JPS62242653A - Production of 5-hydroxynorvaline derivative - Google Patents
Production of 5-hydroxynorvaline derivativeInfo
- Publication number
- JPS62242653A JPS62242653A JP8604986A JP8604986A JPS62242653A JP S62242653 A JPS62242653 A JP S62242653A JP 8604986 A JP8604986 A JP 8604986A JP 8604986 A JP8604986 A JP 8604986A JP S62242653 A JPS62242653 A JP S62242653A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- reaction
- hydroxynorvaline
- group
- glutamic acid
- 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
- CZWARROQQFCFJB-BYPYZUCNSA-N 5-hydroxy norvaline Chemical class OC(=O)[C@@H](N)CCCO CZWARROQQFCFJB-BYPYZUCNSA-N 0.000 title claims description 8
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims abstract 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims abstract 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract 2
- 239000012279 sodium borohydride Substances 0.000 claims description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 239000002904 solvent Substances 0.000 abstract description 6
- -1 N-substituted glutamic acid Chemical class 0.000 abstract description 5
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 abstract description 2
- MOOAHMCRPCTRLV-UHFFFAOYSA-N boron sodium Chemical compound [B].[Na] MOOAHMCRPCTRLV-UHFFFAOYSA-N 0.000 abstract 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Chemical group O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 238000000034 method Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000012448 Lithium borohydride Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- ZOCDRUFCMFNIKQ-UHFFFAOYSA-N 2-benzamido-5-methoxy-5-oxopentanoic acid Chemical compound COC(=O)CCC(C(O)=O)NC(=O)C1=CC=CC=C1 ZOCDRUFCMFNIKQ-UHFFFAOYSA-N 0.000 description 1
- LPJXPACOXRZCCP-UHFFFAOYSA-N 2-benzamidopentanedioic acid Chemical compound OC(=O)CCC(C(O)=O)NC(=O)C1=CC=CC=C1 LPJXPACOXRZCCP-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000003756 stirring Methods 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、Ｎ−置換グルタミン酸エステルヲ水素化ホウ
素ナトリウムでアルコールへ還元する事による５−ヒド
ロキシノルバリン誘導体の製法に関する。DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a process for preparing 5-hydroxynorvaline derivatives by reducing N-substituted glutamate esters to alcohols with sodium borohydride.
５−、ヒドロキシノルバリンはマメ科植物中ニ遊離アミ
ノ酸として存在する天然アミノ酸の一つであシ、プロリ
ンの合成中間体として有用な化合物である。5-Hydroxynorvaline is one of the natural amino acids that exist as a free amino acid in leguminous plants, and is a compound useful as a synthetic intermediate for proline.
（従来の技術）
従来、５−ヒドロキシノルバリン誘導体の製法は種々公
知であるが、グルタミン酸誘導体より変換する方法とし
ては、
（１）Ｎ−置換グルタミン酸５−エステルを、水素化ホ
ウ素リチウムで還元する方法（例えばＡｃｔａＣｈｉｍ
Ａｃａｄ Ｓｃｉ Ｈｕｎｇ ２１ １０５（１９５９
）等）（２）Ｎ−）リルスルホニルグルタミン酸を閉環
し１−トリルスルホニル−５−オキソグロリ／に変換し
、次いで水素化ホウ素リチウムで還元する方法（例えば
Ｂｉｏｃｈｅｍｉｓｔｒｙ ３１５２９（１９６４）等
）（３） グルタミンあるいはグルタミン酸−５−ヒ
ドラジドを電解反応により還元する方法（特開昭等が公
知である。(Prior art) Various methods for producing 5-hydroxynorvaline derivatives are known, but methods for converting from glutamic acid derivatives include (1) reducing N-substituted glutamic acid 5-ester with lithium borohydride; methods (e.g. ActaChim
Acad Sci Hung 21 105 (1959
), etc.) (2) A method of ring-closing N-)lylsulfonylglutamic acid and converting it to 1-tolylsulfonyl-5-oxoglyloride/, and then reducing it with lithium borohydride (for example, Biochemistry 31529 (1964) etc.) (3) Glutamine Alternatively, a method is known in which glutamic acid-5-hydrazide is reduced by an electrolytic reaction (Japanese Patent Application Laid-open No. Sho et al.
