KR100786371B1 - Process for preparing galanthamine - Google Patents

Process for preparing galanthamine Download PDF

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KR100786371B1
KR100786371B1 KR1020060123826A KR20060123826A KR100786371B1 KR 100786371 B1 KR100786371 B1 KR 100786371B1 KR 1020060123826 A KR1020060123826 A KR 1020060123826A KR 20060123826 A KR20060123826 A KR 20060123826A KR 100786371 B1 KR100786371 B1 KR 100786371B1
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최일영
임희종
유옥종
정명희
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한국화학연구원
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

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Abstract

A method for preparing galantamine is provided to synthesize the highly pure galantamine, known to show the excellent dementia treating effect, with high yield. A method for preparing galantamine comprises the steps of: (a) after reacting an oxazolidinone derivative represented by the formula(2) with an aromatic halide derivative represented by the formula(3), removing a hydroxy protection group from the product to prepare a phenol derivative represented by the formula(4b)(wherein X is a halogen atom, and Pro is a hydroxy protection group); (b) subjecting the compound of the formula(4b) in the presence of an oxidizer to an oxidative coupling reaction to prepare a spiro benzo azepine derivative represented by the formula(5); (c) reacting the compound of the formula(5) with morpholine using a Pd catalyst to prepare a stereoselective hydrofuran derivative represented by the formula(6); (d) converting C-6 hydroxy group of the compound of the formula(6) into a hydrogen atom to prepare a compound represented by the formula(7b); (e) reducing C-10 ketone of the compound of the formula(7b) to prepare a compound represented by the formula(8); (f) after hydrolyzing the compound of the formula(8) under the base condition to open an oxazolidinone ring, subjecting the product to an N-methylation reaction to prepare a compound represented by the formula(9b); (g) oxidizing the compound of the formula(9b) to prepare a compound represented by the formula(10); (h) after converting an aldehyde group of the compound of the formula(1) into oxime, dehydrating the product to prepare a compound represented by the formula(11); and (i) reducing C-6 ketone of the compound of the formula(11) and eliminating C-10 carbonitrile of the compound to prepare the galantamine represented by the formula(1).

Description

갈란타민의 제조방법 {Process for preparing Galanthamine} Process for preparing Galanthamine {Process for preparing Galanthamine}

본 발명은 갈란타민의 제조방법에 관한 것으로서, 더욱 상세하게는 산화성 짝지움(oxidative coupling)에 사용되어지는 페놀류 화합물의 구조를 옥사졸리디논과 방향족 할라이드 화합물로부터 특이성 있게 고안하여 반응에 사용함으로써 입체선택적 등의 일련의 제조방법의 특징으로 인하여 치매치료제로 알려진 갈란타민(Galanthamine)을 고 순도 및 고 수율로 전합성하는 제조방법에 관한 것이다.The present invention relates to a method for producing galantamine, and more particularly, by selecting a structure of a phenolic compound used for oxidative coupling from an oxazolidinone and an aromatic halide compound specifically used for reaction. Due to the characteristics of a series of manufacturing methods, such as a method for presynthesizing galantamine (Galanthamine) known as a treatment for dementia in high purity and high yield.

현재 치매 치료약으로 개발되어 시판되고 있는 약물로는 타크린, 도네페질(아리셉트), 리바스티그민, 그리고 갈란타민이 있다. 이 중 타크린은 약효는 뛰어나지만 간 독성이 있어 지금은 거의 사용되지 않고 있으며, 도네페질은 일본의 Eisai사에서 개발하여 가장 무난한 약으로 평가를 받고 있다. 리바스티그민은 구역 구토질의 부작용 발생률이 다른 제품보다 높다. 그리고, 갈란타민(상품명 Reminyl™)은 수선화 (Galanthus woronowii) 식물로부터 분리한 천연 알칼로이드로서, 아세틸콜린 에스테라제를 저해할 뿐 아니라 대뇌의 니코틴 수용체에 작용해 신경전달물질인 아세틸콜린(Acetylcholine)의 활성을 증가시키는 작용[Drugs Future 1996, 21, 621. CNS Drug Rev. 2002, 8, 159]을 갖는 것으로 잘 알려져 있다. 특히, 갈란타민은 다른 치매약에 비교해서 천연물이라 효능에 비하여 부작용이 적으며, 오스트리아에서 제일 먼저 치매약으로 승인된 후 유럽, 미국순서로 승인되어 지금 판매되고 있다. 갈란타민 약물의 최대 단점은 천연물로부터 추출하여 얻을 수 있는 양 (구근에 0.1 내지 2% 함유)이 한정되어 있다는 것이다. 이에, 많은 유기화학자들이 갈란타민의 합성법을 개발하고자 하는 시도가 있어 왔다.Drugs currently being developed and marketed as treatments for dementia include tacrine, donepezil (aricept), rivastigmine, and galantamine. Of these, tacrine has excellent drug efficacy but is rarely used because of its hepatotoxicity. Donepezil is developed by Eisai of Japan and is evaluated as the safest drug. Rivastigmine has a higher incidence of adverse effects of nausea and vomiting than other products. Galantamine (trade name Reminyl ™) is a natural alkaloid isolated from the plant Narcissus ( Galanthus woronowii ). Action to increase activity [ Drugs Future 1996 , 21 , 621 . CNS Drug Rev. 2002 , 8 , 159]. In particular, galantamine is a natural product compared to other dementia drugs, and has fewer side effects than efficacy, and is first sold in Austria and then approved in European and US order. The biggest disadvantage of galantamine drugs is that there is a limited amount (from 0.1 to 2% in the bulb) that can be obtained from natural products. Accordingly, many organic chemists have attempted to develop a method for synthesizing galantamine.

갈란타민의 전합성에 관한 연구는 바톤 (Barton)[J. Chem. Soc. 1962, 806]에 의해 가장 먼저 시도되었다. 그 이후에도 다수의 유기 화학자들이 갈란타민의 라세미 합성[J. Org. Chem. 1971, 36, 1295-1297; Heterocyclic Chem. 1995, 32, 195-199; J. Org. Chem. 1998, 63, 6625-6623; Synth. Commun. 2000, 30, 2833-2846; Angew. Chem. Int. Ed. 2001, 40, 3060-3062; Angew. Chem. Int. Ed. 2001, 40, 4745-4746; Org. Lett. 2006, 8, 1823-1825]과 비대칭 전합성[J. Heterocycles, 1977, 8, 277-282; Angew. Chem. Int. Ed. 2002, 41, 2795-2797; Angew. Chem. Int. Ed. 2004, 43, 2659-2661]에 대한 연구결과를 발표한 바 있다. Studies on the total synthesis of galantamine have been described in Barton [ J. Chem. Soc. 1962 , 806]. Since then, many organic chemists have developed racemic synthesis of galantamine [ J. Org. Chem. 1971 , 36 , 1295-1297; Heterocyclic Chem. 1995 , 32 , 195-199; J. Org. Chem. 1998 , 63 , 6625-6623; Synth. Commun. 2000 , 30 , 2833-2846; Angew. Chem. Int. Ed. 2001 , 40 , 3060-3062; Angew. Chem. Int. Ed. 2001 , 40 , 4745-4746; Org. Lett. 2006 , 8 , 1823-1825] and asymmetric presynthesis [ J. Heterocycles, 1977 , 8 , 277-282; Angew. Chem. Int. Ed. 2002 , 41 , 2795-2797; Angew. Chem. Int. Ed. 2004 , 43 , 2659-2661].

현재까지 알려져 있는 갈란타민의 대표적인 전합성법은 다음과 같이 두 가지 핵심 반응 프로토콜이 있다: a) 금속 산화제 존재하에 페놀릭 산화성 짝지움 반응을 경유하는 생체모방적 접근 (biomimetic approach); b) 분자내 헤크 반응(intramolecular Heck reaction).Representative presynthesis methods of galantamine to date are known to have two key reaction protocols: a) a biomimetic approach via a phenolic oxidative mating reaction in the presence of a metal oxidant; b) Intramolecular Heck reaction.

본 발명의 발명자들은 갈란타민을 고 광학순도로 제조할 수 있는 새로운 전합성법을 개발하고자 연구 노력하였고, 그 결과 산화성 짝지움에 필요한 페놀류 화합물을 옥사졸리디논과 방향족 할라이드를 결합하고 팔라듐 촉매를 사용하여 마이컬 부가반응되어 고리화가 일어나 최종 목적물의 광학 순도 및 수율을 결정짓는 주요 단계임을 인식하게 됨으로써 본 발명을 완성하게 되었다. 즉, 본 발명에서는 페놀류 반응에 사용되어지는 옥사졸리디논 화합물과 방향족 할라이드 화합물의 구조를 특이성 있게 고안하여 반응에 사용함으로써 원하는 이성질체를 절대적으로 우위에 있도록 합성한 것이다. The inventors of the present invention have tried to develop a new presynthesis method for producing galantamine with high optical purity. As a result, phenolic compounds required for oxidative mating are combined with oxazolidinone and aromatic halides and a palladium catalyst is used. The addition of the carboxylic reactions to complete the present invention by recognizing that the ring is a major step to determine the optical purity and yield of the final target. That is, in the present invention, the structures of the oxazolidinone compound and the aromatic halide compound used in the phenolic reaction are specifically designed and used in the reaction to synthesize the desired isomers in an absolute superiority.

따라서, 본 발명은 고 순도의 갈란타민을 고 수율로 전합성하는 개선된 제조방법을 제공하는데 그 목적이 있다.It is therefore an object of the present invention to provide an improved process for the presynthesis of high purity galantamine in high yield.

또한, 본 발명은 갈란타민의 합성과정 중에 중간체로서 합성되는 신규 구조의 화합물을 제공하는데도 다른 목적이 있다.Another object of the present invention is to provide a compound having a novel structure synthesized as an intermediate during the synthesis of galantamine.

본 발명이 합성하는 갈란타민(galanthamine) 다음 화학식 1로 표시된다.Galanthamine synthesized by the present invention is represented by the following formula (1).

Figure 112006090796461-pat00001
Figure 112006090796461-pat00001

본 발명은 다음 반응식 1에 나타낸 바와 같은 일련의 제조과정이 포함되는 갈란타민의 제조방법을 그 특징으로 한다: The present invention is characterized by a process for preparing galantamine, which comprises a series of preparation processes as shown in Scheme 1:

ⅰ) 다음 화학식 2로 표시되는 옥사졸리디논 유도체와 다음 화학식 3으로 표시되는 방향족 할라이드 유도체를 결합반응한 후에, 하이드록시 보호기를 제거하여 다음 화학식 4b로 표시되는 페놀 유도체를 제조하는 과정; Iii) preparing a phenol derivative represented by the following Chemical Formula 4b by combining the oxazolidinone derivative represented by the following Chemical Formula 2 with the aromatic halide derivative represented by the following Chemical Formula 3, and then removing the hydroxy protecting group;

ⅱ) 다음 화학식 4b로 표시되는 화합물을 산화제 존재하에서 산화성 짝지움 (oxidative coupling) 반응하여 다음 화학식 5로 표시되는 스파이로 벤조 아제핀 유도체를 제조하는 과정;Ii) oxidative coupling reaction of the compound represented by Formula 4b in the presence of an oxidant to prepare a spiro benzoazine derivative represented by Formula 5;

ⅲ) 다음 화학식 5로 표시되는 화합물을 모르폴린과 팔라듐 촉매를 사용하여 반응시켜 다음 화학식 6으로 표시되는 입체선택성의 하이드로퓨란 유도체를 제조하는 과정;Iii) reacting the compound represented by Formula 5 with a morpholine and a palladium catalyst to prepare a stereoselective hydrofuran derivative represented by Formula 6;

ⅳ) 다음 화학식 6으로 표시되는 화합물의 C-6 위치 하이드록시기를 수소원자로 전환하여 다음 화학식 7b로 표시되는 화합물을 제조하는 과정;Iii) converting the C-6 position hydroxy group of the compound represented by Formula 6 to a hydrogen atom to prepare a compound represented by Formula 7b;

ⅴ) 다음 화학식 7b로 표시되는 화합물의 C-10 위치 케톤을 환원 반응하여 다음 화학식 8로 표시되는 화합물을 제조하는 과정;Iii) preparing a compound represented by the following Chemical Formula 8 by reducing the C-10 position ketone of the compound represented by the following Chemical Formula 7b;

ⅵ) 다음 화학식 8로 표시되는 화합물을 염기 조건에서 가수분해하여 옥사졸리디논 고리를 개환한 후에, N-메틸화 반응하여 다음 화학식 9b로 표시되는 화합물을 제조하는 과정;Iii) hydrolyzing the compound represented by the following Chemical Formula 8 under basic conditions to ring-open the oxazolidinone ring, followed by N-methylation to prepare a compound represented by the following Chemical Formula 9b;

ⅶ) 다음 화학식 9b로 표시되는 화합물을 산화 반응하여 다음 화학식 10으로 표시되는 화합물을 제조하는 과정;Iii) oxidizing the compound represented by Formula 9b to prepare a compound represented by Formula 10;

ⅷ) 다음 화학식 10으로 표시되는 화합물의 알데히드기를 옥심으로 전환한 후에, 탈수반응하여 다음 화학식 11로 표시되는 화합물을 제조하는 과정; 및Iii) converting the aldehyde group of the compound represented by the following formula (10) to oxime, followed by dehydration to produce a compound represented by the following formula (11); And

ⅸ) 다음 화학식 11로 표시되는 화합물의 C-6 위치 케톤의 환원반응 및 C-10 위치의 카르보나이트릴기 제거반응을 수행하여 다음 화학식 1로 표시되는 갈란타민을 제조하는 과정.Iii) a process for preparing galantamine represented by the following Chemical Formula 1 by performing a reduction reaction of a C-6 position ketone and a carbonitrile group removing reaction of the C-10 position with a compound represented by the following Chemical Formula 11;

Figure 112006090796461-pat00002
Figure 112006090796461-pat00002

상기에서, X는 할로겐원자를 나타내고, Pro는 하이드록시 보호기를 나타낸다.In the above, X represents a halogen atom and Pro represents a hydroxy protecting group.

