JPS6351399A - Production of glutamine derivative - Google Patents

Production of glutamine derivative

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Publication number
JPS6351399A
JPS6351399A JP19636486A JP19636486A JPS6351399A JP S6351399 A JPS6351399 A JP S6351399A JP 19636486 A JP19636486 A JP 19636486A JP 19636486 A JP19636486 A JP 19636486A JP S6351399 A JPS6351399 A JP S6351399A
Authority
JP
Japan
Prior art keywords
ester
glutamine
ammonium salt
glutamic acid
chloroacetyl
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
JP19636486A
Other languages
Japanese (ja)
Other versions
JPH0699473B2 (en
Inventor
Ryonosuke Yoshida
吉田 良之助
Akira Matsuba
松葉 暁
Yoshiteru Katayama
片山 由照
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.)
KATAYAMA SEIYAKUSHIYO KK
Ajinomoto Co Inc
Original Assignee
KATAYAMA SEIYAKUSHIYO KK
Ajinomoto Co Inc
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 KATAYAMA SEIYAKUSHIYO KK, Ajinomoto Co Inc filed Critical KATAYAMA SEIYAKUSHIYO KK
Priority to JP19636486A priority Critical patent/JPH0699473B2/en
Publication of JPS6351399A publication Critical patent/JPS6351399A/en
Publication of JPH0699473B2 publication Critical patent/JPH0699473B2/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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Abstract

PURPOSE:To obtain the titled compound useful as a remedy for gastric ulcer, etc., and stock powder for transfusion liquid, in high purity at a low cost, by reacting a novel N<alpha>-acylglutamic acid gamma-ester ammonium salt with an alkaline aqueous solution. CONSTITUTION:An N<alpha>-acylglutamic acid gamma-ester ammonium salt is made to react with an alkaline aqueous solution such as ammonia water to obtain glycylglutamine. The N<alpha>-acylglutamic acid gamma-ester ammonium salt is a novel compound which can be produced e.g. by producing N-chloroacetyl-glutamic acid gamma-ester from glutamic acid by conventional process and neutralizing the ester with ammonia water in an alcoholic solvent.

Description

【発明の詳細な説明】 窪】」4I旧W氷肛 本発明は、グルタミン誘導体、詳しくはグリシル−グル
タミンの新規製造方法および、それに使用する新規N6
−アシルグルタミンta r−エステルアンモニウム塩
に関するものである。例えば、グリシル−L7グルタミ
ンはL−グルタミンに比し安定なために、L−グルタミ
ンの代わりに輸液用原末または、胃潰瘍および十二指腸
潰瘍医薬として期待されており、工業上安価かつ高純度
に製造できる方法の開発が求められている。
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new method for producing glutamine derivatives, specifically glycyl-glutamine, and a novel N6 used therein.
-Acylglutamine tar-ester ammonium salt. For example, glycyl-L7 glutamine is more stable than L-glutamine, so it is expected to be used as an infusion bulk or as a drug for gastric and duodenal ulcers instead of L-glutamine, and can be produced industrially at low cost and with high purity. Development of methods is required.

従来の技f社 例えば、グリシル−し−グルタミンの製造方法は、従来
し一グルタミンをクロロアセチル化して、N−クロロア
セチル−し−グルタミンを得て、次でこれをアンモニア
水で処理してグリシル−L−グルタミンを得ていた。
For example, the conventional method for producing glycyl-glutamine is to chloroacetylate monoglutamine to obtain N-chloroacetyl-glutamine, which is then treated with aqueous ammonia to produce glycyl-glutamine. -L-glutamine was obtained.

しかし、この方法では、中間体のN−クロロアセチル−
し−グルタミンが水溶性であり、熱に対して鋭敏なため
精製が困難で、特に工業的に精製するのは、極めて困難
であった。
However, in this method, the intermediate N-chloroacetyl-
Since glutamine is water-soluble and sensitive to heat, it is difficult to purify it, especially industrially.

