JPS63246369A - Production of 2,3-dioxopiperazines - Google Patents
Production of 2,3-dioxopiperazinesInfo
- Publication number
- JPS63246369A JPS63246369A JP7750187A JP7750187A JPS63246369A JP S63246369 A JPS63246369 A JP S63246369A JP 7750187 A JP7750187 A JP 7750187A JP 7750187 A JP7750187 A JP 7750187A JP S63246369 A JPS63246369 A JP S63246369A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- reaction
- oxalic acid
- general formula
- 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
- JTHRRMFZHSDGNJ-UHFFFAOYSA-N piperazine-2,3-dione Chemical class O=C1NCCNC1=O JTHRRMFZHSDGNJ-UHFFFAOYSA-N 0.000 title claims description 10
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 30
- -1 oxalic acid diester Chemical class 0.000 claims abstract description 19
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 235000006408 oxalic acid Nutrition 0.000 claims abstract description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 11
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 10
- 125000003118 aryl group Chemical group 0.000 claims abstract description 10
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 7
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000007112 amidation reaction Methods 0.000 claims abstract description 5
- 150000002171 ethylene diamines Chemical class 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 239000002243 precursor Substances 0.000 abstract description 5
- JKRZOJADNVOXPM-UHFFFAOYSA-N Oxalic acid dibutyl ester Chemical compound CCCCOC(=O)C(=O)OCCCC JKRZOJADNVOXPM-UHFFFAOYSA-N 0.000 abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 4
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 abstract description 3
- 239000012442 inert solvent Substances 0.000 abstract description 3
- 229930182555 Penicillin Natural products 0.000 abstract description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 abstract description 2
- 150000001408 amides Chemical class 0.000 abstract description 2
- 238000006482 condensation reaction Methods 0.000 abstract description 2
- KFIGICHILYTCJF-UHFFFAOYSA-N n'-methylethane-1,2-diamine Chemical compound CNCCN KFIGICHILYTCJF-UHFFFAOYSA-N 0.000 abstract description 2
- 229940049954 penicillin Drugs 0.000 abstract description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract description 2
- 239000011259 mixed solution Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000000034 method Methods 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- SCZVXVGZMZRGRU-UHFFFAOYSA-N n'-ethylethane-1,2-diamine Chemical compound CCNCCN SCZVXVGZMZRGRU-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JFCYLCCDNNDPAM-UHFFFAOYSA-N 1-(2-hydroxyethyl)piperazine-2,3-dione Chemical compound OCCN1CCNC(=O)C1=O JFCYLCCDNNDPAM-UHFFFAOYSA-N 0.000 description 1
- ZBEKOEYCWKIMGU-UHFFFAOYSA-N 1-ethylpiperazine-2,3-dione Chemical compound CCN1CCNC(=O)C1=O ZBEKOEYCWKIMGU-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- NULAJYZBOLVQPQ-UHFFFAOYSA-N N-(1-naphthyl)ethylenediamine Chemical compound C1=CC=C2C(NCCN)=CC=CC2=C1 NULAJYZBOLVQPQ-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical class NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- DFPGBRPWDZFIPP-UHFFFAOYSA-N n'-butylethane-1,2-diamine Chemical compound CCCCNCCN DFPGBRPWDZFIPP-UHFFFAOYSA-N 0.000 description 1
