JPH01180862A - Production of l-aldostatin - Google Patents
Production of l-aldostatinInfo
- Publication number
- JPH01180862A JPH01180862A JP364988A JP364988A JPH01180862A JP H01180862 A JPH01180862 A JP H01180862A JP 364988 A JP364988 A JP 364988A JP 364988 A JP364988 A JP 364988A JP H01180862 A JPH01180862 A JP H01180862A
- Authority
- JP
- Japan
- Prior art keywords
- aldostatin
- formula
- formic acid
- mixed
- bityrosine
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 5
- ORWKVZNEPHTCQE-UHFFFAOYSA-N acetic formic anhydride Chemical compound CC(=O)OC=O ORWKVZNEPHTCQE-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 abstract description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 abstract description 9
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 abstract description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 abstract description 7
- 239000003795 chemical substances by application Substances 0.000 abstract description 7
- 239000002904 solvent Substances 0.000 abstract description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 abstract description 6
- 235000019253 formic acid Nutrition 0.000 abstract description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 abstract description 4
- 102000003992 Peroxidases Human genes 0.000 abstract description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 4
- 238000006170 formylation reaction Methods 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 abstract description 4
- 108040007629 peroxidase activity proteins Proteins 0.000 abstract description 4
- 229960004441 tyrosine Drugs 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 abstract description 2
- 102000016912 Aldehyde Reductase Human genes 0.000 abstract description 2
- 108010053754 Aldehyde reductase Proteins 0.000 abstract description 2
- 208000002249 Diabetes Complications Diseases 0.000 abstract description 2
- 206010012655 Diabetic complications Diseases 0.000 abstract description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 230000022244 formylation Effects 0.000 abstract 3
- 208000002177 Cataract Diseases 0.000 abstract 1
- 206010029333 Neurosis Diseases 0.000 abstract 1
- 208000017442 Retinal disease Diseases 0.000 abstract 1
- 206010038923 Retinopathy Diseases 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 208000017169 kidney disease Diseases 0.000 abstract 1
- 208000015238 neurotic disease Diseases 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical group CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000003288 aldose reductase inhibitor Substances 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- HPYNZHMRTTWQTB-UHFFFAOYSA-N 2,3-dimethylpyridine Chemical compound CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 2
- 229940118148 Aldose reductase inhibitor Drugs 0.000 description 2
- OUNKRBSXIMLJRR-UHFFFAOYSA-N Aldostatin Natural products O=CNC(C(=O)O)CC1=CC=C(O)C(C=2C(=CC=C(CC(NC=O)C(O)=O)C=2)O)=C1 OUNKRBSXIMLJRR-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 239000013076 target substance Substances 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- OQALFHMKVSJFRR-UHFFFAOYSA-N dityrosine Chemical compound OC(=O)C(N)CC1=CC=C(O)C(C=2C(=CC=C(CC(N)C(O)=O)C=2)O)=C1 OQALFHMKVSJFRR-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical compound O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000013077 target material Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003548 thiazolidines Chemical class 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明はアルドースレダクターゼ阻害物質Ｌ −アルド
スタチン及びその塩の製造法に関し、更ｅことなり得る
し一アルドヌタチン及びその塩の製造法ｔこ関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing the aldose reductase inhibitor L-aldostatin and its salts, and further relates to a method for producing aldose reductase inhibitor L-aldostatin and its salts, which may vary. .
れらの合併症は、ヘキソースが生体内のアルドースリダ
クターゼｅこよってツルピトーｌしの如きポリオール？
こ変換し、これが蓄積することに起因するとされている
（ザ・二ニー・イングランド・ジャーナル・オブ・メデ
イシン第２ｇｇ巻、ざ３／〜ｇ３乙頁、／り７３年）。These complications are due to the fact that hexoses react with polyols such as aldose reductase and tulpitol in vivo.
This conversion is said to be caused by accumulation (The Second English Journal of Medicine, Vol. 2gg, pp. 3/-g3, 1973).
