KR820002048B1 - Process for preparing gluconolactam derivatives - Google Patents

Process for preparing gluconolactam derivatives Download PDF

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KR820002048B1
KR820002048B1 KR7900591A KR790000591A KR820002048B1 KR 820002048 B1 KR820002048 B1 KR 820002048B1 KR 7900591 A KR7900591 A KR 7900591A KR 790000591 A KR790000591 A KR 790000591A KR 820002048 B1 KR820002048 B1 KR 820002048B1
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benzyl
gluconolactam
preparing
derivatives
substance
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KR7900591A
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히로시 무라이
신고 마쓰무라
요시아끼 아오야기
쇼오이찌 쬬오가이
미쓰히로 마에하라
마사히로 야기
이찌로오 시라하세
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모리시다 히로무
닛본신야구 가부시기가이샤
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Moranolines(I; R=benzyl) were prepd. by redn. of II(R1=H, OH; R2=Me, Et). Thus, 2,3,4,6-tetra-O-benzyl-5-keto methyl gluconate in EtOH was refluxed for 2 hr in the presence of CH3COONa. The reactant was reduced in KOH-contg. EtOH with Raney-Ni for 96 hr followed by filterating, separating and recrystallizing to give I(R=benzyl).

Description

글루코노락탐 유도체의 제조방법Method for preparing a gluconolactam derivative

본 발명은 다음의 일반식(II)The present invention is the following general formula (II)

Figure kpo00001
Figure kpo00001

(식중 R1은 수소 또는 수산기를 나타내고, R2는 메틸 또는 에틸을 나타내고, R은 벤질을 표시한다)으로 표시되는 화합물을 환원하는 것을 특징으로 하는, 다음의 일반식(I)A compound represented by the following general formula (I) characterized by reducing the compound represented by (wherein R 1 represents hydrogen or a hydroxyl group, R 2 represents methyl or ethyl, and R represents benzyl).

Figure kpo00002
Figure kpo00002

(식중 R은 벤질을 나타낸다.)으로 표시되는 신규의 글루코노락탐 유도체에 관한 것이다.It relates to a novel gluconolactam derivative represented by (wherein R represents benzyl).

본 발명자들은 앞서 아래에 보이는 식으로 나타내고 있는 물질을 자연계에서 처음으로 발견하여 단리(單離)하고, 모라노린이라 명명하여 보고하였다(야에기등 : 일본농예화학회지, 50권, 571페이지(1976년)).The present inventors first discovered and isolated the substance represented by the formula shown below in nature, and reported it as monarine (Yaegi et al .: Japanese Journal of Agricultural Chemistry, 50, 571 pages. 1976)).

Figure kpo00003
Figure kpo00003

그후, 본 발명자들은 모라노린이 의약품으로서 매우 유용한 물질이라는 사실을 발견하고 모라노린을 주성분으로 하는 의약품을 발명하여 특허를 출원하였다.Subsequently, the inventors discovered that the molarine was a very useful substance as a medicine, and invented a medicine based on the molarine and applied for a patent.

본 발명들은 계속하여 모라노린의 합성연구에 종사하여 공업적으로 값싼 글루코오스 또는 글루콘산 유도체를 출발원료로 하여 모라노린을 합성하는 일에 성공하였다. 본 발명에 포함되는 물질은 이 합성의 중요한 중간체이며, 유용한 물질이다.The present invention continued to be engaged in the synthesis of the moranorin, and succeeded in synthesizing the moranorin from industrially cheap glucose or gluconic acid derivatives as a starting material. The materials included in the present invention are important intermediates of this synthesis and useful materials.

예컨대, 본 발명에 의한 물질(I)을 수소화 리튬알루미늄, 수소화 알루미늄 또는 디보란(diborane)등의 수소화를 환원제로 환원하여 피페라진 유도체로 하고, 이어서 접촉환원 또는 할로겐수소산 예컨대 취화수소산으로 처리하여 탈 벤질화를 행하면 모라노린을 얻을수가 있다.For example, the substance (I) according to the present invention is reduced to a piperazine derivative by reduction of hydrogenation such as lithium aluminum hydride, aluminum hydride, or diborane with a reducing agent, followed by treatment with catalytic reduction or halogenic acid such as brittle hydroacid. The benzylation yields a moranoline.

본 발명에 의하면 일반식(I)(R은 전기와 같다)으로 나타내는 화합물은, 일반식(II)(R1,R2,R은 전기와 같다)으로 나타내는 화합물을 란네이닉켈, 팔라듐, 산화백금 등의 촉매의 존재하에 접촉환원하므로써 얻을 수 있다.According to the present invention, the compound represented by the general formula (I) (R is the same as the former) is a compound represented by the general formula (II) (R 1 , R 2 , R is the same as the above). It can be obtained by catalytic reduction in the presence of a catalyst such as platinum.