- KFUBMLABCQRXMB-UHFFFAOYSA-N n'-ethenylethane-1,2-diamine Chemical compound NCCNC=C KFUBMLABCQRXMB-UHFFFAOYSA-N 0.000 description 1
- UTPUPJKKYXJFPX-UHFFFAOYSA-N n'-octylethane-1,2-diamine Chemical compound CCCCCCCCNCCN UTPUPJKKYXJFPX-UHFFFAOYSA-N 0.000 description 1
- OCIDXARMXNJACB-UHFFFAOYSA-N n'-phenylethane-1,2-diamine Chemical compound NCCNC1=CC=CC=C1 OCIDXARMXNJACB-UHFFFAOYSA-N 0.000 description 1
- HDRQAYYDCXGPSR-UHFFFAOYSA-N n'-prop-1-enylethane-1,2-diamine Chemical compound CC=CNCCN HDRQAYYDCXGPSR-UHFFFAOYSA-N 0.000 description 1
- SOWBFZRMHSNYGE-UHFFFAOYSA-N oxamic acid Chemical class NC(=O)C(O)=O SOWBFZRMHSNYGE-UHFFFAOYSA-N 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- ZYOYYQRWXITKFF-UHFFFAOYSA-N pyrazine-2,3-dione Chemical class O=C1N=CC=NC1=O ZYOYYQRWXITKFF-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野コ
本発明は、医薬品として極めて優れた性質を有する０合
成ペニシリンおよび合成セファロスポリン系化合物の中
間体として有用な２，３−ジオキソピペラジン類を温和
な条件下に高収率で得る改良された製造法に関する。詳
しくは一般式（１）％式％（１）
（式中Ｒ１はアルキル基、アルケニル基、アリール基及
びこれらに水酸基で置換されたものを示す）
で示されるエチレンジアミン類と一般式（２）％式％（
２）
（式中Ｒ２はアルキル基を示す）
で示されるシュウ酸ジエステル類の縮合反応による、一
般式（３）
％式％（３）
（式中Ｒ１はアルキル基、アルケニル基、アリール基及
びこれらに水酸基で置換されたものを示す）
で示される２、３−ジオキソピペラジン類の改良された
製法に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention provides 2,3-dioxopiperazines useful as intermediates for synthetic penicillin and synthetic cephalosporin compounds, which have extremely excellent properties as pharmaceuticals. The present invention relates to an improved method for the production of a high yield under mild conditions. Specifically, ethylenediamines represented by the general formula (1)% (1) (in the formula, R1 represents an alkyl group, an alkenyl group, an aryl group, and those substituted with a hydroxyl group) and general formula (2)% formula%(
2) (In the formula, R2 represents an alkyl group) General formula (3) % Formula % (3) (In the formula, R1 represents an alkyl group, an alkenyl group, an aryl group, and The present invention relates to an improved method for producing 2,3-dioxopiperazines represented by the following formula (indicating those substituted with a hydroxyl group).
［従来の技術］
２．３−ジオキソピペラジン類は、従来エチレンジアミ
ン類とシュウ酸ジエステル、オキサミド、オキサミド酸
エステル等との反応により合成されている。[Prior Art] 2.3-dioxopiperazines have conventionally been synthesized by reacting ethylenediamines with oxalic acid diesters, oxamides, oxamic acid esters, and the like.
シュウ酸ジエステル類を原料とする方法としては、たと
えば（Ｊ、Ｏ，Ｃ，１５巻６８ページ）にエチレンジア
ミン類とシュウ酸ジメチルを１８０℃まで加熱し、副生
ずるメタノールを留去しながら反応させる一般的合成法
が報告されている。As a method using oxalic acid diesters as raw materials, for example (J, O, C, Vol. 15, p. 68), ethylenediamines and dimethyl oxalate are heated to 180°C and reacted while distilling off methanol as a by-product. A synthetic method has been reported.
同じ方法によるＮ−ヒドロキシエチル−２，３−ジオキ
ソピペラジンの合成が（Ｊ、０．Ｃ，２５巻２０５９ペ
ージ）に報告されているが収率は２０〜３５％と極めて
低収率である。The synthesis of N-hydroxyethyl-2,3-dioxopiperazine by the same method was reported in (J, 0.C, Vol. 25, p. 2059), but the yield was extremely low at 20-35%. .
これらシュウ酸ジエステル類とエチレンジアミン類は、
同じ反応性を有する官能基を共に２個ずつ有するため、
大量に副反応が起こり、２分子間の閉環反応による目的
化合物、２．３−ジオキソピペラジン類の収率は低いと
いう欠点を有していた。These oxalic acid diesters and ethylene diamines are
Because they both have two functional groups with the same reactivity,
It has the disadvantage that a large amount of side reactions occur and the yield of the target compound, 2,3-dioxopiperazine, is low due to the ring-closing reaction between two molecules.
