JPH0338581A - Production of n-carbobenzoxy-l-aspartic anhydride - Google Patents
Production of n-carbobenzoxy-l-aspartic anhydrideInfo
- Publication number
- JPH0338581A JPH0338581A JP17192289A JP17192289A JPH0338581A JP H0338581 A JPH0338581 A JP H0338581A JP 17192289 A JP17192289 A JP 17192289A JP 17192289 A JP17192289 A JP 17192289A JP H0338581 A JPH0338581 A JP H0338581A
- Authority
- JP
- Japan
- Prior art keywords
- carbobenzoxy
- aspan
- anhydride
- reaction
- acetic anhydride
- 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
- OZPYEGOBGWQOSZ-VIFPVBQESA-N benzyl n-[(3s)-2,5-dioxooxolan-3-yl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)N[C@H]1CC(=O)OC1=O OZPYEGOBGWQOSZ-VIFPVBQESA-N 0.000 title claims abstract 5
- 238000004519 manufacturing process Methods 0.000 title description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 54
- XYXYXSKSTZAEJW-VIFPVBQESA-N (2s)-2-(phenylmethoxycarbonylamino)butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 XYXYXSKSTZAEJW-VIFPVBQESA-N 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 239000000463 material Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- DCSRPHQBFSYJNN-UHFFFAOYSA-L disodium 4-[(2-arsonophenyl)diazenyl]-3-hydroxynaphthalene-2,7-disulfonate Chemical compound [Na+].[Na+].Oc1c(N=Nc2ccccc2[As](O)(O)=O)c2ccc(cc2cc1S([O-])(=O)=O)S([O-])(=O)=O DCSRPHQBFSYJNN-UHFFFAOYSA-L 0.000 description 6
- 125000005907 alkyl ester group Chemical group 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 229960005190 phenylalanine Drugs 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- -1 N-carbobenzoxy-L-aspartic acid methyl esters Chemical class 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- FUCKRCGERFLLHP-VIFPVBQESA-N (2s)-4-amino-4-oxo-2-(phenylmethoxycarbonylamino)butanoic acid Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 FUCKRCGERFLLHP-VIFPVBQESA-N 0.000 description 1
- GWKOSRIHVSBBIA-REOHCLBHSA-N (3s)-3-aminooxolane-2,5-dione Chemical compound N[C@H]1CC(=O)OC1=O GWKOSRIHVSBBIA-REOHCLBHSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- CBQJSKKFNMDLON-JTQLQIEISA-N N-acetyl-L-phenylalanine Chemical compound CC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 CBQJSKKFNMDLON-JTQLQIEISA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野］
本発明は、Ｎ−カルボベンゾキシ−Ｌ−アスパラギン酸
（以下、Ｚ−Ｌ−Ａｓｐと略記する）からＮ−カルボベ
ンゾキシ−Ｌ−アスパラギン酸無水物（以下、Ｚ−Ｌ−
ＡｓｐＡｎと略記する）を製造する方法に関するもので
ある。Detailed Description of the Invention [Industrial Application Field] The present invention relates to the production of N-carbobenzoxy-L-asparagine from N-carbobenzoxy-L-aspartic acid (hereinafter abbreviated as Z-L-Asp). Acid anhydride (hereinafter referred to as Z-L-
The present invention relates to a method for producing AspAn).
Ｚ−Ｌ−ＡｓｐＡｎは、甘味料として使用されるα−Ｌ
−アスパルチルーＬ−フェニルアラニン低級アルキルエ
ステル（以下、α−ＡＰＥと略記する）の中間体として
重要な化合物である。例えば、特公昭５７−２５５３８
号公報にはＺ−Ｌ−ＡｓｐＡｎとＬ−フェニルアラニン
低級アルキルエステルとを反応せしめた後、接触還元に
より保護基であるカルボベンゾキシ基を脱離することに
よって、α−ＡＰＲが得られることが示されている。Z-L-AspAn is α-L used as a sweetener.
It is an important compound as an intermediate for -aspartyl-L-phenylalanine lower alkyl ester (hereinafter abbreviated as α-APE). For example, Tokuko Sho 57-25538
The publication discloses that α-APR can be obtained by reacting Z-L-AspAn and L-phenylalanine lower alkyl ester and then removing the carbobenzoxy group, which is a protective group, by catalytic reduction. has been done.
