KR101884729B1

KR101884729B1 - Process for Preparing Eldecalcitol and Intermediate Therefor

Info

Publication number: KR101884729B1
Application number: KR1020160155127A
Authority: KR
Inventors: 이승종; 문형욱; 고은정; 신현익; 이기영; 오창영
Original assignee: 연성정밀화학(주)
Priority date: 2016-11-21
Filing date: 2016-11-21
Publication date: 2018-08-02
Also published as: JP2020189844A; JP6775809B2; WO2018093223A3; JP2019536814A; KR20180057033A; CN109982992A; JP7072273B2; CN109982992B; WO2018093223A2

Abstract

본 발명은 엘더칼시톨의 제조방법 및 그에 사용되는 중간체에 관한 것이다, 본 발명의 제조방법에 따르면, 엘더칼시톨을 복잡하고 긴 제조 과정을 거치지 않고, 효율적이고 경제적으로 제조할 수 있다.The present invention relates to a process for producing eldercalcitol and intermediates used therefor. According to the process of the present invention, eldercalcitol can be produced efficiently and economically without a complicated and long production process.

Description

TECHNICAL FIELD The present invention relates to a process for preparing eldercalcitol and an intermediate therefor,

본 발명은 엘더칼시톨(Eldecalcitol)의 제조방법 및 그를 위한 중간체에 관한 것으로, 보다 상세하게는 엘더칼시톨을 효율적이고 경제적으로 제조하는 방법 및 그에 사용되는 중간체에 관한 것이다.The present invention relates to a process for producing Eldecalcitol and intermediates therewithin, and more particularly to a process for efficiently and economically producing eldercalcitol and intermediates used therein.

각종 비타민 D 유도체가 유용한 생리활성을 가지며, 특히 하기 화학식 I로 나타낸 1α-히드록시비타민 D3 유도체가 칼슘 대사이상으로 인한 질병에 대한 치료제로서 또는 항종양제로서 유용하다는 것이 미국 특허 제4,555,634호에 개시되어 있다. It is disclosed in U.S. Patent No. 4,555,634 that various vitamin D derivatives have useful physiological activities and that 1α-hydroxyvitamin D3 derivatives represented by the following formula (I) are useful as therapeutic agents or antitumor agents for diseases caused by calcium metabolic abnormalities .

[화학식 I](I)

상기 화학식 I로 나타내는 화합물 중 하나인 하기 화학식 1의 엘더칼시톨((1R,2R,3R,5Z,7E)-2-(3-Hydroxypropyloxy)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol)은 골다공증 치료제인 에디롤(Edirol^®)의 활성 약학적 성분(API)이다.(1R, 2R, 3R, 5Z, 7E) -2- (3-Hydroxypropyloxy) -9,10-secocholesta-5,7,10 19) -triene-1,3,25-triol) is the active pharmaceutical ingredient (API) of osteoporosis in eddy roll (Edirol ^®).

[화학식 1] [Chemical Formula 1]

엘더칼시톨은 비타민 D 유도체와 같이 콜레스테롤 유도체로부터 광반응을 이용하여 제조하는 방법과 주요 중간체인 A-ring moiety와 CD-ring moiety를 제조하여 커플링하는 방법이 알려져 있다.Elder chalcitol is known as a method of preparing cholesterol derivatives by using a photoreaction such as vitamin D derivatives, and a method of preparing and coupling a major intermediate, A-ring moiety and CD-ring moiety.

미국 특허 제5,334,740호에는 하기 반응식 1과 같이, 3,4:5,6-O-디이소프로필리덴-D-만니톨(3,4:5,6-O-diisopropylidene-D-mannitol)을 출발물질로 26 단계 이상의 복잡한 공정을 거쳐 주요 중간체인 사이클로헥산트리올 유도체인 A-ring moiety를 제조하고 CD-ring moiety와 반응시킨 후, 탈보호 반응을 진행하여 엘더칼시톨을 제조하는 방법이 개시되어 있다. 그러나 상기 제조방법은 중간체인 A-ring moiety를 제조하기 위하여 긴 제조 과정을 거쳐야 하는 문제점이 있다.U.S. Patent No. 5,334,740 discloses a process for preparing 3,4: 5,6-O-diisopropylidene-D-mannitol by reacting 3,4: 5,6-O-diisopropylidene- , A process for preparing an A-ring moiety, which is a cyclohexanetriol derivative, which is a main intermediate, through a complicated process of 26 steps or more, reacting with a CD-ring moiety, and then conducting a deprotection reaction to prepare eldercalcitol have. However, there is a problem that a long manufacturing process is required to produce an intermediate A-ring moiety.

[반응식 1] [Reaction Scheme 1]

미국 특허 제4,555,634호U.S. Patent No. 4,555,634 미국 특허 제5,334,740호U.S. Patent No. 5,334,740

본 발명자들은 엘더칼시톨의 제조에 있어서 상기한 문제점을 해결하고자 예의 연구 검토한 결과, (3R,4R)-헥사-1,5-디엔-3,4-디올을 출발물질로 이용하여 엘더칼시톨의 주요 중간체인 A-ring moiety를 제조하고, 이를 이용하여 Wittig-Horner 반응을 진행하여 효율적이고 경제적으로 엘더칼시톨을 제조할 수 있음을 알아내고, 본 발명을 완성하게 되었다. DISCLOSURE OF THE INVENTION The present inventors have intensively studied to solve the above problems in the production of eldercalcitol. As a result, it has been found that by using (3R, 4R) -hexa-1,5-diene- The present inventors have found that an A-ring moiety, which is a main intermediate of cital, is prepared and the Wittig-Horner reaction is carried out using the resultant to efficiently and economically produce eldercalcitol.

따라서 본 발명의 목적은 엘더칼시톨을 효율적이고 경제적으로 제조하는 개선된 방법을 제공하는 것이다.It is therefore an object of the present invention to provide an improved method for efficiently and economically producing eldercalcitol.

본 발명의 다른 목적은 상기 제조방법에 사용되는 중간체를 제공하는 것이다.Another object of the present invention is to provide an intermediate used in the above-mentioned production method.

본 발명의 일 실시형태는 하기 화학식 1의 엘더칼시톨의 제조방법에 관한 것으로, 본 발명의 제조방법은 An embodiment of the present invention relates to a process for producing an eldercalcitol represented by the following formula (1)

(i) 하기 화학식 2의 화합물을 산 촉매의 존재 하에 p-아니스알데히드와 반응시켜 하기 화학식 3의 화합물을 수득하는 단계;(i) reacting a compound of formula (2) with p-anisaldehyde in the presence of an acid catalyst to obtain a compound of formula (3);

(ii) 하기 화학식 3의 화합물의 아세탈기를 환원반응시켜 하기 화학식 4의 화합물을 수득하는 단계;(ii) reducing the acetal group of the compound of formula (3) to obtain a compound of formula (4);

(iii) 하기 화학식 4의 화합물의 알릴 알코올기를 비대칭 에폭시화 반응시켜 하기 화학식 5의 화합물을 수득하는 단계;(iii) asymmetrically epoxidizing an allyl alcohol group of a compound of formula (4) to obtain a compound of formula (5);

(iv) 하기 화학식 5의 화합물을 하기 화학식 6의 화합물과 염기의 존재 하에 반응시켜 하기 화학식 7의 화합물을 수득하는 단계;(iv) reacting a compound of formula (5) with a compound of formula (6) in the presence of a base to obtain a compound of formula (7);

(v) 하기 화학식 7의 화합물을 하기 화학식 8의 화합물과 반응시켜 하기 화학식 9의 화합물을 수득하는 단계;(v) reacting a compound of formula (7) with a compound of formula (8) to obtain a compound of formula (9);

(vi) 하기 화학식 9의 화합물의 2급 히드록실기를 보호하여 하기 화학식 10의 화합물을 수득하는 단계;(vi) protecting the secondary hydroxyl group of the compound of formula (9) to obtain a compound of formula (10);

(vii) 하기 화학식 10의 화합물의 PMB기를 선택적으로 탈보호 반응시켜 하기 화학식 11의 화합물을 수득하는 단계;(vii) selectively deprotecting the PMB group of the compound of formula (10) to obtain a compound of formula (11);

(viii) 하기 화학식 11의 화합물의 2급 히드록실기를 보호하여 하기 화학식 12의 화합물을 수득하는 단계;(viii) protecting the secondary hydroxyl group of the compound of formula (11) to obtain a compound of the formula (12);

(ix) 하기 화학식 12의 화합물의 THP기를 선택적으로 탈보호 반응시켜 하기 화학식 13의 화합물을 수득하는 단계;(ix) selectively deprotecting the THP group of the compound of formula (12) to obtain a compound of formula (13);

(x) 하기 화학식 13의 화합물의 아세틸렌기를 환원 반응시키고, 요오드와 반응시켜 하기 화학식 14의 화합물을 수득하는 단계;(x) subjecting an acetylene group of the following formula (13) to a reduction reaction and reacting with iodine to obtain a compound of the following formula (14);

(xi) 하기 화학식 14의 화합물을 고리화 반응시켜 하기 화학식 15의 화합물을 수득하는 단계;(xi) cyclizing the compound of formula (14) to obtain a compound of formula (15);

(xii) 하기 화학식 15의 화합물을 할로겐화 반응시켜 하기 화학식 16의 화합물을 수득하는 단계;(xii) halogenating a compound of formula (15) to obtain a compound of formula (16);

(xiii) 하기 화학식 16의 화합물을 디페닐포스핀과 반응시키고, 산화 반응시켜 하기 화학식 17의 화합물을 수득하는 단계;(xiii) reacting a compound of formula (16) with diphenylphosphine and subjecting it to an oxidation reaction to obtain a compound of formula (17);

(xiv) 하기 화학식 17의 화합물을 하기 화학식 18의 화합물과 위티그-오너 반응시켜 하기 화학식 19의 화합물을 수득하는 단계; 및(xiv) reacting a compound of formula (17) with a compound of formula (18) to obtain a compound of formula (19); And

(xv) 하기 화학식 19의 화합물을 탈보호 반응시키는 단계를 포함한다.(xv) deprotecting the compound of formula (19).

[화학식 1] [Chemical Formula 1]

[화학식 2](2)

[화학식 3](3)

[화학식 4][Chemical Formula 4]

[화학식 5][Chemical Formula 5]

[화학식 6][Chemical Formula 6]

[화학식 7](7)

[화학식 8][Chemical Formula 8]

[화학식 9][Chemical Formula 9]

[화학식 10][Chemical formula 10]

[화학식 11](11)

[화학식 12][Chemical Formula 12]

[화학식 13][Chemical Formula 13]

[화학식 14][Chemical Formula 14]

[화학식 15][Chemical Formula 15]

[화학식 16][Chemical Formula 16]

[화학식 17][Chemical Formula 17]

[화학식 18][Chemical Formula 18]

[화학식 19][Chemical Formula 19]

상기 식에서,In this formula,

PMP는 p-메톡시페닐이고,PMP is p-methoxyphenyl,

PMB는 p-메톡시벤질이며,PMB is p-methoxybenzyl,

TBDPS는 tert-부틸디페닐실릴이고,TBDPS is tert-butyldiphenylsilyl,

TfO는 트리플루오로메탄설포네이트이며,TfO is trifluoromethane sulfonate,

THP는 테트라히드로-2H-피란-2-일이고,THP is tetrahydro-2H-pyran-2-yl,

TBS는 t-부틸디메틸실릴이며,TBS is t-butyldimethylsilyl,

TMS는 트리메틸실릴이다.
TMS is trimethylsilyl.

이하, 본 발명의 제조방법을 하기 반응식 2와 반응식 3을 참조로 보다 상세히 설명한다. 하기 반응식 2와 반응식 3에 기재된 방법은 대표적으로 사용된 방법을 예시한 것일 뿐 반응시약, 반응조건 등은 경우에 따라 얼마든지 변경될 수 있다.Hereinafter, the production method of the present invention will be described in more detail with reference to Reaction Schemes 2 and 3. The method described in the following Reaction Schemes 2 and 3 exemplifies the typical method used, but the reaction reagent, the reaction conditions, and the like may be changed as required.