このような副反応を抑制する方法として、エチレンジア
ミン類と炭酸ガスを反応させた後、シュウ酸ジエステル
と縮合する方法（特開昭５２−２３０８６号）、エチレ
ンジアミン類とシュウ酸ジエステルとの反応を金属アル
コラードの存在下に行う方法（特開昭５６−７７２６６
号）が提案されている。しかしこれらの方法も、反応媒
体として炭酸ガスを用いるため、設備が複雑になること
や、高価なアルカリ金属アルコ−ラードをエチレンジア
ミン類に対し当モル以上使用する必要があることなどに
より、工業的に有利な方法であるとは言い誼い。Methods for suppressing such side reactions include a method in which ethylenediamines are reacted with carbon dioxide gas and then condensed with oxalic acid diester (Japanese Patent Application Laid-Open No. 52-23086); Method carried out in the presence of alcolade (Japanese Patent Application Laid-Open No. 56-77266
No.) has been proposed. However, these methods also use carbon dioxide gas as a reaction medium, which makes the equipment complicated, and requires the use of an expensive alkali metal alcoholide in an amount equal to or more than the equivalent mole of ethylenediamine. It is hard to say that it is an advantageous method.
［本発明が解決しようとする問題点］
本発明者は、上述のような問題点を改善すべく鋭意研究
を重ねた結果、エチレンジアミン類とシュウ酸ジエステ
ル類との縮合反応により２．３−ジオキソピペラジン類
を製造するに際し、閉環反応に先立つ一段目のアミド化
反応を１５℃以下の低温で行なうことにより高収率で２
．３−ジオキソピペラジン類が得られることを発見し、
本発明に至った。[Problems to be Solved by the Present Invention] As a result of extensive research in order to improve the above-mentioned problems, the present inventors have discovered that 2,3-diamines can be solved by a condensation reaction between ethylenediamines and oxalic acid diesters. When producing oxopiperazines, the first amidation reaction prior to the ring-closing reaction is carried out at a low temperature of 15°C or less, resulting in a high yield of 2.
．． discovered that 3-dioxopiperazines could be obtained,
This led to the present invention.
［問題点を解決するための手段］
本発明は一般式（１）
％式％（１）
（式中Ｒ１はアルキル基、アルケニル基、アリール基及
びこれらに水酸基で置換されたものを示す）
で示されるエチレンジアミン類と一般式（２）％式％
（式中Ｒ２はアルキル基を示す）
で示されるシュウ酸ジエステル頭の反応により、一般式
（３）
％式％
（式中Ｒ１はアルキル基、アルケニル基、アリール基及
びこれらに水酸基で置換されたものを示す）
で示される２、３−ジオキソピペラジン類を製造するに
際し、不活性溶剤と一般式（２）のシュウ酸ジエステル
類との混合溶液に、１５℃以下の温度で一般式（１）の
エチレンジアミン類を加え一段目のアミド化反応を行っ
た後、１５〜１５０℃に昇温し、二段目の閉環反応をさ
せることを特徴とする２、３−ジオキソピラジン類の製
造法に関するものである。[Means for Solving the Problems] The present invention is based on the general formula (1) % formula % (1) (wherein R1 represents an alkyl group, an alkenyl group, an aryl group, or a group substituted with a hydroxyl group). By the reaction of the ethylene diamines represented by the general formula (2) with the oxalic acid diester head represented by the general formula (2) % formula % (in the formula, R2 represents an alkyl group), the general formula (3) % formula % (in the formula R1 represents an alkyl group, When producing 2,3-dioxopiperazines represented by alkenyl groups, aryl groups, and those substituted with hydroxyl groups, an inert solvent and an oxalic diester of general formula (2) are mixed. It is characterized by adding ethylene diamines of general formula (1) to the solution at a temperature of 15°C or lower to perform the first amidation reaction, and then raising the temperature to 15 to 150°C to perform the second ring-closing reaction. The present invention relates to a method for producing 2,3-dioxopyrazines.
シュウ酸ジエステル類にエチレンジアミン類を１５℃以
下で加えることの意味は、副反応を抑制することにある
。さらに詳しくは、エチレンジアミン類とシュウ酸ジエ
ステル類が３分子以上縮合した鎖状のポリアミド体の副
生を抑えることにあり、２．３−ジオキソピペラジン類
の前駆体と考えられる一般式（４）で示されるアミド体
を収率よく生成させる点にある。The purpose of adding ethylenediamines to oxalic acid diesters at 15° C. or lower is to suppress side reactions. More specifically, the objective is to suppress the by-product of chain polyamides in which three or more molecules of ethylenediamines and oxalic acid diesters are condensed, and the general formula (4) is considered to be a precursor of 2,3-dioxopiperazines. The point is that the amide compound shown by can be produced in good yield.