본 발명은 상기한 바와 같은 본 발명의 제조방법을 그 과정별로 보다 상세히 설명하면 다음과 같다. The present invention will be described in more detail for each process the manufacturing method of the present invention as described above are as follows.

먼저, ⅰ)과정에서는 상기 화학식 2로 표시되는 옥사졸리디논 유도체와 상기 화학식 3으로 표시되는 다이알릴이 치환된 방향족 할라이드 유도체를 염기(예를 들면, 소디움 하이드라이드(NaH)) 조건하에서 실온에서 결합반응하여 방향족군이 치환된 상기 화학식 4a로 표시되는 옥사졸리디논 유도체를 제조한 후에, 보호기(protecting group) R을 제거하여 상기 화학식 4b로 표시되는 페놀을 가지는 옥사졸리디논 화합물을 제조한다. 이때, 하이드록시 보호기는 당 분야에서 통상적으로 이용되는 것으로, 벤질기, tert-뷰틸다이메틸실릴(TBS), 트라이에틸실릴기 등이 사용될 수 있다. 하이드록시 보호기를 이탈시키는 탈보호 반응 역시 당 분야에서 널리 알려진 공지방법에 의해 수행하는 바, 예를 들면 테트라뷰틸암모늄 풀루오라이드(n-Bu4NF), 팔라듐/챠콜(Pd/C) 등을 사용하는 통상의 방법에 의한다.First, in step iii), the oxazolidinone derivative represented by Chemical Formula 2 and the aromatic halide derivative substituted by diallyl represented by Chemical Formula 3 are bonded at room temperature under base (for example, sodium hydride (NaH)) conditions. After reacting to prepare an oxazolidinone derivative represented by Formula 4a in which an aromatic group is substituted, a protecting group R is removed to prepare an oxazolidinone compound having a phenol represented by Formula 4b. In this case, the hydroxy protecting group is commonly used in the art, benzyl group, tert -butyldimethylsilyl (TBS), triethylsilyl group and the like can be used. The deprotection reaction to remove the hydroxy protecting group is also carried out by well-known methods well known in the art, for example, tetrabutylammonium fluoride (n-Bu 4 NF), palladium / charcoal (Pd / C) and the like. By the usual method used.

그 다음 ⅱ)과정에서는, 상기에서 제조한 화학식 4b로 표시되는 화합물을 산화성 짝지움 반응을 하여 상기 화학식 5로 표시되는 스파이로 벤조 아제핀 유도체를 제조한다. 상기한 산화성 짝지움에 사용되는 산화제로는 페닐아이오딘(Ⅲ) 비스(트라이풀루오로 아세테이트) [phenyliodine(Ⅲ) bis(trifluoroacetate: PIFA)] [J. Org. Chem. 1998, 6625-6633]를 사용할 수 있으며, 그 구조식은 다음과 같다 : Then, in the ii) process, the compound represented by Chemical Formula 4b prepared above is subjected to an oxidative pairing reaction to prepare a spiro benzo azepine derivative represented by Chemical Formula 5. The oxidizing agent used in the above oxidative pairing is phenyliodine (III) bis (trifluoacetate) [phenyliodine (III) bis (trifluoroacetate: PIFA)] [ J. Org. Chem. 1998 , 6625-6633], whose structural formula is:

Figure 112006090796461-pat00003
Figure 112006090796461-pat00003

그 다음 ⅲ)과정에서는, 상기에서 제조한 화학식 5로 표시되는 화합물의 다이알릴기 제거 및 마이컬 부가반응하여 상기 화학식 6으로 표시되는 입체선택성의 하이드로퓨란 유도체를 제조한다. 상기 반응은 모르폴린이 포함된 테트라하이 드로퓨란 용매에서 팔라듐 촉매(예를 들면, 테트라키스트라이페닐포스핀 팔라디움 [Pd(PPh3)4])를 사용하여 실온에서 수행한다. Then, in the step iii), by removing the diallyl group of the compound represented by the formula (5) and the mechanical addition reaction to prepare a stereoselective hydrofuran derivative represented by the formula (6). The reaction is carried out at room temperature using a palladium catalyst (eg, tetrakistriphenylphosphine palladium [Pd (PPh 3 ) 4 ]) in a tetrahydrofuran solvent containing morpholine.

그 다음 ⅳ)과정에서는, 상기에서 제조한 화학식 6으로 표시되는 화합물의 C-6 위치 하이드록시기를 이탈기(예를 들면, 트라이플루오로메테인 술포닐기(Tf))로 전환시켜 상기 화학식 7a로 표시되는 트리플레이트 유도체를 제조한다. 상기 반응은 피리딘 혹은 트라이에틸아민과 같은 염기 하에서 무수 트라이풀루오르메테인술폰산(Tf2O)을 사용하여 -20 ℃ 내지 10 ℃에서 수행한다. 그런 다음, 상기 화학식 7a로 표시되는 화합물에서 트라이풀루오로메테인술폰네이트기(OTf)를 제거하여 상기 화학식 7b로 표시되는 화합물을 제조한다. 상기 반응은 Pd(OAc)2, 포르말린, 트라이에틸아민 염기를 사용하여 40 ℃ 내지 70 ℃에서 약 2시간 수행한다. 그러나 시간이 경과함에 따라 이논(enone)의 이중결합이 환원된 형태가 얻어진다. Then, in step iii), the C-6 position hydroxy group of the compound represented by Chemical Formula 6 prepared above is converted to a leaving group (for example, trifluoromethane sulfonyl group (Tf)) to Chemical Formula 7a. Prepare the indicated triflate derivative. The reaction is carried out at −20 ° C. to 10 ° C. with anhydrous tripulolumethanesulfonic acid (Tf 2 O) under a base such as pyridine or triethylamine. Then, the compound represented by the formula (7b) is prepared by removing the tripulolomethanesulfonate group (OTf) from the compound represented by the formula (7a). The reaction is carried out at 40 ° C. to 70 ° C. for about 2 hours using Pd (OAc) 2 , formalin, triethylamine base. However, as time passes, a reduced form of the double bond of the enone is obtained.

그 다음 ⅴ)과정에서는, 상기에서 제조한 화학식 7b로 표시되는 화합물의 C-10 위치 케톤을 환원하여 상기 화학식 8로 표시되는 화합물을 제조한다. 상기 환원 반응은 L-셀렉트라이드(L-Selectride)를 사용하여 -90 ℃ 내지 -40 ℃에서 수행한다.Then, in step iii), the compound represented by Chemical Formula 8 is prepared by reducing the C-10 position ketone of the compound represented by Chemical Formula 7b. The reduction reaction is performed at -90 ° C to -40 ° C using L-Selectride.

그 다음 ⅵ)과정에서는, 상기 화학식 8로 표시되는 화합물을 염기 조건에서 가수분해하고 옥사졸리디논 고리를 개환반응하여 상기 화학식 9a로 표시되는 화합물을 제조한 후에, N-메틸화 반응하여 상기 화학식 9b로 표시되는 유도체를 제조한 다. 상기 염기 가수분해 반응은 NaOH를 사용하는 통상의 방법으로 수행하였다. 바람직하기로는 KOH, NaOH, Ba(OH)2를 사용할 수 있다. 그리고, N-메틸화 반응은 포름알데하이드, 소디움 사이아노보로하이드라이드 (NaBH3CN), 및 산 촉매(예를 들면, 초산)를 사용하여 수행할 수 있다.Then, in the step iii), the compound represented by the formula (8) is hydrolyzed under basic conditions and the ring opening reaction of the oxazolidinone ring to prepare the compound represented by the formula (9a), and then the N-methylation reaction to the formula (9b) Prepare the derivatives indicated. The base hydrolysis reaction was carried out by a conventional method using NaOH. Preferably, KOH, NaOH, Ba (OH) 2 can be used. In addition, the N-methylation reaction can be carried out using formaldehyde, sodium cyanoborohydride (NaBH 3 CN), and an acid catalyst (eg, acetic acid).

그 다음 ⅶ)과정에서는, 상기에서 제조한 화학식 9b로 표시되는 화합물을 산화하여 화학식 10으로 표시되는 유도체를 제조한다. 상기 반응은 Swern 산화반응으로 옥살릴클로라이드, 다이메틸술폭사이드, 트라이에틸아민을 사용하여 수행 할 수 있다.Then, in the step iii), a derivative represented by the formula (10) is prepared by oxidizing the compound represented by the formula (9b) prepared above. The reaction can be carried out using oxalyl chloride, dimethyl sulfoxide, triethylamine as the Swern oxidation reaction.

그 다음 ⅷ)과정에서는, 상기에서 제조한 화학식 10으로 표시되는 화합물의 알데하이드 부분을 선택적으로 옥심화하고, 통상적인 방법에 의하여 탈수하여 상기 화학식 11로 표시되는 유도체를 제조한다. 상기 옥심반응은 하이드록실아민하이드로클로라이드, 아세트산 나트륨을 사용하고 30 ℃ 내지 70 ℃에서 수행한다. 그리고, 상기 탈수반응은 트라이클로로메틸 클로로포메이트를 사용하여 수행할 수 있다. Then, in step iii), the aldehyde moiety of the compound represented by Chemical Formula 10 prepared above is selectively oximated and dehydrated by a conventional method to prepare a derivative represented by Chemical Formula 11. The oxime reaction is performed at 30 ° C. to 70 ° C. using hydroxylamine hydrochloride and sodium acetate. And, the dehydration reaction can be carried out using trichloromethyl chloroformate.

그 다음 ⅸ)과정에서는, 상기에서 제조한 화학식 11로 표시되는 화합물의 C-6 위치의 케톤기 환원 및 C-10 위치 카르보나이트릴기 제거하여 본 발명이 목적하는 상기 화학식 1로 표시되는 갈란타민을 제조한다. Then, in step iii), the ketone group reduction and the C-10 position carbonitrile group of the compound represented by Chemical Formula 11 prepared above are removed to remove the galantamine represented by Chemical Formula 1 according to the present invention. To prepare.

상기 ⅸ)과정에서는 상기 화학식 11로 표시되는 화합물의 C-6 위치 케톤기를 먼저 환원한 후에, C-10 위치 카르보나이트릴기 제거반응을 수행하여 상기 화학식 1로 표시되는 갈란타민을 제조할 수도 있다. 또한, 상기 화학식 11로 표시되는 화합물의 C-10 위치 카르보나이트릴기를 먼저 제거하여 (-)-나르위딘 화합물을 제조한 후에 C-6 위치의 케톤기를 환원하여 상기 화학식 1로 표시되는 갈란타민을 제조할 수도 있다. 상기 카르보나이트릴 제거반응은 소디움 사이아노보로하이드라이드 (NaBH3CN), 소디움 보로하이드라이드 (NaBH4), 또는 실버 테트라풀루오로보레이트(AgBF4)와 진크 보로하이드라이드 (Zn(BH4)2), 그리고 액체암모니아에서 소디움 사용하여 수행할 수 있다. 그리고, 상기 환원반응에서는 L-셀렉트라이드를 사용할 수 있다. In the step iii), the C-6 position ketone group of the compound represented by Chemical Formula 11 may be first reduced, and then the galantamine represented by Chemical Formula 1 may be prepared by performing a C-10 position carbonitril group removal reaction. . In addition, the C-10 position carbonitrile group of the compound represented by Formula 11 is first removed to prepare a (-)-narwidine compound, and then the ketone group is reduced by reducing the C-6 position to galantamine represented by Formula 1 above. It can also manufacture. The carbonitrile removal reaction is sodium cyanoborohydride (NaBH 3 CN), sodium borohydride (NaBH 4 ), or silver tetrapuloboroborate (AgBF 4 ) and zinc borohydride (Zn (BH 4) ) 2), and it may be carried out by using sodium in liquid ammonia. In the reduction reaction, L-selectide may be used.

상기한 바와 같은 본 발명의 제조방법을 수행하는 중에 중간체로서 생성되는 상기 화학식 4a, 화학식 4b, 화학식 5, 화학식 6, 화학식 7a, 화학식 7b, 화학식 8, 화학식 9a, 화학식 9b, 화학식 10, 화학식 11로 표시되는 화합물은 각각 신규 화합물이며, 또한 본 발명이 목적하는 갈란타민 합성반응에서 중요한 중간체로 사용될 수 있다. 따라서, 본 발명은 본 발명의 제조과정 중에 중간체로서 생성되는 신규 화합물을 그 특징으로 포함한다.Formula 4a, Formula 4b, Formula 5, Formula 6, Formula 7a, Formula 7b, Formula 8, Formula 9a, Formula 9b, Formula 10, Formula 11, generated as intermediates during the preparation of the present invention as described above. Each compound represented by is a novel compound, and may also be used as an important intermediate in the galantamine synthesis reaction desired by the present invention. Thus, the present invention encompasses as a feature the novel compounds produced as intermediates during the preparation of the present invention.

또한, 본 발명이 원료물질로 사용하는 상기 화학식 2및 화학식 3으로 표시되는 각각의 화합물의 제조방법은 다음과 같다. In addition, the preparation method of each compound represented by Formula 2 and Formula 3 used as a raw material of the present invention is as follows.

상기 화학식 2로 표시되는 옥사졸리디논 유도체의 경우는 다음 반응식 2에 표시되는 제조방법으로 제조할 수 있다. In the case of the oxazolidinone derivative represented by the formula (2) can be prepared by the production method shown in the following scheme 2.

Figure 112006090796461-pat00004
Figure 112006090796461-pat00004

상기 반응식 2에서, Pro는 하이드록시 보호기를 나타낸다.In Scheme 2, Pro represents a hydroxy protecting group.