また、中間体のN−クロロアセチル−し−グルタミンを
精製しないでアンモニア水で処理し、グリシル−し−グ
ルタミンとした場合には、副生物ン のグリシ〃などの分離が困難なために、高純度のグリシ
ル−し−グルタミンを得ることが出来なかった・ 本溌明の構成 本発明者らは、高純度のグリシル−グルタミンを安価に
製造するために種々検討した結果、グルタミン酸T−エ
ステルをクロロアセチル化し、得られたN−クロロアセ
チル−グルタミン酸T−エステルをアンモニア水で処理
して、グリシル−グルタミンを得る方法に到達した。し
かし、N−り↓ ロロアセチルーグルタミン酸γエステルは、有機溶剤可
溶性で結晶化が困難なため、副生じたモノクロロ酢酸と
の分離が困難であった。
In addition, when the intermediate N-chloroacetyl-glutamine is treated with aqueous ammonia without purification to produce glycyl-glutamine, it is difficult to separate by-products such as glycyl, resulting in high As a result of various studies to produce high-purity glycyl-glutamine at low cost, the present inventors discovered that it was not possible to obtain pure glycyl-glutamine. A method for obtaining glycyl-glutamine was achieved by treating the N-chloroacetyl-glutamic acid T-ester obtained by acetylation with aqueous ammonia. However, since N-ri↓ loloacetyl-glutamic acid γ ester is soluble in organic solvents and difficult to crystallize, it was difficult to separate it from the monochloroacetic acid produced as a by-product.

本発明者らは、さらにN−クロロアセチル−グルタミン
酸T−エステルの精製法を種々検討した結果、新規N“
−アシルグルタミン酸T−エステルアンモニウム塩の合
成に成功し、かつこれをアルカリ性水溶液と反応せしめ
ることにより目的を達成できることを見出し、この発見
に基き本発明を完成した。例えば、アルコール性溶媒中
、N〜クロロアセチル化グルタミン酸T−エステルにア
ンモニア水を加えて中和して、N−クロロlアセチ仝4
゛ルタミン酸T−エステルアンモニラ1、塩の結晶を、
単離して精製すればよい。
The present inventors further investigated various purification methods for N-chloroacetyl-glutamic acid T-ester, and as a result, discovered a new N"
-Acylglutamic acid T-ester ammonium salt was successfully synthesized, and it was discovered that the object could be achieved by reacting this with an alkaline aqueous solution, and based on this discovery, the present invention was completed. For example, N-chloroacetylated glutamic acid T-ester is neutralized by adding aqueous ammonia in an alcoholic solvent to form N-chloroacetylated glutamic acid T-ester.
Altamic acid T-ester ammonia 1, salt crystals,
It can be isolated and purified.

さらに、このようにして調製したN−クロロアセチノ紗
ルタミン酸γ−エステルアンモニウム塩は、アンモニア
水で処理するだけで、容易に高純度のグリシル−グルタ
ミンを得ることができる。
Furthermore, the N-chloroacetinothalamic acid γ-ester ammonium salt prepared in this manner can easily be used to obtain highly pure glycyl-glutamine simply by treating with aqueous ammonia.

本発明において、N“−アシルグルタミン酸γ−エステ
ルアンモニウム塩の調製に使用するグルタミン酸γ−エ
ステルは、グルタミン酸から従来法によれば容易に合成
出来る。
In the present invention, the glutamic acid γ-ester used in the preparation of the N"-acylglutamic acid γ-ester ammonium salt can be easily synthesized from glutamic acid by a conventional method.