特に、α−ＡＰＥの中のメチルエステル体であるα−Ｌ
・−アスパルチル−し−フェニルアラニンメチルエステ
ルは、ジペプチド系の甘味料として広く知られており、
良質な甘味特性ならびに蔗糖の２００倍近い高甘味度を
有し、ダイエツト甘味剤としてその需要が大きく伸長し
ているものである。In particular, α-L, which is a methyl ester in α-APE,
-Aspartyl-phenylalanine methyl ester is widely known as a dipeptide sweetener.
It has good sweetness characteristics and a sweetness level nearly 200 times that of sucrose, and its demand as a dietary sweetener is growing rapidly.
〔従来の技術及び解決しようとする課題〕従来、Ｚ−Ｌ
−ＡｓｐＡｎを製造する方法として、Ｚ−Ｌ−Ａｓｐを
大過剰の無水酢酸に溶解させ、減圧下に過剰の無水酢酸
との反応によって生成した酢酸を留去し、さらに残香に
有ａ溶剤を添加して残存する酢酸を除去した後、Ｚ−Ｌ
−ＡｓｐＡｎを得る方法（ジャーナル・オブ・アメリカ
ン・ケミカル・ソサエティー鉦、１６７〜１７３（１９
５９）が公知である。[Conventional technology and problems to be solved] Conventionally, Z-L
-As a method for producing AspAn, Z-L-Asp is dissolved in a large excess of acetic anhydride, the acetic acid produced by the reaction with the excess acetic anhydride is distilled off under reduced pressure, and an alkaline solvent is added to the residual aroma. After removing the remaining acetic acid, Z-L
- Method of obtaining AspAn (Journal of American Chemical Society, 167-173 (19
59) is known.
また、Ｚ−Ｌ−Ａｓｐを無水酢酸中、スラリーとし反応
を５０°Ｃ以下で行い、冷却後、エーテルと石油エーテ
ルの混合液を添加して目的物を得る方法（特開昭４６−
１３７０号公報）、あるいはＺ−Ｌ−Ａｓｐと無水酢酸
との反応を芳香族炭化水素の存在下に行う方法（特開昭
４８−７５５４２号公報）が知られている。Alternatively, Z-L-Asp is slurried in acetic anhydride, the reaction is carried out at 50°C or less, and after cooling, a mixture of ether and petroleum ether is added to obtain the desired product (Japanese Unexamined Patent Application Publication No. 46-111).
1370) or a method in which Z-L-Asp and acetic anhydride are reacted in the presence of an aromatic hydrocarbon (Japanese Unexamined Patent Publication No. 75542/1982).
しかしながら、いずれの方法においても無水酢酸を大過
剰用いるために経済的でなく、さらに目的物を単離する
ため減圧下で過剰の無水酢酸および酢酸を留去するか、
溶解度を下げるために引火点の低い有機溶剤を添加しな
ければならないなど工業的に実施するには満足できる方
法ではなかった。However, in either method, it is not economical because acetic anhydride is used in large excess, and in order to further isolate the target product, excess acetic anhydride and acetic acid are distilled off under reduced pressure.
This method was not satisfactory for industrial implementation, as it required the addition of an organic solvent with a low flash point to reduce solubility.
一般にＮ−保護−Ｌ−アスパラギン酸無水物を工業的に
製造する場合、Ｎ−保護−Ｌ−アスパラギン酸無水物を
単離することなく、次いでＬ−フェニルアラニン低級ア
ルキルエステル類と縮合反応させることが操作上望まし
い。Generally, when N-protected-L-aspartic acid anhydride is produced industrially, it is possible to perform a condensation reaction with L-phenylalanine lower alkyl esters without isolating the N-protected-L-aspartic anhydride. Operationally desirable.
しかしながら、脱水剤として無水酢酸を過剰に用いて反
応を行った場合、次のＬ−フェニルアラニン低級アルキ
ルエステル類との縮合においてＮアセチル−Ｌ−フェニ
ルアラニン低級アルキルエステル類が生じる。そのため
、無水酢酸の使用量を極力抑え、無水物化の反応率を高
める製造法が望まれていた。However, when the reaction is carried out using an excess of acetic anhydride as a dehydrating agent, N-acetyl-L-phenylalanine lower alkyl esters are produced in the subsequent condensation with L-phenylalanine lower alkyl esters. Therefore, a production method that minimizes the amount of acetic anhydride used and increases the reaction rate of anhydride conversion has been desired.