상기 반응식 2에 따른 제조방법에 의하면, 우선 상기 화학식 2-1로 표시되는 D-타이로신 메틸 에스터 하이드로클로라이드를 염기 조건하에 에틸 클로로 포메이트로 처리하여 상기 화학식 2-2로 표시되는 에톡시카르보닐아미노 메틸 에스터를 제조한다.[Tetrahedron, 2001, 8313-8322] 그리고, 제조된 상기 화학식 2-2로 표시되는 화합물의 하이드록시기를 통상의 보호기(예를 들면, tert-뷰틸다이메틸실릴기(TBS))로 보호하여 다음 화학식 2-3을 제조한다. 그리고, 제조된 상기 화학식 2-3로 표시되는 화합물을 환원제 예를 들면, 소디움 보로하이드라이드(NaBH4)와 리튬 아이오다이드(LiI)로 환원하여 상기 화학식 2-4로 표시되는 알코올 유도체를 제조한다. 그리고, 제조된 상기 화학식 2-4로 표시되는 화합물을 염기 예를 들면, 탄산칼륨을 가하고 환류하여 에탄올을 제거하면 상기 화학식 2로 표시되는 옥사졸리디논 유도체를 제조할 수 있다 [tetrahedron, 2001, 8313-8322]. According to the preparation method according to Scheme 2, first, the D-tyrosine methyl ester hydrochloride represented by Chemical Formula 2-1 is treated with ethyl chloroformate under basic conditions, and is represented by Chemical Formula 2-2. . to prepare a methyl ester [Tetrahedron, 2001, 8313-8322] then, the hydroxy group of a conventional protective group represented by formula 2-2 prepared compound (e. g., tert - butyldibenzo methyl silyl (TBS) ) To prepare the following Chemical Formula 2-3. In addition, the compound represented by Chemical Formula 2-3 is reduced with a reducing agent, for example, sodium borohydride (NaBH 4 ) and lithium iodide (LiI) to prepare an alcohol derivative represented by Chemical Formula 2-4. do. In addition, an oxazolidinone derivative represented by Chemical Formula 2 may be prepared by adding a base, for example, potassium carbonate and refluxing the prepared compound represented by Chemical Formula 2-4 [ tetrahedron, 2001 , 8313 -8322].

본 발명의 제조방법이 원료물질로 사용하는 상기 화학식 3으로 표시되는 알릴이 치환된 방향족 할라이드 유도체의 경우는 다음 반응식 3에 표시되는 제조방법으로 제조할 수 있다. In the case of the allyl-substituted aromatic halide derivative represented by Chemical Formula 3, which is used as a raw material, the production method of the present invention may be prepared by the production method represented by the following Scheme 3.

Figure 112006090796461-pat00005
Figure 112006090796461-pat00005

상기 반응식 3에 따른 제조방법에 의하면, 우선 상기 화학식 3-1로 표시되는 다이하이드록시메틸 에스터 유도체[Synth. Commun. 1996, 26, 2479-2486]를 탄산칼륨의 염기 조건하에 알릴브로마이드로 알킬화하여 상기 화학식 3-2로 표시되는 화합물을 제조한다. 그리고, 상기 화학식 3-2으로 표시되는 화합물을 환원하여 에스터를 알코올로 전환하여 상기 화학식 3-3으로 표시되는 다이알릴 알코올을 제조한다. 그리고, 상기 화학식 3-3으로 표시되는 화합물을 PBr3를 사용하여 하이드록시기를 브롬으로 전환하여 화학식 3으로 표시되는 알릴이 치환된 방향족 할라이드 유도체를 제조한다. According to the preparation method according to Scheme 3, first, a dihydroxymethyl ester derivative represented by Chemical Formula 3-1 [ Synth. Commun . 1996 , 26 , 2479-2486] is alkylated with allyl bromide under basic conditions of potassium carbonate to prepare the compound represented by Chemical Formula 3-2. Then, the compound represented by Chemical Formula 3-2 is reduced to convert ester into alcohol to prepare diallyl alcohol represented by Chemical Formula 3-3. In addition, the compound represented by Chemical Formula 3-3 is converted to a bromine hydroxyl group using PBr 3 to prepare an aromatic halide derivative substituted with allyl represented by Chemical Formula 3.

이상에서 설명한 바와 같은 본 발명은 다음의 실시예에 의거하여 더욱 상세히 설명하겠는 바, 본 발명이 이에 한정되는 것은 아니다. The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

실시예 1: 3,5-비스-알릴옥시-4-메톡시벤조산메틸에스터Example 1: 3,5-bis-allyloxy-4-methoxybenzoic acid methyl ester

Figure 112006090796461-pat00006
Figure 112006090796461-pat00006

3,5-다이하이드록시 4-메톡시벤조산 메틸에스터 (화학식 3-1; 17.0 g, 85.8 mmol)를 질소 분위기 하에서 DMF (170 mL)에 녹인 후, K2CO3 (47 g, 343.14 mmol)를 가하고 0 ℃에서 알릴 브로마이드(22 mL, 257.4 mmol)를 천천히 가하였다. 반응 혼합물을 실온에서 2 시간 동안 교반한 후 물 (350 mL)을 가하고 에터 (150 mL × 2)로 추출하여 얻은 유기층을 무수 황산마그네슘으로 건조하고 용매를 감압하에 제거하고 실리카겔 관 크로마토그래피 (헥세인 : 아세트산 에틸= 4 : 1)로 분리하여 목적화합물 (화학식 3-2; 23.8 g, 100 %)을 얻었다.3,5-dihydroxy 4-methoxybenzoic acid methyl ester (Formula 3-1; 17.0 g, 85.8 mmol) was dissolved in DMF (170 mL) under a nitrogen atmosphere, and then K 2 CO 3 (47 g, 343.14 mmol) Allyl bromide (22 mL, 257.4 mmol) was added slowly at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours, after which water (350 mL) was added and the organic layer obtained by extraction with ether (150 mL × 2) was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and silica gel column chromatography (hexane : Ethyl acetate = 4: 1) to obtain the target compound (Formula 3-2; 23.8 g, 100%).

1 H NMR (300MHz, CDCl 3 , δ) : 7.29 (s, 2H), 6.07 (ddt, J = 17.3, 10.5, 5.3 Hz, 2H), 5.43 (dq, J = 17.3, 1.6 Hz, 2H), 5.29 (dq, J = 10.5, 1.4 Hz, 2H), 4.63 (dt, J = 5.3, 1.5 Hz, 4H), 3.93 (s, 3H), 3.89 (s, 3H). 1 H NMR (300 MHz, CDCl 3 , δ) : 7.29 (s, 2H), 6.07 (ddt, J = 17.3, 10.5, 5.3 Hz, 2H), 5.43 (dq, J = 17.3, 1.6 Hz, 2H), 5.29 (dq, J = 10.5, 1.4 Hz, 2H), 4.63 (dt, J = 5.3, 1.5 Hz, 4H), 3.93 (s, 3H), 3.89 (s, 3H).

실시예 2: 3,5-비스-알릴옥시-4-메톡시페닐메탄올Example 2: 3,5-bis-allyloxy-4-methoxyphenylmethanol

Figure 112006090796461-pat00007
Figure 112006090796461-pat00007

3,5-비스-알릴옥시-4-메톡시벤조산메틸에스터 (화학식 3-2; 13.4 g, 48.1 mmol)를 질소 분위기 하에서 THF (123 mL)에 녹인 후, 0 ℃로 냉각하고 LiAlH4 (3.65 g, 96.3 mmol)를 천천히 가하였다. 반응 혼합물을 실온에서 10 분 동안 교반한 후, 0 ℃에서 포화 NH4Cl 수용액 (15 mL)를 아주 천천히 가하였다. 반응 혼합물을 셀라이트(Celite 545)를 이용하여 아세트산 에틸로 철저히 세척한 후 여과액을 농축하여 실리카겔 관 크로마토그래피 (헥세인 : 아세트산에틸= 1:1)로 분리하여 목적화합물 (화학식 3-3; 11.8 g, 98%)을 얻었다.3,5-bis-allyloxy-4-methoxybenzoic acid methyl ester (Formula 3-2; 13.4 g, 48.1 mmol) was dissolved in THF (123 mL) under a nitrogen atmosphere, then cooled to 0 ° C. and LiAlH 4 (3.65 g, 96.3 mmol) was added slowly. The reaction mixture was stirred at room temperature for 10 minutes, then saturated NH 4 Cl aqueous solution (15 mL) was added very slowly at 0 ° C. The reaction mixture was washed thoroughly with ethyl acetate using Celite 545, and the filtrate was concentrated and separated by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the target compound (Chemical Formula 3-3; 11.8 g, 98%).

1 H NMR (300MHz, CDCl 3 , δ) : 6.59 (s, 2H), 6.06(dt, J = 17.3, 10.5, 5.2 Hz, 2H), 5.41 (dq, J = 17.3, 1.6 Hz, 2H), 5.27 (dq, J = 10.6, 1.4 Hz, 2H), 4.51-4.57 (m, 5H), 3.86 (s, 3H). 1 H NMR (300 MHz, CDCl 3 , δ) : 6.59 (s, 2H), 6.06 (dt, J = 17.3, 10.5, 5.2 Hz, 2H), 5.41 (dq, J = 17.3, 1.6 Hz, 2H), 5.27 (dq, J = 10.6, 1.4 Hz, 2H), 4.51-4.57 (m, 5H), 3.86 (s, 3H).

실시예 3: 1,3-비스-알릴옥시-5-브로모메틸-2-메톡시벤젠Example 3: 1,3-bis-allyloxy-5-bromomethyl-2-methoxybenzene

Figure 112006090796461-pat00008
Figure 112006090796461-pat00008

3,5-비스알릴옥시-4-메톡시페닐메탄올(화학식 3-3; 8.0 g, 31.9 mmol)을 질소 분위기 하에서 다이클로로메테인 (90 mL)에 녹인 후 -5 ℃에서 냉각하고, PBr3 (2.22 mL, 23.7 mmol)을 다이클로로메테인 (30 mL)에 녹여 반응 혼합물에 가하고 -5 ℃에서 50 분 동안 교반하였다. 반응 혼합물에 얼음 (100 g)을 가하고 포화 NaHCO3 수용액으로 중성화시킨 후 다이클로로메테인 (50 mL × 2)으로 추출하였다. 유기층을 소금물 (50 mL)로 세척하고, 무수 황산나트륨으로 건조하고 용매를 감압하에 제거하고, 실리카겔 관 크로마토그래피 (헥세인 : 아세트산 에틸= 10 : 1)로 분리하여 목적화합물 (화학식 3; 8.0 g, 80%)을 얻었다.3,5-bisallyloxy-4-methoxyphenylmethanol (Formula 3-3; 8.0 g, 31.9 mmol) was dissolved in dichloromethane (90 mL) under a nitrogen atmosphere, and then cooled at -5 ° C, followed by PBr 3 (2.22 mL, 23.7 mmol) was dissolved in dichloromethane (30 mL), added to the reaction mixture, and stirred at −5 ° C. for 50 minutes. Ice (100 g) was added to the reaction mixture, neutralized with saturated aqueous NaHCO 3 solution, and extracted with dichloromethane (50 mL × 2). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and separated by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the target compound (Chemical Formula 3; 8.0 g, 80%).

1 H NMR (300MHz, CDCl 3 , δ): 6.61 (s, 2H), 6.06 (ddt, J = 17.3, 10.4, 5.2 Hz, 2H), 5.43 (dq, J = 17.3, 1,5 Hz, 2H), 5.29 (dd, J = 10.6, 1.4 Hz, 2H), 4.60 (dt, J = 5.3, 1.5 Hz, 4H), 4.42 (s, 2H), 3.87 (s, 3H). 1 H NMR (300 MHz, CDCl 3 , δ) : 6.61 (s, 2H), 6.06 (ddt, J = 17.3, 10.4, 5.2 Hz, 2H), 5.43 (dq, J = 17.3, 1,5 Hz, 2H) , 5.29 (dd, J = 10.6, 1.4 Hz, 2H), 4.60 (dt, J = 5.3, 1.5 Hz, 4H), 4.42 (s, 2H), 3.87 (s, 3H).

실시예 4: (Example 4: ( RR )-2-아미노-) -2-amino- NN -에톡시카르보닐-3-(4-하이드록시페닐)-프로피온산 메틸 에스터-Ethoxycarbonyl-3- (4-hydroxyphenyl) -propionic acid methyl ester

Figure 112006090796461-pat00009
Figure 112006090796461-pat00009

D-타이로신 메틸 에스터 아민 하이드로클로라이드 (화학식 2-1; 5.00 g, 21.6 mmol)에 물 (11 mL)을 가하고 질소 분위기 하에서 탄산칼륨 (2.98 g, 21.6 mmol), 다이클로로메테인 (20 mL), 에틸 클로로포메이트 (2.2 mL, 22.7 mmol)를 차례로 천천히 가한 후 실온에서 10 분 동안 교반하였다. 반응 혼합물에 포화 NaHCO3 수용액 (11 mL)를 가하고 3 시간 30 분 동안 교반 후 유기층을 분리하고 수용액을 다이클로로메테인 (50 mL × 2)로 추출하였다. 합친 유기층을 무수 황산마그네슘으로 건조하고 용매를 제거하여 목적화합물 (화학식 2-2; 5.90 g, 100%)을 얻었다.To D-tyrosine methyl ester amine hydrochloride (Formula 2-1; 5.00 g, 21.6 mmol) was added water (11 mL) and under nitrogen atmosphere potassium carbonate (2.98 g, 21.6 mmol), dichloromethane (20 mL), Ethyl chloroformate (2.2 mL, 22.7 mmol) was added slowly in turn and stirred at room temperature for 10 minutes. Saturated NaHCO 3 aqueous solution (11 mL) was added to the reaction mixture, followed by stirring for 3 hours 30 minutes, and then the organic layer was separated and the aqueous solution was extracted with dichloromethane (50 mL × 2). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was removed to obtain the target compound (Formula 2-2; 5.90 g, 100%).

