KR20220011502A

KR20220011502A - Novel preparing method of inotodiol

Info

Publication number: KR20220011502A
Application number: KR1020200090507A
Authority: KR
Inventors: 김숭현; 고은비; 송민수; 박가영; 이은혜; 배세리; 강지희; 박유진; 최유정
Original assignee: 재단법인 대구경북첨단의료산업진흥재단
Priority date: 2020-07-21
Filing date: 2020-07-21
Publication date: 2022-01-28
Also published as: KR102436114B1

Abstract

The present invention relates to a novel inotodiol preparing method. An inotodiol preparing method provided in one aspect of the present invention has different intermediate structure and process which are passed through compared to an existing inotodiol preparing method, also greatly reduces process steps, and has high yield, thereby being usefully used for manufacture and mass production of inotodiol.

Description

Novel preparing method of inotodiol

본 발명은 신규한 이노토디올의 제조방법에 관한 것이다.The present invention relates to a novel method for preparing inotodiol.

이노토디올(inotodiol)은 차가버섯(Znonotus obliquus)에서 유래하는 트리터펜디올(triterpene diol)로서, 항암 효과가 있는 것으로 알려져 있으며, 러시아와 핀란드 등을 중심으로 활발히 연구가 진행되고 있는 물질이다.Inotodiol is a triterpene diol derived from chaga mushroom ( Znonotus obliquus ), known to have anticancer effects, and is a substance that is being actively studied in Russia and Finland.

비특허문헌 1에서는 하기의 과정에 따라 이노토디올을 얻는 방법을 개시하고 있다. 먼저 라노스테롤(lanosterol)이 3단계를 거쳐 테트라노르-22-올레핀으로 변환되는데, 아세트산 구리(cupric acetate)를 사용하여 탈카복시화(decarboxylation)하는 과정을 포함한다. 이후 과산(peracid)을 사용하여 측쇄 이중결합을 직접 에폭시화시키고, 과량의 이소부테닐(isobutenyl) 그리냐드 시약(Grignard reagent)을 처리하여 이노토디올을 얻는다. 하지만, 비특허문헌 1에서는 상기 방법에서, 에폭사이드 중간체가 생성될 때에 절대배위가 다른 부산물이 형성될 수 있고, 그에 따라 이노토디올이 아니라 이중결합의 위치가 다른 이성질체가 최종 생성물로서 얻어질 수 있는 문제점이 있음을 개시하고 있다.Non-Patent Document 1 discloses a method for obtaining inotodiol according to the following process. First, lanosterol is converted to tetranor-22-olefin through three steps, which includes a process of decarboxylation using copper acetate. Thereafter, the side chain double bond is directly epoxidized using a peracid and treated with an excess of isobutenyl Grignard reagent to obtain inotodiol. However, in Non-Patent Document 1, in the above method, when an epoxide intermediate is produced, a by-product having a different absolute configuration may be formed, and accordingly, an isomer having a different double bond position, not inotodiol, may be obtained as a final product. It discloses that there is a problem.

비특허문헌 2에서는 하기의 과정에 따라 이노토디올을 얻는 방법을 개시하고 있다. 먼저, 라노스테롤로부터 (22E)-3β아세톡시라노스타-8,22-디엔-24-온을 제조하고, H₂O₂를 처리하여 에폭시화물을 얻으며, 히드라진 하이드레이트(hydrazine hydrate)를 처리한 후, 아세틸레이션(acetylation)하고, 소듐 보로하이드라이드(sodium borohydride)와 포스포릴 클로라이드(phosphoryl chloride)를 처리하여 이노토디올을 얻는다. 하지만, 비특허문헌 2에서는 에폭사이드 중간체가 생성될 때에 절대배위가 상이한 부산물이 형성될 수 있고, 이에 따라 히드록시의 절대배위가 상이한 이성질체가 최종 생성물로서 얻어질 수 있는 문제점이 있다.Non-Patent Document 2 discloses a method for obtaining inotodiol according to the following process. First, (22E)-3β acetoxylanosta-8,22-dien-24-one is prepared from lanosterol, and H ₂ O ₂ is treated to obtain an epoxide, and after treatment with hydrazine hydrate , acetylation, and treatment with sodium borohydride and phosphoryl chloride to obtain inotodiol. However, in Non-Patent Document 2, when an epoxide intermediate is produced, a by-product having a different absolute configuration may be formed, and thus there is a problem in that an isomer having a different absolute configuration of hydroxy may be obtained as a final product.

이와 같이 종래의 이노토디올 제조방법에서는 제조과정이 복잡하고, 부산물이 얻어져서 목적하는 이노토디올의 수율이 낮은 문제가 있으므로, 본 발명자들은 신규한 이노토디올 제조방법을 제공하고자 연구하였다. 그 결과, 기존의 이노토디올 제조방법과는 제조과정의 각 단계가 상이하고, 이노토디올의 수율이 높은 제조방법을 발견하였다.As described above, in the conventional method for preparing inotodiol, the manufacturing process is complicated, and a by-product is obtained and there is a problem that the desired yield of inotodiol is low. Therefore, the present inventors studied to provide a novel method for preparing inotodiol. As a result, each step of the manufacturing process is different from the existing inotodiol manufacturing method, and a manufacturing method having a high yield of inotodiol was discovered.

Tetrahedron Volume 30, Issue 8, 1974, Pages 977-986. Tetrahedron Volume 30, Issue 8, 1974, Pages 977-986. Chem. Pharm. Bull. 31(3) 907-911 (1983). Chem. Pharm. Bull. 31(3) 907-911 (1983).

본 발명의 일 측면에서의 목적은 신규한 이노토디올(inotodiol) 합성 전구체의 제조방법을 제공하는 것이다.It is an object of one aspect of the present invention to provide a method for preparing a novel inotodiol synthesis precursor.

본 발명의 다른 일 측면에서의 목적은 상기 신규한 이노토디올 합성 전구체 제조과정에서 제조되는 중간체 화합물, 이의 이성질체, 이의 용매화물, 또는 이의 염을 제공하는 것이다.Another object of the present invention is to provide an intermediate compound, an isomer thereof, a solvate thereof, or a salt thereof prepared in the process of preparing the novel inotodiol synthesis precursor.

본 발명의 또 다른 일 측면에서의 목적은 상기 신규한 이노토디올 합성 전구체로부터, 이노토디올을 제조하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing inotodiol from the novel inotodiol synthesis precursor.

상기 목적을 달성하기 위하여,In order to achieve the above object,

본 발명의 일 측면은,One aspect of the present invention is

하기 반응식 1에 나타낸 바와 같이,As shown in Scheme 1 below,

화학식 1로 표시되는 화합물에 보호기를 도입하여 화학식 2로 표시되는 화합물을 제조하는 단계(단계 1);preparing a compound represented by Formula 2 by introducing a protecting group to the compound represented by Formula 1 (step 1);

상기 단계 1에서 제조한 화학식 2로 표시되는 화합물을 에폭시화 반응시켜 화학식 3으로 표시되는 화합물을 제조하는 단계(단계 2);preparing a compound represented by Formula 3 by epoxidizing the compound represented by Formula 2 prepared in Step 1 (step 2);

상기 단계 2에서 제조한 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계(단계 3); 및preparing a compound represented by Formula 4 by reacting the compound represented by Formula 3 prepared in Step 2 (step 3); and

상기 단계 3에서 제조한 화학식 4로 표시되는 화합물을 반응시켜 화학식 5로 표시되는 화합물을 제조하는 단계(단계 4);를 포함하는, 하기 화학식 5로 표시되는 이노토디올(inotodiol) 합성 전구체의 제조방법을 제공한다.Preparation of an inotodiol synthesis precursor represented by the following Chemical Formula 5, including; preparing a compound represented by Chemical Formula 5 by reacting the compound represented by Chemical Formula 4 prepared in Step 3 (Step 4) provide a way

[반응식 1][Scheme 1]

상기 반응식 1에서,In Scheme 1,

PG¹은 알콜의 보호기이다.PG ¹ is a protecting group of alcohol.

또한, 본 발명의 다른 일 측면은,In addition, another aspect of the present invention,

상기 화학식 3으로 표시되는 중간체 화합물, 이의 이성질체, 이의 용매화물, 또는 이의 염을 제공한다.An intermediate compound represented by Formula 3, an isomer thereof, a solvate thereof, or a salt thereof is provided.

나아가, 본 발명의 또 다른 일 측면은,Furthermore, another aspect of the present invention is

상기 화학식 4로 표시되는 중간체 화합물, 이의 이성질체, 이의 용매화물, 또는 이의 염을 제공한다.An intermediate compound represented by Formula 4, an isomer thereof, a solvate thereof, or a salt thereof is provided.

상기 제조방법으로 제조되는 화학식 5로 표시되는 이노토디올(inotodiol) 합성 전구체로부터, 이노토디올을 제조하는 방법을 제공한다.Provided is a method for preparing inotodiol from an inotodiol synthesis precursor represented by Chemical Formula 5 prepared by the above method.

하기 반응식 2에 나타낸 바와 같이,As shown in Scheme 2 below,

상기 단계 2에서 제조한 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계(단계 3);preparing a compound represented by Formula 4 by reacting the compound represented by Formula 3 prepared in Step 2 (step 3);

상기 단계 3에서 제조한 화학식 4로 표시되는 화합물을 반응시켜 화학식 5로 표시되는 화합물을 제조하는 단계(단계 4);preparing a compound represented by Formula 5 by reacting the compound represented by Formula 4 prepared in Step 3 (step 4);

상기 단계 4에서 제조한 화학식 5로 표시되는 화합물을 에폭시화 반응시켜 화학식 6으로 표시되는 화합물을 제조하는 단계(단계 5);preparing a compound represented by Formula 6 by epoxidizing the compound represented by Formula 5 prepared in step 4 (step 5);

상기 단계 5에서 제조한 화학식 6으로 표시되는 화합물을 반응시켜 화학식 7로 표시되는 화합물을 제조하는 단계(단계 6);preparing a compound represented by Formula 7 by reacting the compound represented by Formula 6 prepared in Step 5 (step 6);

상기 단계 6에서 제조한 화학식 7로 표시되는 화합물을 반응시켜 화학식 8로 표시되는 화합물을 제조하는 단계(단계 7); 및preparing a compound represented by Formula 8 by reacting the compound represented by Formula 7 prepared in Step 6 (step 7); and

상기 단계 7에서 제조한 화학식 8로 표시되는 화합물을 반응시켜 화학식 A로 표시되는 화합물을 제조하는 단계(단계 8);를 포함하는, 하기 화학식 A로 표시되는 이노토디올(inotodiol)의 제조방법을 제공한다.A method for preparing inotodiol represented by the following formula (A), including the step of reacting the compound represented by formula (8) prepared in step 7 to prepare a compound represented by formula (A) (step 8) to provide.

[반응식 2][Scheme 2]

상기 반응식 2에서,In Scheme 2,

PG¹은 알콜의 보호기이다.PG ¹ is a protecting group of alcohol.