また、グルタミン酸は、L体、0体、DL体いずれの光
学異性体も使用することが出来る。例えば、L−グルタ
ミン酸γ−メチルエステル、D−グルタミン酸γ−エチ
ルエステルなどがある。グルタミン酸γ−エステルの例
えば、クロロアセチル化は、クロロアセチルクロリドを
用いるシ3.7テンハウマン法等クロロアセチル化方法
として慣用方法が採用される。N−クロロアセチノ&゛
ルタミン酸T−エステルは、結晶化し難<、油状物とし
て得られる。これをアルコールに溶解し、アンモニア水
を加えてp117〜8に調製すると結晶が析出する。副
生じたモノクロロ酢酸のアンモニウム塩は、溶媒に溶け
るため、純度の高いN−クロロアセチノδ゛ルタミン酸
γ−エステルアンモニウム塩が得られる。
Furthermore, any optical isomer of glutamic acid, such as L-form, 0-form, and DL-form, can be used. Examples include L-glutamic acid γ-methyl ester and D-glutamic acid γ-ethyl ester. For example, for chloroacetylation of glutamic acid γ-ester, a conventional method for chloroacetylation such as the Tenhouman method using chloroacetyl chloride is employed. N-chloroacetino&altamic acid T-ester is difficult to crystallize and is obtained as an oil. When this is dissolved in alcohol and aqueous ammonia is added to adjust the pH to 117 to 8, crystals are precipitated. Since the by-produced ammonium salt of monochloroacetic acid is soluble in the solvent, a highly pure N-chloroacetino δ-altamic acid γ-ester ammonium salt can be obtained.

去泪聞 以下、実施例により本発明の詳細な説明する。mourning Hereinafter, the present invention will be explained in detail with reference to Examples.

実施例I N−クロロアセチル−し−グルタミン酸T−
メチルエステルアンモニウム塩 L−グルタミンMr−メチルエステル80.5 g(0
,6モル)を水500m1に溶解し、水酸化カリウム3
4g (0,6モル)と炭酸カリウム83g(0,6モ
ル)を水150n+j!に溶解した溶液と、クロロアセ
チルクロリド72.8 g Co、65モル)を3°C
以下でp117〜8に保ち、攪拌下に滴下する。
Example I N-chloroacetyl-thi-glutamic acid T-
Methyl ester ammonium salt L-glutamine Mr-methyl ester 80.5 g (0
, 6 mol) in 500 ml of water, 3 mol of potassium hydroxide
4g (0.6 mol) and 83g (0.6 mol) of potassium carbonate in 150n+j of water! and chloroacetyl chloride (72.8 g Co, 65 mol) at 3°C.
The following is maintained at p117-8 and added dropwise while stirring.

滴下終了後、さらに30分攪拌し、酢酸エチル50mA
を加え、濃塩酸140nlでpillに調製する。これ
に、食塩100gを溶かし、酢酸エチル250m6で1
回、150m!で2回抽出する。酢酸エチル層を合わせ
て無水硫酸ナトリウムで乾燥後濃縮して、油状のN−ク
ロロアセチル−L−グルタミン%y−メチルエステル1
31gを得た。
After the dropwise addition was completed, the mixture was further stirred for 30 minutes, and 50 mA of ethyl acetate was added.
and prepare a pill with 140 nl of concentrated hydrochloric acid. Dissolve 100g of common salt in this and add 250m6 of ethyl acetate to
150m twice! Extract twice. The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and concentrated to give an oily N-chloroacetyl-L-glutamine%y-methyl ester.
31 g was obtained.

この油状物をアルコール400m1i!に溶かし、28
%アンモニア水40nlを40°C以下で加えてp11
7〜8とする。析出しなN−クロロアセチル−L −ク
ルタミン酸γ−メチルエステルアンモニウム塩の結晶を
濾取した。
Add this oil to 400ml of alcohol! Dissolve in 28
Add 40nl of % ammonia water at 40°C or less and p11
7-8. The precipitated crystals of N-chloroacetyl-L-curtamic acid γ-methyl ester ammonium salt were collected by filtration.

89.6g(収率70斗%) 融点220”  (分解
)。
89.6g (yield 70%) Melting point 220'' (decomposed).

比施光度〔α〕。−+8.6(C=2.水)実施例2 
グリシル−L−グルタミン N−クロロアセチル−し−グルタミン酸γ−メチルエス
テルアンモニウム塩50gを28%アンモニア水220
nlに溶解し、−夜装置した。減圧にてアンモニアを留
去後、塩酸を加えててp116とし、イオン交換樹脂を
用いて脱塩した。脱塩液を濃1宿し、L40mlのメタ
ノールをカロえてグリシル−L−グルタミンを析晶させ
、濾取した。
Specific luminosity [α]. -+8.6 (C=2.water) Example 2
50 g of glycyl-L-glutamine N-chloroacetyl-glutamic acid γ-methyl ester ammonium salt and 220 g of 28% aqueous ammonia
Dissolved in nl and incubated overnight. After distilling off ammonia under reduced pressure, hydrochloric acid was added to make p116, and the mixture was desalted using an ion exchange resin. The desalted solution was concentrated, and 40 ml of methanol was added to crystallize glycyl-L-glutamine, which was collected by filtration.