（発明が解決しようとする問題点）
しかしながら、前記（１） 、 （２）の方法は触媒と
して（ＬｉＢＨ４）を用いるため、湿った空気中で発火
するため、取扱いが容易でなく、価格も比較的高価であ
シ、且、反応も非水系であシ、実用的に種々の難点があ
る。又、前記（３）の方法は電解反応であるため、大き
な装置を有するため、簡易に利用することができないと
いう欠点がある。(Problems to be solved by the invention) However, since the methods (1) and (2) above use (LiBH4) as a catalyst, they ignite in humid air, so they are not easy to handle, and the prices are also comparable. It is expensive and the reaction is non-aqueous, which poses various practical difficulties. Furthermore, since the method (3) is an electrolytic reaction, it requires a large apparatus and has the disadvantage that it cannot be easily used.
（問題点を解決する為の手段）
本発明者らは、これら欠点を解決すぺ〈鋭意研究の結果
、グルタミン酸から容易に製造される公知化合物、Ｎ−
置換グルタミンｒＲ５−エステルが、水素化ホウ素す）
ＩＪウムにより還元をうけ、好収率でアルコールに変
換される事を見い出し、本発明を完成させるにいたった
。(Means for Solving the Problems) The present inventors have solved these shortcomings.As a result of intensive research, a known compound easily produced from glutamic acid, N-
Substituted glutamine rR5-ester is a borohydride)
It was discovered that it was reduced by IJum and converted into alcohol with good yield, leading to the completion of the present invention.
すなわち本発明は、一般式ＣＩ）
ＯＯＨ
■
ＲＮＨ−ＣＨ−ＣＨ２０Ｍ２ＣＯＯＲ’ （１）Ｃ
式中Ｒはベンゾイル基、ペンジルオキシヵルゲニル基、
トリルスルホニル基、アセチル基ヲ、Ｒ′はメチル基、
エチル基を表わす）で表わされるＮ−置換グルタミン酸
５−エステルを、安価で取り扱いやすぐ、水系で使用出
来る為反応操作面でも容易な水素化ホウ素ナトリウムで
還元する事を特徴とする一般式〔■〕
ＯＯＨ
ＲＮＨ−ＣＨ−ｃＨ２ｃａ２ｃＨ２ｏｎ （ＩＩ）
（式中Ｒは前記と同じ）で表わされる５−ヒドロキシノ
ルバリン誘導体の製法を提供するものである。更に本発
明方法によれば、該反応中にラセミ化等の副反応を伴う
ことなく、光学活性グルタミン酸誘導体から高光学純度
の光学活性５−ヒドロキシノルバリン誘導体を製造出来
る利点もある。That is, the present invention has the general formula CI) OOH ■ RNH-CH-CH20M2COOR' (1)C
In the formula, R is a benzoyl group, a penzyloxycargenyl group,
tolylsulfonyl group, acetyl group, R' is methyl group,
The general formula [■ ] OOH RNH-CH-cH2ca2cH2on (II)
The present invention provides a method for producing a 5-hydroxynorvaline derivative represented by the formula (wherein R is the same as above). Furthermore, the method of the present invention has the advantage that a highly optically pure optically active 5-hydroxynorvaline derivative can be produced from an optically active glutamic acid derivative without side reactions such as racemization occurring during the reaction.
反応は溶媒の存在下実施されるが、使用される溶媒とし
ては反応を阻害しないものであれば適当であるが、水、
含水アルコール、アルコール等が好ましく、また反応系
中に水酸化ナトリウム、水酸化カリウム等のアルカリを
存在させてもよい。The reaction is carried out in the presence of a solvent, and any solvent can be used as long as it does not inhibit the reaction, but water,
Hydrous alcohol, alcohol, etc. are preferred, and an alkali such as sodium hydroxide, potassium hydroxide, etc. may be present in the reaction system.
反応温度は一り０℃〜室温、反応時間は１時間から５時
間程度で十分である。使用される水素化ホウ素ナトリウ
ムはＮ−置換グルタミン酸５−エステルに対して若干過
剰モルの使用が好ましい。A reaction temperature of 0° C. to room temperature and a reaction time of about 1 to 5 hours are sufficient. The sodium borohydride used is preferably used in a slight molar excess relative to the N-substituted glutamic acid 5-ester.