본 발명의 일 측면에서 제공하는 이노토디올(inotodiol)의 제조방법은, 기존의 이노토디올의 제조방법과 비교하여 경유하는 중간체 구조와 과정이 상이할뿐만 아니라 공정 단계가 대폭 축소될 수 있고, 수율이 높으므로, 이노토디올의 제조 및 대량생산에 유용하게 활용 가능한 효과가 있다.In the method for producing inotodiol provided in one aspect of the present invention, compared to the existing method for producing inotodiol, the intermediate structure and process through which it passes are different, and the process steps can be significantly reduced, Since the yield is high, there is an effect that can be usefully used for the production and mass production of inotodiol.

이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.

한편, 본 발명의 실시 형태는 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시 형태로 한정되는 것은 아니다. 또한, 본 발명의 실시 형태는 당해 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다.On the other hand, the embodiment of the present invention can be modified in various other forms, the scope of the present invention is not limited to the embodiments described below. In addition, the embodiments of the present invention are provided in order to more completely explain the present invention to those of ordinary skill in the art.

나아가, 명세서 전체에서 어떤 구성요소를 "포함"한다는 것은 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있다는 것을 의미한다.Furthermore, in the entire specification, "including" a certain element means that other elements may be further included, rather than excluding other elements, unless otherwise stated.

본 발명의 일 측면은,One aspect of the present invention is

하기 반응식 1에 나타낸 바와 같이,As shown in Scheme 1 below,

[반응식 1][Scheme 1]

상기 반응식 1에서,In Scheme 1,

PG¹은 알콜의 보호기이다.PG ¹ is a protecting group of alcohol.

보다 구체적으로, 상기 반응식 1에서 PG¹은 아세틸(Ac), 벤질(Bn), 메톡시메틸(MOM), 2-메톡시에톡시메틸(MEM), 메틸티오메틸(MTM), 테트라히드로피라닐(THP), 벤질옥시메틸(BOM), p-메톡시페닐(PMP), p-메톡시벤질(PMB), p-메톡시벤질옥시메틸(PMBM), 트리이소프로필실릴(TIPS), tert-부틸디메틸실릴(TBDMS), 2-(트리메틸실릴)에톡시메틸(SEM) 및 (페닐디메틸실릴)메톡시메틸(SMOM)로 이루어진 군으로부터 선택되는 1종의 알콜의 보호기일 수 있다.More specifically, in Scheme 1, PG ¹ is acetyl (Ac), benzyl (Bn), methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), benzyloxymethyl (BOM), p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), p-methoxybenzyloxymethyl (PMBM), triisopropylsilyl (TIPS), tert- It may be a protecting group of one alcohol selected from the group consisting of butyldimethylsilyl (TBDMS), 2-(trimethylsilyl)ethoxymethyl (SEM) and (phenyldimethylsilyl)methoxymethyl (SMOM).

본 발명에 따른 상기 반응식 1로 표시되는 제조방법에 있어서,In the manufacturing method represented by Scheme 1 according to the present invention,

상기 단계 1은 화학식 1로 표시되는 화합물에 보호기를 도입하여 화학식 2로 표시되는 화합물을 제조하는 단계이다. 구체적으로, 염기와 용매 존재하에 화학식 1로 표시되는 화합물에 알코올 보호기 형성반응을 수행하여 화학식 2로 표시되는 화합물을 제조하는 단계이다.Step 1 is a step of preparing a compound represented by Formula 2 by introducing a protecting group to the compound represented by Formula 1. Specifically, it is a step of preparing a compound represented by Formula 2 by performing an alcohol protecting group formation reaction on the compound represented by Formula 1 in the presence of a base and a solvent.

이때, 염기로는 다이아이소프로필에틸아민, 1,8-디아자바이사이클로[5,4,0]언덱-7-엔(1,8-Diazabicyclo(5.4.0)undec-7-ene, DBU), 피리딘, 트리에틸아민, 피롤리딘 등과 같은 유기 아민을 사용할 수 있고, 단독 또는 혼합하여 사용할 수 있으나, 이에 한정되는 것은 아니다.At this time, as the base, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene (1,8-Diazabicyclo(5.4.0)undec-7-ene, DBU), Organic amines such as pyridine, triethylamine, pyrrolidine, etc. may be used, and may be used alone or in combination, but is not limited thereto.

또한, 용매로는 디클로로메탄, 테트라하이드로퓨란(THF, tetrahydrofuran), 물, 디메톡시에테인(DME, dimethoxyethane), 디메틸 설폭사이드(DMSO, dimethyl sulfoxide), N,N-디메틸포름아마이드(DMF, N,N-dimethylformamide), 아세토나이트릴(ACN, acetonitrile) 등을 사용할 수 있으며, 이를 단독 또는 혼합하여 용매로 사용할 수 있으나, 이에 한정되는 것은 아니다.In addition, solvents include dichloromethane, tetrahydrofuran (THF, tetrahydrofuran), water, dimethoxyethane (DME, dimethoxyethane), dimethyl sulfoxide (DMSO, dimethyl sulfoxide), N,N -dimethylformamide (DMF, N, N- dimethylformamide), acetonitrile (ACN, acetonitrile), etc. may be used, and these may be used alone or in mixture as a solvent, but the present invention is not limited thereto.

나아가, 상기 알코올 보호기로는 아세틸(Ac), 벤질(Bn), 메톡시메틸(MOM), 2-메톡시에톡시메틸(MEM), 메틸티오메틸(MTM), 테트라히드로피라닐(THP), 벤질옥시메틸(BOM), p-메톡시페닐(PMP), p-메톡시벤질(PMB), p-메톡시벤질옥시메틸(PMBM), 트리이소프로필실릴(TIPS), tert-부틸디메틸실릴(TBDMS), 2-(트리메틸실릴)에톡시메틸(SEM) 및 (페닐디메틸실릴)메톡시메틸(SMOM)로 이루어진 군으로부터 선택되는 1종의 알콜의 보호기일 수 있으며, 본 발명의 일 실시예에서는 알코올 보호기로 메톡시메틸(MOM)을 사용하였다.Further, the alcohol protecting group includes acetyl (Ac), benzyl (Bn), methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), Benzyloxymethyl (BOM), p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), p-methoxybenzyloxymethyl (PMBM), triisopropylsilyl (TIPS), tert-butyldimethylsilyl ( TBDMS), 2-(trimethylsilyl)ethoxymethyl (SEM) and (phenyldimethylsilyl)methoxymethyl (SMOM) may be a protecting group of one alcohol selected from the group consisting of, in one embodiment of the present invention Methoxymethyl (MOM) was used as an alcohol protecting group.

또한, 상기 반응은 0℃ 내지 80℃ 온도범위에서 수행할 수 있으나, 반응이 진행되는 정도에 따라 적절히 반응온도를 조절할 수 있다.In addition, the reaction may be carried out in a temperature range of 0° C. to 80° C., but the reaction temperature may be appropriately adjusted according to the degree to which the reaction proceeds.

나아가, 상기 반응은 7 내지 21시간 동안 수행할 수 있으나, 반응이 진행되는 정도에 따라 적절히 반응시간을 조절할 수 있다.Furthermore, the reaction may be carried out for 7 to 21 hours, but the reaction time may be appropriately adjusted according to the degree to which the reaction proceeds.

상기 단계 2는 상기 단계 1에서 제조한 화학식 2로 표시되는 화합물을 에폭시화 반응시켜 화학식 3으로 표시되는 화합물을 제조하는 단계이다. 구체적으로, 과산화물, 용매 존재하에 화학식 2로 표시되는 화합물을 에폭시화 반응시켜 화학식 3으로 표시되는 화합물을 제조하는 단계이다.Step 2 is a step of preparing a compound represented by Formula 3 by epoxidizing the compound represented by Formula 2 prepared in Step 1. Specifically, it is a step of preparing a compound represented by Formula 3 by epoxidizing the compound represented by Formula 2 in the presence of a peroxide and a solvent.

이때, 상기 과산화물은 m-CPBA, benzoyl peroxide, 과산화수소, t-butyl hydroperoxide 등을 사용할 수 있고, 바람직하게는 m-CPBA를 사용할 수 있으나, 이는 예시일 뿐, 이에 한정되지 않는다.In this case, as the peroxide, m-CPBA, benzoyl peroxide, hydrogen peroxide, t-butyl hydroperoxide, etc. may be used, and preferably m-CPBA may be used, but this is only an example and is not limited thereto.

나아가, 상기 반응은 0℃ 내지 80℃ 온도범위에서 수행할 수 있으나, 반응이 진행되는 정도에 따라 적절히 반응온도를 조절할 수 있다.Furthermore, the reaction may be carried out in a temperature range of 0° C. to 80° C., but the reaction temperature may be appropriately adjusted according to the degree to which the reaction proceeds.

또한, 상기 반응은 7 내지 21시간 동안 수행할 수 있으나, 반응이 진행되는 정도에 따라 적절히 반응시간을 조절할 수 있다.In addition, the reaction may be carried out for 7 to 21 hours, but the reaction time may be appropriately adjusted according to the extent to which the reaction proceeds.

상기 단계 3은 상기 단계 2에서 제조한 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계이다. 구체적으로, 과요오드산, 용매 존재하에 상기 단계 2에서 제조한 화학식 3으로 표시되는 화합물을 과요오드산 산화(Periodic Acid Oxidation) 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계이다.Step 3 is a step of preparing a compound represented by Formula 4 by reacting the compound represented by Formula 3 prepared in Step 2 above. Specifically, it is a step of preparing a compound represented by Formula 4 by subjecting the compound represented by Formula 3 prepared in Step 2 to periodic acid oxidation in the presence of periodic acid and a solvent.

이때, 상기 과요오드산은 HIO₄ 또는 H₅IO₆를 사용할 수 있으나, 특별히 이에 한정되는 것은 아니다.In this case, the periodic acid may be HIO ₄ or H ₅ IO ₆ , but is not particularly limited thereto.

또한, 상기 용매로는 디에틸에터(diethyl ether), 아세토나이트릴(ACN, acetonitrile), 벤젠(benzene), 톨루엔(toluene) 등을 사용할 수 있고, 이를 단독 또는 혼합하여 용매로 사용할 수 있으나, 특별히 이에 한정되지 않는다.In addition, as the solvent, diethyl ether, acetonitrile (ACN, acetonitrile), benzene, toluene, etc. may be used, and these may be used alone or in mixture as a solvent, In particular, it is not limited to this.

또한, 상기 반응은 1 내지 5시간 동안 수행할 수 있으나, 반응이 진행되는 정도에 따라 적절히 반응시간을 조절할 수 있다.In addition, the reaction may be performed for 1 to 5 hours, but the reaction time may be appropriately adjusted according to the degree to which the reaction proceeds.