[반응식 2][Reaction Scheme 2]

[반응식 3][Reaction Scheme 3]

제1단계: 화학식 3의 화합물의 합성Step 1: Synthesis of Compound (3)

화학식 3의 화합물은 화학식 2의 화합물을 산 촉매의 존재 하에 p-아니스알데히드와 반응시켜 제조할 수 있다.The compound of formula (3) can be prepared by reacting the compound of formula (2) with p-anisaldehyde in the presence of an acid catalyst.

상기 산 촉매로는 황산, 캠포설포닉산, p-톨루엔설포닉산 등이 사용될 수 있고, 특히 p-톨루엔설포닉산이 적합하다.As the acid catalyst, sulfuric acid, camphorsulfonic acid, p-toluenesulfonic acid and the like can be used, and p-toluenesulfonic acid is particularly suitable.

반응용매로는 벤젠, 톨루엔, 시클로헥산 등이 사용될 수 있고, 특히 시클로헥산이 바람직하다.As the reaction solvent, benzene, toluene, cyclohexane and the like can be used, and cyclohexane is particularly preferable.

반응온도는 약 40 내지 50 ℃가 적합하고, 반응시간은 약 4 내지 6 시간이 바람직하다.
The reaction temperature is preferably about 40 to 50 DEG C, and the reaction time is preferably about 4 to 6 hours.

제2단계: 화학식 4의 화합물의 합성Step 2: Synthesis of Compound (4)

화학식 4의 화합물은 화학식 3의 화합물의 아세탈기를 환원 반응시켜 제조할 수 있다.The compound of formula (4) can be prepared by a reduction reaction of the acetal group of the compound of formula (3).

상기 환원 반응은 디이소부틸알루미늄 하이드라이드(DIBAL)와 같은 환원제의 존재 하에 수행될 수 있다. The reduction reaction may be carried out in the presence of a reducing agent such as diisobutyl aluminum hydride (DIBAL).

반응용매로는 테트라히드로퓨란, 디클로로메탄, 벤젠, 톨루엔 등이 사용될 수 있고, 특히 톨루엔이 바람직하다.As the reaction solvent, tetrahydrofuran, dichloromethane, benzene, toluene and the like can be used, and toluene is particularly preferable.

반응온도는 약 -10 내지 10 ℃가 적합하고, 반응시간은 약 1 내지 5시간이 바람직하다.
The reaction temperature is preferably about -10 to 10 占 폚, and the reaction time is preferably about 1 to 5 hours.

제3단계: 화학식 5의 화합물의 합성Step 3: Synthesis of Compound (5)

화학식 5의 화합물은 화학식 4의 화합물의 알릴 알코올기를 비대칭 에폭시화 반응(Sharpless asymmetric epoxidation)시켜 제조할 수 있다.The compound of formula (5) can be prepared by subjecting an allyl alcohol group of the compound of formula (4) to asymmetric epoxidation (Sharpless asymmetric epoxidation).

상기 비대칭 에폭시화 반응은 티타늄 이소프로폭사이드(Ti(O-iPr)₄), (+)-디이소프로필 타르트레이트((+)-DIPT) 및 t-부틸 히드로퍼옥사이드(tBuOOH)의 존재 하에 수행될 수 있다. The asymmetric epoxidation reaction is carried out in the presence of titanium isopropoxide (Ti (O-iPr) ₄ ), (+) - diisopropyl tartrate ((+) - DIPT) and t-butyl hydroperoxide (tBuOOH) .

반응용매로는 톨루엔, 벤젠, 디클로로메탄 등이 사용될 수 있고, 특히 디클로로메탄이 바람직하다.As the reaction solvent, toluene, benzene, dichloromethane and the like can be used, and dichloromethane is particularly preferable.

반응온도는 약 0 내지 30 ℃가 적합하고, 반응시간은 약 5 내지 10 시간이 바람직하다.
The reaction temperature is preferably about 0 to 30 占 폚, and the reaction time is preferably about 5 to 10 hours.

제4단계: 화학식 7의 화합물의 합성Step 4: Synthesis of compound of formula (7)

화학식 7의 화합물은 화학식 5의 화합물을 화학식 6의 화합물과 염기의 존재 하에 반응시켜 제조할 수 있다.The compound of formula (7) can be prepared by reacting the compound of formula (5) with a compound of formula (6) in the presence of a base.

상기 염기로는 소듐 t-부톡사이드, 소듐 t-펜톡사이드, 소듐 하이드라이드 등이 사용될 수 있고, 특히 소듐 하이드라이드가 적합하다.As the base, sodium t-butoxide, sodium t-pentoxide, sodium hydride and the like can be used, and in particular, sodium hydride is suitable.

반응용매로는 디메틸포름이미드, 테트라히드로퓨란, 아세토니트릴 등이 사용될 수 있고, 특히 아세토니트릴이 바람직하다.As the reaction solvent, dimethylformimide, tetrahydrofuran, acetonitrile and the like can be used, and acetonitrile is particularly preferable.

반응온도는 약 -10 내지 20 ℃가 적합하고, 반응시간은 약 30분 내지 2 시간이 바람직하다.
The reaction temperature is preferably about -10 to 20 占 폚, and the reaction time is preferably about 30 minutes to 2 hours.

상기 화학식 6의 화합물은 하기 화학식 20의 화합물의 두 개의 히드록실기를 한 부분만 실릴 보호시켜 하기 화학식 21의 화합물을 수득한 후, 이를 무수 트리플릭산과 반응시켜 제조할 수 있다.The compound of formula (6) can be prepared by protecting only one part of two hydroxyl groups of the compound of formula (20) with silyl to obtain a compound of formula (21), followed by reacting it with anhydrous trifric acid.

[화학식 20][Chemical Formula 20]

[화학식 21][Chemical Formula 21]

제5단계: 화학식 9의 화합물의 합성Step 5: Synthesis of Compound (9)

화학식 9의 화합물은 화학식 7의 화합물을 화학식 8의 화합물과 반응시켜 제조할 수 있다.The compound of formula (9) can be prepared by reacting the compound of formula (7) with the compound of formula (8).

상기 반응은 n-부틸리튬과 보론 트리플로라이드 디에틸에테르의 존재 하에 수행될 수 있으나, 이에 제한되는 것은 아니다.The reaction may be carried out in the presence of n-butyllithium and boron trifluoride diethyl ether, but is not limited thereto.

반응용매로는 아세토니트릴, 메틸렌클로라이드, 테트라히드로퓨란 등이 사용될 수 있고, 특히 테트라히드로퓨란이 바람직하다.As the reaction solvent, acetonitrile, methylene chloride, tetrahydrofuran and the like can be used, and tetrahydrofuran is particularly preferable.

반응온도는 약 -78 내지 30 ℃가 적합하고, 반응시간은 약 2 내지 4 시간이 바람직하다.
The reaction temperature is preferably about -78 to 30 占 폚, and the reaction time is preferably about 2 to 4 hours.

제6단계: 화학식 10의 화합물의 합성Step 6: Synthesis of Compound (10)

화학식 10의 화합물은 화학식 9의 화합물의 2급 히드록실기를 보호하여 제조할 수 있다.The compound of formula (10) can be prepared by protecting the secondary hydroxyl group of the compound of formula (9).

상기 보호 반응은 화학식 9의 화합물을 염기의 존재 하에 t-부틸디메틸실릴 클로라이드와 반응시켜 수행될 수 있다.The protecting reaction can be carried out by reacting the compound of formula 9 with t-butyldimethylsilyl chloride in the presence of a base.

상기 염기로는 피리딘, 트리에틸아민, 이미다졸 등이 사용될 수 있고, 특히 이미다졸이 적합하다.As the base, pyridine, triethylamine, imidazole and the like can be used, and imidazole is particularly suitable.

반응용매로는 아세토니트릴, 테트라히드로퓨란, 디메틸포름이미드 등이 사용될 수 있고, 특히 디메틸포름이미드가 바람직하다.As the reaction solvent, acetonitrile, tetrahydrofuran, dimethyl formimide and the like can be used, and dimethyl formimide is particularly preferable.

반응온도는 약 20 내지 80 ℃가 적합하고, 반응시간은 약 12 내지 24 시간이 바람직하다.
The reaction temperature is preferably about 20 to 80 캜, and the reaction time is preferably about 12 to 24 hours.

제7단계: 화학식 11의 화합물의 합성Step 7: Synthesis of compound of formula 11

화학식 11의 화합물은 화학식 10의 화합물의 PMB기를 선택적으로 탈보호 반응시켜 제조할 수 있다.The compound of formula (11) can be prepared by selectively deprotecting the PMB group of the compound of formula (10).

상기 탈보호 반응은 2,3-디클로로-5,6-디시아노-1,4-벤조퀴논(DDQ)을 사용하여 수행될 수 있으나, 이에 제한되는 것은 아니다.The deprotection reaction can be performed using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), but is not limited thereto.

반응용매로는 클로로포름, 디클로로메탄, 물 또는 이들의 혼합용매 등이 사용될 수 있고, 특히 디클로로메탄과 물의 혼합용매가 바람직하다.As the reaction solvent, chloroform, dichloromethane, water or a mixed solvent thereof may be used, and a mixed solvent of dichloromethane and water is particularly preferable.

반응온도는 약 0 내지 30 ℃가 적합하고, 반응시간은 약 30분 내지 2 시간이 바람직하다.
The reaction temperature is preferably about 0 to 30 占 폚, and the reaction time is preferably about 30 minutes to 2 hours.

제8단계: 화학식 12의 화합물의 합성Step 8: Synthesis of compound of formula (12)

화학식 12의 화합물은 화학식 11의 화합물의 2급 히드록실기를 보호하여 제조할 수 있다.The compound of formula (12) can be prepared by protecting the secondary hydroxyl group of the compound of formula (11).

상기 보호 반응은 화학식 11의 화합물을 염기의 존재 하에 t-부틸디메틸실릴 클로라이드와 반응시켜 수행될 수 있다.The protecting reaction can be carried out by reacting the compound of formula 11 with t-butyldimethylsilyl chloride in the presence of a base.

반응온도는 약 20 내지 80 ℃가 적합하고, 반응시간은 약 5 내지 12 시간이 바람직하다.
The reaction temperature is preferably about 20 to 80 캜, and the reaction time is preferably about 5 to 12 hours.

제9단계: 화학식 13의 화합물의 합성Step 9: Synthesis of Compound (13)

화학식 13의 화합물은 화학식 12의 화합물의 THP기를 선택적으로 탈보호 반응시켜 제조할 수 있다.The compound of formula (13) can be prepared by selectively deprotecting the THP group of the compound of formula (12).

상기 탈보호 반응은 산 존재 하에 수행될 수 있으며, 상기 산으로는 마그네슘 브로마이드, 디메틸알루미늄 클로라이드 등이 사용될 수 있고, 특히 디메틸알루미늄 클로라이드가 적합하다.The deprotection reaction may be carried out in the presence of an acid, and examples of the acid include magnesium bromide, dimethylaluminum chloride, and the like, in particular, dimethylaluminum chloride.

반응용매로는 테트라히드로퓨란, 디에틸에테르, 디클로로메탄 등이 사용될 수 있고, 특히 디클로로메탄이 바람직하다.As the reaction solvent, tetrahydrofuran, diethyl ether, dichloromethane and the like can be used, and dichloromethane is particularly preferable.

반응온도는 약 0 내지 30 ℃가 적합하고, 반응시간은 약 3 내지 10 시간이 바람직하다.
The reaction temperature is preferably about 0 to 30 占 폚, and the reaction time is preferably about 3 to 10 hours.

제10단계: 화학식 14의 화합물의 합성Step 10: Synthesis of compound of formula (14)

화학식 14의 화합물은 화학식 13의 화합물의 아세틸렌기를 환원 반응시키고, 요오드와 반응시켜 제조할 수 있다.The compound of formula (14) can be prepared by reducing the acetylene group of the compound of formula (13) and reacting it with iodine.

상기 환원 반응은 소듐 비스(2-메톡시에톡시)알루미늄하이드라이드(Red-Al)와 같은 환원제의 존재 하에 수행될 수 있으며, 이어서 에틸 아세테이트를 사용하여 환원제의 역할을 억제시키고, 요오드와 반응시킬 수 있다.The reduction reaction may be carried out in the presence of a reducing agent such as sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al), followed by the use of ethyl acetate to inhibit the action of the reducing agent and to react with iodine .