1 H NMR (200MHz, CDCl 3 , δ) : 6.93 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 5.30 (br d, J = 8.2 Hz, 1H), 4.55-4.51 (m, 1H), 4.08 (q, J = 6.9 Hz, 2H), 3.69 (s, 3H), 2.99 (d, J = 5.7 Hz, 2H), 2.59 (br s, 1H), 1.20 (t, J = 7.1 Hz, 3H). 1 H NMR (200 MHz, CDCl 3 , δ) : 6.93 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 5.30 (br d, J = 8.2 Hz, 1H), 4.55-4.51 (m, 1H), 4.08 (q, J = 6.9 Hz, 2H), 3.69 (s, 3H), 2.99 (d, J = 5.7 Hz, 2H), 2.59 (br s, 1H), 1.20 (t, J = 7.1 Hz, 3H).

실시예 5: (Example 5: ( RR )-[3-[4-)-[3- [4- terttert -뷰틸다이메틸실릴옥시]페닐-2-에톡시카르보닐아미노프로피온산 메틸에스테르-Butyldimethylsilyloxy] phenyl-2-ethoxycarbonylaminopropionic acid methyl ester

Figure 112006090796461-pat00010
Figure 112006090796461-pat00010

실시예 4에서 합성한 화합물(화학식 2-2; 5.77 g, 21.6 mmol)을 질소 분위기 하에서 다이클로로메테인 (57 mL)에 녹인 후 tert-뷰틸다이메틸실릴 클로라이드(TBSCl; 3.42 g, 22.7 mmol), 트라이에틸아민 (4.5 mL, 32.4 mmol), 다이메틸아미노피리딘 (DMAP; 264 mg, 2.16 mmol)을 가하고 17 시간 30 분 동안 환류 교반하였다. 반응 혼합물을 실온으로 냉각한 다음 분리한 유기층을 0.3 M HCl 수용액 (34 mL), 물 (34 mL), 소금물(34 mL)로 세척한 후, 유기층을 무수 황산마그네슘으로 건조하고 용매를 감압하에 제거하고, 실리카겔 관 크로마토그래피 (헥세인 : 아세트산 에틸 = 4:1)로 분리하여 목적화합물 (화학식 2-3; 7.86 g, 95%)을 무색의 액체로 얻었다.The compound synthesized in Example 4 (Formula 2-2; 5.77 g, 21.6 mmol) was dissolved in dichloromethane (57 mL) under a nitrogen atmosphere, followed by tert -butyldimethylsilyl chloride (TBSCl; 3.42 g, 22.7 mmol). , Triethylamine (4.5 mL, 32.4 mmol), dimethylaminopyridine (DMAP; 264 mg, 2.16 mmol) were added and stirred at reflux for 17 h 30 min. After cooling the reaction mixture to room temperature, the separated organic layer was washed with 0.3 M HCl aqueous solution (34 mL), water (34 mL), brine (34 mL), and then the organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. Then, the residue was separated by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the target compound (Formula 2-3; 7.86 g, 95%) as a colorless liquid.

[α] D 25.0 = -45.0°(c 1.23, CHCl3); 1 H NMR (500MHz, CDCl 3 , δ) : 6.95 (d, J = 8.3 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 5.28 (br d, J = 8.2 Hz, 1H), 4.55 (dd, J = 14.0, 6.2 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.65 (s, 3H), 3.00 (dd, J = 14.0, 6.0 Hz, 2H), 2.96 (dd, J = 14.0, 6.5 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H), 0.94 (s, 9H), 0.15 (s, 6H). [α] D 25.0 = -45.0 ° ( c 1.23, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 , δ) : 6.95 (d, J = 8.3 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 5.28 (br d, J = 8.2 Hz, 1H), 4.55 (dd, J = 14.0, 6.2 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.65 (s, 3H), 3.00 (dd, J = 14.0, 6.0 Hz, 2H), 2.96 (dd, J = 14.0, 6.5 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H), 0.94 (s, 9H), 0.15 (s, 6H).

실시예 6: (Example 6: ( RR )-[2-(4-)-[2- (4- terttert -뷰틸다이메틸실란일옥시페닐)-1-하이드록시메틸에틸]-카르밤산 에틸 에스테르 -Butyldimethylsilaneyloxyphenyl) -1-hydroxymethylethyl] -carbamic acid ethyl ester

Figure 112006090796461-pat00011
Figure 112006090796461-pat00011

메틸 에스터(화학식 2-3; 7.78 g, 20.4 mmol)를 질소 분위기 하에서 THF (120 mL)에 녹인 후 NaBH4 (231 g, 61.2 mmol)와 LiI (2.74 g, 20.4 mmol)를 천천히 가하고 1 시간 동안 환류 교반하였다. 반응 혼합물을 물 (100 mL)로 세척하고, 다이클로로메테인 (60 mL)으로 추출한 후 유기층을 소금물 (5 mL)로 세척하고, 무수 황산마그네슘으로 건조하고 용매를 감압하에 제거하고 실리카겔 관 크로마토그래피 (헥세인 : 아세트산 에틸= 1:1)로 분리하여 목적화합물 (화학식2-4; 6.93 g, 96%)을 얻었다.Methyl ester (Formula 2-3; 7.78 g, 20.4 mmol) was dissolved in THF (120 mL) under nitrogen atmosphere, and then NaBH 4 (231 g, 61.2 mmol) and LiI (2.74 g, 20.4 mmol) were slowly added for 1 hour. It was stirred at reflux. The reaction mixture was washed with water (100 mL), extracted with dichloromethane (60 mL), then the organic layer was washed with brine (5 mL), dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure and silica gel column chromatography (Hexane: ethyl acetate = 1: 1) to obtain the target compound (Formula 2-4; 6.93 g, 96%).

[α] D 26.9 = 14.0°(c 1.03, CHCl3); 1 H NMR (500MHz, CDCl 3 , δ) : 7.04 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 4.81 (br s, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.87 (m, 1H), 3.65-3.62 (m, 1H), 3.58-3.54 (m, 1H), 2.78 (d, J = 7.1 Hz, 2H), 2.31 (br s, 1H), 1.22 (t, J = 7.1 Hz, 3H), 0.98 (s, 9H), 0.19 (s, 6H). [α] D 26.9 = 14.0 ° ( c 1.03, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 , δ) : 7.04 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 4.81 (br s, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.87 (m, 1H), 3.65-3.62 (m, 1H), 3.58-3.54 (m, 1H), 2.78 (d, J = 7.1 Hz, 2H), 2.31 (br s, 1H) , 1.22 (t, J = 7.1 Hz, 3H), 0.98 (s, 9H), 0.19 (s, 6H).

실시예 7: (4Example 7: (4 RR )-(4-)-(4- terttert -뷰틸실란일옥시벤질)-1,3-옥사졸리딘-2-온-Butylsilaneyloxybenzyl) -1,3-oxazolidin-2-one

Figure 112006090796461-pat00012
Figure 112006090796461-pat00012

실시예 6에서 합성한 화합물 (화학식 2-4; 6.50 g, 18.4 mmol)을 질소 분위기 하에서 톨루엔 (34 mL)에 녹인 후 탄산칼슘 (508 mg, 3.68 mmol)을 가하였다. 딘-스탁(Dean-Stark) 장치를 이용하여 반응 혼합물을 6 시간 동안 환류 교반하고 톨루엔을 제거한 후 에탄올을 가해 1 시간 동안 교반하였다. 반응 혼합물을 셀라이트를 통하여 여과하고 여과액을 농축하여 실리카겔 관 크로마토그래피 (헥세인 : 아세트산 에틸= 1:1)로 분리하여 목적화합물 (화학식 2; 5.59 g, 99%)을 얻었다.The compound synthesized in Example 6 (Formula 2-4; 6.50 g, 18.4 mmol) was dissolved in toluene (34 mL) under a nitrogen atmosphere, and calcium carbonate (508 mg, 3.68 mmol) was added thereto. The reaction mixture was stirred under reflux for 6 hours using a Dean-Stark apparatus, toluene was removed and ethanol was added and stirred for 1 hour. The reaction mixture was filtered through celite and the filtrate was concentrated and separated by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the target compound (Formula 2; 5.59 g, 99%).

[α] D 28 .8 = 49.7°(c 1.20, CHCl3); 1 H NMR (500 MHz , CDCl 3 , δ) : 7.02 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 5.35 (br s, 1H), 4.45 (t, J = 8.4 Hz, 1H), 4.13 (dd, J = 8.7, 5.6 Hz, 1H), 4.05 - 4.01 (m, 1H), 2.80 (d, J = 1.4 Hz, 1H), 2.79 (d, J = 2.8 Hz, 1H), 0.98 (s, 9H), 0.19 (s, 6H). [α] D 28 .8 = 49.7 ° ( c 1.20, CHCl 3 ); 1 H NMR (500 MHz , CDCl 3 , δ) : 7.02 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 5.35 (br s, 1H), 4.45 (t, J = 8.4 Hz, 1H), 4.13 (dd, J = 8.7, 5.6 Hz, 1H), 4.05-4.01 (m, 1H), 2.80 (d, J = 1.4 Hz, 1H), 2.79 (d, J = 2.8 Hz , 1H), 0.98 (s, 9H), 0.19 (s, 6H).

실시예 8: 3-(3,5-비스알릴옥시-4-메톡시벤질)-(4Example 8: 3- (3,5-bisallyloxy-4-methoxybenzyl)-(4 RR )-(4-)-(4- terttert -뷰틸다이메틸실란일옥시벤질)-1,3-옥사졸린-2-온-Butyldimethylsilanyloxybenzyl) -1,3-oxazolin-2-one

Figure 112006090796461-pat00013
Figure 112006090796461-pat00013

실시예 7에서 합성한 화합물 (화학식 2; 814 mg, 2.65 mmol)을 질소 분위기 하에서 THF (11 mL)에 녹인 후 NaH (95 mg, 0.732 mmol)를 천천히 가하고 실온에서 30 분 동안 교반하였다. 실시예 3에서 합성한 화합물 (화학식 3; 1.23 g, 3.19 mmol)를 THF (8.5 mL)에 녹여 반응 혼합물에 가하고 실온에서 12 시간 동안 교반하였다. 반응 혼합물에 물 (1 mL)를 가하고 아세트산 에틸 (10 mL × 2)로 추출하고 유기층을 소금물 (1 mL) 로 씻은 후 무수 황산나트륨으로 건조하고 용매를 감압하에 제거하고 실리카겔 관 크로마토그래피 헥세인 : 아세트산 에틸 = 3:1)로 분리하여 목적 화합물 (화학식 4a; 1.27 g, 88%)를 얻었다.The compound synthesized in Example 7 (Formula 2; 814 mg, 2.65 mmol) was dissolved in THF (11 mL) under a nitrogen atmosphere, and NaH (95 mg, 0.732 mmol) was slowly added thereto, and stirred at room temperature for 30 minutes. The compound synthesized in Example 3 (Formula 3; 1.23 g, 3.19 mmol) was dissolved in THF (8.5 mL), added to the reaction mixture, and stirred at room temperature for 12 hours. Water (1 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (10 mL × 2), the organic layer was washed with brine (1 mL), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, silica gel column chromatography hexane: acetic acid Elution with ethyl = 3: 1) gave the desired compound (Formula 4a; 1.27 g, 88%).

[α] D 28 .1 = 7.70°(c 1.22, CHCl3) 1 H NMR (500 MHz , CDCl 3 , δ) : 6.91 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.4 Hz, 2H), 6.45 (s, 2H), 6.04 (ddt, J = 17.3, 10.5, 5.2 Hz, 2H), 5.40 (dq, J = 17.3, 1.5 Hz, 2H), 5.26 (dq, J = 10.5, 1.4 Hz, 2H), 4.74 (d, J = 15.0 Hz, 1H), 4.57 (d, J = 5.2 Hz, 4H), 4.12 (t, J = 8.6 Hz, 1H), 3.99 (dd, J = 8.8, 6.1 Hz, 1H), 3.94 (d, J = 15.0 Hz, 1H), 3.87 (s, 3H), 3.79-3.72 (m, 1H), 3.00 (dd, J = 13.7, 4.9 Hz, 1H), 2.57 (dd, J = 13.7, 8.8 Hz, 1H), 0.96 (s, 9H), 0.16 (s, 6H). [a] D 28 .1 = 7.70 ° ( c 1.22, CHCl 3 ) 1 H NMR (500 MHz , CDCl 3 , δ) : 6.91 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.4 Hz , 2H), 6.45 (s, 2H), 6.04 (ddt, J = 17.3, 10.5, 5.2 Hz, 2H), 5.40 (dq, J = 17.3, 1.5 Hz, 2H), 5.26 (dq, J = 10.5, 1.4 Hz, 2H), 4.74 (d, J = 15.0 Hz, 1H), 4.57 (d, J = 5.2 Hz, 4H), 4.12 (t, J = 8.6 Hz, 1H), 3.99 (dd, J = 8.8, 6.1 Hz, 1H), 3.94 (d, J = 15.0 Hz, 1H), 3.87 (s, 3H), 3.79-3.72 (m, 1H), 3.00 (dd, J = 13.7, 4.9 Hz, 1H), 2.57 (dd , J = 13.7, 8.8 Hz, 1H), 0.96 (s, 9H), 0.16 (s, 6H).