反応生成物は反応終了後、酸を添加する事により残存し
ている水素化ホウ素ナトリウムを分解の後、析出する結
晶を口取し、適当な溶媒系、例えばベンゼン−エタノー
ル等より再結晶する事により、あるいは濃縮後残渣を適
当な溶媒、例えば酢酸エチル、クロロホルム等で抽出し
、有機層を乾燥濃縮し残渣を適当な溶媒系、例えばアル
コール−水系により結晶化する事により、容易に単離す
る事が出来る。After the reaction product is finished, acid is added to decompose the remaining sodium borohydride, and the precipitated crystals are collected and recrystallized from an appropriate solvent system, such as benzene-ethanol. or by extracting the residue after concentration with a suitable solvent such as ethyl acetate, chloroform, etc., drying and concentrating the organic layer, and crystallizing the residue with a suitable solvent system such as an alcohol-water system. I can do things.
（実施例） 以下実施例を挙げて本発明を説明する。(Example) The present invention will be explained below with reference to Examples.
実施例１゜
水２Ｑ＊ｌに水素化ホウ素ナトリウム１．３？を溶解し
、水冷攪拌下Ｎ−ベンゾイルーＤＬ−グルタミン酸５−
メチルエステル４Ｐを徐々に加えた。Example 1゜Sodium borohydride 1.3 to 2Q*l water? Dissolve N-benzoyl-DL-glutamic acid 5- under water cooling and stirring.
Methyl ester 4P was added slowly.
添加終了後頁に室温で４時間攪拌した。反応終了後塩酸
にて微酸性とし過剰の水素化ホウ素ナトリウムを分解後
、反応液を減圧下濃縮した。残渣に酢酸エチルを加え抽
出後、有機層を減圧下濃縮、残渣をエタノール−エーテ
ルよシ結晶化する事によ、９Ｎ−ベンゾイル−５−ヒド
ロキシ−ＤＬ−ノルバリン２．６ｙ−を得た。融点１４
０−２℃。After the addition was completed, the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was made slightly acidic with hydrochloric acid to decompose excess sodium borohydride, and the reaction solution was concentrated under reduced pressure. After extraction by adding ethyl acetate to the residue, the organic layer was concentrated under reduced pressure, and the residue was crystallized from ethanol-ether to obtain 9N-benzoyl-5-hydroxy-DL-norvaline 2.6y-. Melting point 14
0-2℃.
本化合物は、公知化合物との混融試験および赤外線吸収
スペクトルの比較により、その構造を確認した。The structure of this compound was confirmed through mixing tests with known compounds and comparison of infrared absorption spectra.
実施例２゜
０．０５Ｎ水酸化ナトリウム溶液３０−に水素化ホウ素
ナトリウム１．３１を溶解し、水冷攪拌下、Ｎ−） ９
ルスルホニルーＬ−グルタミン酸５−エチルエステル４
？を徐々に加えた。添加終了後頁に室温で５時間攪拌し
た。Example 2 1.31 of sodium borohydride was dissolved in 0.05N sodium hydroxide solution (30-), and the mixture was cooled with water and stirred (N-) 9
Rusulfonyl-L-glutamic acid 5-ethyl ester 4
? was added gradually. After the addition was completed, the mixture was stirred at room temperature for 5 hours.
反応終了後塩酸にて微酸性とし過剰の水素化ホウ素ナト
リウムを分解後頁に塩酸を加えｐＨ２とし冷蔵庫に一晩
放置した。析出した沈澱を口取しエタノールーペンゼ／
より再結晶する事によｆｉＮ−トリルスルホニル−５−
ヒドロキシ−Ｌ−ノルバリン２．１？を得た。After the reaction was completed, the mixture was made slightly acidic with hydrochloric acid to decompose excess sodium borohydride, and then hydrochloric acid was added to the mixture to adjust the pH to 2, and the mixture was left in a refrigerator overnight. Collect the precipitate and add ethanol-penze/
By recrystallizing from fiN-tolylsulfonyl-5-
Hydroxy-L-norvaline 2.1? I got it.
融点 １６１−３℃
〔α）ＤＬ６．８° （Ｃ＝２ 、 ＥｔｏＨ）実施例
３゜
実施例１において、水２ＯｆｆＬ／に代えて１０％含水
エタノール２０−を使用し以下実施例１と同様に処理す
る事によりＮ−ベンゾイル−５−ヒドロキシ−ＤＬ−ノ
ルバリン２．Ｏ？を得た。Melting point 161-3°C [α) DL6.8° (C=2, EtoH) Example 3 In Example 1, 10% aqueous ethanol 20- was used instead of water 2 Off L/, and the following procedure was carried out in the same manner as in Example 1. By treatment, N-benzoyl-5-hydroxy-DL-norvaline2. O? I got it.