반응용매로는 톨루엔, 디클로로메탄, 테트라히드로퓨란, 디에틸에테르 등이 사용될 수 있고, 특히 디에틸에테르, 테트라히드로퓨란이 바람직하다.As the reaction solvent, toluene, dichloromethane, tetrahydrofuran, diethyl ether and the like can be used. Particularly, diethyl ether and tetrahydrofuran are preferable.

반응온도는 약 -78 내지 30 ℃가 적합하고, 반응시간은 약 5 내지 10 시간이 바람직하다.
The reaction temperature is preferably about -78 to 30 占 폚, and the reaction time is preferably about 5 to 10 hours.

제11단계: 화학식 15의 화합물의 합성Step 11: Synthesis of compound of formula (15)

화학식 15의 화합물은 화학식 14의 화합물을 고리화 반응시켜 제조할 수 있다.The compound of formula (15) can be prepared by the cyclization of the compound of formula (14).

상기 고리화 반응은 염기 및 팔라듐 촉매(Pd(PPh₃)₄)의 존재 하에 수행될 수 있다.The cyclization reaction may be carried out in the presence of a base and a palladium catalyst _{_{(Pd (PPh 3) 4)}} .

상기 염기로는 탄산 칼슘, 탄산 은, 트리에틸아민 등이 사용될 수 있고, 특히 트리에틸아민이 적합하다.As the base, calcium carbonate, silver carbonate, triethylamine and the like can be used, and triethylamine is particularly suitable.

반응온도는 약 20 내지 90 ℃가 적합하고, 반응시간은 약 1 내지 10 시간이 바람직하다.
The reaction temperature is preferably about 20 to 90 占 폚, and the reaction time is preferably about 1 to 10 hours.

제12단계: 화학식 16의 화합물의 합성Step 12: Synthesis of Compound (16)

화학식 16의 화합물은 화학식 15의 화합물을 할로겐화 반응시켜 알릴 알코올을 알릴 클로라이드로 전환하여 제조할 수 있다.The compound of formula (16) can be prepared by halogenating the compound of formula (15) and converting the allyl alcohol to allyl chloride.

상기 할로겐화 반응은 N-클로로숙신이미드 및 디메틸설파이드 등을 사용하여 수행될 수 있으나, 이에 제한되는 것은 아니다.The halogenation reaction can be performed using N-chlorosuccinimide, dimethyl sulfide, or the like, but is not limited thereto.

반응온도는 약 -30 내지 30 ℃가 적합하고, 반응시간은 약 1 내지 5 시간이 바람직하다.
The reaction temperature is preferably about -30 to 30 占 폚, and the reaction time is preferably about 1 to 5 hours.

제13단계: 화학식 17의 화합물의 합성Step 13: Synthesis of Compound (17)

화학식 17의 화합물은 화학식 16의 화합물을 디페닐포스핀과 반응시키고, 산화 반응시켜 제조할 수 있다.The compound of formula (17) can be prepared by reacting the compound of formula (16) with diphenylphosphine and subjecting it to an oxidation reaction.

상기 디페닐포스핀과의 반응은 염기의 존재 하에 수행될 수 있으며, 상기 염기로는 n-부틸리튬 등을 사용할 수 있으나, 이에 제한되는 것은 아니다.The reaction with the diphenylphosphine can be carried out in the presence of a base, and as the base, n-butyllithium and the like can be used, but the present invention is not limited thereto.

반응용매로는 디클로로메탄, 디에틸에테르, 테드라히드로퓨란 등이 사용될 수 있고, 특히 테트라히드로퓨란이 바람직하다.As the reaction solvent, dichloromethane, diethyl ether, tetrahydrofuran and the like can be used, and tetrahydrofuran is particularly preferable.

반응온도는 약 -78 내지 0 ℃가 적합하고, 반응시간은 약 1 내지 5 시간이 바람직하다.
The reaction temperature is preferably about -78 to 0 占 폚, and the reaction time is preferably about 1 to 5 hours.

상기 산화 반응은 과산화수소와 같은 산화제를 사용하여 수행될 수 있다. The oxidation reaction may be carried out using an oxidizing agent such as hydrogen peroxide.

이때, 반응용매로는 디클로로메탄, 클로로포름 등이 사용될 수 있고, 특히 클로로포름이 바람직하다.As the reaction solvent, dichloromethane, chloroform and the like can be used, and chloroform is particularly preferable.

반응온도는 약 0 내지 30 ℃가 적합하고, 반응시간은 약 1 내지 5 시간이 바람직하다.
The reaction temperature is preferably about 0 to 30 占 폚, and the reaction time is preferably about 1 to 5 hours.

제14단계: 화학식 19의 화합물의 합성Step 14: Synthesis of compound of formula 19

화학식 19의 화합물은 화학식 17의 화합물을 화학식 18의 화합물과 위티그-오너(Wittig-Horner) 반응시켜 제조할 수 있다.The compound of formula (19) can be prepared by reacting a compound of formula (17) with a compound of formula (18) according to the Wittig-Horner reaction.

상기 위티그-오너(Wittig-Horner) 반응은 염기의 존재 하에 수행될 수 있으며, 상기 염기로는 n-부틸리튬 등을 사용할 수 있으나, 이에 제한되는 것은 아니다.The Wittig-Horner reaction may be carried out in the presence of a base, and examples of the base include n-butyllithium, but are not limited thereto.

반응온도는 약 -78 내지 30 ℃가 적합하고, 반응시간은 약 1 내지 5 시간이 바람직하다.
The reaction temperature is preferably about -78 to 30 占 폚, and the reaction time is preferably about 1 to 5 hours.

제15단계: 화학식 1의 화합물의 제조Step 15: Preparation of compound of formula (1)

화학식 1의 화합물은 화학식 19의 화합물을 탈보호 반응시켜 제조할 수 있다.The compound of formula (1) can be prepared by deprotecting the compound of formula (19).

상기 탈보호 반응은 산 촉매의 존재 하에 수행될 수 있으며, 상기 산 촉매로는 캠퍼설포닉산, 메탄설포닉산, p-톨루엔설포닉산 등이 사용될 수 있고, 특히 p-톨루엔설포닉산이 적합하다.The deprotection reaction may be carried out in the presence of an acid catalyst. As the acid catalyst, camphorsulfonic acid, methanesulfonic acid, p-toluenesulfonic acid and the like may be used, and p-toluenesulfonic acid is particularly suitable.

반응용매로는 메탄올, 에탄올, 디클로로메탄, 이들의 혼합용매 등이 사용될 수 있고, 특히 메탄올과 디클로로메탄의 혼합용매가 바람직하다.As the reaction solvent, methanol, ethanol, dichloromethane, mixed solvent thereof and the like can be used, and a mixed solvent of methanol and dichloromethane is particularly preferable.

반응온도는 약 0 내지 30 ℃가 적합하고, 반응시간은 약 2 내지 10 시간이 바람직하다.
The reaction temperature is preferably about 0 to 30 占 폚, and the reaction time is preferably about 2 to 10 hours.

본 발명의 일 실시형태는 엘더칼시톨의 제조 중간체인 하기 화학식 5의 화합물에 관한 것이다.An embodiment of the present invention relates to a compound of formula (5), which is a production intermediate of elder calcitol.

[화학식 5][Chemical Formula 5]

상기 식에서,In this formula,

PMB는 p-메톡시벤질이다.
PMB is p-methoxybenzyl.

본 발명의 다른 실시형태는 엘더칼시톨의 제조 중간체인 하기 화학식 7의 화합물에 관한 것이다.Another embodiment of the present invention relates to a compound of formula (7), which is a production intermediate of elder calcitol.

[화학식 7] (7)

상기 식에서,In this formula,

PMB는 p-메톡시벤질이고,PMB is p-methoxybenzyl,

TBDPS는 tert-부틸디페닐실릴이다.
TBDPS is tert-butyldiphenylsilyl.

본 발명의 또 다른 실시형태는 엘더칼시톨의 제조 중간체인 하기 화학식 9의 화합물에 관한 것이다.Another embodiment of the present invention relates to a compound of formula (9), which is a production intermediate of elder calcitol.

[화학식 9][Chemical Formula 9]

상기 식에서,In this formula,

PMB는 p-메톡시벤질이고,PMB is p-methoxybenzyl,

TBDPS는 tert-부틸디페닐실릴이며,TBDPS is tert-butyldiphenylsilyl,

THP는 테트라히드로-2H-피란-2-일이다.
THP is tetrahydro-2H-pyran-2-yl.

본 발명의 일 실시형태는 엘더칼시톨의 제조 중간체인 상기 화학식 17의 화합물의 제조방법에 관한 것으로, 본 발명의 일 실시형태에 따른 제조방법은 One embodiment of the present invention relates to a method for producing the compound of formula (17), which is an intermediate for the production of eldercalcitol, and the production method according to one embodiment of the present invention

(xii) 하기 화학식 15의 화합물을 할로겐화 반응시켜 하기 화학식 16의 화합물을 수득하는 단계; 및(xii) halogenating a compound of formula (15) to obtain a compound of formula (16); And

(xiii) 하기 화학식 16의 화합물을 디페닐포스핀과 반응시키고, 산화 반응시키는 단계를 포함한다.(xiii) reacting a compound represented by the following formula (16) with diphenylphosphine and subjecting it to an oxidation reaction.

[화학식 9][Chemical Formula 9]

[화학식 10][Chemical formula 10]

[화학식 11](11)

[화학식 12][Chemical Formula 12]

[화학식 13][Chemical Formula 13]

[화학식 14][Chemical Formula 14]

[화학식 15][Chemical Formula 15]

[화학식 16][Chemical Formula 16]

[화학식 17][Chemical Formula 17]

상기 식에서,In this formula,

PMB는 p-메톡시벤질이고,PMB is p-methoxybenzyl,

TBDPS는 tert-부틸디페닐실릴이며,TBDPS is tert-butyldiphenylsilyl,

TBS는 t-부틸디메틸실릴이다.
TBS is t-butyldimethylsilyl.

상기 화학식 17의 화합물의 제조방법에 대한 상세한 설명은 엘더칼시톨의 제조방법과 관련하여 상술한 제6단계 내지 제13단계와 동일하므로, 중복을 피하기 위해 구체적인 설명을 생략한다.The detailed description of the method for preparing the compound of formula (17) is the same as the sixth to thirteenth steps described above with respect to the method for producing eldercalcitol, so that a detailed description thereof will be omitted in order to avoid duplication.

본 발명의 제조방법에 따르면, 엘더칼시톨을 복잡하고 긴 제조 과정을 거치지 않고, 효율적이고 경제적으로 제조할 수 있다.According to the production method of the present invention, elder calcitol can be produced efficiently and economically without complicated and long manufacturing process.

이하, 실시예에 의해 본 발명을 보다 구체적으로 설명하고자 한다. 이들 실시예는 오직 발명을 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업자에게 있어서 자명하다.
Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to those skilled in the art that these embodiments are for illustrative purposes only and that the scope of the invention is not limited to these examples.

실시예Example 1: 화학식 3의 화합물의 제조 1: Preparation of the compound of formula (3)

(3R,4R)-헥사-1,5-디엔-3,4-디올(2) (503 g)을 시클로헥산(5,000 ml)에 희석하였다. p-아니스알데히드(2,027 ml), p-톨루엔설포닉산(1,170 g)을 가하고 반응액의 온도를 약 45 내지 50 ℃로 승온하여 4 시간 동안 교반하였다. 반응의 진행을 박층 크로마토그래피(헥산 : 에틸아세테이트 = 2 : 1)에 의해 관측하였다. 반응 완료 후, 반응액을 실온으로 냉각하고 5% 중조수(3,000 ml)을 넣어 교반하였다. 유기층을 분리하여 10% 아황산수소나트륨(6,940 ml)를 가하여 교반하였다. 유기층을 분리하여 5% 중조수(1,780 ml)를 가하여 교반하였다. 유기층을 분리하고 무수황산나트륨 중에 건조하였다. 무수황산나트륨을 여과 후 여과액을 진공 중에 농축하여 불순물이 함유되어 있는 (4R,5R)-2-(4-메톡시페닐)-4,5-디비닐-1,3-디옥소란(3)을 수득하였다. 더 이상의 정제과정 없이 다음 단계의 반응을 진행하였다.(3R, 4R) -hexa-1,5-diene-3,4-diol (2) (503 g) was diluted in cyclohexane (5,000 ml). p-Anisaldehyde (2,027 ml) and p-toluenesulfonic acid (1,170 g) were added. The temperature of the reaction solution was raised to about 45 to 50 캜 and stirred for 4 hours. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 2: 1). After completion of the reaction, the reaction solution was cooled to room temperature, and 5% aqueous sulfuric acid solution (3,000 ml) was added thereto and stirred. The organic layer was separated, 10% sodium hydrogen sulfite (6,940 ml) was added, and the mixture was stirred. The organic layer was separated and 5% aqueous sodium hydroxide (1,780 ml) was added and stirred. The organic layer was separated and dried in anhydrous sodium sulfate. (4R, 5R) -2- (4-methoxyphenyl) -4,5-divinyl-1,3-dioxolane (3) in which an impurity is contained in the filtrate, &Lt; / RTI > The next step was carried out without further purification.

