ
ｒｒＬのカラム（Ｈ”−サイクル）を蟻酸−酢酸：水の
容積比１：４：４５の混液（ｐ）］二２．１）で予め平
衡となし、とのカラムに前記−２，５に調節した溶液を
注液する。次いで前記と同様の蟻酸−酢酸−水混液を注
液することにより溶離する。主注液開始時すぐに溶離液
を集液するが、主注液終了後１６０ゴの溶離液が溶出し
た後は集液を中断する。溶液を減圧下で濃縮する。結晶
性の残渣とデシケータ−中背性アルカリ上で乾燥し、そ
してジメチルホルムアミドと水との容積比で８＝２の混
液から再結晶する。母液は濃縮し、得られた残渣を同様
にして再結晶する。２つの再結晶クロップを一緒にする
。１．８５１！のガンマ−Ｌ−グルタミルタウリン（７
３％）が得られる。融点２２２〜２２６℃。Adjust to 2.5. 2, 2x4oc filled with Dowex 50 W X 2 resin (100-200 mesh)
The column of rrL (H”-cycle) was equilibrated in advance with a mixture (p) of formic acid-acetic acid:water at a volume ratio of 1:4:45 (22.1), and the above-mentioned -2.5 was added to the column of Inject the adjusted solution. Next, elute by injecting the same formic acid-acetic acid-water mixture as above. The eluent is collected immediately at the start of the main injection, but after 160 g after the main injection ends. The collection is discontinued after the eluent has eluted.The solution is concentrated under reduced pressure.The crystalline residue is dried in a desiccator over a medium-sized alkali, and the volume ratio of dimethylformamide to water is 8= 2. The mother liquor is concentrated and the resulting residue is recrystallized in the same way. The two recrystallized crops are combined. 1.851! of gamma-L-glutamyltaurine (7
3%) is obtained. Melting point 222-226°C.
〔αＦ”＝＋２ｏ、ｇ°（水、Ｃ＝３．６）。Ｐ紙電気
泳動り
法易動度（システィン酸に対し、 ） ｐＨ６，５で０
．７５ 。[αF”=+2o, g° (water, C=3.6).P paper electrophoresis mobility (relative to cystic acid) 0 at pH 6.5
．． 75.
ｐＨ２で０５３゜涙紙クロマトグラフィの几ｆ１直０１
９（ブタノール−ピリジン−氷酢酸−水の１５：１０１
：１２ 混液中）。ＣｙＨｔ４ＮｔＯａＳ （２５４，
２６）とした元素分析
計算値Ｃ３３，０７チ Ｈ５，５５チ Ｎ１１．０２％
０！１７．７５％ ８１２．６１チ
実測値Ｃ３３，１１％ Ｈ５，７１％ Ｎ１０．９７％
０３７．５８％ Ｓ１２．’７６チ
実施例２
フタリル−Ｄ−グルタミン酸無水物をタウリンと反応さ
せた以外は、実施例１記載の操作を反復した。１．８０
ｇのガンマ−Ｄ−グルタミルタウリン（７１１を得た
。融点２２０〜２２２℃。053° tear paper chromatography at pH 2 f1 direct 01
9 (butanol-pyridine-glacial acetic acid-water 15:101
:12 in the mixture). CyHt4NtOaS (254,
26) Elemental analysis calculation value C33.07chi H5.55chi N11.02%
0!17.75% 812.61chi Actual value C33,11% H5,71% N10.97%
037.58% S12. '76 Example 2 The procedure described in Example 1 was repeated, except that phthalyl-D-glutamic anhydride was reacted with taurine. 1.80
g of gamma-D-glutamyltaurine (711) was obtained. Melting point 220-222°C.
〔α〕”＝−２０，４°（水中、Ｃ＝５．１）。[α]”=−20.4° (in water, C=5.1).