特開昭５８−１６７５７７号公報には、Ｚ−Ｌ−Ａｓｐ
と無水酢酸との反応を各種金属の酸化物、水酸化物もし
くは塩または有機塩基化合物の存在下に行う方法が示さ
れている。In JP-A-58-167577, Z-L-Asp
and acetic anhydride in the presence of various metal oxides, hydroxides or salts or organic basic compounds.
上記の方法においては、原料、生成物、溶媒、無水酢酸
以外の第三物質の添加を行っている。そのため、後工程
に影響を及ぼす可能性があり、影響を考慮する必要があ
る。In the above method, a third substance other than the raw material, product, solvent, and acetic anhydride is added. Therefore, there is a possibility that it will affect the subsequent process, and it is necessary to consider the effect.
このように従来公知のＺ−Ｌ−ＡｓｐＡｎの製造方法は
それぞれ欠点を有し、工業的製造法とするには必ずしも
満足できる方法ではない。As described above, the conventionally known methods for producing Z-L-AspAn each have their own drawbacks, and are not necessarily satisfactory for industrial production.
本発明者らは、Ｚ−Ｌ−ＡｓｐＡｎの製造法に於いて上
記のような従来法の欠点がなく、しかも高収率・短時間
に目的化合物Ｚ−Ｌ−ＡｓｐＡｎを得る方法を鋭意検討
の結果、本無水物化反応において、あらかじめＺ−Ｌ−
ＡｓｐＡｎを添加すれば反応速度が著しく増大し、短時
間に高収率で目的化合物Ｚ−Ｌ−ＡｓｐＡｎを得ること
ができることを見出し、本発明を完成した。The present inventors have conducted extensive studies to find a method for producing Z-L-AspAn that does not have the drawbacks of the conventional methods as described above and that can obtain the target compound Z-L-AspAn in a high yield and in a short time. As a result, in this anhydration reaction, Z-L-
The present invention was completed based on the discovery that the addition of AspAn significantly increases the reaction rate and allows the target compound Z-L-AspAn to be obtained in a short period of time and in high yield.
すなわち、本発明はＮ−カルボベンゾキシ−しアスパラ
ギン酸と無水酢酸をＺ−Ｌ−ＡｓｐＡｎの存在下に反応
せしめることを特徴とするＮ−カルボベンゾキシ−Ｌ−
アスパラギン酸無水物の製造方法である。That is, the present invention is characterized in that N-carbobenzoxy-L-aspartic acid and acetic anhydride are reacted in the presence of Z-L-AspAn.
This is a method for producing aspartic acid anhydride.
あらかじめ添加するＺ−Ｌ−ＡｓｐＡｎの添加量は、溶
媒の種類により幾分異にするが、＠量共存すれば良く、
例えば、実施例３に示す如く、Ｚ−ＡｓｐＡｎの添加量
はＺ−Ｌ−Ａｓｐに対し、０．１重量％であり、このよ
うにａｆｌ共存しても有効な触媒作用を示すことがわか
る０本発明を工業的に実施する場合に存在せしめるこの
化合物の量は、Ｚ−Ｌ−Ａｓｐに対する重量％で０．０
１以上あれば良く、好ましくは０．１％以上であり、上
限は特にないが、経済上重量％で５０以下が望ましい。The amount of Z-L-AspAn added in advance varies somewhat depending on the type of solvent, but it is sufficient that the amount coexists.
For example, as shown in Example 3, the amount of Z-AspAn added was 0.1% by weight with respect to Z-L-Asp, and it can be seen that even when afl coexists in this way, it exhibits an effective catalytic action. The amount of this compound present when carrying out the invention industrially is 0.0% by weight relative to Z-L-Asp.
It is sufficient if it is 1 or more, preferably 0.1% or more, and there is no particular upper limit, but it is preferably 50 or less in terms of weight from an economical point of view.