실시예 9: 3-(3,5-비스알릴옥시-4-메톡시벤질)-(4Example 9: 3- (3,5-bisallyloxy-4-methoxybenzyl)-(4 RR )-(4-하이드록시벤질)-1,3-옥사졸리딘-2-온)-(4-hydroxybenzyl) -1,3-oxazolidin-2-one

Figure 112006090796461-pat00014
Figure 112006090796461-pat00014

실시예 8에서 합성한 사일릴 화합물 (화학식 4a; 901 mg, 1.47 mmol)을 질소 분위기 하에서 THF (16 mL)에 녹인 후 n-Bu4NF (2.2 mL, 2.21 mmol, 1.0 M THF 용액)를 가하고 실온에서 20 분 동안 교반하였다. 반응 혼합물에 포화 NH4Cl 수용액 (0.5 mL)과 물 (2 mL)로 가하고 에터 (5 mL × 2)로 추출한 후, 무수 황산 마그 네슘으로 건조하고, 용매를 감압하에 제거하고 실리카겔 관 크로마토그래피 (헥세인 : 아세트산 에틸= 1:1)로 분리하여 목적화합물 (화학식 4b; 701 mg, 96%)를 얻었다.The silyl compound (Formula 4a; 901 mg, 1.47 mmol) synthesized in Example 8 was dissolved in THF (16 mL) under a nitrogen atmosphere, and n- Bu 4 NF (2.2 mL, 2.21 mmol, 1.0 M THF solution) was added thereto. Stir at room temperature for 20 minutes. To the reaction mixture was added saturated aqueous NH 4 Cl solution (0.5 mL) and water (2 mL), extracted with ether (5 mL × 2), dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure and silica gel column chromatography ( Hexane: ethyl acetate = 1: 1 to obtain the target compound (Formula 4b; 701 mg, 96%).

[α] D 22 .5 = 18.0°(c 1.53, CHCl3) 1 H NMR (500 MHz , CDCl 3 , δ) : 6.92 (d, J = 8.5 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 6.45 (s, 2H), 6.04 (ddt, J = 17.3, 10.5, 5.2 Hz, 1H), 5.43 (dd, J = 17.3, 1.6 Hz, 1H), 5.39 (dq, J = 10.5, 1.4 Hz, 1H), 5.00 (br s, 1H), 4.76 (d, J = 15.0 Hz, 1H), 4.58 (d, J = 5.1 Hz, 4H), 4.14 (t, J = 8.6 Hz, 1H), 3.99 (dd, J = 8.9, 6.1 Hz, 1H), 3.97 (d, J = 15.0 Hz, 1H), 3.87 (s, 3H), 3.80-3.74 (m, 1H), 2.99 (dd, J = 13.8, 4.9 Hz, 1H), 2.59 (dd, J = 13.8, 8.6 Hz, 1H). [α] D 22 .5 = 18.0 ° (c 1.53, CHCl 3) 1 H NMR (500 MHz, CDCl 3, δ): 6.92 (d, J = 8.5 Hz, 1H), 6.77 (d, J = 8.5 Hz , 1H), 6.45 (s, 2H), 6.04 (ddt, J = 17.3, 10.5, 5.2 Hz, 1H), 5.43 (dd, J = 17.3, 1.6 Hz, 1H), 5.39 (dq, J = 10.5, 1.4 Hz, 1H), 5.00 (br s, 1H), 4.76 (d, J = 15.0 Hz, 1H), 4.58 (d, J = 5.1 Hz, 4H), 4.14 (t, J = 8.6 Hz, 1H), 3.99 (dd, J = 8.9, 6.1 Hz, 1H), 3.97 (d, J = 15.0 Hz, 1H), 3.87 (s, 3H), 3.80-3.74 (m, 1H), 2.99 (dd, J = 13.8, 4.9 Hz, 1H), 2.59 (dd, J = 13.8, 8.6 Hz, 1H).

실시예 10: (9Example 10: (9 S,S, 10a10a RR )-1,4,10,10a-테트라하이드로-6,8-비스(알릴옥시)-7-메톡시-2-옥사졸로[2]벤조아제핀-4'-옥소-9-스파이로-1'-사이클로헥사-2',5'-다이인-3-온) -1,4,10,10a-tetrahydro-6,8-bis (allyloxy) -7-methoxy-2-oxazolo [2] benzoazine-4'-oxo-9-spiro-1 '-Cyclohexa-2', 5'-diyne-3-one

Figure 112006090796461-pat00015
Figure 112006090796461-pat00015

실시예 9에서 합성한 화합물 (화학식 4b, 3.40 g, 7.99 mmol)을 질소 분위기 하에서 트라이풀루오로에탄올 (80 mL)에 녹인 후 페닐아이오딘(Ⅲ) 비스(트라이풀 루오로 아세테이트(PIFA; 3.78 g, 8.79 mmol)을 트라이풀루오로에탄올 (40 mL)에 녹여 반응 혼합물에 천천히 가하고 -40 ℃에서 10 분 동안 교반하였다. 용매를 감압하에 제거하고 실리카겔 관 크로마토그래피 (아세트산 에틸)로 분리하여 목적화합물 (화학식 5; 3.17 g, 94%)을 얻었다.The compound synthesized in Example 9 (Formula 4b, 3.40 g, 7.99 mmol) was dissolved in tripulouroethanol (80 mL) under a nitrogen atmosphere, and then phenyliodine (III) bis (tripool uroacetate (PIFA; 3.78) g, 8.79 mmol) was dissolved in tripulouroethanol (40 mL) and slowly added to the reaction mixture and stirred for 10 minutes at -40 ° C. The solvent was removed under reduced pressure and separated by silica gel column chromatography (ethyl acetate) to yield Compound (Formula 5; 3.17 g, 94%) was obtained.

[α] D 25 .4 = -69.8°(c 1.23, CHCl3) 1 H NMR (500 MHz , CDCl 3 , δ) : 7.32 (t, J = 8.3 Hz, 2H), 6.70 (s, 1H), 6.33 (d, J = 10.0 Hz, 1H), 6.16 (d, J = 9.9 Hz, 1H), 6.06 (ddt, J = 17.2, 10.5, 5.2 Hz, 1H), 5.86 (ddt, J = 17.2, 10.5, 5.2 Hz, 1H), 5.44 (dq, J = 17.2, 1.5 Hz, 1H), 5.31 (dq, J = 10.5, 1.3 Hz, 1H), 5.21 (dd, J = 17.2, 1.5 Hz, 1H), 5.16 (dd, J = 10.5,1.1 Hz, 1H), 4.75 (d, J = 16.0 Hz, 1H), 4.60 (dt, J = 5.3, 1.4 Hz, 1H), 4.54 (d, J = 16.0 Hz, 1H), 4.45 (t, J = 8.7 Hz, 1H), 4.26-4.22 (m, 1H), 4.21 (dd, J = 11.5, 5.8 Hz, 1H), 4.09 (dd, J = 11.6, 6.1 Hz, 1H), 3.92 (dd, J = 8.9, 6.1 Hz, 1H), 3.82 (s, 3H), 2.27 (dd, J = 14.3, 10.0 Hz, 1H), 1.98 (dd, J = 14.3, 2.8 Hz, 1H). [a] D 25 .4 = -69.8 ° ( c 1.23, CHCl 3 ) 1 H NMR (500 MHz , CDCl 3 , δ) : 7.32 (t, J = 8.3 Hz, 2H), 6.70 (s, 1H), 6.33 (d, J = 10.0 Hz, 1H), 6.16 (d, J = 9.9 Hz, 1H), 6.06 (ddt, J = 17.2, 10.5, 5.2 Hz, 1H), 5.86 (ddt, J = 17.2, 10.5, 5.2 Hz, 1H), 5.44 (dq, J = 17.2, 1.5 Hz, 1H), 5.31 (dq, J = 10.5, 1.3 Hz, 1H), 5.21 (dd, J = 17.2, 1.5 Hz, 1H), 5.16 ( dd, J = 10.5, 1.1 Hz, 1H), 4.75 (d, J = 16.0 Hz, 1H), 4.60 (dt, J = 5.3, 1.4 Hz, 1H), 4.54 (d, J = 16.0 Hz, 1H), 4.45 (t, J = 8.7 Hz, 1H), 4.26-4.22 (m, 1H), 4.21 (dd, J = 11.5, 5.8 Hz, 1H), 4.09 (dd, J = 11.6, 6.1 Hz, 1H), 3.92 (dd, J = 8.9, 6.1 Hz, 1H), 3.82 (s, 3H), 2.27 (dd, J = 14.3, 10.0 Hz, 1H), 1.98 (dd, J = 14.3, 2.8 Hz, 1H).

실시예 11: (8aExample 11: (8a SS ,12a, 12a SS ,13, 13 RR )-1,4,8a,9,13,13a-헥사하이드로-6-하이드록시-7-메톡시-2-옥사졸로-벤조퓨로[3a,3,2-ef][2]벤조아제핀-3,10-다이온) -1,4,8a, 9,13,13a-hexahydro-6-hydroxy-7-methoxy-2-oxazolo-benzofuro [3a, 3,2-ef] [2] benzoazine -3,10-dione

Figure 112006090796461-pat00016
Figure 112006090796461-pat00016

실시예 10에서 합성한 화합물 (화학식 6; 3.0 g, 7.08 mmol)을 질소 분위기 하에서 25% 모르포린/THF (70 mL)에 녹인 후 Pd(PPh3)4 (819 mg, 0.708 mmol)를 가하여 실온에서 1 시간 30 분 동안 교반하였다. 반응 혼합물을 용매를 감압하에 제거하고 실리카겔 관 크로마토그래피 (아세트산 에틸)로 분리한 후 얻은 불순한 고체를 다이클로로메테인으로 처리하여 목적화합물 (화학식 6; 2.22 g, 91%)을 얻었다.The compound synthesized in Example 10 (Formula 6; 3.0 g, 7.08 mmol) was dissolved in 25% morpholine / THF (70 mL) under a nitrogen atmosphere, and then Pd (PPh 3 ) 4 (819 mg, 0.708 mmol) was added to the room temperature. Stir for 1 h 30 min. The reaction mixture was removed under reduced pressure, separated by silica gel column chromatography (ethyl acetate), and the resulting impure solid was treated with dichloromethane to obtain the target compound (Formula 6; 2.22 g, 91%).

[α] D 29 .0 = -363.8°(c 1.00, pyridine); 1 H NMR (500 MHz , CDCl 3 , δ) : 6.74 (dd, J = 10.4, 2.1 Hz, 1H), 6.41 (s, 1H), 6.01 (d, J = 10.4 Hz, 1H), 5.71 (s, 1H), 4.77 (d, J = 16.3 Hz, 1H), 4.67 (m, 1H), 4.46 (t, J = 8.5 Hz, 1H), 4.23-4.19 (m, 1H), 4.21 (d, J = 16.2 Hz, 1H), 3.88 (dd, J = 8.7, 5.1 Hz, 1H), 3.87 (s, 3H), 3.07 (dd, J = 17.8, 2.4 Hz, 1H), 2.70 (ddd, J = 17.8, 3.7, 1.7 Hz, 1H), 2.11 (dd, J = 13.1, 3.0 Hz, 1H), 2.06 (dd, J = 13.2, 11.2 Hz, 1H). [α] D 29 .0 = −363.8 ° ( c 1.00, pyridine); 1 H NMR (500 MHz , CDCl 3 , δ) : 6.74 (dd, J = 10.4, 2.1 Hz, 1H), 6.41 (s, 1H), 6.01 (d, J = 10.4 Hz, 1H), 5.71 (s, 1H), 4.77 (d, J = 16.3 Hz, 1H), 4.67 (m, 1H), 4.46 (t, J = 8.5 Hz, 1H), 4.23-4.19 (m, 1H), 4.21 (d, J = 16.2 Hz, 1H), 3.88 (dd, J = 8.7, 5.1 Hz, 1H), 3.87 (s, 3H), 3.07 (dd, J = 17.8, 2.4 Hz, 1H), 2.70 (ddd, J = 17.8, 3.7, 1.7 Hz, 1H), 2.11 (dd, J = 13.1, 3.0 Hz, 1H), 2.06 (dd, J = 13.2, 11.2 Hz, 1 H).

실시예 12: (8aExample 12: (8a SS ,12a, 12a SS ,13, 13 RR )-1,4,8a,9,13,13a-헥사하이드로-6-트라이풀루오로메테인술폰일옥시-7-메톡시-2-옥사졸로-벤조퓨로[3a,3,2-ef][2]벤조아제핀-3,10-다이온) -1,4,8a, 9,13,13a-hexahydro-6-trifuluromethanesulfonyloxy-7-methoxy-2-oxazolo-benzofuro [3a, 3,2-ef ] [2] benzoazine-3,10-dione

Figure 112006090796461-pat00017
Figure 112006090796461-pat00017

실시예 11에서 합성한 화합물 (화학식 6, 2.0 g, 5.83 mmol)을 질소 분위기 하에서 피리딘 (20 mL)에 녹인 후 0 ℃에서 트라이풀루오르메테인술폰산 무수물(Tf2O; 2.35 mL, 13.98 mmol)을 가하고 반응 혼합물을 실온으로 높여 2 시간 동안 교반하였다. 반응 혼합물에 포화 CuSO4 수용액 (5 mL)을 가하고 다이클로로메테인 (25 mL × 2)으로 추출하였다. 유기층을 물 (20 mL × 5)로 세척하고 무수 황산마그네슘으로 건조하고 용매를 감압하에 제거하여 실리카겔 관 크로마토그래피 (에틸 아세테이트)로 분리하여 목적화합물 (화학식 7a; 2.70 g, 97%)를 얻었다.The compound synthesized in Example 11 (Formula 6, 2.0 g, 5.83 mmol) was dissolved in pyridine (20 mL) under a nitrogen atmosphere, and then trifulluormethanesulfonic anhydride (Tf 2 O; 2.35 mL, 13.98 mmol) at 0 ° C. The reaction mixture was added to room temperature and stirred for 2 hours. To the reaction mixture was added saturated CuSO 4 aqueous solution (5 mL) and extracted with dichloromethane (25 mL × 2). The organic layer was washed with water (20 mL × 5), dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and separated by silica gel column chromatography (ethyl acetate) to obtain the target compound (Formula 7a; 2.70 g, 97%).