実施例４゜
実施例１において、Ｎ−ベンゾイル−ＤＬ−グルタミン
酸５−メチルエステル４？のかわシにＮ−アセチル−Ｌ
−グルタミン酸５−メチルエステル３．５Ｐを使用し以
下実施例１と同様に処理することにより、Ｎ−アセチル
−５−ヒドロキシ−Ｉ、−ノルバリン２．１ψを得た。Example 4 In Example 1, N-benzoyl-DL-glutamic acid 5-methyl ester 4? N-acetyl-L for kawashi
By using 3.5P of -glutamic acid 5-methyl ester and treating in the same manner as in Example 1, 2.1ψ of N-acetyl-5-hydroxy-I,-norvaline was obtained.
実施例５゜
０．０５Ｎ水酸化す） ＩＪウム溶液３０νに水素化ホ
ウ素ナトリウム１．３Ｌ？を溶解し、水冷攪拌下、Ｎ−
ペンジルオキシカルデニルーＬ−グルタミン酸５−メチ
ルエステル４１を徐々に加えた。添加終了後頁に室温で
４時間攪拌した。反応終了後塩酸にて微酸性とし過剰の
水素化ホウ素ナトリウムを分解後、反応液を減圧下濃縮
した。残渣に酢酸エチルを加え抽出後、有機層を減圧下
濃縮、残渣を水−エタノールより結晶化することにより
、Ｎ−ペンジルオキシカルブニル−５−ヒドロキシ−Ｌ
−ノルパリン２．２？を得た。Example 5 1.3L of sodium borohydride in 30ν of IJium solution (0.05N hydroxide) was dissolved and stirred with water cooling, N-
Penzyloxycardenyl-L-glutamic acid 5-methyl ester 41 was slowly added. After the addition was completed, the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was made slightly acidic with hydrochloric acid to decompose excess sodium borohydride, and the reaction solution was concentrated under reduced pressure. After extraction by adding ethyl acetate to the residue, the organic layer was concentrated under reduced pressure, and the residue was crystallized from water-ethanol to obtain N-penzyloxycarbunyl-5-hydroxy-L.
- Norpaline 2.2? I got it.
融点 １１８−１２２℃
（効果）
以上説明してきた様に本発明の方法によれば、Ｎ−置換
グルタミン酸５−エステルを還元し５−ヒドロキシノル
バリン誘導体を製造するに際し、還元剤として水素化ホ
ウ素ナトリウムを使用する事により水系溶媒下で安価で
取扱いやすく反応操作も容易に反応を実施する事が出来
る。Melting point: 118-122°C (Effect) As explained above, according to the method of the present invention, when reducing N-substituted glutamic acid 5-ester to produce a 5-hydroxynorvaline derivative, sodium borohydride is used as a reducing agent. By using , the reaction can be carried out in an aqueous solvent at low cost, easy to handle, and easy to operate.
Claims (1)
、トリルスルホニル基、アセチル基を、Ｒ′はメチル基
、エチル基を表わす）で表わされるＮ−置換グルタミン
酸５−エステルを、水素化ホウ素ナトリウムで還元する
事を特徴とする一般式〔II〕 ▲数式、化学式、表等があります▼〔II〕 （式中Ｒは前記と同じ）で表わされる５−ヒドロキシノ
ルバリン誘導体の製法。[Claims] General formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, R is a benzoyl group, benzyloxycarbonyl group, tolylsulfonyl group, or acetyl group, and R' is a methyl group. , representing an ethyl group) is reduced with sodium borohydride [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[II] (Formula A method for producing a 5-hydroxynorvaline derivative represented by (wherein R is the same as above).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8604986A JPS62242653A (en) | 1986-04-16 | 1986-04-16 | Production of 5-hydroxynorvaline derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8604986A JPS62242653A (en) | 1986-04-16 | 1986-04-16 | Production of 5-hydroxynorvaline derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS62242653A true JPS62242653A (en) | 1987-10-23 |
Family
ID=13875825
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8604986A Pending JPS62242653A (en) | 1986-04-16 | 1986-04-16 | Production of 5-hydroxynorvaline derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62242653A (en) |
-
1986
- 1986-04-16 JP JP8604986A patent/JPS62242653A/en active Pending
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