¹H NMR (300 MHz, CDCl₃) : δ 7.45-7.43 (2H, dd, J = 1.8, 6.6 Hz), 6.92-6.89 (2H, dd, J = 1.9, 6.7 Hz), 6.00-5.85 (2H, m), 5.45-5.35 (2H, m), 4.37-4.19 (2H, m), 3.81 (3H, s).
^{1 H NMR (300 MHz, CDCl} 3): δ 7.45-7.43 (2H, dd, J = 1.8, 6.6 Hz), 6.92-6.89 (2H, dd, J = 1.9, 6.7 Hz), 6.00-5.85 (2H, m), 5.45-5.35 (2H, m), 4.37-4.19 (2H, m), 3.81 (3H, s).

실시예Example 2: 화학식 4의 화합물의 제조 2: Preparation of the compound of formula (4)

불순물이 함유되어 있는 (4R,5R)-2-(4-메톡시페닐)-4,5-디비닐-1,3-디옥소란(3) (200 g)을 톨루엔(1,800 ml)에 희석하였다. 반응액의 온도를 약 -5 내지 0 ℃로 냉각하고, 디이소부틸알루미늄 하이드라이드(DIBAL, 1.2 M in toluene) (1,552 ml)를 0 ℃를 유지하면서 적가하였다. 반응액을 등 온도에서 약 1 내지 2 시간 동안 교반하고, 반응의 진행을 박층 크로마토그래피(헥산 : 에틸아세테이트 = 2 : 1)에 의해 관측하였다. 반응 완료 후, 반응액에 메탄올(50.3 ml)을 적가하여 반응을 종료시키고 5% NaOH 수용액(50.3 ml)을 10 ℃ 이하로 유지하면서 적가하였다. 반응액을 약 10 내지 20 분 동안 교반하고, 유기층을 분리하여 무수황산나트륨 중에 건조하였다. 무수황산나트륨을 여과 후 여과액을 진공 중에 농축하여 혼합물을 수득하였고, 외부온도 120 ℃에서 진공 중에 증류하여 순수한 (3R,4R)-4-(4-메톡시벤질옥시)헥사-1,5-디엔-3-올(4) (127 g, 35%)을 수득하였다.(200 g) of (4R, 5R) -2- (4-methoxyphenyl) -4,5-divinyl-1,3-dioxolane containing impurities was diluted with toluene Respectively. The temperature of the reaction solution was cooled to about -5 to 0 占 폚, and diisobutyl aluminum hydride (DIBAL, 1.2 M in toluene) (1,552 ml) was added dropwise at 0 占 폚. The reaction solution was stirred at the same temperature for about 1 to 2 hours, and the progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 2: 1). After completion of the reaction, methanol (50.3 ml) was added dropwise to the reaction solution to complete the reaction, and 5% NaOH aqueous solution (50.3 ml) was added dropwise while keeping the temperature at 10 캜 or lower. The reaction solution was stirred for about 10 to 20 minutes, and the organic layer was separated and dried in anhydrous sodium sulfate. After filtration of anhydrous sodium sulfate, the filtrate was concentrated in vacuo to obtain a mixture. The mixture was distilled under vacuum at an external temperature of 120 ° C to obtain pure (3R, 4R) -4- (4-methoxybenzyloxy) hexa- 3-ol (4) (127 g, 35%).

¹H NMR (300 MHz, CDCl₃) : δ 7.27-7.24 (2H, d, J = 8.7 Hz), 6.90-6.87 (2H, dd, J = 1.9, 6.7 Hz), 5.86-5.67 (2H, m), 5.99-5.35 (2H, m), 5.32-5.28 (1H, m), 5.22-5.17 (1H, dt, J = 1.5, 10.5 Hz), 4.61-4.29 (2H, dd, J = 11.1, 86.1 Hz), 4.07-4.01 (1H, m), 3.80 (3H, s), 3.67-3.62 (1H, t, J = 7.5 Hz), 2.77-2.76 (1H, d, J = 3.0 Hz).
^{1 H NMR (300 MHz, CDCl} 3): δ 7.27-7.24 (2H, d, J = 8.7 Hz), 6.90-6.87 (2H, dd, J = 1.9, 6.7 Hz), 5.86-5.67 (2H, m) , 5.99-5.35 (2H, m), 5.32-5.28 (1H, m), 5.22-5.17 (1H, dt, J = 1.5, 10.5 Hz), 4.61-4.29 (2H, dd, J = 11.1, 86.1 Hz) , 4.07-4.01 (IH, m), 3.80 (3H, s), 3.67-3.62 (IH, t, J = 7.5 Hz), 2.77-2.76 (IH, d, J = 3.0 Hz).

실시예Example 3: 화학식 5의 화합물의 제조 3: Preparation of the compound of formula (5)

디클로로메탄(960 ml)에 분자체(molecular sieve) 3 Å (80 g), 티타늄 이소프로폭사이드(245 ml), (+)-디이소프로필 타르트레이트(203 ml)를 가하여 실온에서 약 20 분 동안 교반하였다. (3R,4R)-4-(4-메톡시벤질옥시)헥사-1,5-디엔-3-올(4) (162 g)을 디클로로메탄(640 ml)에 희석하여 적가하고 실온에서 약 20 분 동안 교반하였다. t-부틸 히드로퍼옥사이드(248 ml)를 20 ℃ 이하를 유지하면서 적가하고 실온에서 약 5 시간 동안 교반하였고 반응의 진행을 박층 크로마토그래피(헥산 : 에틸아세테이트 = 2 : 1)에 의해 관측하였다. 반응 완료 후, 셀라이트(celite)를 이용하여 녹지 않는 고체를 여과하여 제거하고, 여액에 황산제일철7수화물(230 g), 구연산(79.5 g)을 물(2,400 ml)에 녹여 가하였다. 반응 혼합액을 실온에서 1 시간 동안 교반하고, 셀라이트를 이용하여 녹지 않는 고체를 여과하여 제거하고 여액의 유기층을 분리시켰다. 수산화나트륨(115 g)을 20% 소금물(1,615 ml)에 녹이고, 분리된 유기층에 가하여 실온에서 약 30 분 동안 교반하였다. 반응에 사용된 (+)-디이소프로필 타르트레이트가 제거되는 반응의 진행을 박층 크로마토그래피(헥산 : 에틸아세테이트 = 2 : 1)에 의해 관측하였다. 유기층을 분리하여 1 N 염산수용액(500 ml)을 가하고 약 10 분 동안 교반하였다. 유기층을 분리하여 5% 중조수(1,600 ml)을 가하고 약 10분 동안 교반하였다. 유기층을 분리하여 무수황산나트륨 중에 건조하였다. 무수황산나트륨을 여과 후 여과액을 진공 중에 농축하여 혼합물을 수득하였고, 외부온도 140 ℃에서 진공 중에 증류하여 순수한 (1S,2R)-2-(4-메톡시벤질옥시)-1-((R)-옥시란-2-일)부트-3-엔-1-올(5) (160 g, 93%)을 수득하였다.To the suspension was added molecular sieve 3 Å (80 g), titanium isopropoxide (245 ml) and (+) - diisopropyl tartrate (203 ml) to dichloromethane (960 ml) Lt; / RTI > (162 g) of (3R, 4R) -4- (4-methoxybenzyloxy) hexa-1,5-dien-3-ol was added dropwise to dichloromethane (640 ml) Lt; / RTI > butyl hydroperoxide (248 ml) was added dropwise while maintaining the temperature below 20 ° C, and the mixture was stirred at room temperature for about 5 hours. The progress of the reaction was monitored by thin layer chromatography (hexane: ethyl acetate = 2: 1). After completion of the reaction, the insoluble solid was removed by filtration using celite, and ferrous sulfate heptahydrate (230 g) and citric acid (79.5 g) were dissolved in water (2,400 ml). The reaction mixture was stirred at room temperature for 1 hour, and the insoluble solid was removed by filtration using Celite, and the organic layer of the filtrate was separated. Sodium hydroxide (115 g) was dissolved in 20% brine (1,615 ml), added to the separated organic layer, and stirred at room temperature for about 30 minutes. The progress of the reaction to remove (+) - diisopropyltartrate used in the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 2: 1). The organic layer was separated, and a 1 N aqueous hydrochloric acid solution (500 ml) was added thereto, followed by stirring for about 10 minutes. The organic layer was separated, 5% aqueous sodium hydroxide solution (1,600 ml) was added, and the mixture was stirred for about 10 minutes. The organic layer was separated and dried in anhydrous sodium sulfate. After filtration of anhydrous sodium sulfate, the filtrate was concentrated in vacuo to give a mixture which was distilled in vacuo at an external temperature of 140 ° C to give pure (1S, 2R) -2- (4-methoxybenzyloxy) Yl) but-3-en-1-ol (5) (160 g, 93%).

¹H NMR (300 MHz, CDCl₃) : δ 7.27-7.24 (2H, d, J = 8.4 Hz), 6.90-6.87 (2H, d, J = 8.7 Hz), 5.92-5.80 (1H, m), 5.42 (1H, s), 5.39-5.37 (1H, d, J = 8.4 Hz), 4.64-4.33 (1H, dd, J = 11.4, 81.9 Hz), 3.93-3.89 (1H, m), 3.81 (3H, s), 3.50-3.46 (1H, t, J = Hz ), 3.66-3.61 (1H, t, J = 5.1 Hz), 3.05-3.01 (1H, m), 2.75-2.77 (2H, d, J = 3.3 Hz).
^{1 H NMR (300 MHz, CDCl} 3): δ 7.27-7.24 (2H, d, J = 8.4 Hz), 6.90-6.87 (2H, d, J = 8.7 Hz), 5.92-5.80 (1H, m), 5.42 (1H, s), 5.39-5.37 (1H, d, J = 8.4 Hz), 4.64-4.33 (1H, dd, J = 11.4,81.9 Hz), 3.93-3.89 ), 3.50-3.46 (1H, t, J = Hz), 3.66-3.61 (1H, t, J = 5.1 Hz), 3.05-3.01 (1H, m), 2.75-2.77 (2H, d, J = 3.3 Hz ).