従って、生体内組織でのポリオール蓄積を抑制し、糖尿
病性合併症を予防、治療するために種々のアルドースリ
ダクターゼ阻害剤が開発されており、例えばクロマン誘
導体（特開昭３３−３３乙５３号、同５７−≠Ｓ／ざ５
号）、チアゾリジン誘導体（特開昭Ｓ乙−ＩＯ’１ｇ７
６号）等が報告されている。また、本発明者らは先しこ
、シュードユーロチウム・シナタムの培養液中Ｑこ新規
ナアルドーヌリダクターゼ阻害物質であるし一アルドス
クチンが存在することを見出し、単離した（特開昭６２
−２０３０９３号）。Therefore, various aldose reductase inhibitors have been developed to suppress polyol accumulation in in vivo tissues and to prevent and treat diabetic complications. Same 57-≠S/za5
No.), thiazolidine derivatives (JP-A-Sho S-IO'1g7
No. 6) etc. have been reported. In addition, the present inventors have previously discovered and isolated the presence of aldoscutin, a novel aldone reductase inhibitor, in the culture solution of Pseudoeurotium sinatum (Japanese Patent Application Laid-Open No. 62-200222).
-203093).
しかしながら、上記のＬ−アルドスタチンは、発酵法シ
こよって得られるものであるため、製造、精製ｔこ非常
に時間がかかり、また収率？こおいても不満足なもので
あった。However, since the above-mentioned L-aldostatin is obtained by fermentation, it takes a lot of time to manufacture and purify it, and the yield is low. Again, this was unsatisfactory.
本発明者らは有利ｔこアルドースリダクターゼ阻害剤、
特ンこＬ−アルドスタチンの効率良い製造法について研
究を続ケた結果、Ｌ−チロシン３こアルカリ条件下でパ
ーオキシダーゼ及び過酸化水素を作用させて得たＬＬ−
ビチロシンをジホルミル化すること（こより化学的手段
によってＬ−アルドスタチンが得られることを見出し、
本発明を完成した。The inventors have found advantageous aldose reductase inhibitors,
As a result of continuing research on an efficient method for producing L-aldostatin, we found that L-tyrosine was produced by treating peroxidase and hydrogen peroxide under alkaline conditions.
It was discovered that L-aldostatin could be obtained by chemical means by diformylating bityrosine,
The invention has been completed.
すなわち、本発明の目的は次の式（■）字２
門
Ｈ２ＮＴｈＣ４ＨＨ２ＮＴｈ９４Ｈ
て表わされるＬＬ−ビチロシンをジホルミｌし化するこ
とを特徴とする式ｔｌ）
ＰＮ２ 門
αＩローｍ４ｕ：ＯＨ■４１４Ｈ
■１ の１
て表わされるし一アルドスタチンまたはその塩の製造法
を提供することにある。That is, the purpose of the present invention is to solve the following equation (■) character 2
Provided is a method for producing aldostatin or a salt thereof, which is characterized by diformylating LL-bityrosine represented by the following formula: PN2 αI lo m4u:OH 414H 1 It's about doing.
本発明の式（１）で表わされるＬ−アルドスタチンは、
例えば次の式？こ従ってＬＬ−ビチロシン（■）ヲシホ
ルミル化することりこより製造される。L-aldostatin represented by formula (1) of the present invention is
For example, the following expression? Accordingly, LL-vityrosine (■) is produced from cyformylated Kotoriko.
Ｈ２Ｎド→４ ＨＨ２Ｎ ） Ｃ４Ｈ
■１ （３）Ｈ
ｔｌ）
出発原料であるＬＬ−ビチ０”：／１ｌｌ）は、例えば
下式ｔこ従ってＬ−チロシン（ＩＩＩＩ ｔこ過酸化水
素とパーオキシダーゼを作用することンこより得られる
（ Ａｍａｄ 。H2N do → 4 HH2N ) C4H ■1 (3) H tl) The starting material LL-Bichi0":/1ll) can be converted into L-tyrosine (III) using the following formula, for example, and hydrogen peroxide and peroxidase. (Amad)
ｅｔ ａｌ、、 Ｍｅｔｈｏｄｓ ｉｎＥｎｚｙｍｏｌ
ｏｇｙ、 ／ ０７ 、 ３７７−リーＣ４ＨｐＨ９
，２
（Ｄ：１Ｈ
（Ｉｌｌ
化合物（ｎ）のホルミル化反応は、以下の方法により実
施することができる。すなわち、溶媒の存在又は不存在
下、ギ酸−無水酢酸、ギ酸−Ｎ、Ｎ’−ジシクロへキシ
ルカルボジイミド（ＤＣＣ）、ギ酸−水溶性力ルポジイ
ミド等の混合ホルミル化剤を作用させること？こより実
施される。et al., Methods in Enzymol
ogy, /07, 377-LeeC4HpH9
,2 (D:1H (Ill) The formylation reaction of compound (n) can be carried out by the following method. Namely, in the presence or absence of a solvent, formic acid-acetic anhydride, formic acid-N, N'- This is carried out by applying a mixed formylating agent such as dicyclohexylcarbodiimide (DCC) or formic acid-water soluble dilupodiimide.