又、添加法としてはＺ−ＡｓｐＡｎを固体状態で添加す
る以外に、溶媒に溶解もしくは懸濁させて添加を行った
り、あるいは、Ｚ−Ｌ−Ａｓｐの無水物化の反応マスを
そのまま一部残存させたり、種々の添加法で行うことが
可能である。すなわち添加法の違いは本発明の本質を損
なうものではなく、いかなる添加法も可能である。In addition, as an addition method, in addition to adding Z-AspAn in a solid state, it may be added by dissolving or suspending it in a solvent, or by leaving a part of the reaction mass of Z-L-Asp anhydride as it is. Alternatively, various addition methods can be used. That is, the difference in the addition method does not impair the essence of the present invention, and any addition method is possible.
本発明において用いられる溶媒としては、反応物び生成
物に特に活性なものでなければ、いかなる溶媒も用いる
ことができる。アセトン、メチルエチルケトンの如きケ
トン類、ジエチルエーテル、テトラヒドロフラン、ジオ
キサンの如きエーテル類、アセトニトリルの如きニトリ
ル類、酢酸エチル、プロピオン酸メチルの如きエステル
類、キ酸、酢酸、プロピオン酸の如きカルボン酸類、ク
ロロホルム、ジクロルメタン、エチレンジクロリドの如
きハロゲン化炭化水素類、トルエン、キシレン、ヘキサ
ン、シクロヘキサンの如き炭化水素類、その他ジメチル
ホルムアξドの如きアミド類、ジメチルスルホキシド、
γ−ブチロラクトン、ニトロメタンなど、およびこれら
のうちの任意の２種以上からなる混合溶媒が代表的なも
のである。As the solvent used in the present invention, any solvent can be used as long as it is not particularly active against the reactants and products. Ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, tetrahydrofuran and dioxane, nitriles such as acetonitrile, esters such as ethyl acetate and methyl propionate, carboxylic acids such as chloroform, acetic acid and propionic acid, chloroform, Halogenated hydrocarbons such as dichloromethane and ethylene dichloride, hydrocarbons such as toluene, xylene, hexane, and cyclohexane, amides such as dimethylformamide, dimethyl sulfoxide,
Typical examples include γ-butyrolactone, nitromethane, etc., and mixed solvents consisting of any two or more of these.
又、本発明において使用される無水酢酸量は、Ｚ−Ｌ−
Ａｓｐに対して０．５モル比以上２モル比以下が好まし
い、特に好ましくは、０．９モル比以上１．０５モル比
以下である。一方、反応温度は生成物のラセミ化を抑制
する観点より １００″Ｃ以下−ｌＯ°Ｃ以上、好まし
くは８０°Ｃ以下０“Ｃ以上である。Moreover, the amount of acetic anhydride used in the present invention is ZL-
The molar ratio to Asp is preferably 0.5 to 2 molar ratio, particularly preferably 0.9 to 1.05 molar ratio. On the other hand, from the viewpoint of suppressing racemization of the product, the reaction temperature is 100°C or lower - lO°C or higher, preferably 80°C or lower and 0"C or higher.
以下、実施例、比較例により本発明をさらに詳細に説明
する。Hereinafter, the present invention will be explained in more detail with reference to Examples and Comparative Examples.
実施例１
Ｚ−Ｌ−Ａｓ ｐ６７．０ｇ （０，２５モル）とＺ−
ＬＡ ｓ ｐ Ａ ｎ Ｏ，６７ｇ （２，６９ｘｌＯ
−３モル）をトルエン１２９．４ ｇに懸濁し、無水酢
酸（純度９３Ｘ） ２６．９ ｇを添加し、反応温度５
５℃で３時間反応を行った。Example 1 Z-L-As p67.0g (0.25 mol) and Z-
LA sp A n O, 67g (2,69xlO
-3 mol) was suspended in 129.4 g of toluene, 26.9 g of acetic anhydride (purity 93X) was added, and the reaction temperature was increased to 5.
The reaction was carried out at 5°C for 3 hours.
得られた反応液より適量分取し、５重量パーセントのト
リエチルアミンを含むメタノール液に溶解せしめ、Ｚ−
Ｌ−ＡｓｐＡｎとメタノールの反応により生成したα及
びβのＮ−カルボベンゾキシ−Ｌ−アスパラギン酸メチ
ルエステルと残存するＺ−Ｌ−Ａｓｐを高速液体クロマ
トグラフィーにより定量した。定量した値よりＺ−Ｌ−
ＡｓｐＡｎの反応収率を算出した。An appropriate amount was taken from the obtained reaction solution, dissolved in a methanol solution containing 5% by weight of triethylamine, and Z-
α and β N-carbobenzoxy-L-aspartic acid methyl esters produced by the reaction of L-AspAn and methanol and remaining Z-L-Asp were quantified by high performance liquid chromatography. From the quantified value, Z-L-
The reaction yield of AspAn was calculated.