실시예Example 4: 화학식 6의 화합물의 제조 4: Preparation of the compound of formula (6)

1,3-프로판디올(75.6 g)을 디클로로메탄(1,130 ml)에 희석시키고, 트리에틸아민(139 ml)을 가하여 교반하였다. 반응물의 온도를 0℃로 냉각시키고, t-부틸디페닐실릴 클로라이드(258 ml)를 적가하였다. 반응물의 온도를 실온으로 승온시키고, 24 시간 동안 교반하였다. 반응의 진행을 박층 크로마토그래피(헥산 : 에틸아세테이트 = 4 : 1)에 의해 관측하였다. 반응 완료 후, 물(1,130 ml)을 가하여 약 10 분 동안 교반하였다. 유기층을 분리하여 무수황산나트륨 중에 건조하였다. 무수황산나트륨을 여과 후 여과액을 진공 중에 농축하여 혼합물을 수득하였고, 외부온도 150 ℃에서 진공 중에 증류하여 순수한 3-(tert-부틸디페닐실릴옥시)프로판-1-올(284 g, 91%)을 수득하였다. 얻어진 3-(tert-부틸디페닐실릴옥시)프로판-1-올(284 g)을 헵탄(2,840 ml)에 녹이고, 디이소프로필에틸아민(165 ml)을 가하였다. 반응물의 온도를 약 10 ℃로 냉각시키고, 무수트리플릭산(152 ml)을 적가하였다. 반응물의 온도를 약 10 ℃를 유지하면서 30 분 동안 교반하였다. 반응의 진행을 박층 크로마토그래피(헥산 : 에틸아세테이트 = 4 : 1)에 의해 관측하였다. 반응 완료 후, 물(1,420 ml)을 가하여 약 10 분 동안 교반하였다. 유기층을 분리하여 무수황산나트륨 중에 건조하였다. 무수황산나트륨을 여과 후 여과액을 진공 중에 농축하여 3-(tert-부틸디페닐실릴옥시)프로필 트리플루오로메탄설포네이트(6) (395 g, 98%)를 수득하였다.1,3-Propanediol (75.6 g) was diluted with dichloromethane (1,130 ml), triethylamine (139 ml) was added and the mixture was stirred. The temperature of the reaction was cooled to 0 < 0 > C and t-butyldiphenylsilyl chloride (258 ml) was added dropwise. The temperature of the reaction was raised to room temperature and stirred for 24 hours. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 4: 1). After completion of the reaction, water (1,130 ml) was added and stirred for about 10 minutes. The organic layer was separated and dried in anhydrous sodium sulfate. After filtration of anhydrous sodium sulfate, the filtrate was concentrated in vacuo to obtain a mixture. Distillation in vacuo at an external temperature of 150 ° C afforded pure 3- (tert-butyldiphenylsilyloxy) propan-1-ol (284 g, 91% &Lt; / RTI > The resulting 3- (tert-butyldiphenylsilyloxy) propan-1-ol (284 g) was dissolved in heptane (2,840 ml) and diisopropylethylamine (165 ml) was added. The temperature of the reaction was cooled to about 10 < 0 > C and anhydrous triflic acid (152 ml) was added dropwise. The temperature of the reaction was stirred for 30 minutes while maintaining about 10 < 0 > C. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 4: 1). After completion of the reaction, water (1,420 ml) was added and stirred for about 10 minutes. The organic layer was separated and dried in anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give 3- (tert-butyldiphenylsilyloxy) propyltrifluoromethanesulfonate (6) (395 g, 98%).

¹H NMR (300 MHz, CDCl₃) : δ 7.66-7.63 (4H, m), 7.47-7.35 (6H, m), 4.76-4.72 (2H, t, J = 6.2 Hz), 3.79-3.75 (2H, t, J = 5.7 Hz), 2.05-1.97 (1H, m), 1.07-1.04 (9H, m).
¹ H NMR (300 MHz, CDCl ₃ ):? 7.66-7.63 (4H, m), 7.47-7.35 (6H, m), 4.76-4.72 (2H, t, J = 6.2 Hz), 3.79-3.75 t, J = 5.7Hz), 2.05-1.97 (1H, m), 1.07-1.04 (9H, m).

실시예Example 5: 화학식 7의 화합물의 제조 5: Preparation of the compound of formula (7)

60% 소듐하이드라이드(35.4 g)를 아세토니트릴(990 ml)에 천천히 가하여 현탁시키고, 반응물의 온도를 -5 ℃로 냉각시켰다. (1S,2R)-2-(4-메톡시벤질옥시)-1-((R)-옥시란-2-일)부트-3-엔-1-올(5) (142.9 g)을 아세토니트릴(425 ml)에 희석하여 0 ℃ 이하를 유지하면서 천천히 적가하였다. 3-(tert-부틸디페닐실릴옥시)프로필 트리플루오로메탄설포네이트(6) (420 g)를 아세토니트릴(285 ml)에 희석하여 0 ℃ 이하를 유지하면서 천천히 적가하고, 실온으로 서서히 승온하여 약 1 시간 동안 교반하였다. 반응의 진행을 박층 크로마토그래피 (헥산 : 에틸아세테이트 = 4 : 1)에 의해 관측하였다. 반응 완료 후, 메탄올 (46 ml)을 가하여 반응을 종료시키고, 물(1,400 ml), 에틸아세테이트(1,400 ml)를 가하여 약 10 분 동안 교반하였다. 유기층을 분리하여 물(1,400 ml)을 가하여 약 10 분 동안 교반한 후, 유기층을 분리하여 무수황산나트륨 중에 건조하였다. 무수황산나트륨을 여과 후 여과액을 진공 중에 농축하여 혼합물을 수득하였고, 실리카겔을 사용한 칼럼 크로마토그래피 (헥산 : 에틸아세테이트 = 10 : 1)로 정제하여 순수한 (3R,4S)-1-(4-메톡시페닐)-11,11-디메틸-4-((R)-옥시란-2-일)-10,10-디페닐-3-비닐-2,5,9-트리옥사-10-실라도데칸(7) (262 g, 84%)을 수득하였다. 60% Sodium hydride (35.4 g) was slowly added to acetonitrile (990 ml) and suspended, and the temperature of the reaction was cooled to -5 占 폚. Yl) but-3-en-1-ol (5) (142.9 g) was added to a mixture of acetonitrile (425 ml) and slowly added dropwise while maintaining the temperature below 0 ° C. (6) (420 g) was diluted with acetonitrile (285 ml), slowly dropped while keeping the temperature at or below 0 ° C, and the temperature was gradually raised to room temperature to obtain a solution of 3- (tert- butyldiphenylsilyloxy) propyltrifluoromethanesulfonate And stirred for about 1 hour. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 4: 1). After completion of the reaction, methanol (46 ml) was added to terminate the reaction, and water (1,400 ml) and ethyl acetate (1,400 ml) were added thereto and stirred for about 10 minutes. The organic layer was separated, water (1,400 ml) was added thereto, and the mixture was stirred for about 10 minutes. The organic layer was separated and dried in anhydrous sodium sulfate. After filtering off the anhydrous sodium sulfate, the filtrate was concentrated in vacuo to give a mixture which was purified by column chromatography using silica gel (hexane: ethyl acetate = 10: 1) to give pure (3R, 4S) -1- Phenyl) -11,11-dimethyl-4 - ((R) -oxiran-2-yl) -10,10-diphenyl-3-vinyl-2,5,9-trioxa-10-siladodecane 7) (262 g, 84%).

¹H NMR (300 MHz, CDCl₃) : δ 7.67-7.61 (4H, m), 7.44-7.33 (6H, m), 7.25-7.22 (2H, m), 6.86-6.83 (2H, m), 5.91-5.81 (1H, m), 5.31-5.24 (2H, m), 4.62-4.58 (1H, d, J = 12.0 Hz), 4.36-4.32 (1H, d, J = 11.7 Hz), 3.93-3.90 (1H, q, J = 3.9 Hz), 3.78 (3H, s), 3.76-3.68 (3H, m), 3.64-3.56 (1H, m), 3.23-3.20 (1H, t, J = 4.5 Hz), 3.10-3.06 (1H, m), 2.76-2.72 (2H, m), 1.83-1.74 (2H, m), 1.03 (9H, s).
^{1 H NMR (300 MHz, CDCl} 3): δ 7.67-7.61 (4H, m), 7.44-7.33 (6H, m), 7.25-7.22 (2H, m), 6.86-6.83 (2H, m), 5.91- 5.81 (1H, m), 5.31-5.24 (2H, m), 4.62-4.58 (1H, d, J = 12.0 Hz), 4.36-4.32 (1H, d, J = 11.7 Hz), 3.93-3.90 (1H, q, J = 3.9 Hz), 3.78 (3H, s), 3.76-3.68 (3H, m), 3.64-3.56 (1H, m), 3.23-3.20 (1H, t, J = 4.5 Hz), 3.10-3.06 (1H, m), 2.76-2.72 (2H, m), 1.83-1.74 (2H, m), 1.03 (9H, s).

실시예Example 6: 화학식 9의 화합물의 제조 6: Preparation of the compound of formula (9)

2-(프로피-2-이닐옥시)테트라히드로-2H-피란(8) (75 g)을 테트라히드로퓨란(750 ml)에 희석하고, 반응물의 온도를 -65 ℃ 이하로 냉각시켰다. n-부틸리튬(2.5 M in hexane, 200 ml)을 - 60 ℃ 이하를 유지하면서 적가하였다. 반응물을 등 온도에서 30 분 동안 교반하고, (3R,4S)-1-(4-메톡시페닐)-11,11-디메틸-4-((R)-옥시란-2-일)-10,10-디페닐-3-비닐-2,5,9-트리옥사-10-실라도데칸(7) (98 g)을 테트라히드로퓨란(250 ml)에 희석하여 - 60 ℃ 이하를 유지하면서 적가하였다. 보론 트리플로라이드 디에틸 에테르(BF₃·OEt₂) (24.3 ml)을 - 60 ℃ 이하를 유지하면서 적가하고, 반응물의 온도를 서서히 실온으로 승온하여 약 1 시간 동안 교반하였다. 반응의 진행을 박층 크로마토그래피 (헥산 : 에틸아세테이트 = 5 : 1)에 의해 관측하였다. 반응 완료 후, 10% 염화암모늄(980 ml)을 가하여 반응을 종료시키고, 에틸 아세테이트(1,500 ml)를 가하여 10 분 동안 교반하였다. 유기층을 분리하여 무수황산나트륨 중에 건조하였다. 무수황산나트륨을 여과 후 여과액을 진공 중에 농축하여 불순물이 함유되어 있는 (3R,4R,5R)-4-(3-(tert-부틸디페닐실릴옥시)프로폭시)-3-(4-메톡시벤질옥시)-9-(테트라히드로-2H-피란-2-일옥시)논-1-엔-7-인-5-올(9)을 수득하였다. 더 이상의 정제 과정 없이 다음 단계의 반응을 진행하였다.2- (Prop-2-ynyloxy) tetrahydro- 2H -pyran (8) (75 g) was diluted in tetrahydrofuran (750 ml) and the temperature of the reaction was cooled to below -65 캜. n-Butyllithium (2.5 M in hexane, 200 ml) was added dropwise at -60 캜 or lower. The reaction was stirred at the same temperature for 30 minutes, and (3R, 4S) -1- (4-methoxyphenyl) -11,11-dimethyl- 10-Diphenyl-3-vinyl-2,5,9-trioxa-10-siladodecane (7) (98 g) was diluted with tetrahydrofuran (250 ml) . Boron triflouroide diethyl ether (BF ₃ OEt ₂ ) (24.3 ml) was added dropwise while keeping the temperature below -60 캜, the temperature of the reaction was gradually raised to room temperature, and the mixture was stirred for about 1 hour. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 5: 1). After completion of the reaction, 10% ammonium chloride (980 ml) was added to terminate the reaction. Ethyl acetate (1,500 ml) was added and the mixture was stirred for 10 minutes. The organic layer was separated and dried in anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered out and the filtrate was concentrated in vacuo to give (3R, 4R, 5R) -4- (3- (tert- butyldiphenylsilyloxy) propoxy) -3- -Benzyloxy) -9- (tetrahydro-2H-pyran-2-yloxy) non-1-en-7-yn-5-ol (9). The next step was carried out without further purification.

¹H NMR (300 MHz, CDCl₃) : δ 7.66-7.63 (4H, m), 7.45-7.34 (6H, m), 7.25-7.21 (2H, m), 6.88-6.83 (1H, dt, J = 2.5, 9.2 Hz), 5.98-5.86 (1H, m), 5.35-5.29 (2H, m), 4.80-4.78 (1H, t, J = 3.3 Hz ), 4.61-4.57 (1H, d, J = 11.7 Hz), 4.32-4.28 (1H, d, J = 11.7 Hz), 4.27-4.23 (2H, m), 4.11-4.07 (1H, m), 3.87-3.82 (2H, m), 3.79 (3H, s), 3.75-3.65 (4H, m), 3.55-3.46 (1H, m), 3.37-3.34 (1H, m), 3.00-2.98 (1H, d, J = 4.8 Hz), 2.56-2.40 (2H, m), 1.82-1.49 (8H, m), 1.04 (9H, s).
^{1 H NMR (300 MHz, CDCl} 3): δ 7.66-7.63 (4H, m), 7.45-7.34 (6H, m), 7.25-7.21 (2H, m), 6.88-6.83 (1H, dt, J = 2.5 , 9.2 Hz), 5.98-5.86 (1H , m), 5.35-5.29 (2H, m), 4.80-4.78 (1H, t, J = 3.3 Hz), 4.61-4.57 (1H, d, J = 11.7 Hz) , 4.32-4.28 (1H, d, J = 11.7 Hz), 4.27-4.23 (2H, m), 4.11-4.07 (1H, m), 3.87-3.82 (2H, m), 3.79 (3H, s), 3.75 -3.65 (4H, m), 3.55-3.46 (1H, m), 3.37-3.34 (1H, m), 3.00-2.98 (1H, d, J = 4.8 Hz), 2.56-2.40 (2H, m), 1.82 -1.49 (8H, m), 1.04 (9H, s).