実施例６
フタリルＤＬ−グルタミン酸無水物をタウリンと反応さ
せた以外は、実施例１記載の操作を反復した。１．８８
ｇのガンマ−ＤＬ−グルタミルタウリン（７４チ）を得
た。融点２０９〜２１２℃。Example 6 The procedure described in Example 1 was repeated, except that phthalyl DL-glutamic anhydride was reacted with taurine. 1.88
g of gamma-DL-glutamyltaurine (74 g) was obtained. Melting point: 209-212°C.
特許出願人 キノイン・ジョージセル・ニーシュ・ヴエ
ジエーセテイ・テルメーケク・ジャーラ・エルチーPatent Applicant: Kinoin Georgsel Nis Vuegiesetei Telmekek Jarrah Erci
Claims (2)
、そのラセミ混合物およびそれらの薬学的に使用可能な
塩を製造する忙あたシ１式（Ｕ）Ｈ，Ｎ−ｃＨｔ−ＣＨ
，−８０，ＯＨ（Ｉ）のタウリンを式（２） の７タリルグルタミン酸無水物と反応させ、そして生成
した式■ 曙 の７タリルーガンマーグルタミルタウリンのフタリル保
護基を除去し、そして所望なら得られた式（１）の化合
物を塩に変えることを特徴とする方法。(1) A project for producing two enantiomers of gamma-glutamyl taurine of formula (1), their racemic mixtures and their pharmaceutically usable salts, formula (U)H,N- cHt-CH
, -80,OH(I) is reacted with 7thalylglutamic anhydride of formula (2) and the phthalyl protecting group of the resulting formula ■ Akebono's 7thalyl gamma glutamyl taurine is removed and, if desired, the obtained A method characterized by converting the compound of formula (1) into a salt.
酸結合剤の存在下で打身い、そして保護基をしかるべき
薬剤好ましくは水利ヒドラジンでもって除去することを
特徴とする特許請求の範囲第（１）項記載の方法。(2) The reaction of the compounds of formula (1) and formula (I) is characterized in that the reaction of the compounds of formula (1) and formula (I) is carried out in solution in the presence of an acid binding agent and the protecting group is removed with a suitable agent, preferably hydrazine. A method according to claim (1).
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU81776A HU185632B (en) | 1981-03-27 | 1981-03-27 | New process for preparing gamma-glutamyl-taurine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60204754A true JPS60204754A (en) | 1985-10-16 |
| JPH0637456B2 JPH0637456B2 (en) | 1994-05-18 |
Family
ID=10951288
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59059656A Expired - Lifetime JPH0637456B2 (en) | 1981-03-27 | 1984-03-29 | Gamma-glutamyl taurine manufacturing method |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPH0637456B2 (en) |
| AT (1) | AT379588B (en) |
| CH (1) | CH661502A5 (en) |
| HU (1) | HU185632B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0436612A4 (en) * | 1988-09-30 | 1992-05-20 | Australian Commercial Research & Development Limited | Amino acid transport proteins, amino acid analogues, assay apparatus, uses thereof for treatment and diagnosis of cancer |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS514121A (en) * | 1974-04-29 | 1976-01-14 | Chinoin Gyogyszer Es Vegyeszet |
-
1981
- 1981-03-27 HU HU81776A patent/HU185632B/en not_active IP Right Cessation
-
1984
- 1984-03-15 AT AT0086484A patent/AT379588B/en not_active IP Right Cessation
- 1984-03-28 CH CH1573/84A patent/CH661502A5/en not_active IP Right Cessation
- 1984-03-29 JP JP59059656A patent/JPH0637456B2/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS514121A (en) * | 1974-04-29 | 1976-01-14 | Chinoin Gyogyszer Es Vegyeszet |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0637456B2 (en) | 1994-05-18 |
| CH661502A5 (en) | 1987-07-31 |
| AT379588B (en) | 1986-01-27 |
| HU32056A (en) | 1984-06-28 |
| ATA86484A (en) | 1985-06-15 |
| HU185632B (en) | 1985-03-28 |
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