[α] D 24 .5 = -197.8°(c 1.17, CHCl3) 1 H NMR (500 MHz , CDCl 3 , δ) : 6.82 (dd, J = 10.4, 1.8 Hz, 1H), 6.75 (s, 1H), 6.16 (d, J = 10.4 Hz, 1H), 4.89 (d, J = 16.4 Hz, 1H), 4.84 (m, 1H), 4.53 (t, J = 8.6 Hz, 1H), 4.33 (d, J= 16.3 Hz, 1H), 4.34-4.29 (m, 1H), 4.00 (s, 3H), 3.97 (dd, J = 8.7, 5.2 Hz, 1H), 3.17 (dd, J = 17.9, 2.2 Hz, 1H), 2.80 (dd, J = 17.9, 3.7 Hz, 1H), 2.23 (dd, J = 13.3, 3.0 Hz, 1H), 2.18 (dd, J = 13.3, 11.2 Hz, 1H). [α] D 24 .5 = -197.8 ° ( c 1.17, CHCl 3 ) 1 H NMR (500 MHz , CDCl 3 , δ) : 6.82 (dd, J = 10.4, 1.8 Hz, 1H), 6.75 (s, 1H), 6.16 (d, J = 10.4 Hz, 1H), 4.89 (d, J = 16.4 Hz, 1H), 4.84 (m, 1H ), 4.53 (t, J = 8.6 Hz, 1H), 4.33 (d, J = 16.3 Hz, 1H), 4.34-4.29 (m, 1H), 4.00 (s, 3H), 3.97 (dd, J = 8.7, 5.2 Hz, 1H), 3.17 (dd, J = 17.9, 2.2 Hz, 1H), 2.80 (dd, J = 17.9, 3.7 Hz, 1H), 2.23 (dd, J = 13.3, 3.0 Hz, 1H), 2.18 ( dd, J = 13.3, 11.2 Hz, 1H).

실시예 13: (8aExample 13: (8a SS ,12a, 12a SS ,13, 13 RR )-1,4,8a,9,13,13a-헥사하이드로-7-메톡시-2-옥사졸로-벤 조퓨로[3a,3,2-ef][2]벤조아제핀-3,10-다이온) -1,4,8a, 9,13,13a-hexahydro-7-methoxy-2-oxazolo-benzopuro [3a, 3,2-ef] [2] benzoazine-3,10- Dion

Figure 112006090796461-pat00018
Figure 112006090796461-pat00018

실시예 12에서 합성한 화합물 (화학식 7a; 2.7 g, 5.68 mmol)을 질소 분위기 하에서 다이메틸포름아마이드 (30 mL)에 녹인 후 트라이에틸아민 (12 mL, 85.2 mmol), Pd(OAc)2 (255 mg, 1.14 mmol), 트라이페닐포스핀 (596 mg, 2.27 mmol)을 가하고 60 ℃에서 2 시간 동안 교반하였다. 반응 혼합물에 물 (30 mL)을 가하고 다이클로로메테인 (50 mL × 2)로 추출한 후 유기층을 무수 황산마그네슘으로 건조하고 용매를 감압하에 제거하고 실리카겔 관 크로마토그래피 (아세트산 에틸)로 분리하여 목적화합물 (화학식 7b; 1.78 g, 96%)을 얻었다.The compound synthesized in Example 12 (Formula 7a; 2.7 g, 5.68 mmol) was dissolved in dimethylformamide (30 mL) under a nitrogen atmosphere, and then triethylamine (12 mL, 85.2 mmol), Pd (OAc) 2 (255 mg, 1.14 mmol), triphenylphosphine (596 mg, 2.27 mmol) were added and stirred at 60 ° C. for 2 hours. Water (30 mL) was added to the reaction mixture, followed by extraction with dichloromethane (50 mL × 2). The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and separated by silica gel column chromatography (ethyl acetate) to obtain the target compound. (Formula 7b; 1.78 g, 96%) was obtained.

[α] D 28 .6 = -232.9°(c 1.01, CHCl3) 1 H NMR (500 MHz , CDCl 3 , δ) : 0.81 (dd, J = 10.4, 2.0 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.07 (d, J = 10.4 Hz, 1H), 4.90 (d, J = 16.2 Hz, 1H), 4.73 (m, 1H), 4.50 (t, J = 8.6 Hz, 1H), 4.32-4.26 (m, 1H), 4.31 (d, J = 15.7 Hz, 1H), 3.92 (dd, J = 8.7, 5.3 Hz, 1H), 3.83 (s, 3H), 3.18 (dd, J = 17.9, 1.7 Hz, 1H), 2.75 (dd, J = 17.9, 3.8 Hz, 1H), 2.18 (dd, J = 13.2, 2.8 Hz, 1H), 2.13 (dd, J= 13.2, 11.4 Hz, 1H). [α] D 28 .6 = -232.9 ° ( c 1.01, CHCl 3 ) 1 H NMR (500 MHz , CDCl 3 , δ) : 0.81 (dd, J = 10.4, 2.0 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H) , 6.07 (d, J = 10.4 Hz, 1H), 4.90 (d, J = 16.2 Hz, 1H), 4.73 (m, 1H), 4.50 (t, J = 8.6 Hz, 1H), 4.32-4.26 (m, 1H), 4.31 (d, J = 15.7 Hz, 1H), 3.92 (dd, J = 8.7, 5.3 Hz, 1H), 3.83 (s, 3H), 3.18 (dd, J = 17.9, 1.7 Hz, 1H), 2.75 (dd, J = 17.9, 3.8 Hz, 1H), 2.18 (dd, J = 13.2, 2.8 Hz, 1H), 2.13 (dd, J = 13.2, 11.4 Hz, 1H).

실시예 14: (8aExample 14: (8a SS ,6, 6 RR -12a-12a SS ,13, 13 RR )-1,4,8a,9,13,13a-헥사하이드로-10-하이드록시-7-메톡시-2-옥사졸로-6) -1,4,8a, 9,13,13a-hexahydro-10-hydroxy-7-methoxy-2-oxazolo-6 HH -벤조퓨로[3a,3,2-ef][2]벤조아제핀-3-온-Benzofuro [3a, 3,2-ef] [2] benzoazin-3-one

Figure 112006090796461-pat00019
Figure 112006090796461-pat00019

실시예 13에서 합성한 화합물 (화학식 7b; 3.94 g, 12.0 mmol)을 건조한 THF (80 mL)에 녹인 후 -78℃에서 L-셀렉트라이드(L-Selectride; 43.3 mL, 43.3 mmol, 1.0 M THF 용액)을 천천히 가하고 40분 동안 교반하였다. 반응이 종결되어 반응물을 0 ℃에서 30분 동안 교반 후 에틸 아세테이트(50 mL × 3)로 추출하였다. 유기층을 무수 황산마그네슘으로 건조하고 용매를 감압하에 제거하고 실리카겔 관 크로마토그래피 (아세트산 에틸)로 분리하여 목적화합물 (화학식 8; 3.77 mg, 95%)을 얻었다.The compound synthesized in Example 13 (Formula 7b; 3.94 g, 12.0 mmol) was dissolved in dry THF (80 mL) and L-Selectride (43.3 mL, 43.3 mmol, 1.0 M THF solution) at -78 ° C. ) Was added slowly and stirred for 40 minutes. The reaction was terminated and the reaction was stirred at 0 ° C. for 30 min and then extracted with ethyl acetate (50 mL × 3). The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and separated by silica gel column chromatography (ethyl acetate) to obtain the target compound (Formula 8; 3.77 mg, 95%).

[α] D 28 .1 = -34.3°(c 1.05, CHCl3) 1 H NMR (500 MHz , CDCl 3 ) δ 6.80 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 6.09 (dd, J = 10.2, 5.1 Hz, 1H), 5.96 (d, J = 10.2 Hz, 1H), 4.86 (d, J = 16.0 Hz, 1H), 4.62 (br s, 1H), 4.48 (t, J = 8.5 Hz, 1H), 4.33 (m, 1H), 4.31 (d, J = 15.6 Hz, 1H), 4.17 (br s, 1H), 3.89 (dd, J = 8.6, 5.5 Hz, 1H), 3.84 (s, 3H), 2.73 (dt, J = 15.5, 1.7Hz, 1H), 2.35 (br s, 1H), 2.03 (ddd, J = 15.8, 5.0, 2.5 Hz, 1H), 1.96 (dd, J = 13.1, 11.0 Hz, 1H), 1.91 (dd, J = 13.1, 3.2 Hz, 1H). [a] D 28 .1 = -34.3 ° ( c 1.05, CHCl 3 ) 1 H NMR (500 MHz , CDCl 3 ) δ 6.80 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 6.09 (dd, J = 10.2, 5.1 Hz, 1H), 5.96 (d, J = 10.2 Hz, 1H), 4.86 (d, J = 16.0 Hz, 1H), 4.62 (br s, 1H), 4.48 (t, J = 8.5 Hz, 1H), 4.33 (m, 1H), 4.31 (d, J = 15.6 Hz, 1H), 4.17 (br s, 1H), 3.89 (dd, J = 8.6, 5.5 Hz, 1H ), 3.84 (s, 3H), 2.73 (dt, J = 15.5, 1.7 Hz, 1H), 2.35 (br s, 1H), 2.03 (ddd, J = 15.8, 5.0, 2.5 Hz, 1H), 1.96 (dd , J = 13.1, 11.0 Hz, 1H), 1.91 (dd, J = 13.1, 3.2 Hz, 1H).

실시예 15: (4aExample 15: (4a SS ,6, 6 RR , 8a, 8a SS ,10, 10 RR )-4a,5,9,10,11,12-헥사하이드로-6-하이드록시-3-메톡시-6) -4a, 5,9,10,11,12-hexahydro-6-hydroxy-3-methoxy-6 HH -벤조퓨로[3a,3,2-ef][2]벤조아제핀-10-메탄올-Benzofuro [3a, 3,2-ef] [2] benzoazin-10-methanol

Figure 112006090796461-pat00020
Figure 112006090796461-pat00020

실시예 14에서 합성한 화합물 (화학식 8; 2.12 g, 6.44 mmol)을 질소 분위기 하에서 메탄올 (52 mL)에 녹인 후 8 N NaOH (52 mL)을 가하고 2 시간 동안 교반하였다. 반응 혼합물에 진한 염산을 가하여 pH를 8 내지 9로 한 후, 다이클로로메테인 (10 mL)로 추출하고 유기층을 무수 황산마그네슘으로 건조하고 용매를 감압하에 제거하고 실리카겔 관 크로마그래피 (다이클로로메테인:메탄올 = 10:1)로 분리하여 목적화합물 (화학식 9a; 1.47 g, 75%)를 흰색 고체로 얻었다. The compound synthesized in Example 14 (Formula 8; 2.12 g, 6.44 mmol) was dissolved in methanol (52 mL) under a nitrogen atmosphere, and then 8 N NaOH (52 mL) was added and stirred for 2 hours. Concentrated hydrochloric acid was added to the reaction mixture to pH 8-9, extracted with dichloromethane (10 mL), the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and silica gel column chromatography (dichloromethane) : Methanol = 10: 1) to separate the target compound (9a; 1.47 g, 75%) was obtained as a white solid.

[α] D 26 .6 = -78.0°(c 1.12, CHCl3) 1 H NMR (500 MHz , CDCl 3 , δ) : 6.66 (d, J = 8.2 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.01 (dd, J = 10.2, 4.2 Hz, 1H), 5.94 (d, J = 10.2 Hz, 1H), 4.58 (br s, 1H), 4.14 (t, J = 4.6 Hz, 1H), 4.07 (d, J = 16.0 Hz, 1H), 3.99 (d, J = 16.0 Hz, 1H), 3.83 (s, 3H), 3.58 (dd, J = 10.2, 3.9 Hz, 1H), 3.32-3.27 (m, 1H), 3.22 (t, J = 9.6 Hz, 1H), 2.69 (dt, J = 15.7, 1.7 Hz, 1H), 2.37 (br s, 3H), 2.01 (ddd, J = 15.8, 5.1, 2.4 Hz, 1H), 1.77 (dd, J = 13.2, 1.2 Hz, 1H), 1.43 (dd, J = 13.2, 11.3 Hz, 1H). [a] D 26 .6 = -78.0 ° ( c 1.12, CHCl 3 ) 1 H NMR (500 MHz , CDCl 3 , δ) : 6.66 (d, J = 8.2 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.01 (dd, J = 10.2, 4.2 Hz, 1H), 5.94 (d, J = 10.2 Hz, 1H), 4.58 (br s, 1H), 4.14 (t, J = 4.6 Hz, 1H) , 4.07 (d, J = 16.0 Hz, 1H), 3.99 (d, J = 16.0 Hz, 1H), 3.83 (s, 3H), 3.58 (dd, J = 10.2, 3.9 Hz, 1H), 3.32-3.27 ( m, 1H), 3.22 (t, J = 9.6 Hz, 1H), 2.69 (dt, J = 15.7, 1.7 Hz, 1H), 2.37 (br s, 3H), 2.01 (ddd, J = 15.8, 5.1, 2.4 Hz, 1H), 1.77 (dd, J = 13.2, 1.2 Hz, 1H), 1.43 (dd, J = 13.2, 11.3 Hz, 1H).