ホルミル
ンこより適宜変更することができ、例えば混合ホルミル
化剤として、ギ酸−無水酢酸を用いる場合、これらは１
モルのＬＬ−ビチロシンｔＩｌｊｔこ対して大過剰に用
いれば良く、また溶媒としてはジオキサン、アセトン等
が好ましい。更ｔこ、反応は一２０℃〜５０℃て３０分
〜Ｓ時間おこなうことが好ましく、特ｅこ一２０℃〜０
℃が好ましい。また、混合ホルミル
ＬＬ−ビチロシン［Ｉｌｌｔこ対し、ギ酸は２〜５モル
程度、ＤＣＣは２モル程度の割合で用いればよく、溶媒
はピリジン、ジメチルホルムアミド、テトラヒドロフラ
ン等が好ましく、反応は一り０℃〜ＳＯ℃で２〜７０時
間おこなうことが好ましい。更ンこ、ギ酸ー水溶性力ル
ポジイミドを混合ホルミル化剤として用いる場合Ｑこは
、溶媒としてはＮ−メチルモルホリン、ジメチルピリジ
ン等が好ましく、それらの使用比率としては、１モルの
ＬＬ−ビチロシン（■）＆こ対し、ギ酸は２〜７０モル
程度、水溶性カルボジイミドはΩ〜Ｓモル程度の割合で
用いればよく、溶媒としてＮ−メチルモルホリンを用い
る場合？こは、これを２〜３モル程度とすれば良しｈｏ
本発明方法においては、上記混合ホルミル化剤のうち、
ギ酸−無水酢酸を用いることが特ｅこ好ましい。Formyl can be changed as appropriate. For example, when formic acid-acetic anhydride is used as a mixed formylating agent, these are 1
It is sufficient to use a large excess of the molar amount of LL-bityrosine tIljt, and dioxane, acetone, etc. are preferred as the solvent. Further, the reaction is preferably carried out at -20°C to 50°C for 30 minutes to S hours, especially at 20°C to 0°C.
°C is preferred. In addition, for mixed formyl LL-bityrosine [Illt], formic acid may be used in a proportion of about 2 to 5 moles and DCC in a proportion of about 2 moles, and the solvent is preferably pyridine, dimethylformamide, tetrahydrofuran, etc., and the reaction is carried out at 0°C. It is preferable to carry out the reaction at ˜SO° C. for 2 to 70 hours. When using formic acid-water-soluble lupodiimide as a mixed formylating agent, the solvent is preferably N-methylmorpholine, dimethylpyridine, etc., and the ratio of their use is 1 mol of LL-bityrosine ( ■) On the other hand, formic acid should be used in a proportion of about 2 to 70 moles, and water-soluble carbodiimide should be used in a proportion of about Ω to S mole. What if N-methylmorpholine is used as a solvent? This may be about 2 to 3 moles. In the method of the present invention, among the mixed formylating agents,
It is particularly preferred to use formic acid-acetic anhydride.
このようにして得られたＬ−アルドスタチンは、その物
理化学的性質並びに生物学的性質から特開昭６２−２０
３０９３号明細書記載のし一アルドスタチンと同一化合
物であることが同定された。L-aldostatin obtained in this way was disclosed in Japanese Patent Application Laid-Open No. 62-2010 due to its physicochemical and biological properties.
It was identified that this compound is the same as aldostatin described in the specification of No. 3093.
本発明ｅこよれば従来の醗酵法と比べ収率良くＬ−アル
ドスタチンを得ることができ、また、容易ｅこ分離、精
製をおこなうことができるので、経済的？こ有利である
。According to the present invention, L-aldostatin can be obtained in a higher yield than conventional fermentation methods, and it can be easily separated and purified, making it economical. This is advantageous.