이 경우 수산기를 벤질에테르로 보호한 형으로 환원하는 것이 본 발명의 중요한 특징이고, 만약 수산기를 유리상태로 환원한 경우는 유용성이 부족한 이도오스형 입체배위를 가진(IV)물질이 우선적으로 생성한다.In this case, the reduction of the hydroxyl group to the benzyl ether-protected form is an important feature of the present invention, and if the hydroxyl group is reduced to the free state, a substance having an iodoose stereoconfiguration (IV) which lacks usefulness is preferentially produced. .

본 발명에 포함되는 화합물은 글루코오스 혹은 5-케토글루콘산을 원료로하여 여러가지 방법으로 합성 할수가 있다.The compound included in the present invention can be synthesized by various methods using glucose or 5-ketogluconic acid as a raw material.

예컨대 화합물(III)(IV)은, 2,3,4,6-테트라-0-벤질글루코오스를 DMSO-무수초산으로 산화하여, 2,3,4,6-테트라-0-벤질글루콘산-γ-락톤으로하고, 이어서 촉매량의 염화수소를 함유하는 메탄올로 처리하여 락톤환을 개환하여 하이드록시-메틸에스테르체로 하고, 이어서 DMSO-무수초산으로 수산기를 산화하여, 2,3,4,6-테트라-0-벤질-5-케토글루콘산 메틸에스테르(V)로 한다. (V)를 옥심화하면 화합물(II)(R : 벤질, R1:수산기, R2:메틸)이 얻어진다.Compound (III) (IV), for example, oxidizes 2,3,4,6-tetra-0-benzylglucose into DMSO-acetic anhydride, thereby producing 2,3,4,6-tetra-0-benzylgluconic acid-γ. -Lactone, and then treated with methanol containing a catalytic amount of hydrogen chloride to open the lactone ring to form a hydroxy-methyl ester, followed by oxidation of a hydroxyl group with DMSO-acetic anhydride, followed by 2,3,4,6-tetra- Let it be 0-benzyl-5-ketogluconic acid methyl ester (V). Oxidation of (V) yields compound (II) (R: benzyl, R 1 : hydroxyl group, R 2 : methyl).

이하에 본 발명에 관계되는 물질을 들어 그들의 물리적 특징을 표시한다.The substance which concerns on this invention is shown below, and their physical characteristics are shown.

Figure kpo00004
Figure kpo00004

이하 본 발명에 관한 제법을 실시예에 의하여 상세하게 설명한다.Hereinafter, the manufacturing method concerning this invention is demonstrated in detail by an Example.

[실시예 1] 화합물(III)(IV)의 함성Example 1 Synthesis of Compound (III) (IV)

2,3,4,6-테트라-0-벤질-5-케토글루큰산 메틸을 메탄올 중에서 초산소오다 존재하에 염산 히드록실아민과 2시간 가열환류하여 얻어지는 옥심체(유상물) 17g을 가성칼륨 5.0g을 함유하는 에탄올 200ml에용해하고, 라네니켈촉매 약 25ml을 가하여 상온상압에서 96시간 접촉환원한다. 반응종료후 촉매를 여별(濾別)하고, 여액을 감압하에 건조하고, 잔류물을 벤젠에 용해하여 묽알 칼리묽은산으로 세척한후 벤젠을 유거하면 반응성의 유액을 얻는다. 이 반응성 유액을 고속액체 크로마토 (분취용, 컬럼 : 포라실, 용매 : 클로로포름 : n-헥산 : 이소푸로판올=100:50:1)로서 분리정제하고, 메탄올에서 재결정하여 (II)물질 11.4g(III)물질(결정화 곤난, 유상물) 3.5g를 얻었다.17 g of oxime (oil) obtained by heating and refluxing 2,3,4,6-tetra-0-benzyl-5-ketoglucanate methyl in methanol in the presence of sodium acetate for 2 hours was dissolved in caustic potassium 5.0 It is dissolved in 200 ml of ethanol containing g, and about 25 ml of a Rane nickel catalyst is added thereto, followed by catalytic reduction at room temperature and atmospheric pressure for 96 hours. After completion of the reaction, the catalyst is filtered off, the filtrate is dried under reduced pressure, the residue is dissolved in benzene, washed with dilute aqueous solution, and the benzene is distilled off to obtain a reactive emulsion. The reactive emulsion was separated and purified by high performance liquid chromatography (for preparative column: forasil, solvent: chloroform: n-hexane: isopropanol = 100: 50: 1), and recrystallized from methanol to obtain 11.4 g of (II) substance. III) 3.5 g of a substance (difficult crystallization, oily substance) was obtained.

Claims (1)

하기구조식(II)의 화합물을 환원시켜서 하기구조식(I)의 글루코노락탐 유도체를 제조하는 방법A method for preparing a gluconolactam derivative of formula (I) by reducing the compound of formula (II)
Figure kpo00005
Figure kpo00005
 윗식에서 R1온 수소 또는 수산기R 1 on hydrogen or hydroxyl in the formula R2는 메틸 또는 에틸R 2 is methyl or ethyl R은 벤질임.R is benzyl.
KR7900591A 1979-02-26 1979-02-26 Process for preparing gluconolactam derivatives KR820002048B1 (en)

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