・・・（４） Ｒ２−０−Ｃ−Ｃ−ＮＨＣＨ２ＣＨ２ＮＨＲ。...(4) R2-0-C-C-NHCH2CH2NHR.
（式中Ｒ１はアルキル基、アルケニル基、アリール基及
びこれらに水酸基で置換されたものを示す。(In the formula, R1 represents an alkyl group, an alkenyl group, an aryl group, and those substituted with a hydroxyl group.
Ｒ２はアルキル基を示す、）
本発明によれば、たとえば下記構造を有する一般式（５
）
％式％（５）
（式中Ｒ１はアルキル基、アルケニル基、アリール基及
びこれらに水酸基で置換されたものを示す）および一般
式（６）
％式％（６）
（式中Ｒ１はアルキル基、アルケニル基、アリール基及
びこれらに水酸基で置換されたものを示す。R2 represents an alkyl group) According to the present invention, for example, the general formula (5
) %Formula %(5) (In the formula, R1 represents an alkyl group, an alkenyl group, an aryl group, and those substituted with a hydroxyl group) and General formula (6) %Formula%(6) (In the formula, R1 represents an alkyl group group, alkenyl group, aryl group, and those substituted with a hydroxyl group.
Ｒ２はアルキル基を示す、）
で示される高次の縮合物を生成するような副反応が抑制
され、一般式（４）で示される前駆体の選択性が向上し
、結果として目的物である２、３−ジオキソピペラジン
類が高収率で得られる。又前駆体である一般式（４）で
示されるアミド体の選択性を上げるためには、シュウ酸
ジエステル類にエチレンジアミン類を加えてゆく方法が
好ましい。R2 represents an alkyl group) Side reactions that produce a higher order condensate represented by the formula (4) are suppressed, and the selectivity of the precursor represented by the general formula (4) is improved, resulting in the formation of the desired product. 2,3-dioxopiperazines are obtained in high yield. In order to increase the selectivity of the amide compound represented by the general formula (4) as a precursor, it is preferable to add ethylenediamines to oxalic acid diesters.
本発明に用いられる不活性溶剤の意味は、エスチル基と
アミノ基とのアミド化反応に対し不活性であることを意
味し、たとえば、メタノール、エタノール、イングロパ
ノール等のアルコール系溶剤、テトラヒドロフラン、ジ
オキサン、メトキシエタノール、ジエチルエーテル等の
エーテル系溶剤、ベンゼン、トルエン、キシレン等の升
香族系溶剤等のＩＮまたは２種以上の混合物として用い
られる。The inert solvent used in the present invention means inert to the amidation reaction between an ethyl group and an amino group, and includes, for example, alcoholic solvents such as methanol, ethanol, and ingropanol, tetrahydrofuran, It is used as IN or a mixture of two or more of ether solvents such as dioxane, methoxyethanol and diethyl ether, and aromatic solvents such as benzene, toluene and xylene.
反応温度は、上述のように、シュウ酸ジエステル中へエ
チレンジアミン類を加える温度を１５℃以下の低温とし
、前駆体のアミド体とした後、１５ ”Ｃ乃至１５０℃
に昇温し、二段目の閉環反応を完結させる。この際の温
度は実質的に１５°Ｃ乃至使用する溶剤の常圧における
沸点である０反応時間は１時間乃至３時間で十分である
。沸点以上の温度でも反応にさしつかえはない。As mentioned above, the reaction temperature is such that the ethylenediamine is added to the oxalic acid diester at a low temperature of 15°C or lower to form the amide form of the precursor, and then from 15''C to 150°C.
to complete the second ring-closing reaction. At this time, the temperature is substantially 15° C. and the boiling point of the solvent used at normal pressure is 0.0 reaction time is sufficient to be 1 to 3 hours. There is no problem with the reaction even at temperatures above the boiling point.