斯くして得られるＬ−アルドスタチン（１）は、常法に
より反応混合物から分離精製される。また、Ｌ−アルド
スタチンは、更ンこ必要ンこ応シ、公知ノ手段によって
その塩とすることもできる。塩の例としては、ナトリウ
ム、カリウム、リチウム、カルシウム等の金属塩及びア
ンモニウム塩が挙げられる。L-aldostatin (1) thus obtained is separated and purified from the reaction mixture by a conventional method. Further, L-aldostatin can also be converted into a salt thereof by a known method. Examples of salts include metal salts such as sodium, potassium, lithium, calcium and ammonium salts.
上記したようｅこ、本発明はＬ−アルドスタチンの収率
の良好な、かつ精製が簡便な化学的手段ｔこより合成す
る製法を提供できる。As described above, the present invention can provide a method for synthesizing L-aldostatin by chemical means with a good yield and simple purification.
次？こ実施例及び参考例を挙げて本発明を更ｔこ詳しく
説明するが、本発明はこれらｔこよって何んら限定され
るものではない。Next? The present invention will be explained in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereby in any way.
参考例 ／
Ｌ−チロシン／Ｖをｇｏｏｍｌの水ｔこ溶解し、ＳＮ水
酸化ナトリウム水溶液でｐＨ９２とし、０７％過酸化水
素水５０属を加えた。更に９０００ユニツトのパーオキ
シダーゼ（ベーリンガー山之内社製）を加え、良（攪拌
後、３０℃，２時間放置した。２Ｎ亜硫酸水素ナトリウ
ム、２０Ｍを加え反応を停止させた。次いで３Ｎ塩酸水
溶液？こてｐＨ７０＆こ調整し、カーボンカラム（／３
０ｍｌ）＆こチャージし、目的物を吸着させ水洗後（ｌ
１３０ｍｌ）、メタノール：０３Ｎアンモニア水（／：
／）混液で熔出した。２Ｑｍｌずつ分画し、フラクショ
ンＸざ〜彰２２までを集め、減圧下約２ｍｌまで濃縮し
、濃アンモニア水０／ｒｎｌを添加し、更シこメタノー
ル、！Ｑｍｌを加え良く攪拌し、生じた沈澱物を除去し
た。回収したメタノール上清液を減圧下濃縮し約／Ｑｍ
ｌとしＩ ＲＡ４？／ ０ （ｃｚ） ／ Ｏｍｌ（ｆ
）カラムＩｔｃチャージし、通過液約１０ｍｌ及び水洗
液３０ｍｌを得た。これら通過液及び水洗液を濃縮し、
約１０ゴとしｐＨ乙Ｏｋ’Ｃ調整後、更ｃＨＰ−２０（
３ｍｌ）のカラムを通過させ、通過液約／Ｑｍｌ及び水
洗液／３；ｍｌを合わせ、ｐ Ｈ ７ ０ ｋこ調整し
た。この溶液を予め水ｔこて作製したアルミナカラム（
７３ｍｌ）に通し、目的物を吸着させ、水洗後（３９ｍ
ｌ）０／Ｎアンモニア水溶液で目的物の溶出を行ない３
ｍｌずつ分画した。フラクションｘ３〜蔦７を集め、
濃縮し、／Ｎ塩酸でｐ Ｈ ３． Ｏ ｔこ調整した。Reference Example / L-Tyrosine/V was dissolved in 1 ml of water, the pH was adjusted to 92 with SN sodium hydroxide aqueous solution, and 07% hydrogen peroxide solution was added. Further, 9000 units of peroxidase (manufactured by Boehringer Yamanouchi Co., Ltd.) was added, and after stirring, the mixture was left at 30°C for 2 hours. 2N sodium hydrogen sulfite, 20M was added to stop the reaction. Then, 3N aqueous hydrochloric acid solution was added to pH 70 with a trowel. Adjust this and add carbon column (/3
After rinsing with water, charge the target material (0 ml) and
130ml), methanol: 03N ammonia water (/:
/) It was melted with a mixed solution. Fractionate into 2Qml portions, collect fractions X to Akira 22, concentrate under reduced pressure to approximately 2ml, add 0/rnl of concentrated aqueous ammonia, and add methanol. Qml was added and stirred well, and the resulting precipitate was removed. The collected methanol supernatant was concentrated under reduced pressure to approximately /Qm.