실시예 16: (4aExample 16: (4a SS ,6, 6 RR ,8a, 8a SS ,10, 10 RR )-4a,5,9,10,11,12-헥사하이드로-6-하이드록시-3-메톡시-11-메틸-6) -4a, 5,9,10,11,12-hexahydro-6-hydroxy-3-methoxy-11-methyl-6 HH -벤조퓨로[3a,3,2-ef][2]벤조아제핀-10-메탄올-Benzofuro [3a, 3,2-ef] [2] benzoazin-10-methanol

Figure 112006090796461-pat00021
Figure 112006090796461-pat00021

실시예 15에서 합성한 화합물 (화학식 9a; 400 mg, 1.32 mmol)을 아세트나이트릴 (24.0 mL)에 녹이고 질소 분위기하에 실온에서 35% 포름알데하이드 (8.90 mL) 과 NaBH3CN (520 mg, 8.28 mmol )를 가하였다. 0 ℃로 냉각 후, 초산 (160 mL, 2.80 mmol)을 가하고 그 온도에서 4시간 교반한 다음 포화 NaHCO3로 반응을 종결하였다. 반응 혼합물을 다이클로로메테인(2 × 10 mL)으로 추출하고, 유기층을 무수 황산마그네슘으로 건조하고 용매를 감압하에 제거하고 실리카젤 관 크로마토그래피(다이클로로메테인:메탄올 = 20:1)로 분리하여 목적화합물(화학식 9b; 384 mg, 91% 수율)을 흰색 고체로 얻었다. The compound synthesized in Example 15 (Formula 9a; 400 mg, 1.32 mmol) was dissolved in acetnitrile (24.0 mL) and 35% formaldehyde (8.90 mL) and NaBH 3 CN (520 mg, 8.28 mmol) at room temperature under nitrogen atmosphere. ) Was added. After cooling to 0 ° C., acetic acid (160 mL, 2.80 mmol) was added and stirred at that temperature for 4 hours and then the reaction was terminated with saturated NaHCO 3 . The reaction mixture was extracted with dichloromethane (2 × 10 mL), the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure and separated by silica gel column chromatography (dichloromethane: methanol = 20: 1). The target compound (Formula 9b; 384 mg, 91% yield) was obtained as a white solid.

[α] D 28.9 = -58.8°(c 1.16, CHCl3) 1 H NMR (500MHz, CDCl 3 , δ) : 6.70 (d, J = 8.2 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 5.99 (dd, J = 10.4, 4.6 Hz, 1H), 5.96 (dd, J = 10.4, 1.2 Hz, 1H), 4.59 (brs, 1H), 4.26 (d, J = 15.7 Hz, 1H), 4.13 (m, 1H), 3.94 (d, J = 15.7 Hz, 1H), 3.84 (s, 3H), 3.57 (td, J = 10.7, 5.1 Hz, 1H), 3.39 (dd, J = 10.4, 5.3 Hz, 1H), 3.34 (q, J = 10.4 Hz, 1H), 2.69 (dt, J= 15.7, 1.7 Hz, 1H), 2.08 (s, 3H), 2.00 (ddd, J = 15.7, 5.1, 2.3 Hz, 1H), 1.80 (dd, J = 13.5, 11.9 Hz, 1H), 1.27 (dd, J = 13.6, 1.2 Hz, 1H). [α] D 28.9 = -58.8 ° ( c 1.16, CHCl 3 ) 1 H NMR (500 MHz, CDCl 3 , δ) : 6.70 (d, J = 8.2 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 5.99 (dd , J = 10.4, 4.6 Hz, 1H), 5.96 (dd, J = 10.4, 1.2 Hz, 1H), 4.59 (brs, 1H), 4.26 (d, J = 15.7 Hz, 1H), 4.13 (m, 1H) , 3.94 (d, J = 15.7 Hz, 1H), 3.84 (s, 3H), 3.57 (td, J = 10.7, 5.1 Hz, 1H), 3.39 (dd, J = 10.4, 5.3 Hz, 1H), 3.34 ( q, J = 10.4 Hz, 1H), 2.69 (dt, J = 15.7, 1.7 Hz, 1H), 2.08 (s, 3H), 2.00 (ddd, J = 15.7, 5.1, 2.3 Hz, 1H), 1.80 (dd , J = 13.5, 11.9 Hz, 1H), 1.27 (dd, J = 13.6, 1.2 Hz, 1H).

실시예 17: (4aExample 17: (4a SS ,8a, 8a SS ,10, 10 RR )-4a,5,9,10,11,12-헥사하이드로-3-메톡시-11-메틸-6-옥소-벤조퓨로[3a,3,2-ef][2]벤조아제핀-10-카르복스알데하이드) -4a, 5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6-oxo-benzofuro [3a, 3,2-ef] [2] benzoazine-10 Carboxaldehyde

Figure 112006090796461-pat00022
Figure 112006090796461-pat00022

옥살릴클로라이드(148 mL, 1.66 mmol)을 다이클로메테인(15.0 mL)에 녹이고, 78 ℃에서 다이클로메테인 (2.0 mL)에 녹인 다이메틸 술폭사이드 (215 mL, 3.02 mmol)를 가하고, 5분 후에 다이클로로메테인 (5.0 mL)에 녹인 알코올 (화학식 9b; 240 mg, 0.756 mmol)을 5분 이내로 가하고, -78 ℃에서 15분 동안 교반한 다음, 트라이에틸 아민 (636 mL, 4.54 mmol)을 가하고, 다시 5분 동안 교반 후 반응혼합물을 실온으로 온도를 올렸다. 물을 가하고 다이클로로메테인층을 분리하고 무수 황산마그네슘으로 건조하고, 감압하에 용매를 제거하고 실리카겔 관 크로마토그래피 (다이클로로메테인:메탄올 = 20:1)로 분리하여 목적화합물 (화학식 10; 36 mg, 93%)을 흰색 고체로 얻었다.Oxalylchloride (148 mL, 1.66 mmol) was dissolved in diclomethane (15.0 mL), dimethyl sulfoxide (215 mL, 3.02 mmol) dissolved in diclomethane (2.0 mL) at 78 ° C. was added, 5 After minutes, alcohol (Formula 9b; 240 mg, 0.756 mmol) dissolved in dichloromethane (5.0 mL) was added within 5 minutes, stirred at −78 ° C. for 15 minutes, and then triethyl amine (636 mL, 4.54 mmol) After the addition, the mixture was stirred for 5 minutes and the reaction mixture was heated to room temperature. Water was added, the dichloromethane layer was separated, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and separated by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain the target compound (Formula 10; 36). mg, 93%) was obtained as a white solid.

[α] D 28 .2 = -2.1°(c 1.13, CHCl3) 1 H NMR (500 MHz , CDCl 3 , δ) : 9.77 (s, 1H), 6.76 (dd, J = 10.4, 2.1 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.03 (d, J = 10.4 Hz, 1H), 4.78 (m, 1H), 4.42 (d, J = 16.0 Hz, 1H), 4.02 (d, J = 16.0 Hz, 1H), 3.91 (dd, J = 12.0, 1.7 Hz, 1H), 3.85 (s, 3H), 3.19 (ddd, J = 17.9, 2.4, 0.7 Hz, 1H), 2.82 (dd, J = 17.9, 3.7 Hz, 1H), 2.25 (dd, J = 14.2, 2.0 Hz, 1H), 2.19 (s, 3H), 2.06 (dd, J = 14.2, 12.2 Hz, 1H). [α] D 28 .2 = -2.1 ° ( c 1.13, CHCl 3 ) 1 H NMR (500 MHz , CDCl 3 , δ) : 9.77 (s, 1H), 6.76 (dd, J = 10.4, 2.1 Hz, 1H ), 6.75 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.03 (d, J = 10.4 Hz, 1H), 4.78 (m, 1H), 4.42 (d, J = 16.0 Hz, 1H), 4.02 (d, J = 16.0 Hz, 1H), 3.91 (dd, J = 12.0, 1.7 Hz, 1H), 3.85 (s, 3H), 3.19 (ddd, J = 17.9, 2.4, 0.7 Hz, 1H), 2.82 (dd, J = 17.9, 3.7 Hz, 1H), 2.25 (dd, J = 14.2, 2.0 Hz, 1H), 2.19 (s, 3H), 2.06 (dd, J = 14.2, 12.2 Hz, 1H).

실시예 18: (4aExample 18: (4a SS ,8a, 8a SS ,10, 10 RR )-4a,5,9,10,11,12-헥사하이드로-3-메톡시-11-메틸-6-옥소-벤조퓨로[3a,3,2-ef][2]벤조아제핀-10-카르보나이트릴) -4a, 5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6-oxo-benzofuro [3a, 3,2-ef] [2] benzoazine-10 Carbon Nitrile

Figure 112006090796461-pat00023
Figure 112006090796461-pat00023

실시예 17에서 합성한 알데하이드 (화학식 10; 100 mg, 0.319 mmol) 을 아세토나이트릴 (3.0 mL)에 녹인 후 하이드록실아민 하이드로 클로라이드 (29 mg, 0.415 mmol) 과 아세트산 나트륨 (52 mg, 0.638 mmol)을 가하고 50 ℃에서 30분간 교반하였다. 반응혼합물을 냉각 후 NaHCO3로 염기화하고 다이클로로메테인으로 추출하고, 유기층을 무수 황산 마그네슘으로 건조 후 용매를 제거하였다. 불순한 옥심을 아세토나이트릴 (3.0 mL)에 녹이고 트라이클로로메틸 클로로포메이트 (50 mL, 0.415 mmol)를 가하고 실온에서 10분 동안 교반 후 반응혼합물을 0 ℃로 냉각 후 포화 NaHCO3 수용액을 가하여 염기화 하였다. 에틸 아세테이트로 추출하고 무수 황산마그네슘으로 건조 후 용매를 감압하에 제거하고 실리카겔 관 크로마토그래피로 (헥세인: 아세트산 에틸 = 1:1)로 분리하여 목적화합물 (화학식 11; 52 mg, 53% 2 단계)을 얻었다. The aldehyde synthesized in Example 17 (Formula 10; 100 mg, 0.319 mmol) was dissolved in acetonitrile (3.0 mL), followed by hydroxylamine hydrochloride (29 mg, 0.415 mmol) and sodium acetate (52 mg, 0.638 mmol). Was added and stirred at 50 ° C. for 30 minutes. The reaction mixture was cooled, basified with NaHCO 3 , extracted with dichloromethane, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed. Impure oxime was dissolved in acetonitrile (3.0 mL), trichloromethyl chloroformate (50 mL, 0.415 mmol) was added, stirred at room temperature for 10 minutes, the reaction mixture was cooled to 0 ° C. and saturated aqueous NaHCO 3 solution was added. It was basified by addition. Extracted with ethyl acetate, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure and separated by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the target compound (Formula 11; 52 mg, 53% step 2) Got.

[α] D 25 .6 = -298.8°(c 1.01, CHCl3); 1 H NMR (500 MHz , CD 3 COCD 3 , δ) : 7.13 (d, J = 10.1 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 5.95 (d, J = 10.3 Hz, 1H), 4.78 (br s, 1H), 4.32 (br s, 1H), 3.92 (d, J = 16.0 Hz, 1H), 3.78 (s, 3H), 3.06 (dd, J = 17.6, 3.3 Hz, 1H), 2.92 (dd, J= 17.6, 2.4 Hz, 1H), 2.55 (br s, 1H), 2.47 (br s, 5H). [α] D 25 .6 = -298.8 ° ( c 1.01, CHCl 3 ); 1 H NMR (500 MHz , CD 3 COCD 3 , δ) : 7.13 (d, J = 10.1 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H) , 5.95 (d, J = 10.3 Hz, 1H), 4.78 (br s, 1H), 4.32 (br s, 1H), 3.92 (d, J = 16.0 Hz, 1H), 3.78 (s, 3H), 3.06 ( dd, J = 17.6, 3.3 Hz, 1H), 2.92 (dd, J = 17.6, 2.4 Hz, 1H), 2.55 (br s, 1H), 2.47 (br s, 5H).

실시예 19: (-)-나르위딘 Example 19: (-)-Narwidine

Figure 112006090796461-pat00024
Figure 112006090796461-pat00024

실시예 18에서 합성한 나이트릴 화합물 (화학식 11: 40 mg, 0.016 mmol)을 메탄올 (1 mL)에 녹인 후 NaBH3CN (32.4 mg, 0.064 mmol)을 가하고 2시간 동안 환류 교반하였다. 반응혼합물에 포화 NaHCO3수용액을 가하고 다이클로로메테인으로 추출한 다음 무수 황산마그네슘으로 건조하고 감압하에 용매를 제거하고 실리카겔 관 크로마토그래피(다이클로로메테인: 메탄올 = 20:1)로 분리하여 목적화합물 (화학식 12; 18.4 mg, 51%)을 얻었다.The nitrile compound synthesized in Example 18 (Formula 11: 40 mg, 0.016 mmol) was dissolved in methanol (1 mL), and NaBH 3 CN (32.4 mg, 0.064 mmol) was added thereto, and the mixture was stirred under reflux for 2 hours. Saturated NaHCO 3 aqueous solution was added to the reaction mixture, extracted with dichloromethane, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and separated by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain the target compound ( 18.4 mg, 51%).

[α] D 25 .6 = -401°(c 1.31, CHCl3); 1 H NMR (200 MHz , CDCl 3 , δ) : 6.96 (d, J = 10.2 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 6.04 (d, J = 10.2 Hz, 1H), 4.74(m, 1H), 4.10 (d, J = 15.2 Hz, 1H), 3.84 (s, 3H), 3.74 (d, J = 15.4 Hz, 1H), 3.22 - 3.10 (m, 3H), 2.75 (dd, J = 17.9, 3.7 Hz, 1H), 2.45 (s, 3H), 2.28 (td, J = 13.8, 4.1 Hz, 1H), 1.91-1.81 (m, 1H). [α] D 25 .6 = −401 ° ( c 1.31, CHCl 3 ); 1 H NMR (200 MHz , CDCl 3 , δ) : 6.96 (d, J = 10.2 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 6.04 (d, J = 10.2 Hz, 1H), 4.74 (m, 1H), 4.10 (d, J = 15.2 Hz, 1H), 3.84 (s, 3H), 3.74 (d, J = 15.4 Hz, 1H), 3.22 -3.10 (m, 3H), 2.75 (dd, J = 17.9, 3.7 Hz, 1H), 2.45 (s, 3H), 2.28 (td, J = 13.8, 4.1 Hz, 1H), 1.91-1.81 (m, 1H ).