실시예Example 7: 화학식 10의 화합물의 제조 7: Preparation of the compound of formula (10)

불순물이 함유되어 있는 (3R,4R,5R)-4-(3-(tert-부틸디페닐실릴옥시)프로폭시)-3-(4-메톡시벤질옥시)-9-(테트라히드로-2H-피란-2-일옥시)논-1-엔-7-인-5-올(9) (123 g, 이론 수율)을 디메틸포름이미드(1,230 ml)에 희석하고, 이미다졸(3.1 g), t-부틸디메틸실릴 클로라이드(60.7 g)를 가하였다. 반응물의 온도를 약 60 내지 70 ℃로 승온하여 12 시간 이상 교반하였다. 반응의 진행을 박층 크로마토그래피 (헥산 : 에틸아세테이트 = 5 : 1)에 의해 관측하였다. 반응 완료 후, 5% 염화암모늄(1,000 ml)을 가하여 반응을 종료시키고, 에틸 아세테이트(1,000 ml)를 가하여 10 분 동안 교반하였다. 유기층을 분리하여 물(1,000 ml)을 가하여 10 분 동안 교반하고, 유기층을 분리하여 무수황산나트륨 중에 건조하였다. 무수황산나트륨을 여과 후 여과액을 진공 중에 농축하여 불순물이 함유되어 있는 (5R,6S)-6-((R)-1-(4-메톡시벤질옥시)알릴)-2,2,3,3,13,13-헥사메틸-12,12-디페닐-5-(4-(테트라히드로-2H-피란-2-일옥시)부트-2-이닐)-4,7,11-트리옥사-3,12-디실라테트라데칸(10)을 수득하였다. 더 이상의 정제 과정 없이 다음 단계의 반응을 진행하였다.(3R, 4R, 5R) -4- (3- (tert-butyldiphenylsilyloxy) propoxy) -3- (4-methoxybenzyloxy) -9- (tetrahydro- Ol (9 g, 123 g, theoretical yield) was diluted with dimethylformamide (1,230 ml), imidazole (3.1 g), sodium hydride t-Butyldimethylsilyl chloride (60.7 g) was added. The temperature of the reaction product was raised to about 60 to 70 캜 and stirred for 12 hours or more. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 5: 1). After completion of the reaction, 5% ammonium chloride (1,000 ml) was added to terminate the reaction, and ethyl acetate (1,000 ml) was added thereto, followed by stirring for 10 minutes. The organic layer was separated, water (1,000 ml) was added, and the mixture was stirred for 10 minutes. The organic layer was separated and dried in anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered out and the filtrate was concentrated in vacuo to give (5R, 6S) -6 - ((R) -1- (4- methoxybenzyloxy) allyl) -2,2,3,3 , 13,13-hexamethyl-12,12-diphenyl-5- (4- (tetrahydro-2H-pyran-2-yloxy) , 12-disilatetradecane (10). The next step was carried out without further purification.

¹H NMR (300 MHz, CDCl₃) : δ 7.68-7.64 (4H, m), 7.43-7.33 (6H, m), 7.23-7.20 (2H, m), 6.84-6.79 (1H, dt, J = 2.5, 9.2 Hz), 5.93-5.81 (1H, m), 5.31-5.28 (1H, m), 5.25 (1H, s), 4.30-4.21 (3H, m), 3.97-3.74 (10H, m), 3.53-3.47 (1H, m), 3.38-3.34 (1H, m), 2.51-2.49 (1H, m), 1.89-1.48 (8H, m), 1.04 (9H, s), 0.86 (9H, s), 0.07 (3H, s), 0.01 (3H, s).
^{1 H NMR (300 MHz, CDCl} 3): δ 7.68-7.64 (4H, m), 7.43-7.33 (6H, m), 7.23-7.20 (2H, m), 6.84-6.79 (1H, dt, J = 2.5 (1H, m, 3H), 3.53-5.81 (1H, m), 5.31-5.28 (1H, m), 3.47 (1H, m), 3.38-3.34 (1H, m), 2.51-2.49 (1H, m), 1.89-1.48 3H, s), 0.01 (3H, s).

실시예Example 8: 화학식 11의 화합물의 제조 8: Preparation of the compound of formula (11)

불순물이 함유되어 있는 (5R,6S)-6-((R)-1-(4-메톡시벤질옥시)알릴)-2,2,3,3,13,13-헥사메틸-12,12-디페닐-5-(4-(테트라히드로-2H-피란-2-일옥시)부트-2-이닐)-4,7,11-트리옥사-3,12-디실라테트라데칸(10) (143.6 g, 이론 수율)을 메틸렌클로라이트(1,430 ml)에 희석하고, 물(70.2 ml)을 가하였다. 반응액에 2,3-디클로로-5,6-디시아노-1,4-벤조퀴논(DDQ) (40.7 g)을 가하여, 실온에서 약 1 내지 1.5 시간 동안 교반하였다. 반응의 진행을 박층 크로마토그래피 (헥산 : 에틸아세테이트 = 5 : 1)에 의해 관측하였다. 반응 완료 후, 수산화나트륨(10.8 g)을 물(1,500 ml)에 녹여 가하여 10 분 동안 교반하였다. 유기층을 분리하여 아황산 수소나트륨(280 g), 물(1,000 ml)을 가하여 10 분 동안 교반하고, 유기층을 분리하여 무수황산나트륨 중에 건조하였다. 무수황산나트륨을 여과 후 여과액을 진공 중에 농축하여 불순물이 함유되어 있는 (3R,4S,5R)-5-(tert-부틸디메틸실릴옥시)-4-(3-(tert-부틸디페닐실릴옥시)프로폭시)-9-(테트라히드로-2H-피란-2-일옥시)논-1-엔-7-인-3-올(11)을 수득하였다. 더 이상의 정제 과정 없이 다음 단계의 반응을 진행하였다.(5R, 6S) -6 - ((R) -1- (4-methoxybenzyloxy) allyl) -2,2,3,3,13,13-hexamethyl- Synthesis of diphenyl-5- (4- (tetrahydro-2H-pyran-2-yloxy) but-2-ynyl) -4,7,11-trioxa-3,12-disilatetradecane (10) g, theoretical yield) was diluted with methylene chloride (1,430 ml) and water (70.2 ml) was added. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (40.7 g) was added to the reaction solution, and the mixture was stirred at room temperature for about 1 to 1.5 hours. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 5: 1). After completion of the reaction, sodium hydroxide (10.8 g) was dissolved in water (1,500 ml) and stirred for 10 minutes. The organic layer was separated, sodium hydrogen sulfite (280 g) and water (1,000 ml) were added and stirred for 10 minutes. The organic layer was separated and dried in anhydrous sodium sulfate. The filtrate was concentrated in vacuo to obtain (3R, 4S, 5R) -5- (tert-butyldimethylsilyloxy) -4- (3- (tert- butyldiphenylsilyloxy) Propoxy) -9- (tetrahydro-2H-pyran-2-yloxy) non-1-en-7-in-3-ol (11). The next step was carried out without further purification.

¹H NMR (300 MHz, CDCl₃) : δ 7.67-7.64 (4H, m), 7.45-7.35 (6H, m), 5.99-5.88 (1H, m), 5.38-5.31 (1H, dt, J = 1.7, 17.2 Hz), 5.20-5.16 (1H, dt, J = 1.5, 10.5 Hz), 4.81-4.79 (1H, t, J = 3.1 Hz), 4.31-4.22 (3H, m), 3.93-3.79 (3H, m), 3.75-3.64 (3H, m), 3.54-3.47 (1H, m), 3.35-3.31 (1H, dd, J = 3.9, 5.7 Hz), 2.67-2.65 (1H, d, J = 6.3 Hz), 2.58-2.43 (2H, m), 1.87-1.65 (4H, m), 1.61-1.50 (4H, m), 1.04 (9H, s), 0.90 (9H, s), 0.11 (3H, s), 0.09 (3H, s).
^{1 H NMR (300 MHz, CDCl} 3): δ 7.67-7.64 (4H, m), 7.45-7.35 (6H, m), 5.99-5.88 (1H, m), 5.38-5.31 (1H, dt, J = 1.7 (1H, d, J = 3.1 Hz), 5.20-5.16 (1H, dt, J = 1.5,10.5 Hz), 4.81-4.79 (1H, t, J = 3.1 Hz), 4.31-4.22 (3H, m), 3.93-3.79 m), 3.75-3.64 (3H, m ), 3.54-3.47 (1H, m), 3.35-3.31 (1H, dd, J = 3.9, 5.7 Hz), 2.67-2.65 (1H, d, J = 6.3 Hz) , 2.58-2.43 (2H, m), 1.87-1.65 (4H, m), 1.61-1.50 (4H, m), 1.04 (9H, s), 0.90 (3H, s).

실시예Example 9: 화학식 12의 화합물의 제조 9: Preparation of the compound of formula (12)

불순물이 함유되어 있는 (3R,4S,5R)-5-(tert-부틸디메틸실릴옥시)-4-(3-(tert-부틸디페닐실릴옥시)프로폭시)-9-(테트라히드로-2H-피란-2-일옥시)논-1-엔-7-인-3-올(11) (122.1 g, 이론 수율)을 디메틸포름이미드(1,220 ml)에 희석하고, 이미다졸(19.5 g), t-부틸디메틸실릴클로라이드(40.5 g)를 가하였다. 반응물의 온도를 약 50 내지 60 ℃로 승온하여 약 4 내지 5 시간 이상 교반하였다. 반응의 진행을 박층 크로마토그래피 (헥산 : 에틸아세테이트 = 5 : 1, 10 : 1)에 의해 관측하였다. 반응 완료 후, 5% 염화암모늄(1,000 ml)을 가하여 반응을 종료시키고, 에틸 아세테이트(1,000 ml)를 가하여 10 분 동안 교반하였다. 유기층을 분리하여 물(1,000 ml)을 가하여 10 분 동안 교반하고, 유기층을 분리하여 무수황산나트륨 중에 건조하였다. 무수황산나트륨을 여과 후 여과액을 진공 중에 농축하여 혼합물을 수득하였고, 실리카겔을 사용한 칼럼 크로마토그래피 (헥산 : 에틸아세테이트 = 30 : 1)로 정제하여 순수한 (5R,6R)-6-((1R)-1-(tert-부틸디메틸실릴옥시)-5-(테트라히드로-2H-피란-2-일옥시)펜트-3-이닐)-2,2,3,3,13,13-헥사메틸-12,12-디페닐-5-비닐-4,7,11-트리옥사-3,12-디실라테트라데칸(12) (89 g, 62%)을 수득하였다. (3R, 4S, 5R) -5- (tert-butyldimethylsilyloxy) -4- (3- (tert- butyldiphenylsilyloxy) propoxy) -9- (tetrahydro- Ol (11.1) (122.1 g, theoretical yield) was diluted with dimethylformamide (1,220 ml), and imidazole (19.5 g), t-Butyldimethylsilyl chloride (40.5 g) was added. The temperature of the reaction product was raised to about 50 to 60 캜 and stirred for about 4 to 5 hours. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 5: 1, 10: 1). After completion of the reaction, 5% ammonium chloride (1,000 ml) was added to terminate the reaction, and ethyl acetate (1,000 ml) was added thereto, followed by stirring for 10 minutes. The organic layer was separated, water (1,000 ml) was added, and the mixture was stirred for 10 minutes. The organic layer was separated and dried in anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give a mixture which was purified by column chromatography using silica gel (hexane: ethyl acetate = 30: 1) to give pure (5R, 6R) -6- ( (Tetrahydro-2H-pyran-2-yloxy) pent-3-ynyl) -2,2,3,3,13,13-hexamethyl- 12-diphenyl-5-vinyl-4,7,11-trioxa-3,12-disilatetradecane (12) (89 g, 62%).