反応収率 ９２．６ ％
比較例
Ｚ −Ｌ−Ａ ｓ ｐ６７．０ｇ （０，２５モル）を
トルエン１２９．４ ｇに懸濁し、無水酢酸（純度９３
χ） ２６．９ ｇを添加し、反応温度５５℃で３時間
反応を行った。Reaction yield 92.6% Comparative example Z
χ) 26.9 g was added, and the reaction was carried out at a reaction temperature of 55° C. for 3 hours.
得られた反応液より適量分取し、５重量パーセントのト
リエチルアミンを含むメタノール液に熔解せしめ、Ｚ−
Ｌ−ＡｓｐＡｎとメタノールの反応により生成したα及
びβのＮ−カルボベンゾキシ−Ｌ−アスパラギン酸メチ
ルエステルと残存するＺ−Ｌ−Ａｓｐを高速液体クロマ
トグラフィーにより定量した。定量した値よりＺ−Ｌ−
ＡｓｐＡｎの反応収率を算出した。An appropriate amount was taken from the obtained reaction solution and dissolved in a methanol solution containing 5% by weight of triethylamine.
α and β N-carbobenzoxy-L-aspartic acid methyl esters produced by the reaction of L-AspAn and methanol and remaining Z-L-Asp were quantified by high performance liquid chromatography. From the quantified value, Z-L-
The reaction yield of AspAn was calculated.
反応収率 ４２．３ ％
実施例２〜５
溶媒を変える以外の反応条件は、実施例１と同様に行っ
た。Reaction yield: 42.3% Examples 2 to 5 The reaction conditions were the same as in Example 1 except for changing the solvent.
実施例６〜７
無水酢酸の添加量を変える以外の反応条件は、実施例１
と同様に行った。Examples 6-7 Reaction conditions other than changing the amount of acetic anhydride were as in Example 1.
I did the same thing.
実施例８〜ｌＯ
あらかじめ添加するＺ−ＡｓｐＡｎの添加量以外の反応
条件は、実施例１と同様に行った。Example 8-IO The reaction conditions were the same as in Example 1 except for the amount of Z-AspAn added in advance.
実施例２〜ｌＯの結果を表−■に示す。The results of Examples 2 to 1O are shown in Table-■.
本発明によれば、原料、生成物、溶媒、無水酢酸以外の
第三物質を添加することなく、工業上極めて有用なα−
ＡＰＲの原料化合物であるＺ、−Ｌ−ＡｓｐＡｎを短時
間でしかも高収率で得ることができる。According to the present invention, industrially extremely useful α-
Z, -L-AspAn, which is a raw material compound for APR, can be obtained in a short time and in high yield.
Claims (1)
酢酸をＮ−カルボベンゾキシ−Ｌ−アスパラギン酸無水
物の存在下に反応せしめることを特徴とするＮ−カルボ
ベンゾキシ−Ｌ−アスパラギン酸無水物の製造方法。1) N-carbobenzoxy-L-aspartic anhydride, which is obtained by reacting N-carbobenzoxy-L-aspartic acid and acetic anhydride in the presence of N-carbobenzoxy-L-aspartic anhydride. How things are manufactured.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17192289A JP2788496B2 (en) | 1989-07-05 | 1989-07-05 | Method for producing N-carbobenzoquine-L-aspartic anhydride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17192289A JP2788496B2 (en) | 1989-07-05 | 1989-07-05 | Method for producing N-carbobenzoquine-L-aspartic anhydride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0338581A true JPH0338581A (en) | 1991-02-19 |
| JP2788496B2 JP2788496B2 (en) | 1998-08-20 |
Family
ID=15932338
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17192289A Expired - Lifetime JP2788496B2 (en) | 1989-07-05 | 1989-07-05 | Method for producing N-carbobenzoquine-L-aspartic anhydride |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2788496B2 (en) |
-
1989
- 1989-07-05 JP JP17192289A patent/JP2788496B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JP2788496B2 (en) | 1998-08-20 |
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