상기 단계 4는 상기 단계 3에서 제조한 화학식 4로 표시되는 화합물을 반응시켜 화학식 5로 표시되는 화합물을 제조하는 단계이다. 보다 구체적으로, 상기 단계 3에서 제조한 화학식 4로 표시되는 화합물에 2-아이오도벤조산(2-Iodoxybenzoic acid, IBX)와 트리플루오로아세트산(TFA)를 처리하여 2개의 수소가 제거되고 이중결합이 생긴 화학식 5로 표시되는 화합물을 제조하는 단계이다.Step 4 is a step of preparing a compound represented by Formula 5 by reacting the compound represented by Formula 4 prepared in Step 3 above. More specifically, by treating the compound represented by Formula 4 prepared in step 3 with 2-iodoxybenzoic acid (IBX) and trifluoroacetic acid (TFA), two hydrogens are removed and a double bond is formed This is a step for preparing a compound represented by the resulting Chemical Formula 5.

이때, 사용 가능한 용매로는 디메틸 설폭사이드(DMSO, dimethyl sulfoxide), 디클로로메탄, 테트라하이드로퓨란(THF, tetrahydrofuran), 물, 디메톡시에테인(DME, dimethoxyethane), N,N-디메틸포름아마이드(DMF, N,N-dimethylformamide), 아세토나이트릴(ACN, acetonitrile) 등을 사용할 수 있으며, 이를 단독 또는 혼합하여 용매로 사용할 수 있으나, 이에 한정되는 것은 아니다.At this time, available solvents include dimethyl sulfoxide (DMSO), dichloromethane, tetrahydrofuran (THF, tetrahydrofuran), water, dimethoxyethane (DME, dimethoxyethane), N,N -dimethylformamide (DMF, N,N- dimethylformamide), acetonitrile (ACN, acetonitrile), etc. may be used, and these may be used alone or in mixture as a solvent, but the present invention is not limited thereto.

나아가, 상기 반응은 5시간 내지 12일 동안 수행할 수 있으나, 반응이 진행되는 정도에 따라 적절히 반응시간을 조절할 수 있다.Furthermore, the reaction may be carried out for 5 hours to 12 days, but the reaction time may be appropriately adjusted according to the degree to which the reaction proceeds.

상기 단계로 제조되는 화합물은 신규한 구조의 이노토디올(inotodiol) 합성 전구체로, 후술하는 바와 같이 이노토디올(inotodiol) 합성에 사용되어, 이노토디올의 전체적인 합성효율을 대폭 증가시킬 수 있다.The compound prepared in the above step is an inotodiol synthesis precursor having a novel structure, and is used for inotodiol synthesis as described below, thereby greatly increasing the overall synthesis efficiency of inotodiol.

본 발명의 다른 일 측면은, 상기 화학식 3으로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 또는 이의 염을 제공한다.Another aspect of the present invention provides a compound represented by Formula 3, an isomer thereof, a solvate thereof, or a salt thereof.

본 발명의 또 다른 일 측면은, 상기 화학식 4로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 또는 이의 염을 제공한다.Another aspect of the present invention provides a compound represented by Formula 4, an isomer thereof, a solvate thereof, or a salt thereof.

이때, 상기 이성질체는 입체 이성질체(stereoisomer)일 수 있고, 더욱 구체적으로는 광학 이성질체(optical isomer)일 수 있다.In this case, the isomer may be a stereoisomer, and more specifically, an optical isomer.

또한, 상기 염은 약학적으로 허용가능한 염일 수 있다.In addition, the salt may be a pharmaceutically acceptable salt.

본 발명의 다른 일 측면은,Another aspect of the present invention is

상기 제조방법으로 제조되는 화학식 5로 표시되는 이노토디올(inotodiol) 합성 전구체를 경유하여, 이노토디올을 제조하는 전체적인 합성 스킴은 하기 반응식을 하기 반응식 2에 나타내었다.The overall synthesis scheme for preparing inotodiol via the inotodiol synthesis precursor represented by Formula 5 prepared by the above method is shown in Scheme 2 below.

즉, 본 발명은, 하기 반응식 2에 나타낸 바와 같이,That is, the present invention, as shown in Scheme 2 below,

[반응식 2][Scheme 2]

상기 반응식 2에서,In Scheme 2,

PG¹은 알콜의 보호기이다.PG ¹ is a protecting group of alcohol.

구체적으로, 상기 반응식 2에서 PG¹은 아세틸(Ac), 벤질(Bn), 메톡시메틸(MOM), 2-메톡시에톡시메틸(MEM), 메틸티오메틸(MTM), 테트라히드로피라닐(THP), 벤질옥시메틸(BOM), p-메톡시페닐(PMP), p-메톡시벤질(PMB), p-메톡시벤질옥시메틸(PMBM), 트리이소프로필실릴(TIPS), tert-부틸디메틸실릴(TBDMS), 2-(트리메틸실릴)에톡시메틸(SEM) 및 (페닐디메틸실릴)메톡시메틸(SMOM)로 이루어진 군으로부터 선택되는 1종의 알콜의 보호기일 수 있다.Specifically, in Scheme 2, PG ¹ is acetyl (Ac), benzyl (Bn), methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl ( THP), benzyloxymethyl (BOM), p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), p-methoxybenzyloxymethyl (PMBM), triisopropylsilyl (TIPS), tert-butyl It may be a protecting group of one alcohol selected from the group consisting of dimethylsilyl (TBDMS), 2-(trimethylsilyl)ethoxymethyl (SEM), and (phenyldimethylsilyl)methoxymethyl (SMOM).

본 발명에 따른 상기 반응식 2로 표시되는 제조방법에 있어서,In the manufacturing method represented by Scheme 2 according to the present invention,

상기 단계 2는 상기 단계 1에서 제조한 화학식 2로 표시되는 화합물을 에폭시화 반응시켜 화학식 3으로 표시되는 화합물을 제조하는 단계이다. 구체적으로, 과산화물, 용매 존재하에 화학식 2로 표시되는 화합물을 에폭시화 반응시켜 화학식 3으로 표시되는 화합물을 제조하는 단계이다.Step 2 is a step of preparing a compound represented by Formula 3 by epoxidizing the compound represented by Formula 2 prepared in Step 1 above. Specifically, it is a step of preparing a compound represented by Formula 3 by epoxidizing the compound represented by Formula 2 in the presence of a peroxide and a solvent.

상기 단계 3은 상기 단계 2에서 제조한 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계이다. 구체적으로, 과요오드산, 용매 존재하에 상기 단계 2에서 제조한 화학식 3으로 표시되는 화합물을 과요오드산 산화(Periodic Acid Oxidation) 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계이다.Step 3 is a step of preparing a compound represented by Formula 4 by reacting the compound represented by Formula 3 prepared in Step 2 above. Specifically, in the presence of periodic acid and a solvent, the compound represented by Formula 3 prepared in Step 2 is subjected to periodic acid oxidation to prepare a compound represented by Formula 4.

상기 단계 5는 화학식 5로 표시되는 화합물을 에폭시화반응시켜 화학식 6으로 표시되는 화합물이 제조되는 단계이다. 구체적으로, 과산화물, 유기 아민, 용매 존재하에 화학식 5로 표시되는 화합물을 에폭시화 반응시켜 화학식 6으로 표시된 화합물이 제조되는 단계이다. 상기 단계 5는 유기용매에서 과산화수소의 이동을 원할하게 하여 반응을 촉진시키기 위해 상전이 촉매로서 클로랄 수화물을 사용할 수 있다. 상기 상전이 촉매로는 테트라부틸암모니움 클로라이드(n-Bu₄N⁺Cl^-), 아세톤, 클로로아세톤, 1,3-디클로로아세톤, 1,1,1-트리클로로아세톤, 클로랄 수화물 등을 사용할 수 있고, 바람직하게는 클로랄 수화물을 사용할 수 있으나, 이는 하나의 구체적인 예시일 뿐, 이에 한정되는 것은 아니다.Step 5 is a step in which the compound represented by Formula 6 is prepared by epoxidation of the compound represented by Formula 5. Specifically, in the presence of a peroxide, an organic amine, and a solvent, the compound represented by the formula (5) is subjected to an epoxidation reaction to prepare the compound represented by the formula (6). In step 5, chloral hydrate may be used as a phase transfer catalyst to facilitate the movement of hydrogen peroxide in the organic solvent to promote the reaction. As the phase transfer catalyst, tetrabutylammonium chloride (n-Bu ₄ N ⁺ Cl ^- ), acetone, chloroacetone, 1,3-dichloroacetone, 1,1,1-trichloroacetone, chloral hydrate, etc. may be used. and preferably, chloral hydrate may be used, but this is only one specific example and is not limited thereto.

또한, 상기 과산화물은 m-CPBA, benzoyl peroxide, 과산화수소, t-butyl hydroperoxide 등을 사용할 수 있고, 바람직하게는 과산화수소를 사용할 수 있으나, 이는 예시일 뿐, 이에 한정되지 않는다.In addition, as the peroxide, m-CPBA, benzoyl peroxide, hydrogen peroxide, t-butyl hydroperoxide, etc. may be used, and hydrogen peroxide may be preferably used, but this is only an example and is not limited thereto.

나아가, 상기 유기 아민은 피롤리딘, 다양한 카이랄 프롤린 계열의 유기 아민 등을 당량 또는 촉매량으로 사용할 수 있으며, 사용될 수 있는 유기 아민은 이에 한정되는 것은 아니다.Furthermore, as the organic amine, pyrrolidine, various chiral proline-based organic amines, etc. may be used in equivalent or catalytic amounts, and the organic amines that may be used are not limited thereto.

또한, 상기 용매는 테트라하이드로퓨란(THF, tetrahydrofuran), 물, 디메톡시에테인(DME, dimethoxyethane), 디메틸 설폭사이드(DMSO, dimethyl sulfoxide), N,N-디메틸포름아마이드(DMF, N,N-dimethylformamide), 아세토나이트릴(ACN, acetonitrile), 디클로로메테인(DCM, dichloromethane) 등을 사용할 수 있으며, 이를 단독 또는 혼합하여 용매로 사용할 수 있으나, 이에 한정되는 것은 아니다.In addition, the solvent is tetrahydrofuran (THF, tetrahydrofuran), water, dimethoxyethane (DME, dimethoxyethane), dimethyl sulfoxide (DMSO, dimethyl sulfoxide), N,N -dimethylformamide (DMF, N,N -dimethylformamide) ), acetonitrile (ACN, acetonitrile), dichloromethane (DCM, dichloromethane), etc. may be used, and these may be used alone or in mixture as a solvent, but are not limited thereto.

나아가, 상기 단계 5의 반응온도는 0℃ 내지 35℃일 수 있으나, 특별히 이에 한정되는 것은 아니며, 반응이 진행되는 정도에 따라 적절히 반응온도를 조절할 수 있다.Furthermore, the reaction temperature of step 5 may be 0° C. to 35° C., but is not particularly limited thereto, and the reaction temperature can be appropriately adjusted according to the degree to which the reaction proceeds.

또한, 상기 단계 5의 반응시간은 10분 내지 24시간일 수 있으나, 특별히 이에 한정되는 것은 아니며, 반응이 진행되는 정도에 따라 적절히 반응시간을 조절할 수 있다.In addition, the reaction time of step 5 may be 10 minutes to 24 hours, but is not particularly limited thereto, and the reaction time may be appropriately adjusted according to the degree to which the reaction proceeds.