¹H NMR (300 MHz, CDCl₃) : δ 7.68-7.64 (4H, m), 7.44-7.34 (6H, m), 5.93-5.81 (1H, m), 5.27-5.20 (1H, dt, J = 1.5, 17.4 Hz), 5.14-5.10 (1H, m), 4.79-4.78 (1H, m), 4.30-4.25 (1H, m), 4.20-4.13 (2H, m), 3.98-3.94 (1H, m), 3.86-3.67 (5H, m), 3.54-3.47 (1H, m), 3.27-3.25 (1H, dd, J = 1.5, 6.6 Hz), 2.51-2.33 (2H, m), 1.86-1.47 (8H, m), 1.04 (9H, s), 0.89 (9H, s), 0.87 (9H, s), 0.08 (3H, s), 0.06 (3H, s), 0.04 (3H, s), 0.02 (3H, s).
^{1 H NMR (300 MHz, CDCl} 3): δ 7.68-7.64 (4H, m), 7.44-7.34 (6H, m), 5.93-5.81 (1H, m), 5.27-5.20 (1H, dt, J = 1.5 (2H, m), 3.98-3.94 (1H, m), 4.40-4.25 (1H, m) (1H, m), 3.86-3.67 (5H, m), 3.54-3.47 (1H, m), 3.27-3.25 (1H, dd, J = 1.5, 6.6Hz), 2.51-2.33 ), 1.04 (9H, s), 0.89 (9H, s), 0.87 (9H, s), 0.08 (3H, s), 0.06 .

실시예Example 10: 화학식 13의 화합물의 제조 10: Preparation of the compound of formula (13)

(5R,6R)-6-((1R)-1-(tert-부틸디메틸실릴옥시)-5-(테트라히드로-2H-피란-2-일옥시)펜트-3-이닐)-2,2,3,3,13,13-헥사메틸-12,12-디페닐-5-비닐-4,7,11-트리옥사-3,12-디실라테트라데칸(12) (80 g)을 디클로로메탄(800 ml)에 희석하고, 반응물의 온도를 0 ℃로 냉각시켰다. 디메틸알루미늄 클로라이드(201.2 ml, 0.9 M in heptane)를 적가하고, 실온으로 승온하여 약 5 내지 6 시간 동안 교반하였다. 반응의 진행을 박층 크로마토그래피 (헥산 : 에틸아세테이트 = 5 : 1, 10 : 1)에 의해 관측하였다. 반응 완료 후, 반응물의 온도를 0 ℃로 냉각시키고, 메탄올(12.3 ml)을 적가하여 10 분 동안 교반하여 반응을 종료시켰다. 수산화나트륨(28.2 g)을 물(800 ml)에 녹여 반응물에 적가하고, 10 분 동안 교반하였다. 유기층을 분리하여 무수황산나트륨 중에 건조하였다. 무수황산나트륨을 여과 후 여과액을 진공 중에 농축하여 혼합물을 수득하였고, 실리카겔을 사용한 칼럼 크로마토그래피 (헥산 : 에틸아세테이트 = 10 : 1)로 정제하여 순수한 (5R,6R,7R)-5,7-비스(tert-부틸디메틸실릴옥시)-6-(3-(tert-부틸디페닐실릴옥시)프로폭시)논-8-엔-2-인-1-올(13) (72 g, 74%)을 수득하였다.(5R, 6R) -6 - ((1R) -1- (tert-butyldimethylsilyloxy) -5- (tetrahydro- 3,3,13,13-hexamethyl-12,12-diphenyl-5-vinyl-4,7,11-trioxa-3,12-disilatetradecane (12) (80 g) was dissolved in dichloromethane 800 ml) and the temperature of the reaction was cooled to 0 < 0 > C. Dimethylaluminum chloride (201.2 ml, 0.9 M in heptane) was added dropwise, and the mixture was warmed to room temperature and stirred for about 5-6 hours. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 5: 1, 10: 1). After completion of the reaction, the temperature of the reaction was cooled to 0 캜, methanol (12.3 ml) was added dropwise, and the reaction was terminated by stirring for 10 minutes. Sodium hydroxide (28.2 g) was dissolved in water (800 ml), added dropwise to the reaction, and stirred for 10 minutes. The organic layer was separated and dried in anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered out and the filtrate was concentrated in vacuo to give a mixture which was purified by column chromatography using silica gel (hexane: ethyl acetate = 10: 1) to give pure (5R, 6R, 7R) 8-en-2-yn-1-ol (13) (72 g, 74%) was added to a solution of (3- (tert- butyldimethylsilyloxy) .

¹H NMR (300 MHz, CDCl₃) : δ 7.68-7.64 (4H, m), 7.44-7.34 (6H, m), 5.93-5.81 (1H, m), 5.27-5.20 (1H, dt, J = 1.6, 17.3 Hz), 5.15-5.10 (1H, dt, J = 1.5, 10.5 Hz), 4.29-4.21 (2H, m), 4.18-4.13 (1H, m), 3.98-3.93 (1H, m), 3.87-3.67 (4H, m), 3.28-3.25 (1H, dd, J = 1.8, 6.6 Hz), 2.49-2.34 (2H, m), 1.87-1.78 (2H, m), 1.39-1.35 (1H, t, J = 6.0 Hz), 1.04 (9H, s), 0.89 (9H, s), 0.88 (9H, s), 0.09 (3H, s), 0.06 (3H, s), 0.05 (3H, s), 0.02 (3H, s).
^{1 H NMR (300 MHz, CDCl} 3): δ 7.68-7.64 (4H, m), 7.44-7.34 (6H, m), 5.93-5.81 (1H, m), 5.27-5.20 (1H, dt, J = 1.6 (1H, m), 3.87-3.93 (1H, m), 3.87-3.13 (2H, m), 5.15-5.10 (1H, dt, J = 1.5,10.5 Hz), 4.29-4.21 M), 1.87-1.78 (2H, m), 1.39-1.35 (1H, t, J ), 3.67 (4H, m), 3.28-3.25 (1H, dd, J = 1.8,6.6Hz) = 6.0 Hz), 1.04 (9H, s), 0.89 (9H, s), 0.88 (9H, s), 0.09 (3H, s), 0.06 , s).

실시예Example 11: 화학식 14의 화합물의 제조 11: Preparation of the compound of formula (14)

(5R,6R,7R)-5,7-비스(tert-부틸디메틸실릴옥시)-6-(3-(tert-부틸디페닐실릴옥시)프로폭시)논-8-엔-2-인-1-올(13) (75 g)을 디에틸 에테르(1,120 ml)에 희석하고, 반응물의 온도를 0 ℃로 냉각시켰다. 소듐 비스(2-메톡시에톡시)알루미늄하이드라이드(Red-Al) (82.3 ml, 60% in toluene)를 적가하고, 실온으로 승온하여 약 4 시간 내지 5 시간 동안 교반하였다. 반응의 진행을 박층 크로마토그래피 (헥산 : 에틸아세테이트 = 5 : 1)에 의해 관측하였다. 반응 완료 후, 에틸 아세테이트(10.3 ml)를 가하고, 실온에서 약 30 분 동안 교반하였다. 반응물의 온도를 약 -65 내지 -60 ℃로 냉각시키고, 요오드(53.5 g)를 테트라히드로퓨란(150 ml)에 녹여 -60 ℃ 이하를 유지하면서 적가하였다. 반응물을 약 -65 내지 -60 ℃에서 30 분 동안 교반한 후, 실온으로 서서히 승온하여 반응을 완료시켰다. 반응의 진행을 박층 크로마토그래피 (헥산 : 에틸아세테이트 = 5 : 1)에 의해 관측하였다. 반응 완료 후, 10% 염화암모늄 수용액(750 ml)을 가하여 10 분 동안 교반하였다. 유기층을 분리하여 10% 티오황산 나트륨 수용액(750 ml)을 가하여 10 분 동안 교반하였다. 유기층을 분리하여 무수황산나트륨 중에 건조하였다. 무수황산나트륨을 여과 후 여과액을 진공 중에 농축하여 혼합물을 수득하였고, 실리카겔을 사용한 칼럼 크로마토그래피 (헥산 : 에틸아세테이트 = 7 : 1)로 정제하여 순수한 (5R,6R,7R,Z)-5,7-비스(tert-부틸디메틸실릴옥시)-6-(3-(tert-부틸디페닐실릴옥시)프로폭시)-3-아이오도노나-2,8-디엔-1-올(14) (62 g, 70%)를 수득하였다.(5R, 6R, 7R) -5,7-bis (tert-butyldimethylsilyloxy) -6- (3- (tert- butyldiphenylsilyloxy) propoxy) -Ol (13) (75 g) was diluted in diethyl ether (1,120 ml) and the temperature of the reaction was cooled to 0 < 0 > C. (2-methoxyethoxy) aluminum hydride (Red-Al) (82.3 ml, 60% in toluene) was added dropwise, and the mixture was heated to room temperature and stirred for about 4 hours to 5 hours. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 5: 1). After completion of the reaction, ethyl acetate (10.3 ml) was added, and the mixture was stirred at room temperature for about 30 minutes. The temperature of the reaction product was cooled to about -65 to -60 DEG C, iodine (53.5 g) was dissolved in tetrahydrofuran (150 ml), and the dropwise addition was maintained at -60 DEG C or lower. The reaction was stirred at about -65 to -60 < 0 > C for 30 minutes and then slowly warmed to room temperature to complete the reaction. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 5: 1). After completion of the reaction, a 10% aqueous ammonium chloride solution (750 ml) was added and the mixture was stirred for 10 minutes. The organic layer was separated, 10% aqueous sodium thiosulfate solution (750 ml) was added, and the mixture was stirred for 10 minutes. The organic layer was separated and dried in anhydrous sodium sulfate. The filtrate was concentrated in vacuo to give a mixture which was purified by column chromatography using silica gel (hexane: ethyl acetate = 7: 1) to give pure (5R, 6R, 7R, Butyldimethylsilyloxy) -6- (3- (tert-butyldiphenylsilyloxy) propoxy) -3-iodonona-2,8-dien-1-ol 14 (62 g , 70%).

¹H NMR (300 MHz, CDCl₃) : δ 7.69-7.62 (4H, m), 7.45-7.34 (6H, m), 5.93-5.76 21H, m), 5.34-5.27 (1H, dt, J = 1.5, 17.3 Hz), 5.20-5.16 (1H, dt, J = 1.4, 10.5 Hz), 4.20-4.01 (4H, m), 3.89-3.69 (4H, m), 3.29-3.26 (1H, dd, J = 0.9, 7.5 Hz), 2.74-2.67 (1H, m), 2.61-2.56 (1H, m), 1.89-1.80 (2H, m), 1.41-1.37 (1H, t, J = 6.0 Hz), 1.05 (9H, s), 0.90 (9H, s), 0.84 (9H, s), 0.06 (3H, s), 0.05 (3H, s), 0.02 (3H, s).
^{1 H NMR (300 MHz, CDCl} 3): δ 7.69-7.62 (4H, m), 7.45-7.34 (6H, m), 5.93-5.76 21H, m), 5.34-5.27 (1H, dt, J = 1.5, M), 3.29-3.26 (1H, dd, J = 0.9, 1H), 5.20-5.16 (1H, dt, J = 1.4,10.5 Hz), 4.20-4.01 (4H, m), 3.89-3.69 M), 1.81-1.80 (2H, m), 1.41-1.37 (1H, t, J = 6.0 Hz), 1.05 (9H, s), 2.74-2.67 ), 0.90 (9H, s), 0.84 (9H, s), 0.06 (3H, s), 0.05 (3H, s), 0.02 (3H, s).