一般式（１）のエチレンジアミン類としては、Ｎ−メチ
ルエチレンジアミン、Ｎ−エチルエチレンジアミン、Ｎ
−プロピルエチレンジアミン、Ｎ−ブチルエチレンジア
ミン、Ｎ−オクチルエチレンジアミン等のアルキルエチ
レンジアミン、Ｎ−ビニルエチレンジアミン、Ｎ−プロ
ペニルエチレンジアミン等のアリールエチレンジアミン
、Ｎ−フェニルエチレンジアミン、Ｎ−ナフチルエチレ
ンジアミン等のアリールエチレンジアミンがあげられる
。又これらはさらに水酸基で置換されてもよい。Ethylenediamines of general formula (1) include N-methylethylenediamine, N-ethylethylenediamine, N-ethylethylenediamine, and N-ethylethylenediamine.
Examples include alkylethylenediamines such as -propylethylenediamine, N-butylethylenediamine, and N-octylethylenediamine; arylethylenediamines such as N-vinylethylenediamine and N-propenylethylenediamine; and arylethylenediamines such as N-phenylethylenediamine and N-naphthylethylenediamine. Moreover, these may be further substituted with a hydroxyl group.
−ａ式（２）のシュウ酸ジエステル類としては、シュウ
酸ジメチル、シュウ酸ジエチル、シュウ酸ジブチル等が
あげられる。-a Examples of the oxalic acid diesters of formula (2) include dimethyl oxalate, diethyl oxalate, dibutyl oxalate, and the like.
上記の如く本発明は、容易に入手できるエチレンジアミ
ン類とシュウ酸ジエステル類を不活性ｍ削中、第３の成
分を何ら加えることなく高収率で２．３−ジオキソピペ
ラジン類を得ることのできる優れた工業的製造法である
。As described above, the present invention is capable of obtaining 2,3-dioxopiperazines in high yield during inert milling of easily available ethylene diamines and oxalic acid diesters without adding any third component. This is an excellent industrial manufacturing method.
［実 施 例］
以下実施例により本発明を具体的に説明するが、これら
の実施例は例示であり、本発明はこれらに限定されるも
のではない。[Examples] The present invention will be specifically described below with reference to Examples, but these Examples are merely illustrative and the present invention is not limited thereto.
実施例−１
かくはん機付フラスコに、温度計、還流冷却器及び滴下
ロートをセットした１反応フラスコに溶剤のエタノール
１５０グラムとシュウ酸ジエチル１４９グラム（１，０
２モル）を仕込み１５℃以下に冷却し１５℃以下の温度
を維持しながら滴下ロートよりＮ−エチルエチレンジア
ミン８８グラム（１，００モル）を約３０分で滴下した
０滴下終了ｆ＆５０℃に昇温し、１時間保持した後さら
に昇温し、溶剤のエタノールを留出させながら１４０℃
まで昇温した。残留物に酢酸エチル２００グラムを加え
析出する結晶を枦別することによりＮ−エチル−２，３
−ジオキソピペラジンの白色結晶を得た。この結晶をエ
タノールより再結晶することにより融点１２４℃のプリ
ズム状の白色結晶１２１グラムを得た。用いたＮ−エチ
ルエチレンジアミンに対する収率は８５モル％であった
。Example-1 150 grams of ethanol as a solvent and 149 grams of diethyl oxalate (1,0
2 mol) was charged and cooled to below 15°C, and 88 grams (1,00 mol) of N-ethylethylenediamine was added dropwise from the dropping funnel over about 30 minutes while maintaining the temperature below 15°C. 0 Drops completed f& Temperature increased to 50°C After holding for 1 hour, the temperature was further raised to 140°C while distilling off the solvent ethanol.
The temperature rose to . N-ethyl-2,3 was obtained by adding 200 grams of ethyl acetate to the residue and separating the precipitated crystals.
-White crystals of dioxopiperazine were obtained. The crystals were recrystallized from ethanol to obtain 121 grams of prismatic white crystals with a melting point of 124°C. The yield based on the N-ethylethylenediamine used was 85 mol%.