상기 단계 6은 상기 단계 5에서 제조한 화학식 6으로 표시되는 화합물을 반응시켜 화학식 7로 표시되는 화합물을 제조하는 단계이다. 구체적으로, 올레핀화 시약, 용매, 염기 존재하에 상기 단계 5에서 얻은 화학식 6으로 표시되는 화합물을 올레핀화 반응시켜 화학식 7로 표시된 화합물이 제조되는 단계이다.Step 6 is a step of preparing a compound represented by Formula 7 by reacting the compound represented by Formula 6 prepared in Step 5. Specifically, in the presence of an olefination reagent, a solvent, and a base, the compound represented by Formula 7 is prepared by subjecting the compound represented by Formula 6 obtained in Step 5 to an olefination reaction.

이때, 상기 올레핀화 시약으로는 5-(이소프로필설포닐)-1-1페닐-1H-테트라졸, 1-(이소프로필설포닐)페닐, 1-(이소프로필설포닐)-3,5-디(트리플로로메틸)페닐, 2-(이소프로필설포닐)-1-1메틸-1H-벤조이미다졸, 2-(이소프로필설포닐)-벤조싸이아졸, 2-(이소프로필설포닐)-1-피리딘, 5-(이소프로필설포닐)-1-1터셔리부틸-1H-테트라졸, 이소프로필트리페닐포스포니움브로마이드 (i-PrP⁺Ph₃Br^-), 이소프로필터셔리부틸디페닐실란 (i-PrSiPh₂t-Bu) 등을 사용할 수 있으나, 특별히 이에 한정되지 않는다.In this case, as the olefination reagent, 5-(isopropylsulfonyl)-1-1phenyl-1H-tetrazole, 1-(isopropylsulfonyl)phenyl, 1-(isopropylsulfonyl)-3,5- Di(trifluoromethyl)phenyl, 2-(isopropylsulfonyl)-1-1methyl-1H-benzoimidazole, 2-(isopropylsulfonyl)-benzothiazole, 2-(isopropylsulfonyl) -1-pyridine, 5-(isopropylsulfonyl)-1-1 tertbutyl-1H-tetrazole, isopropyltriphenylphosphonium bromide (i-PrP ⁺ Ph ₃ Br ^- ), isopropyl tertbutyl Diphenylsilane (i-PrSiPh ₂ t-Bu) may be used, but is not particularly limited thereto.

또한, 상기 염기로는 t-BuOK(Potassium tert-butoxide), n-BuLi(n-Butyl lithium), sec-BuLi (sec-Butyl lithium), t-BuLi(t-Butyl lithium), LDA(Lithium diisopylamide), LiHMDS(Lithium bis(trimethylsilyl)amide), NaHMDS(Sodium bis(trimethylsilyl)amide), KHMDS(Potassium bis(trimethylsilyl)amide) 등을 사용할 수 있고, 단독 또는 혼합하여 사용할 수 있으나, 특별히 이에 한정되는 것은 아니다.In addition, as the base, t-BuOK (Potassium tert-butoxide), n-BuLi (n-Butyl lithium), sec-BuLi (sec-Butyl lithium), t-BuLi (t-Butyl lithium), LDA (Lithium diisopylamide) ), LiHMDS (Lithium bis (trimethylsilyl) amide), NaHMDS (Sodium bis (trimethylsilyl) amide), KHMDS (Potassium bis (trimethylsilyl) amide), etc. can be used, and can be used alone or in combination, but not particularly limited thereto no.

나아가, 상기 용매로는 디에틸에터(diethyl ether), 아세토나이트릴(ACN, acetonitrile), 벤젠(benzene), 톨루엔(toluene) 등을 사용할 수 있으며, 이를 단독 또는 혼합하여 용매로 사용할 수 있으나, 이에 한정되지 않는다.Furthermore, as the solvent, diethyl ether, acetonitrile (ACN, acetonitrile), benzene, toluene, etc. may be used, and these may be used alone or in mixture as a solvent, However, the present invention is not limited thereto.

또한, 상기 단계 6의 반응온도는 -100 ℃내지 -50 ℃ 또는 0 ℃ 내지 35 ℃일 수 있으나, 특별히 이에 한정되는 것은 아니며, 반응이 진행되는 정도에 따라 적절히 반응온도를 조절할 수 있다.In addition, the reaction temperature of step 6 may be -100 °C to -50 °C or 0 °C to 35 °C, but is not particularly limited thereto, and the reaction temperature can be appropriately adjusted according to the degree to which the reaction proceeds.

나아가, 상기 단계 6의 반응시간은 10분 내지 24시간일 수 있으나, 특별히 이에 한정되는 것은 아니며, 반응이 진행되는 정도에 따라 적절히 반응시간을 조절할 수 있다.Furthermore, the reaction time of step 6 may be 10 minutes to 24 hours, but is not particularly limited thereto, and the reaction time may be appropriately adjusted according to the degree to which the reaction proceeds.

상기 단계 7은 상기 단계 6에서 제조한 화학식 7로 표시되는 화합물을 반응시켜 화학식 8로 표시되는 화합물을 제조하는 단계이다. 구체적으로, 수소음이온 시약, 염, 용매 존재하에 상기 단계 6에서 얻은 화학식 7로 표시되는 화합물을 위치 선택적으로 환원반응시켜 화학식 8로 표시된 화합물이 제조되는 단계이다.Step 7 is a step of preparing a compound represented by Formula 8 by reacting the compound represented by Formula 7 prepared in Step 6. Specifically, the compound represented by Formula 8 is prepared by regioselectively reducing the compound represented by Formula 7 obtained in Step 6 in the presence of a hydrogen anion reagent, a salt, and a solvent.

이때, 상기 수소음이온 시약은 NaBH₃CN, LiBH₃CN, NaBH₄, LiAlH₄, NaBH(OAc)₃, DIBAL, Red-Al, L-Selectride, K-Selectride, N-Selectride, LS-Selectride, KS-Selectride, Super-Hydride 등을 사용할 수 있으나, 이에 한정되지 않는다.At this time, the hydrogen anion reagent is NaBH ₃ CN, LiBH ₃ CN, NaBH ₄ , LiAlH ₄ , NaBH(OAc) ₃ , DIBAL, Red-Al, L-Selectride, K-Selectride, N-Selectride, LS-Selectride, KS -Selectride, Super-Hydride, etc. can be used, but are not limited thereto.

또한, 상기 염은 ZnCl₂, ZnI₂등을 사용할 수 있고, 단독 또는 혼합하여 사용할 수 있으나, 이에 한정되는 것은 아니다.In addition, the salt may be ZnCl ₂ , ZnI ₂ , and the like, and may be used alone or in combination, but is not limited thereto.

나아가, 상기 용매는 테트라하이드로퓨란(THF, tetrahydrofuran), 물, 디메톡시에테인(DME, dimethoxyethane), 디메틸 설폭사이드(DMSO, dimethyl sulfoxide), N,N-디메틸포름아마이드(DMF, N,N-dimethylformamide), 아세토나이트릴(ACN, acetonitrile), 디클로로메테인(DCM, dichloromethane) 등을 사용할 수 있으며, 이를 단독 또는 혼합하여 용매로 사용할 수 있으나, 이에 한정되는 것은 아니다.Furthermore, the solvent is tetrahydrofuran (THF, tetrahydrofuran), water, dimethoxyethane (DME, dimethoxyethane), dimethyl sulfoxide (DMSO, dimethyl sulfoxide), N,N -dimethylformamide (DMF, N,N -dimethylformamide) ), acetonitrile (ACN, acetonitrile), dichloromethane (DCM, dichloromethane), etc. may be used, and these may be used alone or in mixture as a solvent, but are not limited thereto.

또한, 상기 단계 7의 반응온도는 0 ℃내지 35 ℃일 수 있으나, 특별히 이에 한정되는 것은 아니며, 반응이 진행되는 정도에 따라 적절히 반응온도를 조절할 수 있다.In addition, the reaction temperature of step 7 may be 0 °C to 35 °C, but is not particularly limited thereto, and the reaction temperature can be appropriately adjusted according to the degree to which the reaction proceeds.

나아가, 상기 단계 7의 반응시간은 10분 내지 5일일 수 있으나, 특별히 이에 한정되는 것은 아니며, 반응이 진행되는 정도에 따라 적절히 반응시간을 조절할 수 있다.Furthermore, the reaction time of step 7 may be 10 minutes to 5 days, but is not particularly limited thereto, and the reaction time may be appropriately adjusted according to the degree to which the reaction proceeds.

상기 단계 8은 상기 단계 7에서 제조한 화학식 8로 표시되는 화합물을 반응시켜 화학식 A로 표시되는 화합물을 제조하는 단계이다. 구체적으로, 상기 단계 7에서 얻은 화학식 8로 표시되는 화합물을 치환반응으로 히드록시기의 입체화학을 바꾸고 동시에 가수분해 반응시켜 화학식 A로 표시되는 화합물(이노토디올)이 제조되는 단계이다.Step 8 is a step of preparing a compound represented by Formula A by reacting the compound represented by Formula 8 prepared in Step 7 above. Specifically, it is a step in which the compound represented by Formula 8 obtained in Step 7 is subjected to a substitution reaction to change the stereochemistry of a hydroxyl group and at the same time to hydrolyze it to prepare a compound represented by Formula A (inotodiol).

상기 치환반응에서는, 상기 화학식 8로 표시되는 화합물의 히드록시가 좋은 이탈기를 가진 친전자체인 MsCl, TsCl, TfCl 등과 반응하여, 치환반응이 일어나기 쉬운 -OMs, -OTs, -OTf로 전환된 후에, 상전이 촉매인 18-크라운-6에 의해 자유로워진 슈퍼옥사이드 친핵체가 치환반응을 일으켜 하이드록시기의 입체화학을 바꾸고 동시에 가수분해 반응으로 알코올의 보호기를 탈보호시키어 화학식 A로 표시된 화합물(이노토디올)이 제조된다.In the substitution reaction, the hydroxy of the compound represented by Formula 8 reacts with MsCl, TsCl, TfCl, etc., which are electrophiles having a good leaving group, and is converted into -OMs, -OTs, -OTf, which are prone to substitution reactions, The superoxide nucleophile freed by the phase transfer catalyst, 18-crown-6, undergoes a substitution reaction to change the stereochemistry of the hydroxyl group and at the same time deprotect the protecting group of the alcohol through a hydrolysis reaction to a compound represented by formula A (inotodiol) It is manufactured.