27.4g(収率b8.7%) 融点195° (分解
)比施光度〔α)D−1,2(C=1.水)実施例3 
N−クロロアセチル−L−グルタミン酸γ−エチルエス
テルアンモニウム塩 実施例1と同様にして、出発物質し一グルタミン酸4チ
ルエステル1了、’l;g(0,1モル)t−使用し標
題物質を製造することができる。
27.4g (Yield b8.7%) Melting point 195° (Decomposition) Specific light intensity [α) D-1,2 (C=1.Water) Example 3
N-Chloroacetyl-L-glutamic acid γ-ethyl ester ammonium salt In the same manner as in Example 1, the title substance was prepared using the starting material monoglutamic acid 4-methyl ester (0.1 mol). can do.

18.3  g (収率68%) 融点220° (分
解)。
18.3 g (yield 68%) Melting point 220° (decomposition).

比施光度〔α) o =+9.2 (C=2.水)実施
例4 グリシル−L−グルタミン 実施例2と同様にして、N−クロロアセチル−し−グル
タミン酸γ−エチルエステルアンモニウム塩を使用し標
題物質19.8  g (収率ら8%)を製造すること
ができる。
Specific optical density [α) o = +9.2 (C = 2. water) Example 4 Glycyl-L-glutamine Same as Example 2, using N-chloroacetyl-glutamic acid γ-ethyl ester ammonium salt 19.8 g (yield: 8%) of the title substance can be produced.

実施例5 N−クロロアセチル−l−グルタミンMT−
メチルエステルアンモニウム塩 実施例1と同様にして、出発物’ID−グルタミン酸γ
−メチルエステル3.2 g (0,02モル)を使用
し標題物質35 g (収率68.7%)を製造するこ
とができる。
Example 5 N-chloroacetyl-l-glutamine MT-
Methyl ester ammonium salt Analogously to Example 1, the starting material 'ID-glutamic acid γ
Using 3.2 g (0.02 mol) of -methyl ester, 35 g (yield 68.7%) of the title substance can be prepared.

、融点220°(分解)、比施光度〔α)D=−8,6
(C=2.水) 実施例6 グリシル−D−グルタミン ム塩を使用し標題物質  1g(収率了O%)を製造す
ることができる。融点195° (分解)。
, melting point 220° (decomposition), specific light intensity [α) D=-8,6
(C=2.water) Example 6 Using glycyl-D-glutamine salt, 1 g (yield: 0%) of the title substance can be produced. Melting point 195° (decomposition).

比施光度〔α)o =+1.2 (C=l水)実施例7
 グリシル−DL−グルタミン実施例1,2に準じて、
同様にDL−グルタミン酸γ−メチルエステルを出発物
質として使用し。
Specific light intensity [α) o = +1.2 (C=l water) Example 7
Glycyl-DL-glutamine According to Examples 1 and 2,
Similarly, DL-glutamic acid γ-methyl ester was used as the starting material.

グリシル−DL−グルタミンを製造することができる。Glycyl-DL-glutamine can be produced.

発明の効果 前記から明らかな如く、本発明によれば工業上安価にか
つ高純度のグリシル−グルタミンを製造することができ
、故に本発明は産業上極めて有用である。
Effects of the Invention As is clear from the foregoing, according to the present invention, glycyl-glutamine can be produced industrially at low cost and with high purity, and therefore the present invention is extremely useful industrially.