比較例−１
かくはん機付フラスコに、温度計、還流冷却器及び滴下
ロートをセットした０反応フラスコにエタノール１５０
グラムとシュウ酸ジエチル１４９グラム（１，０２モル
）を仕込み５０℃まで昇温した。５０℃に維持しながら
滴下ロートよりＮ−エチルエチレンジアミン８８グラム
（１，００モル）を約３０分を要し滴下した０滴下終了
後５０℃で１時間保持した後さらに昇温し、溶剤のエタ
ノールを留出させながら１４０″Ｃまで昇温した。Comparative Example-1 A thermometer, a reflux condenser, and a dropping funnel were set in a stirrer flask, and 150 ethanol was added to a reaction flask.
gram and 149 grams (1.02 mol) of diethyl oxalate were charged, and the temperature was raised to 50°C. While maintaining the temperature at 50°C, 88 grams (1,00 mol) of N-ethylethylenediamine was added dropwise from the dropping funnel over a period of about 30 minutes.After the dropwise addition was completed, the temperature was held at 50°C for 1 hour, and the temperature was further raised, and the solvent ethanol was added. The temperature was raised to 140''C while distilling off.
残留物に酢酸エチル２００グラムを加え析出する結晶を
ｒ別することによりＮ−エチル−２，３−ジオキソピペ
ラジンの白色結晶を得な、この結晶をエタノールより再
結晶することにより融点１２２℃の白色結晶７８グラム
を得た。用いたＮ−エチルエチレンジアミンに対する収
率は５５モル％であった。Add 200 grams of ethyl acetate to the residue and separate the precipitated crystals to obtain white crystals of N-ethyl-2,3-dioxopiperazine, which have a melting point of 122°C by recrystallizing them from ethanol. 78 grams of white crystals were obtained. The yield based on the N-ethylethylenediamine used was 55 mol%.
Claims (1)
式中Ｒ＿１はアルキル基、アルケニル基、アリール基及
びこれらに水酸基で置換されたものを示す） で示されるエチレンジアミン類と、 一般式（２） ▲数式、化学式、表等があります▼・・・（２） （式中Ｒ＿２はアルキル基を示す） で示されるシュウ酸ジエステル類との反応により、▲数
式、化学式、表等があります▼・・・（３） （式中Ｒ＿１はアルキル基、アルケニル基、アリール基
及びこれらに水酸基で置換されたものを示す） で示される２，３−ジオキソピペラジン類を製造するに
際し、不活性溶剤と一般式（２）のシュウ酸ジエステル
類との混合溶液に、１５℃以下の温度で一般式（１）の
エチレンジアミン類を加えアミド化反応させた後、１５
〜１５０℃で閉環反応させることを特徴とする２，３−
ジオキソピラペジン類の製造法。(1) General formula (1) R_1-NHCH_2CH_2NH_2...(1)(
In the formula, R_1 represents an alkyl group, an alkenyl group, an aryl group, or a group substituted with a hydroxyl group) Ethylenediamines represented by the general formula (2) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...( 2) (In the formula, R_2 represents an alkyl group) Due to the reaction with oxalic acid diesters, there are ▲mathematical formulas, chemical formulas, tables, etc.▼...(3) (In the formula, R_1 represents an alkyl group, an alkenyl group) , aryl group and those substituted with a hydroxyl group) When producing 2,3-dioxopiperazines represented by , After adding ethylenediamine of general formula (1) at a temperature of 15°C or lower and causing an amidation reaction, 15
2,3- characterized by ring-closing reaction at ~150°C
Method for producing dioxopyrapezines.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7750187A JPH0730048B2 (en) | 1987-04-01 | 1987-04-01 | Method for producing 2,3-dioxopiperazines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7750187A JPH0730048B2 (en) | 1987-04-01 | 1987-04-01 | Method for producing 2,3-dioxopiperazines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63246369A true JPS63246369A (en) | 1988-10-13 |
| JPH0730048B2 JPH0730048B2 (en) | 1995-04-05 |
Family
ID=13635714
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7750187A Expired - Lifetime JPH0730048B2 (en) | 1987-04-01 | 1987-04-01 | Method for producing 2,3-dioxopiperazines |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0730048B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100542820B1 (en) * | 2002-09-17 | 2006-01-20 | 이재호 | Method of Preparing 1-Ethyl-2,3-Dioxopiperazine using oxalyl chloride |
-
1987
- 1987-04-01 JP JP7750187A patent/JPH0730048B2/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100542820B1 (en) * | 2002-09-17 | 2006-01-20 | 이재호 | Method of Preparing 1-Ethyl-2,3-Dioxopiperazine using oxalyl chloride |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0730048B2 (en) | 1995-04-05 |
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