상기 상전이 촉매는 슈퍼옥사이드(O₂ ^-)의 용해도를 높이는 역할을 하며, 슈퍼옥사이드는 LiOH, NaOH, KOH, HOOH 등의 히드록시기보다 좋은 산소 친핵체(oxygen nucleophile)로 작용할 수 있고, 이들은 -OMs, -OTs, -OTf 등의 좋은 이탈기를 떼어내고 히드록시기의 입체화학을 바꾸는 치환반응이 일어나고, 동시에 알코올의 아실보호기를 가수분해반응으로 제거하는 두 가지 역할을 한다. 상기 산소 친핵체는 KO₂가 사용될 수 있고, LiOH, NaOH, KOH, HOOH, tBuOOH 등의 일반적인 산소 친핵체도 사용될 수 있으며, 이에 한정되는 것은 아니다.The phase transfer catalyst _{serves to increase the solubility of superoxide (O 2} ⁻ ), and the superoxide may act as an oxygen nucleophile better than a hydroxy group such as LiOH, NaOH, KOH, HOOH, and these are -OMs, - A substitution reaction occurs that removes good leaving groups such as OTs and -OTf and changes the stereochemistry of the hydroxyl group, and at the same time plays two roles of removing the acyl protecting group of alcohol by hydrolysis. As the oxygen nucleophile, KO ₂ may be used, and general oxygen nucleophiles such as LiOH, NaOH, KOH, HOOH, and tBuOOH may also be used, but the present invention is not limited thereto.

또한, 상기 치환반응에서 반응온도는 -20℃ 내지 35℃일 수 있으나, 이에 한정되는 것은 아니며, 반응이 진행되는 정도에 따라 적절히 반응온도를 조절할 수 있으며, 반응시간은 10분 내지 4일일 수 있으나, 이에 한정되는 것은 아니며, 반응이 진행되는 정도에 따라 적절히 반응시간을 조절할 수 있다.In addition, the reaction temperature in the substitution reaction may be -20 ° C to 35 ° C, but is not limited thereto, and the reaction temperature can be appropriately adjusted according to the degree to which the reaction proceeds, and the reaction time may be 10 minutes to 4 days, but , but is not limited thereto, and the reaction time may be appropriately adjusted according to the degree to which the reaction proceeds.

나아가, 상기 상전이 촉매로는 18-크라운-6, 6-크라운-2, 9-크라운-3, 12-크라운-4, 15-크라운-5, 21-크라운-7 등을 사용할 수 있으나, 이에 한정되지 않는다.Furthermore, 18-crown-6, 6-crown-2, 9-crown-3, 12-crown-4, 15-crown-5, 21-crown-7, etc. may be used as the phase transfer catalyst, but limited thereto doesn't happen

또한, 상기 용매로는 테트라하이드로퓨란(THF, tetrahydrofuran), 물, 디메톡시에테인(DME, dimethoxyethane), 디메틸 설폭사이드(DMSO, dimethyl sulfoxide), N,N-디메틸포름아마이드(DMF, N,N-dimethylformamide), 아세토나이트릴(ACN, acetonitrile), 디클로로메테인(DCM, dichloromethane) 등을 사용할 수 있으며, 이를 단독 또는 혼합하여 용매로 사용할 수 있으나, 특별히 이에 한정되는 것은 아니다.In addition, as the solvent, tetrahydrofuran (THF, tetrahydrofuran), water, dimethoxyethane (DME, dimethoxyethane), dimethyl sulfoxide (DMSO, dimethyl sulfoxide), N,N -dimethylformamide (DMF, N,N- dimethylformamide), acetonitrile (ACN, acetonitrile), dichloromethane (DCM, dichloromethane), etc. may be used, and these may be used alone or in mixture as a solvent, but are not particularly limited thereto.

나아가, 상기 탈보호화 반응의 반응조건은 알콜의 보호기 종류에 따라 상이하며, 통상적인 탈보호 반응 조건을 사용하여 수행할 수 있으며, 이는 예시일뿐 이에 한정되지 않는다.Furthermore, the reaction conditions of the deprotection reaction are different depending on the type of protecting group of the alcohol, and may be carried out using conventional deprotection reaction conditions, which are exemplary only, but not limited thereto.

본 발명의 일 측면에서 제공하는 이노토디올(inotodiol)의 제조방법은, 기존의 이노토디올의 제조방법과 비교하여 경유하는 중간체 구조와 과정이 상이할뿐만 아니라 공정 단계가 대폭 축소될 수 있고, 수율이 높으므로, 이노토디올의 제조 및 대량생산에 유용하게 활용 가능한 효과가 있으며, 이는 후술하는 실시예에 의해 뒷받침된다.In the method for producing inotodiol provided in one aspect of the present invention, compared to the existing method for producing inotodiol, the intermediate structure and process through which it passes are different, and the process steps can be significantly reduced, Since the yield is high, there is an effect that can be usefully used for the production and mass production of inotodiol, which is supported by the Examples to be described later.

이하, 본 발명을 실시예 및 실험예를 통해 상세히 설명한다.Hereinafter, the present invention will be described in detail through Examples and Experimental Examples.

단, 후술하는 실시예 및 실험예는 본 발명을 일 측면에서 구체적으로 예시하는 것일 뿐, 본 발명이 이에 제한되는 것은 아니다.However, the Examples and Experimental Examples described below are merely illustrative of the present invention in detail in one aspect, and the present invention is not limited thereto.

<실시예 1> 이노토디올(inotodiol) 합성 전구체의 제조<Example 1> Preparation of inotodiol (inotodiol) synthesis precursor

단계 1: (3S,5R,10S,13R,14R,17R)-3-(메톡시메톡시)-4,4,10,13,14-펜타메틸-17-((R)-6-메틸헵트-5-엔-2-일)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌 제조Step 1: (3S,5R,10S,13R,14R,17R)-3-(methoxymethoxy)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept -5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenane Tren Manufacturing

라노스테롤 (4 g, 5.91 mmol, 1 eq, purity 55%)과 아이오딘화 나트륨(NaI) (0.089 g, 0.591 mmol, 10 mol %)을 디클로로메탄(50 ml)에 용해 시킨 후, 클로로메틸 메틸 에테르(맘 클로라이드, MOMCl) (1.346 ml, 17.72 mmol, 3 eq)를 첨가하였다. 반응물에 N,N-다이아이소프로필에틸아민 (4.73 ml, 27.2 mmol, 4.6 eq)을 0℃에서 천천히 첨가하였다. 반응물을 12시간 동안 50℃에서 환류 교반하였다. 반응물을 0℃로 식힌 후, 동일 온도에서 아이오딘화 나트륨(NaI) (0.044 g, 0.295 mmol, 5 mol %), 클로로메틸 메틸 에테르(맘 클로라이드, MOMCl) (0.673 ml, 8.86 mmol, 1.5 eq), N,N-다이아이소프로필에틸아민(2.366 ml, 13.58 mmol, 2.2 eq)을 첨가한 후, 반응물을 2시간 동안 50℃에서 환류 교반하였다. 반응 종결 후, 포화 NaHCO₃ 수용액을 첨가하고 디클로로메탄으로 추출하였다. 유기층을 순서대로 H₂O, 브라인으로 세정한 후, 무수 Na₂SO₄로 건조시키고 감압 하에서 용매를 제거하였다. 이후, 별도의 정제없이 (3S,5R,10S,13R,14R,17R)-3-(메톡시메톡시)-4,4,10,13,14-펜타메틸-17-((R)-6-메틸헵트-5-엔-2-일)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌 화합물을 수득하였다.After dissolving lanosterol (4 g, 5.91 mmol, 1 eq, purity 55%) and sodium iodide (NaI) (0.089 g, 0.591 mmol, 10 mol %) in dichloromethane (50 ml), chloromethyl methyl Ether(mom chloride, MOMCl) (1.346 ml, 17.72 mmol, 3 eq) was added. To the reaction was slowly added N,N-diisopropylethylamine (4.73 ml, 27.2 mmol, 4.6 eq) at 0°C. The reaction was stirred at reflux at 50 °C for 12 h. After the reaction was cooled to 0 °C, sodium iodide (NaI) (0.044 g, 0.295 mmol, 5 mol %), chloromethyl methyl ether (mam chloride, MOMCl) (0.673 ml, 8.86 mmol, 1.5 eq) at the same temperature , N,N-diisopropylethylamine (2.366 ml, 13.58 mmol, 2.2 eq) was added, and the reaction was stirred at reflux at 50° C. for 2 hours. After completion of the reaction, saturated NaHCO ₃ aqueous solution was added, and the mixture was extracted with dichloromethane. The organic layer was sequentially washed with H ₂ O and brine _{, dried over anhydrous Na 2} SO ₄ , and the solvent was removed under reduced pressure. Thereafter, without further purification (3S,5R,10S,13R,14R,17R)-3-(methoxymethoxy)-4,4,10,13,14-pentamethyl-17-((R)-6 -Methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[ a] A phenanthrene compound was obtained.

¹H NMR (400 MHz, CDCl₃) δ 4.75 (d, J = 6.8 Hz, 1H), 4.61 (d, J = 6.7 Hz, 1H), 3.39 (s, 3H), 3.15 - 3.07 (m, 1H), 2.02 (m, 6H), 1.68 (s, 3H), 1.60 (s, 3H), 0.99 (d, J = 2.0 Hz, 6H), 0.87 (s, 6H), 0.84 (s, 3H), 0.69 (s, 3H). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.75 (d, J = 6.8 Hz, 1H), 4.61 (d, J = 6.7 Hz, 1H), 3.39 (s, 3H), 3.15 - 3.07 (m, 1H) , 2.02 (m, 6H), 1.68 (s, 3H), 1.60 (s, 3H), 0.99 (d, J = 2.0 Hz, 6H), 0.87 (s, 6H), 0.84 (s, 3H), 0.69 ( s, 3H).

Mass (GCMS) : 470 (M⁺).Mass (GCMS): 470 (M ⁺ ).

단계 2: 3-((R)-3-((3S,5R,10S,13R,14R,17R)-3-(메톡시메톡시)-4,4,10,13,14-펜타메틸-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-17-일)부틸)-2,2-다이메틸옥시래인 제조Step 2: 3-((R)-3-((3S,5R,10S,13R,14R,17R)-3-(methoxymethoxy)-4,4,10,13,14-pentamethyl-2 ,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)butyl)-2, Preparation of 2-dimethyloxylane

상기 단계 1에서 합성된 (3S,5R,10S,13R,14R,17R)-3-(메톡시메톡시)-4,4,10,13,14-펜타메틸-17-((R)-6-메틸헵트-5-엔-2-일)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌 (5.195 g, 11.04 mmol, 1 eq)을 디클로로메탄(50 ml)에 용해시킨 후, 메타-클로로퍼옥시 벤조산 (m-CPBA) (1.904 g, 7.72 mmol, 0.7 eq)과 탄산 수소 나트륨 (NaHCO₃) (0.983 g, 11.70 mmol, 1.06 eq)을 0℃에서 첨가하였다. 반응물을 상온에서 12시간 교반하였다. 반응 종결 후, 여과하였고 여액을 10 % NaHCO₃ 수용액과 브라인으로 세정하였다. 무수 MgSO₄로 건조시키고 감압 하에서 용매를 제거하였다. 이후, 별도의 정제없이 3-((R)-3-((3S,5R,10S,13R,14R,17R)-3-(메톡시메톡시)-4,4,10,13,14-펜타메틸-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-17-일)부틸)-2,2-다이메틸옥시래인 화합물을 수득하였다.(3S,5R,10S,13R,14R,17R)-3-(methoxymethoxy)-4,4,10,13,14-pentamethyl-17-((R)-6 synthesized in step 1 above -Methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[ a]phenanthrene (5.195 g, 11.04 mmol, 1 eq) was dissolved in dichloromethane (50 ml), followed by meta-chloroperoxybenzoic acid (m-CPBA) (1.904 g, 7.72 mmol, 0.7 eq) and hydrogen carbonate Sodium (NaHCO ₃ ) (0.983 g, 11.70 mmol, 1.06 eq) was added at 0°C. The reaction was stirred at room temperature for 12 hours. After completion of the reaction, it was filtered and the filtrate was washed with 10% NaHCO ₃ aqueous solution and brine. It was dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure. Thereafter, without separate purification 3-((R)-3-((3S,5R,10S,13R,14R,17R)-3-(methoxymethoxy)-4,4,10,13,14-penta methyl-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)butyl) -2,2-dimethyloxirane compound was obtained.