Claims (1)

【特許請求の範囲】 1、N^α−アシルグルタミン酸γ−エステルアンモニ
ウム塩をアルカリ性水溶液と反応せしめることを特徴と
するグリシルグルタミンの製造方法。 2、アルカリ性水溶液がアンモニア水である特許請求の
範囲第1項記載の方法。 3、アシルがクロロアセチルである特許請求の範囲第1
項記載の方法。 4、γ−エステルが低級アルキルエステルである特許請
求の範囲第1項記載の方法。 5、N^α−アシルグルタミン酸γ−エステルアンモニ
ウム塩。 6、アシルがクロロアセチルである特許請求の範囲第5
項記載の塩。 7、γ−エステルが低級アルキルエステルである特許請
求の範囲第5項記載の塩。
[Scope of Claims] 1. A method for producing glycylglutamine, which comprises reacting N^α-acylglutamic acid γ-ester ammonium salt with an alkaline aqueous solution. 2. The method according to claim 1, wherein the alkaline aqueous solution is aqueous ammonia. 3. Claim 1 in which acyl is chloroacetyl
The method described in section. 4. The method according to claim 1, wherein the γ-ester is a lower alkyl ester. 5. N^α-acylglutamic acid γ-ester ammonium salt. 6. Claim 5 in which acyl is chloroacetyl
Salt as described in section. 7. The salt according to claim 5, wherein the γ-ester is a lower alkyl ester.
JP19636486A 1986-08-21 1986-08-21 Glycyl-Glutamine production method Expired - Fee Related JPH0699473B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP19636486A JPH0699473B2 (en) 1986-08-21 1986-08-21 Glycyl-Glutamine production method

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP19636486A JPH0699473B2 (en) 1986-08-21 1986-08-21 Glycyl-Glutamine production method

Related Child Applications (1)

Application Number Title Priority Date Filing Date
JP6122150A Division JP2531501B2 (en) 1994-06-03 1994-06-03 N-chloroacetyl glutamic acid γ-lower alkyl ester ammonium salt

Publications (2)

Publication Number Publication Date
JPS6351399A true JPS6351399A (en) 1988-03-04
JPH0699473B2 JPH0699473B2 (en) 1994-12-07

Family

ID=16356620

Family Applications (1)

Application Number Title Priority Date Filing Date
JP19636486A Expired - Fee Related JPH0699473B2 (en) 1986-08-21 1986-08-21 Glycyl-Glutamine production method

Country Status (1)

Country Link
JP (1) JPH0699473B2 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5380934A (en) * 1992-10-29 1995-01-10 Kyowa Hakko Kogyo Co., Ltd. Process for producing alanylgutamine
EP0678501A1 (en) * 1994-04-18 1995-10-25 Kyowa Hakko Kogyo Co., Ltd. Process for producing N-chloroacetylglutamine
US6281436B1 (en) 1997-08-05 2001-08-28 Tdk Corporation Encapsulated surface mounting electronic part
CN100343275C (en) * 2003-03-19 2007-10-17 四川三高生化股份有限公司 Process for preparing glycyl gtutamine
CN106083635A (en) * 2016-06-30 2016-11-09 山东诚汇双达药业有限公司 A kind of preparation method of N (chloracetyl) L glutamic acid methyl ester

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5380934A (en) * 1992-10-29 1995-01-10 Kyowa Hakko Kogyo Co., Ltd. Process for producing alanylgutamine
US5550283A (en) * 1992-10-29 1996-08-27 Kyowa Hakko Kogyo Co., Ltd. Process for producing alanylglutamine
EP0678501A1 (en) * 1994-04-18 1995-10-25 Kyowa Hakko Kogyo Co., Ltd. Process for producing N-chloroacetylglutamine
US5780677A (en) * 1994-04-18 1998-07-14 Kyowa Hakko Kogyo Co., Ltd. Process for producing glutamine derivative
US6281436B1 (en) 1997-08-05 2001-08-28 Tdk Corporation Encapsulated surface mounting electronic part
CN100343275C (en) * 2003-03-19 2007-10-17 四川三高生化股份有限公司 Process for preparing glycyl gtutamine
CN106083635A (en) * 2016-06-30 2016-11-09 山东诚汇双达药业有限公司 A kind of preparation method of N (chloracetyl) L glutamic acid methyl ester

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JPH0699473B2 (en) 1994-12-07

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