실시예 20: (-)-갈란타민Example 20 (-)-galantamine

Figure 112006090796461-pat00025
Figure 112006090796461-pat00025

실시예 19에서 합성한 화합물 (화학식 12: 18.0 mg, 0.063 mmol)을 THF (1 mL)에 녹인 후 L-셀렉트라이드(Sectride; 95 mL, 0.095 mmol)을 가하고 -78 ℃에서 1시간 동안 교반하였다. 부가적으로 실온에서 1시간동안 더 교반하였다. 반응혼합물에 물을 가하고 에틸 아세테이트로 추출한 다음 무수 황산마그네슘으로 건조하고, 여과, 감압 농축하였다. 잔류물을 실리카겔 관 크로마토그래피(다이클로로메테인: 메탄올 = 20:1)로 분리하여 목적화합물 (화학식 1; 16.3 mg, 90%)을 얻었다.The compound synthesized in Example 19 (Formula 12: 18.0 mg, 0.063 mmol) was dissolved in THF (1 mL), and then L-selectide (95 mL, 0.095 mmol) was added thereto, and the mixture was stirred at -78 ° C for 1 hour. . Additionally stirred for 1 h at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate, dried over anhydrous magnesium sulfate, filtration and concentration under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain the target compound (Formula 1; 16.3 mg, 90%).

[α] D 25 .6 = -104.2°(c 1.01, CHCl3); 1 H NMR (200 MHz , CDCl 3 , δ) : 6.67 (d, J = 10.2 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.04 (d, J = 10.4 Hz, 1H), 6.00 (dd, J = 10.2, 4.6 Hz, 1H), 4.62 (br s, 1H), 4.14 (t, J = 4.9 Hz, 1H), 4.09 (d, J = 15.3 Hz, 1H), 3.84 (s, 3H), 3.70 (d, J = 15.3 Hz, 1H), 3.28 (d, J = 13.6 Hz, 1H), 3.06 (d, J = 13.6 Hz, 1H), 2.69 (dd, J = 15.6, 4.9 Hz, 1H), 2.41 (s, 3H), 2.11 (dd, J = 13.5, 5.3 Hz, 1H), 2.01 (dd, J = 15.5, 4.9, 2.6 Hz, 1H), 1.59 (m, 1H). [α] D 25 .6 = −104.2 ° ( c 1.01, CHCl 3 ); 1 H NMR (200 MHz , CDCl 3 , δ) : 6.67 (d, J = 10.2 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.04 (d, J = 10.4 Hz, 1H), 6.00 (dd, J = 10.2, 4.6 Hz, 1H), 4.62 (br s, 1H), 4.14 (t, J = 4.9 Hz, 1H), 4.09 (d, J = 15.3 Hz, 1H), 3.84 (s, 3H ), 3.70 (d, J = 15.3 Hz, 1H), 3.28 (d, J = 13.6 Hz, 1H), 3.06 (d, J = 13.6 Hz, 1H), 2.69 (dd, J = 15.6, 4.9 Hz, 1H) ), 2.41 (s, 3H), 2.11 (dd, J = 13.5, 5.3 Hz, 1H), 2.01 (dd, J = 15.5, 4.9, 2.6 Hz, 1H), 1.59 (m, 1H).

이상에서 설명한 바와 같이, 본 발명의 제조방법에 의하면 치매 효과가 우수한 것으로 알려져 있는 갈란타민을 고 순도 및 고 수율로 전합성을 가능케 하며 활성이 탁월한 치매치료제 개발을 용이하게 할 수 있다. As described above, according to the manufacturing method of the present invention, galantamine, which is known to be excellent in dementia effects, enables total synthesis in high purity and high yield, and facilitates the development of an excellent dementia therapeutic agent.

Claims (11)

ⅰ) 다음 화학식 2로 표시되는 옥사졸리디논 유도체와 다음 화학식 3으로 표시되는 방향족 할라이드 유도체를 결합반응한 후에, 하이드록시 보호기를 제거하여 다음 화학식 4b로 표시되는 페놀 유도체를 제조하는 과정; Iii) preparing a phenol derivative represented by the following Chemical Formula 4b by combining the oxazolidinone derivative represented by the following Chemical Formula 2 with the aromatic halide derivative represented by the following Chemical Formula 3, and then removing the hydroxy protecting group;
Figure 112006090796461-pat00026
Figure 112006090796461-pat00026
 상기에서, X는 할로겐원자를 나타내고, Pro는 하이드록시 보호기를 나타낸다:In the above, X represents a halogen atom and Pro represents a hydroxy protecting group: ⅱ) 다음 화학식 4b로 표시되는 화합물을 산화제 존재하에서 산화성 짝지움 (oxidative coupling) 반응하여 다음 화학식 5로 표시되는 스파이로 벤조 아제핀 유도체를 제조하는 과정;Ii) oxidative coupling reaction of the compound represented by Formula 4b in the presence of an oxidant to prepare a spiro benzoazine derivative represented by Formula 5;
Figure 112006090796461-pat00027
Figure 112006090796461-pat00027
 ⅲ) 다음 화학식 5로 표시되는 화합물을 모르폴린과 팔라듐 촉매를 사용하여 반응시켜 다음 화학식 6으로 표시되는 입체선택성의 하이드로퓨란 유도체를 제조하는 과정;Iii) reacting the compound represented by Formula 5 with a morpholine and a palladium catalyst to prepare a stereoselective hydrofuran derivative represented by Formula 6;
Figure 112006090796461-pat00028
Figure 112006090796461-pat00028
 ⅳ) 다음 화학식 6으로 표시되는 화합물의 C-6 위치 하이드록시기를 수소원자로 전환하여 다음 화학식 7b로 표시되는 화합물을 제조하는 과정;Iii) converting the C-6 position hydroxy group of the compound represented by Formula 6 to a hydrogen atom to prepare a compound represented by Formula 7b;
Figure 112006090796461-pat00029
Figure 112006090796461-pat00029
 ⅴ) 다음 화학식 7b로 표시되는 화합물의 C-10 위치 케톤을 환원 반응하여 다음 화학식 8로 표시되는 화합물을 제조하는 과정;Iii) preparing a compound represented by the following Chemical Formula 8 by reducing the C-10 position ketone of the compound represented by the following Chemical Formula 7b;
Figure 112006090796461-pat00030
Figure 112006090796461-pat00030
 ⅵ) 다음 화학식 8로 표시되는 화합물을 염기 조건에서 가수분해하여 옥사졸리디논 고리를 개환한 후에, N-메틸화 반응하여 다음 화학식 9b로 표시되는 화합물을 제조하는 과정;Iii) hydrolyzing the compound represented by the following Chemical Formula 8 under basic conditions to ring-open the oxazolidinone ring, followed by N-methylation to prepare a compound represented by the following Chemical Formula 9b;
Figure 112006090796461-pat00031
Figure 112006090796461-pat00031
 ⅶ) 다음 화학식 9b로 표시되는 화합물을 산화 반응하여 다음 화학식 10으로 표시되는 화합물을 제조하는 과정;Iii) oxidizing the compound represented by Formula 9b to prepare a compound represented by Formula 10;
Figure 112006090796461-pat00032
Figure 112006090796461-pat00032
 ⅷ) 다음 화학식 10으로 표시되는 화합물의 알데히드기를 옥심으로 전환한 후에, 탈수반응하여 다음 화학식 11로 표시되는 화합물을 제조하는 과정; 및Iii) converting the aldehyde group of the compound represented by the following formula (10) to oxime, followed by dehydration to produce a compound represented by the following formula (11); And
Figure 112006090796461-pat00033
Figure 112006090796461-pat00033
 ⅸ) 다음 화학식 11로 표시되는 화합물의 C-6 위치 케톤의 환원반응 및 C-10 위치의 카르보나이트릴기 제거반응을 수행하여 다음 화학식 1로 표시되는 갈란타민을 제조하는 과정; Iii) preparing a galantamine represented by the following Chemical Formula 1 by performing a reduction reaction of a C-6 position ketone and a carbonitrile group removing reaction of a C-10 position with a compound represented by the following Chemical Formula 11;
Figure 112006090796461-pat00034
Figure 112006090796461-pat00034
 을 포함하여 이루어지는 것을 특징으로 하는 갈란타민의 제조방법:Method for producing galantamine, characterized in that consisting of: 제 1 항에서, 상기 화학식 2로 표시되는 옥사졸리디논 유도체는 The oxazolidinone derivative represented by Formula 2 is a) 다음 화학식 2-1로 표시되는 D-타이로신 메틸 에스터 하이드로클로라이드를 염기 조건하에 에틸 클로로 포메이트로 처리하여 다음 화학식 2-2로 표시되는 에톡시카르보닐 아미노 메틸 에스터를 제조하고,a) treating the D-tyrosine methyl ester hydrochloride represented by the following Chemical Formula 2-1 with ethyl chloro formate under basic conditions to prepare an ethoxycarbonyl amino methyl ester represented by the following Chemical Formula 2-2, b) 다음 화학식 2-2로 표시되는 화합물의 하이드록시기를 보호기(protecting group)로 보호하여 다음 화학식 2-3으로 표시되는 화합물을 제조하고,b) preparing a compound represented by the following Chemical Formula 2-3 by protecting the hydroxyl group of the compound represented by the following Chemical Formula 2-2 with a protecting group; c) 다음 화학식 2-3으로 표시되는 화합물을 환원하여 다음 화학식 2-4로 표시되는 알코올 유도체를 제조하고,c) reducing the compound represented by the following Chemical Formula 2-3 to prepare an alcohol derivative represented by the following Chemical Formula 2-4, d) 다음 화학식 2-4로 표시되는 화합물을 염기 조건하에서 가열 환류 반응하여 다음 화학식 2로 표시되는 옥사졸리디논 유도체를 제조하여 사용하는 것을 특징으로 하는 제조방법 : d) A method for preparing an oxazolidinone derivative represented by the following Chemical Formula 2 by heating and refluxing the compound represented by the following Chemical Formula 2-4 under basic conditions:
Figure 112006090796461-pat00035
Figure 112006090796461-pat00035
 상기에서, Pro는 하이드록시 보호기를 나타낸다.In the above, Pro represents a hydroxy protecting group. 제 1 항에서, 상기 화학식 3로 표시되는 방향족 할라이드 유도체는The method of claim 1, wherein the aromatic halide derivative represented by Formula 3 is a) 다음 화학식 3-1로 표시되는 다이하이드록시메틸 에스터 유도체를 염기 조건하에 알릴브로마이드로 알킬화하여 다음 화학식 3-2로 표시되는 화합물을 제조하고,a) alkylating the dihydroxymethyl ester derivative represented by the following Chemical Formula 3-1 with allyl bromide under basic conditions to prepare a compound represented by the following Chemical Formula 3-2, b) 다음 화학식 3-2로 표시되는 화합물을 환원반응하여 에스터를 알코올로 전환하여 다음 화학식 3-3으로 표시되는 다이알릴 알코올 유도체를 제조하고,b) reducing the compound represented by the following Chemical Formula 3-2 to convert the ester into an alcohol to prepare a diallyl alcohol derivative represented by the following Chemical Formula 3-3, c) 다음 화학식 3-3으로 표시되는 화합물을 브롬화하여 하이드록시기를 브롬으로 전환하여 다음 화학식 3으로 표시되는 알릴이 치환된 방향족 할라이드 유도체를 제조하여 사용하는 것을 특징으로 하는 제조방법.c) a method of producing and using an allyl-substituted aromatic halide derivative represented by the following Formula 3 by brominating the compound represented by the following Formula 3-3 to convert the hydroxy group to bromine.
Figure 112006090796461-pat00036
Figure 112006090796461-pat00036
 상기에서, X는 할로겐원자를 나타낸다.In the above, X represents a halogen atom. 제 1 항에 있어서, 상기 ⅱ)산화성 짝지움 반응에는 페닐아이오딘(Ⅲ) 비스(트라이풀루오로 아세테이트)가 산화제로 사용되는 것을 특징으로 하는 제조방법.The method of claim 1, wherein ii) phenyliodine (III) bis (tripulouro acetate) is used as an oxidizing agent in the oxidative mating reaction. 제 1 항에 있어서, 상기 ⅲ)반응은 모르폴린이 포함된 테트라하이드로퓨란 용매에서 테트라키스트라이페닐포스핀 팔라디움 [Pd(PPh3)4]를 사용하여 실온에서 수행하는 것을 특징으로 하는 제조방법.The method according to claim 1, wherein the reaction (iii) is performed at room temperature using tetrakistriphenylphosphine palladium [Pd (PPh 3 ) 4 ] in a tetrahydrofuran solvent containing morpholine. 다음 화학식 5로 표시되는 화합물.The compound represented by the following formula (5).
Figure 112006090796461-pat00037
Figure 112006090796461-pat00037
 다음 화학식 6으로 표시되는 화합물.The compound represented by the following formula (6).
Figure 112006090796461-pat00038
Figure 112006090796461-pat00038
 다음 화학식 7b로 표시되는 화합물.The compound represented by the following formula (7b).
Figure 112006090796461-pat00039
Figure 112006090796461-pat00039
 다음 화학식 8로 표시되는 화합물.The compound represented by the following formula (8).
Figure 112006090796461-pat00040
Figure 112006090796461-pat00040
 다음 화학식 9b로 표시되는 화합물.The compound represented by the following formula (9b).
Figure 112006090796461-pat00041
Figure 112006090796461-pat00041
 다음 화학식 11로 표시되는 화합물.The compound represented by the following formula (11).
Figure 112006090796461-pat00042
Figure 112006090796461-pat00042
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