¹H NMR (400 MHz, CDCl₃) δ 4.75 (d, J = 6.8 Hz, 1H), 4.61 (d, J = 6.7 Hz, 1H), 3.39 (s, 3H), 3.11 (dd, J = 11.7, 4.0 Hz, 1H), 2.69 (s, 1H), 2.02 (s, 3H), 1.96 - 1.85 (m, 2H), 1.75 (s, 1H), 1.71 (s, 1H), 1.31 (s, 3H), 1.26 (d, J = 4.5 Hz, 4H), 0.99 (d, J = 1.7 Hz, 6H), 0.93 - 0.89 (m, 3H), 0.87 (s, 3H), 0.84 (s, 3H), 0.69 (d, J = 3.4 Hz, 3H). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.75 (d, J = 6.8 Hz, 1H), 4.61 (d, J = 6.7 Hz, 1H), 3.39 (s, 3H), 3.11 (dd, J = 11.7, 4.0 Hz, 1H), 2.69 (s, 1H), 2.02 (s, 3H), 1.96 - 1.85 (m, 2H), 1.75 (s, 1H), 1.71 (s, 1H), 1.31 (s, 3H), 1.26 (d, J = 4.5 Hz, 4H), 0.99 (d, J = 1.7 Hz, 6H), 0.93 - 0.89 (m, 3H), 0.87 (s, 3H), 0.84 (s, 3H), 0.69 (d) , J = 3.4 Hz, 3H).

Mass (GCMS) : 486 (M⁺).Mass (GCMS): 486 (M ⁺ ).

단계 3: (R)-4-((3S,5R,10S,13R,14R,17R)-3-(메톡시메톡시)-4,4,10,13,14-펜타메틸-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-17-일)펜타날 제조Step 3: (R)-4-((3S,5R,10S,13R,14R,17R)-3-(methoxymethoxy)-4,4,10,13,14-pentamethyl-2,3, Preparation of 4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanal

상기 단계 2에서 합성된 3-((R)-3-((3S,5R,10S,13R,14R,17R)-3-(메톡시메톡시)-4,4,10,13,14-펜타메틸-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-17-일)부틸)-2,2-다이메틸옥시래인(4.55 g, 9.35 mmol, 1 eq)을 다이에틸 에테르(50 ml)에 용해 시킨 후, 과아이오딘산 (6.39 g, 28.0 mmol, 3 eq)을 첨가하였다. 반응 혼합물을 상온 질소 기류 하에서 3시간 동안 교반하였다. 반응 종결 후, 다이에틸에테르로 추출하였다. 유기층을 H₂O로 세정하고 무수 MgSO₄ 로 건조시킨 후, 감압 하에서 용매를 제거하였다. MPLC로 분리 및 정제하여 (R)-4-((3S,5R,10S,13R,14R,17R)-3-(메톡시메톡시)-4,4,10,13,14-펜타메틸-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-17-일)펜타날 (1.327 g, 2.98 mmol)을 하얀색 고체로 32%의 수율로 수득하였다.3-((R)-3-((3S,5R,10S,13R,14R,17R)-3-(methoxymethoxy)-4,4,10,13,14-penta synthesized in step 2 above methyl-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)butyl) -2,2-dimethyloxirane (4.55 g, 9.35 mmol, 1 eq) was dissolved in diethyl ether (50 ml), followed by addition of periodic acid (6.39 g, 28.0 mmol, 3 eq) . The reaction mixture was stirred for 3 hours under a nitrogen stream at room temperature. After completion of the reaction, extraction was performed with diethyl ether. The organic layer was washed with H ₂ O and dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. Separation and purification by MPLC (R)-4-((3S,5R,10S,13R,14R,17R)-3-(methoxymethoxy)-4,4,10,13,14-pentamethyl-2 ,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanal (1.327 g , 2.98 mmol) was obtained as a white solid in a yield of 32%.

¹H NMR (400 MHz, CDCl₃) δ 9.77 (t, J = 1.8 Hz, 1H), 4.75 (d, J = 6.7 Hz, 1H), 4.61 (d, J = 6.7 Hz, 1H), 3.39 (s, 3H), 3.11 (dd, J = 11.7, 4.2 Hz, 2H), 2.02 (s, 6H), 0.99 (s, 6H), 0.90 (d, J = 6.0 Hz, 3H), 0.87 (s, 3H), 0.84 (s, 3H). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.77 (t, J = 1.8 Hz, 1H), 4.75 (d, J = 6.7 Hz, 1H), 4.61 (d, J = 6.7 Hz, 1H), 3.39 (s) , 3H), 3.11 (dd, J = 11.7, 4.2 Hz, 2H), 2.02 (s, 6H), 0.99 (s, 6H), 0.90 (d, J = 6.0 Hz, 3H), 0.87 (s, 3H) , 0.84 (s, 3H).

Mass (GCMS) : 444 (M⁺).Mass (GCMS): 444 (M ⁺ ).

단계 4: (R,E)-4-((3S,5R,10S,13R,14R,17R)-3-(메톡시메톡시)-4,4,10,13,14-펜타메틸-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-17-일)펜트-2-에날 제조Step 4: (R,E)-4-((3S,5R,10S,13R,14R,17R)-3-(methoxymethoxy)-4,4,10,13,14-pentamethyl-2, 3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)pent-2-enal production

상기 단계 3에서 합성된 (R)-4-((3S,5R,10S,13R,14R,17R)-3-(메톡시메톡시)-4,4,10,13,14-펜타메틸-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-17-일)펜타날 (0.792 g, 1.781 mmol, 1 eq)을 다이메틸 설폭사이드 (DMSO) (50 ml)에 용해시킨 후, 2-아이오도벤조산 (2-Iodoxybenzoic acid, IBX) (997 mg, 3.56 mmol, 2 eq)과 트리플루오로 아세트산(TFA) (0.048ml, 0.623 mmol, 35 mol%)을 첨가하였다. 반응물을 상온에서 12시간 동안 교반 하였다. 반응물에 2-아이오도벤조산 (2-Iodoxybenzoic acid, IBX) (498 mg, 1.78 mmol, 1 eq)과 트리플루오로 아세트산(TFA) (0.14 ml, 1.78 mmol, 1 eq)을 첨가하고 상온에서 9일 동안 교반하였다. 반응이 종결 될때까지 모니터링을 진행하였다. 반응 종결 후, 포화 NaHCO₃ 수용액을 첨가하고 에틸 아세테이트(EA)로 추출하였다. 유기층을 순서대로 H₂O, 브라인으로 세정한 후, 무수 Na₂SO₄ 로 건조시키고 셀라이트를 깔고 여과하였다. 감압 하에서 용매를 제거하고, 반응 종결 후, 포화 NaHCO₃ 수용액을 첨가하고 디클로로메탄으로 추출하였다. 유기층을 순서대로 H₂O, 브라인으로 세정한 후, 무수 Na₂SO₄로 건조시키고 감압 하에서 용매를 제거하였다. MPLC로 분리 및 정제하여 (R,E)-4-((3S,5R,10S,13R,14R,17R)-3-(메톡시메톡시)-4,4,10,13,14-펜타메틸-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-17-일)펜트-2-에날 (32 mg, 0.072 mmol)을 노란색 고체, 4% 수율로 수득하였다.(R)-4-((3S,5R,10S,13R,14R,17R)-3-(methoxymethoxy)-4,4,10,13,14-pentamethyl-2 synthesized in step 3 above ,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanal (0.792 g , 1.781 mmol, 1 eq) was dissolved in dimethyl sulfoxide (DMSO) (50 ml), followed by 2-Iodoxybenzoic acid (IBX) (997 mg, 3.56 mmol, 2 eq) and trifluoro acetic acid (TFA) (0.048 ml, 0.623 mmol, 35 mol%) was added. The reaction was stirred at room temperature for 12 hours. 2-Iodoxybenzoic acid (IBX) (498 mg, 1.78 mmol, 1 eq) and trifluoroacetic acid (TFA) (0.14 ml, 1.78 mmol, 1 eq) were added to the reaction mixture, and then at room temperature for 9 days. stirred for a while. Monitoring was continued until the reaction was completed. After completion of the reaction, saturated NaHCO ₃ aqueous solution was added, followed by extraction with ethyl acetate (EA). The organic layer was sequentially washed with H ₂ O and brine _{, dried over anhydrous Na 2} SO ₄ , and filtered over Celite. The solvent was removed under reduced pressure, and after completion of the reaction, saturated NaHCO ₃ aqueous solution was added, followed by extraction with dichloromethane. The organic layer was sequentially washed with H ₂ O and brine _{, dried over anhydrous Na 2} SO ₄ , and the solvent was removed under reduced pressure. Isolated and purified by MPLC (R,E)-4-((3S,5R,10S,13R,14R,17R)-3-(methoxymethoxy)-4,4,10,13,14-pentamethyl -2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)pent-2 -enal (32 mg, 0.072 mmol) was obtained as a yellow solid, 4% yield.

¹H NMR (400 MHz, CDCl₃) δ 9.49 (d, J = 7.9 Hz, 1H), 6.72 (dd, J = 15.5, 8.4 Hz, 1H), 6.06 (dd, J = 15.5, 7.5 Hz, 1H), 4.75 (d, J = 6.7 Hz, 1H), 4.62 (d, J = 6.6 Hz, 1H), 3.39 (s, 3H), 3.11 (dd, J = 11.5, 3.9 Hz, 1H), 2.06 - 1.96 (m, 3H), 1.00 (d, J = 4.3 Hz, 6H), 0.87 (t, J = 5.5 Hz, 8H), 0.84 (s, 3H), 0.75 (s, 1H), 0.69 (s, 1H). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.49 (d, J = 7.9 Hz, 1H), 6.72 (dd, J = 15.5, 8.4 Hz, 1H), 6.06 (dd, J = 15.5, 7.5 Hz, 1H) , 4.75 (d, J = 6.7 Hz, 1H), 4.62 (d, J = 6.6 Hz, 1H), 3.39 (s, 3H), 3.11 (dd, J = 11.5, 3.9 Hz, 1H), 2.06 - 1.96 ( m, 3H), 1.00 (d, J = 4.3 Hz, 6H), 0.87 (t, J = 5.5 Hz, 8H), 0.84 (s, 3H), 0.75 (s, 1H), 0.69 (s, 1H).