I RA4? / 0 (cz) / Oml (f
) The column Itc was charged to obtain about 10 ml of the pass-through liquid and 30 ml of the washing liquid. Concentrate these passing liquids and washing liquid,
After adjusting the pH to about 10% and adjusting the pH to 20% HP-20 (
3 ml) of the column, about 1/Q ml of the passing liquid and 3/3 ml of the washing liquid were combined, and the pH was adjusted to 70 k. This solution was applied to an alumina column prepared in advance using a water trowel (
73ml) to adsorb the target substance, and after washing with water (39ml)
l) Elute the target substance with a 0/N ammonia aqueous solution.3
It was fractionated into ml portions. Collect fraction x3 ~ vine 7,
Concentrate and pH 3. with /N hydrochloric acid. I made some adjustments.
この物をセファデックスＧ−ｉｓｒこチャージし、水テ
展開しＩｇｆｆずつ分画した。フラクションｆ乙ｇ〜７
乙を集め、濃縮し、アセトンを添加すると沈澱が生じた
。この沈澱物を集め、乾燥するとＬＬ−ビチロシン塩酸
塩／ ００ｍ９が白色粉末として得られた。This product was charged with Sephadex G-isr, developed with water, and fractionated into Igff. Fraction f g~7
A was collected, concentrated, and acetone was added to form a precipitate. The precipitate was collected and dried to obtain LL-vityrosine hydrochloride/00m9 as a white powder.
実施例 ／
参考例／で得られたＬＬ−ビチロシン塩酸塩粉末３０ｍ
９を９９％ギ酸７ｍｌに溶解し、水冷下で攪拌しながら
無水酢酸０２３ｍｌを加え、水冷下で３０分間攪拌した
後、室温ｅこ７時間放置した。水０３ ｍｌを加え反応
を停止後、濃縮し凍結乾燥した。30 m of LL-vityrosine hydrochloride powder obtained in Example/Reference Example/
9 was dissolved in 7 ml of 99% formic acid, 023 ml of acetic anhydride was added while stirring under water cooling, and after stirring for 30 minutes under water cooling, the mixture was left at room temperature for 7 hours. After terminating the reaction by adding 03 ml of water, the mixture was concentrated and freeze-dried.
この物を水２５ゴに溶解し、ｐＨ≠０に調整し、ＨＰ−
２０（７，３ｒｄ）ｔこチャージし、充分水洗後、５０
％メタノール水３３；ｍｌで溶出を行った。この溶出液
を濃縮し、凍結乾燥してＬ−アルドスタチン遊離体の白
色粉末３３■が得られた。Dissolve this substance in 25 g of water, adjust the pH≠0, and
After charging 20 (7,3rd)t and washing thoroughly with water, 50
Elution was performed with 33 ml of % methanol water. This eluate was concentrated and lyophilized to obtain 33 cm of white powder of free L-aldostatin.
尚、上記の方法で得られたし一アルドスタチンの物性は
、発酵法により得られたＬ−アルドスタチン（特開昭６
２−２０３０９！；号）の物性と同一であった。In addition, the physical properties of L-aldostatin obtained by the above method are different from that of L-aldostatin obtained by fermentation method (JP-A-6
2-20309! The physical properties were the same as those of
Claims (1)
を特徴とする次の式（ I ） ▲数式、化学式、表等があります▼（ I ） で表わされるＬ−アルドスタチンまたはその塩の製造法
。 ２、ジホルミル化をギ酸−無水酢酸存在下で行なうこと
を特徴とする特許請求の範囲第１項記載の製造法。[Claims] 1. The following formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) The following formula (I) characterized by diformylating LL-bityrosine represented by ▲ Mathematical formula , chemical formula, table, etc. ▼(I) Manufacturing method of L-aldostatin or its salts. 2. The production method according to claim 1, wherein the diformylation is carried out in the presence of formic acid-acetic anhydride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP364988A JPH01180862A (en) | 1988-01-11 | 1988-01-11 | Production of l-aldostatin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP364988A JPH01180862A (en) | 1988-01-11 | 1988-01-11 | Production of l-aldostatin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01180862A true JPH01180862A (en) | 1989-07-18 |
Family
ID=11563326
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP364988A Pending JPH01180862A (en) | 1988-01-11 | 1988-01-11 | Production of l-aldostatin |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01180862A (en) |
-
1988
- 1988-01-11 JP JP364988A patent/JPH01180862A/en active Pending
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