Mass (GCMS) : 442 (M⁺).Mass (GCMS): 442 (M ⁺ ).

<실시예 2> 이노토디올(inotodiol) 제조<Example 2> Preparation of inotodiol

상기 <실시예 1>에서 제조한 이노토디올 합성 전구체를 사용하여 아래와 같이 이노토디올(inotodiol)을 제조하였다.Using the inotodiol synthesis precursor prepared in <Example 1>, inotodiol was prepared as follows.

상기 <실시예 1>의 단계 1 내지 4 이후,After steps 1 to 4 of <Example 1>,

단계 5: (3S,5R,10S,13R,14R,17R)-17-((1S)-1-(3-포르밀옥시란-2-일)에틸)-4,4,10,13,14-펜타메틸-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-3-일 아세테이트 제조Step 5: (3S,5R,10S,13R,14R,17R)-17-((1S)-1-(3-formyloxiran-2-yl)ethyl)-4,4,10,13,14 -Pentamethyl-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate Produce

상기 화합물 6(543 mg, 1.32 mmol, 1 eq)을 디클로로메탄 (5 ml)에 용해시킨 후, 피롤리딘 (0.10 ml, 1.23 mmol, 1 eq)를 첨가하였다. 반응물에 클로랄 수화물(Chloral hydrate)(20.38 mg, 0.123 mmol, 0.1 eq)을 첨가한 후, 과산화수소 30 wt% (0.25 ml, 2.464 mmol, 2 eq)를 첨가하였다. 반응물을 상온에서 3시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 추출하고, 유기층을 순서대로 H₂O, 브라인으로 세정하고, 무수 Na₂SO₄로 건조시켰다. 감압 하에서 용매를 제거한 후, MPLC로 분리 및 정제하여 (3S,5R,10S,13R,14R,17R)-17-((1S)-1-(3-포르밀옥시란-2-일)에틸)-4,4,10,13,14-펜타메틸-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-3-일 아세테이트 (237 mg, 0.519 mmol)를 42 %의 수율로 수득하였다.The compound 6 (543 mg, 1.32 mmol, 1 eq) was dissolved in dichloromethane (5 ml), and pyrrolidine (0.10 ml, 1.23 mmol, 1 eq) was added. Chloral hydrate (20.38 mg, 0.123 mmol, 0.1 eq) was added to the reaction mixture, and then 30 wt% of hydrogen peroxide (0.25 ml, 2.464 mmol, 2 eq) was added. The reaction was stirred at room temperature for 3 hours. After completion of the reaction, extraction was performed with dichloromethane, and the organic layer was washed sequentially with H ₂ O and brine, and dried over anhydrous Na ₂ SO ₄ . After removal of the solvent under reduced pressure, separation and purification by MPLC (3S,5R,10S,13R,14R,17R)-17-((1S)-1-(3-formyloxiran-2-yl)ethyl) -4,4,10,13,14-pentamethyl-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta [a]Phenanthren-3-yl acetate (237 mg, 0.519 mmol) was obtained in a yield of 42%.

¹H NMR (400 MHz, CDCl₃) : δ9.01 (d, J = 6.3 Hz, 1H), 4.52 (d, J = 4.5 Hz, 1H), 3.13 - 3.04 (m, 2H), 2.06 - 2.01 (m, 6H), 1.00 (s, 3H),0.97 (d, J = 6.6 Hz, 3H), 0.91 (s, 3H), 0.88 (s, 6H), 0.69 (s, 3H). ¹ H NMR (400 MHz, CDCl ₃ ): δ9.01 (d, J = 6.3 Hz, 1H), 4.52 (d, J = 4.5 Hz, 1H), 3.13 - 3.04 (m, 2H), 2.06 - 2.01 ( m, 6H), 1.00 (s, 3H), 0.97 (d, J = 6.6 Hz, 3H), 0.91 (s, 3H), 0.88 (s, 6H), 0.69 (s, 3H).

Mass (GCMS) : 456 (M⁺).Mass (GCMS): 456 (M ⁺ ).

단계 6: (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-펜타메틸-17-((1S)-1-(3-(2-메틸프로프-1-엔-1-일)옥시란-2-일)에틸)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-3-일 아세테이트 제조Step 6: (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((1S)-1-(3-(2-methylprop-1) -en-1-yl)oxiran-2-yl)ethyl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H -Cyclopenta[a]phenanthren-3-yl acetate preparation

상기 단계 5에서 합성한 화합물(237 mg, 0.519 mmol, 1 eq)과 5-(이소프로필설포닐)-1-페닐-1H-테트라졸(157 mg, 0.623 mmol,1.2 eq)을 톨루엔 (2 ml)에 용해시킨 후, -78℃에서 포타슘 비스(트리메틸실릴)아마이드 (KHMDS)(0.5 M 톨루엔 용액) (1.2 ml, 0.623 mmol, 1.2 eq)를 첨가하였다. 반응물을 -78℃에서 1 시간 동안 교반하였다. 반응물을 상온으로 올리고, 5-(이소프로필설포닐)-1-페닐-1H-테트라졸(157 mg, 0.623 mmol,1.2 eq)과 포타슘 비스(트리메틸실릴)아마이드 (KHMDS)(0.5 M 톨루엔 용액) (1.2 ml, 0.623 mmol, 1.2 eq)를 첨가하였다. 반응물을 상온에서 1시간 동안 교반하였다. 반응물에 5-(이소프로필설포닐)-1-페닐-1H-테트라졸(157 mg, 0.623 mmol,1.2 eq)과 포타슘 비스(트리메틸실릴)아마이드 (KHMDS)(0.5 M 톨루엔 용액) (1.2 ml, 0.623 mmol, 1.2 eq)를 첨가하였다. 반응물을 상온에서 1시간 동안 교반하였다. 반응 종결 후, 과포화 염화 암모늄 수용액을 사용해 중화를 시켰고 다이에틸에터로 추출하였다. 무수 MgSO₄로 건조시킨 후, 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-펜타메틸-17-((1S)-1-(3-(2-메틸프로프-1-엔-1-일)옥시란-2-일)에틸)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-3-일 아세테이트 (10 mg, 0.021 mmol)를 4%의 수율로 수득하였다.The compound synthesized in step 5 (237 mg, 0.519 mmol, 1 eq) and 5-(isopropylsulfonyl)-1-phenyl-1H-tetrazole (157 mg, 0.623 mmol, 1.2 eq) were mixed with toluene (2 ml ), potassium bis(trimethylsilyl)amide (KHMDS) (0.5 M toluene solution) (1.2 ml, 0.623 mmol, 1.2 eq) was added at -78°C. The reaction was stirred at -78 °C for 1 h. The reaction was brought to room temperature, 5-(isopropylsulfonyl)-1-phenyl-1H-tetrazole (157 mg, 0.623 mmol, 1.2 eq) and potassium bis(trimethylsilyl)amide (KHMDS) (0.5 M toluene solution) (1.2 ml, 0.623 mmol, 1.2 eq) was added. The reaction was stirred at room temperature for 1 hour. In the reaction mixture, 5-(isopropylsulfonyl)-1-phenyl-1H-tetrazole (157 mg, 0.623 mmol, 1.2 eq) and potassium bis(trimethylsilyl)amide (KHMDS) (0.5 M toluene solution) (1.2 ml, 0.623 mmol, 1.2 eq) was added. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, it was neutralized using a supersaturated aqueous ammonium chloride solution and extracted with diethyl ether. After drying over anhydrous MgSO ₄ , the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((1S)-1-(3- (2-methylprop-1-en-1-yl)oxiran-2-yl)ethyl)-2,3,4,5,6,7,10,11,12,13,14,15,16 ,17-Tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate (10 mg, 0.021 mmol) was obtained in a yield of 4%.

¹H NMR (400 MHz, CDCl₃) : δ5.33 - 5.25 (m, 1H), 4.50 (dd, J = 11.7, 4.6 Hz, 1H), 3.21 - 3.06 (m, 2H), 2.05 - 2.00 (m, 6H), 1.75 (s, 3H), 1.63 (s, 3H), 1.09 (s, 3H), 1.08 (s, 3H), 1.00 (s, 3H), 0.90 (s, 3H), 0.88 (s, 3H), 0.71 (s, 3H). ¹ H NMR (400 MHz, CDCl ₃ ): δ5.33 - 5.25 (m, 1H), 4.50 (dd, J = 11.7, 4.6 Hz, 1H), 3.21 - 3.06 (m, 2H), 2.05 - 2.00 (m) , 6H), 1.75 (s, 3H), 1.63 (s, 3H), 1.09 (s, 3H), 1.08 (s, 3H), 1.00 (s, 3H), 0.90 (s, 3H), 0.88 (s, 3H), 0.71 (s, 3H).

Mass (GCMS) : 482 (M⁺).Mass (GCMS): 482 (M ⁺ ).

단계 7: (3S,5R,10S,13R,14R,17R)-17-((2S,3S)-3-하이드록시-6-메틸헵트-5-엔-2-일)-4,4,10,13,14-펜타메틸-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-3-일 아세테이트 제조Step 7: (3S,5R,10S,13R,14R,17R)-17-((2S,3S)-3-hydroxy-6-methylhept-5-en-2-yl)-4,4,10 ,13,14-pentamethyl-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene- 3-yl acetate preparation

상기 단계 6에서 합성한 화합물(10 mg, 0.021 mmol, 1 eq)를 디클로로메탄 (50 μl)과 테트라하이드로퓨란(THF) (5 μl)에 용해 시킨 후, 염화 아연(II) (8.47 mg, 0.062 mmol, 3 eq)과 나트륨 시아노보로하이드라이드 (3.91 mg, 0.062 mmol,3 eq)을 첨가 하였다. 반응물을 상온에서 3일 동안 교반하였다. 반응물에 염화 아연(II) (8.47 mg, 0.062 mmol, 3 eq)과 나트륨 시아노보로하이드라이드 (3.91 mg, 0.062 mmol, 3 eq)을 첨가하고, 상온에서 12시간 동안 교반하였다. 반응 종결 후, 디클로로메탄으로 추출하였다. 유기층을 순서대로 H₂O, 브라인으로 세정하고, 무수 Na₂SO₄로 건조시켰다. 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 (3S,5R,10S,13R,14R,17R)-17-((2S,3S)-3-하이드록시-6-메틸헵트-5-엔-2-일)-4,4,10,13,14-펜타메틸-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-3-일 아세테이트 (4 mg, 8.46 μmol)를 40%의 수율로 수득하였다.After dissolving the compound (10 mg, 0.021 mmol, 1 eq) synthesized in step 6 in dichloromethane (50 μl) and tetrahydrofuran (THF) (5 μl), zinc (II) chloride (8.47 mg, 0.062) mmol, 3 eq) and sodium cyanoborohydride (3.91 mg, 0.062 mmol, 3 eq) were added. The reaction was stirred at room temperature for 3 days. Zinc(II) chloride (8.47 mg, 0.062 mmol, 3 eq) and sodium cyanoborohydride (3.91 mg, 0.062 mmol, 3 eq) were added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, extraction was performed with dichloromethane. The organic layer was washed sequentially with H ₂ O, brine, and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to (3S,5R,10S,13R,14R,17R)-17-((2S,3S)-3-hydroxy-6-methylhept-5-en-2- yl)-4,4,10,13,14-pentamethyl-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H- Cyclopenta[a]phenanthren-3-yl acetate (4 mg, 8.46 μmol) was obtained in a yield of 40%.

¹H NMR (400 MHz, CDCl₃) : δ5.15 (t, J = 7.1 Hz, 1H), 4.50 (dd, J = 11.6, 4.5 Hz, 1H), 3.67 (dd, J = 8.0, 4.5 Hz, 1H), 2.06 - 1.97 (m, 6H) 1.76 - 1.70 (m, 3H), 1.65 - 1.62 (m, 3H), 1.58 (s, 3H), 1.25 (s, 3H), 1.01 (s, 3H), 0.90 (s, 3H), 0.88 (s, 3H), 0.70 (s, 3H). ¹ H NMR (400 MHz, CDCl ₃ ): δ5.15 (t, J = 7.1 Hz, 1H), 4.50 (dd, J = 11.6, 4.5 Hz, 1H), 3.67 (dd, J = 8.0, 4.5 Hz, 1H), 2.06 - 1.97 (m, 6H) 1.76 - 1.70 (m, 3H), 1.65 - 1.62 (m, 3H), 1.58 (s, 3H), 1.25 (s, 3H), 1.01 (s, 3H), 0.90 (s, 3H), 0.88 (s, 3H), 0.70 (s, 3H).

Mass (GCMS) : 484 (M⁺).Mass (GCMS): 484 (M ⁺ ).

단계 8: 이노토디올(inotodiol)Step 8: Inotodiol

상기 단계 7에서 합성한 화합물(4 mg, 8.46 μmol)를 0℃에서 피리딘 (100 μl)에 용해시킨 후, 과량의 메탄설포닐 클로라이드(50 μl)를 첨가하였다. 반응물을 0℃에서 5시간 동안 교반 하였다. 반응 종결 후, 반응물에 얼음을 첨가하고 다이에틸에터로 추출하였다. 유기층을 순서대로 H₂O, 브라인으로 세정하고, 무수 Na₂SO₄로 건조시켰다. 감압 하에서 용매를 제거하였다. 별도의 정제없이 (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-펜타메틸-17-((2S,3S)-6-메틸-3-((메틸설포닐)옥시)헵트-5-엔-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-3-일 아세테이트(5 mg)를 수득하였다.The compound synthesized in step 7 (4 mg, 8.46 μmol) was dissolved in pyridine (100 μl) at 0° C., and then an excess of methanesulfonyl chloride (50 μl) was added. The reaction was stirred at 0 °C for 5 hours. After completion of the reaction, ice was added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was washed sequentially with H ₂ O, brine, and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure. (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((2S,3S)-6-methyl-3-((methylsulf Ponyl)oxy)hept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclo Obtained penta[a]phenanthren-3-yl acetate (5 mg).

이후, 합성된 (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-펜타메틸-17-((2S,3S)-6-메틸-3-((메틸설포닐)옥시)헵트-5-엔-2-일)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-3-일 아세테이트(5 mg)와 18-크라운-6 (7.66 mg, 0.029 mmol, 3.4 eq)를 다이메틸 설폭사이드(DMSO)(50 μl)와 디메틸포름아마이드(DMF)(50 μl)에 용해 시킨 후, 과산화칼륨 (2.71 mg, 0.038 mmol, 4.5 eq)를 첨가하였다. 반응물을 상온 질소 기류 하에서 5시간 동안 교반하였다. 반응물에 과산화칼륨 (17 mg, 0.24 mmol, 24 eq), 18-크라운-6 (23 mg, 0.087 mmol, 9 eq)을 첨가한 후, 상온 질소 기류 하에서 12시간 동안 교반하였다. 반응 종결 후, 몇 방울의 1 N HCl를 첨가하고 디클로로메탄으로 추출하였다. 유기층을 순서대로 H₂O, 브라인으로 세정하고, 무수 Na₂SO₄로 건조시키고 감압 하에서 용매를 제거하였다. 이후, 반응 혼합물을 MPLC로 분리 및 정제하여 이노토다이올 (0.6 mg, 1.35 μmol)을 16 %의 수율로 수득하였다.Then, the synthesized (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((2S,3S)-6-methyl-3-((methylsulf Ponyl)oxy)hept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclo Penta[a]phenanthren-3-yl acetate (5 mg) and 18-crown-6 (7.66 mg, 0.029 mmol, 3.4 eq) were mixed with dimethyl sulfoxide (DMSO) (50 μl) and dimethylformamide (DMF) (50 μl), potassium peroxide (2.71 mg, 0.038 mmol, 4.5 eq) was added. The reaction was stirred for 5 hours under a nitrogen stream at room temperature. Potassium peroxide (17 mg, 0.24 mmol, 24 eq) and 18-crown-6 (23 mg, 0.087 mmol, 9 eq) were added to the reaction mixture, followed by stirring at room temperature under a nitrogen stream for 12 hours. After completion of the reaction, a few drops of 1 N HCl was added, followed by extraction with dichloromethane. The organic layer was sequentially washed with H ₂ O and brine _{, dried over anhydrous Na 2} SO ₄ , and the solvent was removed under reduced pressure. Thereafter, the reaction mixture was separated and purified by MPLC to obtain inotodiol (0.6 mg, 1.35 μmol) in a yield of 16%.

¹H NMR (400 MHz, CDCl₃) : δ5.22 - 5.14 (m, 1H), 3.70 - 3.63 (m, 1H), 3.24 (dd, J = 11.1, 4.3 Hz, 1H), 2.04 (dd, J = 21.3, 14.3 Hz, 6H), 1.75 (s, 3H), 1.66 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 0.87 (s, 3H), 0.81 (s, 3H), 0.72 (s, 3H). ¹ H NMR (400 MHz, CDCl ₃ ): δ5.22 - 5.14 (m, 1H), 3.70 - 3.63 (m, 1H), 3.24 (dd, J = 11.1, 4.3 Hz, 1H), 2.04 (dd, J) = 21.3, 14.3 Hz, 6H), 1.75 (s, 3H), 1.66 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H) , 0.87 (s, 3H), 0.81 (s, 3H), 0.72 (s, 3H).

Mass (GCMS) : 442 (M⁺).Mass (GCMS): 442 (M ⁺ ).

이상, 본 발명을 바람직한 제조예, 실시예 및 실험예를 통해 상세히 설명하였으나, 본 발명의 범위는 특성 실시예에 한정되는 것은 아니며, 첨부된 특허청구범위에 의하여 해석되어야 할 것이다. 또한, 이 기술분야에서 통상의 지식을 습득한 자라면, 본 발명의 범위에서 벗어나지 않으면서도 많은 수정과 변형이 가능함을 이해하여야 할 것이다.As mentioned above, although the present invention has been described in detail through preferred preparation examples, examples and experimental examples, the scope of the present invention is not limited to the characteristic examples, and should be interpreted by the appended claims. In addition, those skilled in the art will understand that many modifications and variations are possible without departing from the scope of the present invention.

Claims

As shown in Scheme 1 below,
preparing a compound represented by Formula 2 by introducing a protecting group to the compound represented by Formula 1 (step 1);
preparing a compound represented by Formula 3 by epoxidizing the compound represented by Formula 2 prepared in Step 1 (step 2);
preparing a compound represented by Formula 4 by reacting the compound represented by Formula 3 prepared in Step 2 (step 3); and
Preparation of an inotodiol synthesis precursor represented by the following Chemical Formula 5, including; preparing a compound represented by Chemical Formula 5 by reacting the compound represented by Chemical Formula 4 prepared in Step 3 (Step 4) Way:
[Scheme 1]

In Scheme 1,
PG ¹ is a protecting group of alcohol.

According to claim 1,
The PG ¹ is acetyl (Ac), benzyl (Bn), methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), benzyloxymethyl (BOM), p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), p-methoxybenzyloxymethyl (PMBM), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), 2- (trimethylsilyl) ethoxymethyl (SEM) and (phenyldimethylsilyl) methoxymethyl (SMOM) a method for producing a method, characterized in that the protecting group of one alcohol selected from the group consisting of.

A compound represented by Formula 3 of claim 1, an isomer thereof, a solvate thereof, or a salt thereof.

A compound represented by Formula 4 of claim 1, an isomer thereof, a solvate thereof, or a salt thereof.

5. The method of claim 3 or 4,
The isomer is a compound, characterized in that it is a stereoisomer, an isomer thereof, a solvate thereof, or a salt thereof.

6. The method of claim 5,
The stereoisomer is a compound, characterized in that the optical isomer (optical isomer), an isomer thereof, a solvate thereof, or a salt thereof.

5. The method of claim 3 or 4,
The salt is a compound, characterized in that it is a pharmaceutically acceptable salt, an isomer thereof, a solvate thereof, or a salt thereof.

A method for producing inotodiol from the inotodiol synthesis precursor represented by Formula 5 prepared by the method of claim 1 .

As shown in Scheme 2 below,
preparing a compound represented by Formula 2 by introducing a protecting group to the compound represented by Formula 1 (step 1);
preparing a compound represented by Formula 3 by epoxidizing the compound represented by Formula 2 prepared in Step 1 (step 2);
preparing a compound represented by Formula 4 by reacting the compound represented by Formula 3 prepared in Step 2 (step 3);
preparing a compound represented by Formula 5 by reacting the compound represented by Formula 4 prepared in Step 3 (step 4);
preparing a compound represented by Formula 6 by epoxidizing the compound represented by Formula 5 prepared in step 4 (step 5);
preparing a compound represented by Formula 7 by reacting the compound represented by Formula 6 prepared in Step 5 (step 6);
preparing a compound represented by Formula 8 by reacting the compound represented by Formula 7 prepared in Step 6 (step 7); and
A method for preparing inotodiol represented by the following formula (A), including the step of reacting the compound represented by formula (8) prepared in step 7 to prepare a compound represented by formula (A) (step 8):
[Scheme 2]

In Scheme 2,
PG ¹ is a protecting group of alcohol.

10. The method of claim 9,
The PG ¹ is acetyl (Ac), benzyl (Bn), methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), benzyloxymethyl (BOM), p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), p-methoxybenzyloxymethyl (PMBM), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), 2- (trimethylsilyl) ethoxymethyl (SEM) and (phenyldimethylsilyl) methoxymethyl (SMOM) a method for producing a method, characterized in that the protecting group of one alcohol selected from the group consisting of.