실시예Example 12: 화학식 15의 화합물의 제조 12: Preparation of the compound of formula (15)

(5R,6R,7R,Z)-5,7-비스(tert-부틸디메틸실릴옥시)-6-(3-(tert-부틸디페닐실릴옥시)프로폭시)-3-아이오도노나-2,8-디엔-1-올(14) (62 g)을 아세토니트릴(1,860 ml)에 희석하였다. 테트라키스(트리페닐포스핀)팔라듐(0) (4.3 g), 트리에틸아민(11.1 ml)을 가하고 약 1 시간 동안 환류교반하였다. 반응의 진행을 박층 크로마토그래피 (헥산 : 에틸아세테이트 = 5 : 1)에 의해 관측하였다. 반응 완료 후, 반응물을 실온으로 냉각하고, 진공 중에 농축하여 혼합물을 수득하였고, 실리카겔을 사용한 칼럼 크로마토그래피 (헥산 : 에틸아세테이트 = 7 : 1)로 정제하여 순수한 (Z)-2-((3R,4R,5R)-3,5-비스-(tert-부틸디메틸실릴옥시)-4-3-(tert-부틸디페닐실릴옥시)프로폭시)-2-메틸렌시클로헥실리덴)에탄올(15) (49 g, 93%)을 수득하였다.Butyldimethylsilyloxy) -6- (3- (tert-butyldiphenylsilyloxy) propoxy) -3-iodonona-2, Dien-1-ol (14) (62 g) was diluted in acetonitrile (1860 ml). Tetrakis (triphenylphosphine) palladium (0) (4.3 g) and triethylamine (11.1 ml) were added and the mixture was refluxed for about 1 hour. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 5: 1). After completion of the reaction, the reaction was cooled to room temperature and concentrated in vacuo to give a mixture which was purified by column chromatography using silica gel (hexane: ethyl acetate = 7: 1) to give pure (Z) -2- Propyloxy) -2-methylenecyclohexylidene) ethanol (15) ((4-fluorophenyl) -4,5- 49 g, 93%).

¹H NMR (300 MHz, CDCl₃) : δ 7.67-7.64 (4H, m), 7.44-7.33 (6H, m), 5.54-5.50 (1H, t, J = 6.7 Hz), 5.23 (1H, s), 4.84-4.82 (1H, m), 4.25-4.09 (4H, m), 3.80-3.62 (4H, m), 3.19-3.16 (1H, dd, J = 2.1, 6.9 Hz), 2.43-2.36 (1H, m), 2.26-2.17 (1H, m), 1.88-1.79 (2H, m), 1.04 (9H, s), 0.89 (9H, s), 0.86 (9H, s), 0.06 (3H, s), 0.04-0.03 (9H, m).
^{1 H NMR (300 MHz, CDCl} 3): δ 7.67-7.64 (4H, m), 7.44-7.33 (6H, m), 5.54-5.50 (1H, t, J = 6.7 Hz), 5.23 (1H, s) , 4.84-4.82 (1H, m), 4.25-4.09 (4H, m), 3.80-3.62 (4H, m), 3.19-3.16 (IH, dd, J = 2.1, 6.9 Hz), 2.43-2.36 m), 2.26-2.17 (1H, m), 1.88-1.79 (2H, m), 1.04 (9H, s), 0.89 (9H, s), 0.86 -0.03 (9H, m).

실시예Example 13: 화학식 16의 화합물의 제조 13: Preparation of the compound of formula (16)

N-클로로숙신이미드(15.5 g)을 디클로로메탄(375 ml)에 희석하고 반응액의 온도를 0 ℃로 냉각하였다. 디메틸설파이드(9.14 ml)을 적가하고 약 0 ℃에서 30 분 동안 교반하였다. 반응액의 온도를 -20 ℃로 냉각하고 (Z)-2-((3R,4R,5R)-3,5-비스-(tert-부틸디메틸실릴옥시)-4-3-(tert-부틸디메틸실릴옥시)프로폭시)-2-메틸렌시클로헥실리덴)에탄올(15) (40 g)을 디클로로메탄(229 ml)에 희석하여 적가하였다. 적가 완료 후, 약 10 내지 20 분 동안 등 온도에서 교반하고, 천천히 실온으로 승온하였다. 반응의 진행을 박층 크로마토그래피 (헥산 : 에틸아세테이트 = 10 : 1)에 의해 관측하였다. 반응 완료 후, 반응물에 물(375 ml)을 가하여 10 분 동안 교반하고 유기층을 분리하여 무수황산나트륨 중에 건조하였다. 진공 중에 농축하여 혼합물을 수득하였고, 실리카겔을 사용한 칼럼 크로마토그래피 (헥산 : 에틸아세테이트 : 트리에틸아민 = 10 : 1)로 정제하여 순수한 ((1R,2R,3R,Z)-2-(3-(tert-부틸디페닐실릴옥시)프로폭시)-5-(2-클로로에틸리덴)-4-메틸렌시클로헥산-1,3-디일)비스(옥시)비스(tert-부틸디메틸실란) (16) (40 g, 98%)을 수득하였다.N-Chlorosuccinimide (15.5 g) was diluted with dichloromethane (375 ml) and the temperature of the reaction solution was cooled to 0 占 폚. Dimethyl sulfide (9.14 ml) was added dropwise and stirred at about 0 ° C for 30 minutes. The reaction solution was cooled to -20 캜, and (Z) -2 - ((3R, 4R, 5R) -3,5-bis- Propyloxy) propoxy) -2-methylenecyclohexylidene) ethanol (15) (40 g) was diluted with dichloromethane (229 ml) and added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for about 10 to 20 minutes, and the temperature was slowly raised to room temperature. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 10: 1). After completion of the reaction, water (375 ml) was added to the reaction mixture and the mixture was stirred for 10 minutes. The organic layer was separated and dried in anhydrous sodium sulfate. (1R, 2R, 3R, Z) -2- (3- ((1R) -2- butyldiphenylsilyloxy) propoxy) -5- (2-chloroethylidene) -4-methylenecyclohexane-1,3-diyl) bis (oxy) bis (tert- butyldimethylsilane) (40 g, 98%).

¹H NMR (300 MHz, CDCl₃) : δ 7.67-7.63 (4H, m), 7.44-7.34 (6H, m), 5.54-5.49 (1H, t, J = 7.8 Hz), 5.29 (1H, s), 5.04-5.03 (1H, m), 4.26-4.23 (1H, d, J = 7.2 Hz), 4.19-4.09 (3H, m), 3.79-3.62 (4H, m), 3.17-3.15 (1H, m), 2.42-2.36 (1H, dd, J = 6.9, 13.5 Hz), 2.23-2.17 (1H, m), 1.88-1.79 (2H, m), 1.04 (9H, s), 0.89 (9H, s), 0.85 (9H, s), 0.06 (3H, s), 0.04 (3H, s), 0.03 (3H, s), 0.02 (3H, s).
^{1 H NMR (300 MHz, CDCl} 3): δ 7.67-7.63 (4H, m), 7.44-7.34 (6H, m), 5.54-5.49 (1H, t, J = 7.8 Hz), 5.29 (1H, s) (1H, m), 5.04-5.03 (1H, m), 4.26-4.23 (IH5 d, J = 7.2 Hz), 4.19-4.09 (3H, m), 3.79-3.62 , 2.42-2.36 (1H, dd, J = 6.9,13.5 Hz), 2.23-2.17 (1H, m), 1.88-1.79 (2H, m), 1.04 (9H, s), 0.89 (9H, s), 0.06 (3H, s), 0.04 (3H, s), 0.03 (3H, s), 0.02 (3H, s).

실시예Example 14: 화학식 17의 화합물의 제조 14: Preparation of compound of formula (17)

디페닐포스핀(14.52 ml)을 테트라히드로퓨란(500 ml)에 희석하고 반응물의 온도를 0℃ 로 냉각하였다. n-부틸리튬(33.4 ml, 2.0 M in 헥산)을 적가하고 약 30 분 동안 0℃에서 교반하였다. 다른 반응기에 ((1R,2R,3R,Z)-2-(3-(tert-부틸디페닐실릴옥시)프로폭시)-5-(2-클로로에틸리덴)-4-메틸렌시클로헥산-1,3-디일)비스(옥시)비스(tert-부틸디메틸실란) (16) (40.6 g)을 테트라히드로퓨란(500 ml)에 희석하였다. 반응물의 온도를 -65 ℃ 이하로 냉각하고 제조된 리튬 디페닐포스핀 용액을 적가하였다. 반응물을 -65 ℃ 이하로 유지하면서 약 1 시간 동안 교반하였다. 반응의 진행을 박층 크로마토그래피 (헥산 : 에틸아세테이트 = 10 : 1)에 의해 관측하였다. 반응 완료 후, 물(5.5 ml)을 적가하여 10 분 동안 교반하여 반응을 종료시켰다. 실온으로 승온하여 진공 중에 농축하여 혼합물을 수득하였고, 농축 잔사물을 클로로포름(715 ml)에 녹이고 5% 과산화수소(340 ml)를 가하여 약 1 시간 동안 교반하였다. 반응의 진행을 박층 크로마토그래피 (헥산 : 에틸아세테이트 = 1 : 1)에 의해 관측하였다. 반응 완료 후, 유기층을 분리하여 10% 티오황산 나트륨 수용액 (400 ml)를 가하여 약 1 시간 동안 교반하였다. 유기층을 분리하여 무수황산나트륨 중에 건조하였다. 진공 중에 농축하여 혼합물을 수득하였고, 실리카겔을 사용한 칼럼 크로마토그래피 (헥산 : 에틸아세테이트 : 트리에틸아민 = 1 : 1 : 0.1 )로 정제하여 순수한 (Z)-[2-{(3R,4R,5R)-3,5-비스(tert-부틸디메틸실라닐옥시)-2-메틸렌-4-(3-(tert-부틸디페닐실라닐옥시)프로폭시)시클로헥실리덴}디페닐포스핀 옥사이드(17) (41.3 g, 83%)를 수득하였다.Diphenylphosphine (14.52 ml) was diluted in tetrahydrofuran (500 ml) and the temperature of the reaction was cooled to 0 < 0 > C. n-Butyl lithium (33.4 ml, 2.0 M in hexane) was added dropwise and stirred at 0 캜 for about 30 minutes. To another reactor was added ((1R, 2R, 3R, Z) -2- (3- (tert- butyldiphenylsilyloxy) propoxy) -5- (2- chloroethylidene) -4-methylenecyclohexane- , 3-diyl) bis (oxy) bis (tert-butyldimethylsilane) (16) (40.6 g) was diluted in tetrahydrofuran (500 ml). The temperature of the reaction was cooled to -65 캜 or lower, and the prepared lithium diphenylphosphine solution was added dropwise. The reaction was stirred for about 1 hour while keeping the temperature below -65 < 0 > C. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 10: 1). After completion of the reaction, water (5.5 ml) was added dropwise, and the reaction was terminated by stirring for 10 minutes. The mixture was heated to room temperature and concentrated in vacuo to give a mixture. The concentrated residue was dissolved in chloroform (715 ml), and 5% hydrogen peroxide (340 ml) was added thereto and stirred for about 1 hour. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 1: 1). After completion of the reaction, the organic layer was separated, 10% aqueous sodium thiosulfate solution (400 ml) was added, and the mixture was stirred for about 1 hour. The organic layer was separated and dried in anhydrous sodium sulfate. The crude (Z) - [2 - {(3R, 4R, 5R) -5-methyl- (Tert-butyldimethylsilanyloxy) -2-methylene-4- (3- (tert-butyldiphenylsilanyloxy) propoxy) cyclohexylidene} diphenylphosphine oxide (17 ) (41.3 g, 83%).

¹H NMR (300 MHz, CDCl₃) : δ 7.78-7.71 (4H, m), 7.70-7.66 (4H, m), 7.59-7.37 (12H, m), 5.39-5.32 (1H, dd, J = 7.2, 14.4 Hz), 5.26 (1H, s), 4.84-4.83 (1H, t, J = 1.8 Hz), 4.28-4.25 (1H, d, J = 7.5 Hz), 4.15-4.11 (1H, m), 3.79-3.64 (4H, m), 3.43-3.31 (1H, m), 3.28-3.15 (1H, m), 3.13-3.10 (1H, dd, J = 2.0, 7.7 Hz), 2.38-2.33 (1H, m), 2.23-215 (1H, m), 1.91-1.82 (2H, m), 1.07 (9H, s), 0.93 (9H, s), 0.83 (3H, s), 0.10 (3H, s), 0.05-0.03 (9H, m).
^{1 H NMR (300 MHz, CDCl} 3): δ 7.78-7.71 (4H, m), 7.70-7.66 (4H, m), 7.59-7.37 (12H, m), 5.39-5.32 (1H, dd, J = 7.2 (1H, d, J = 7.5 Hz), 4.26 (1H, s), 4.84-4.83 (1H, t, J = 1.8 Hz), 4.28-4.25 (1H, m), 3.28-3.15 (1H, m), 3.13-3.10 (1H, dd, J = 2.0,7.7 Hz), 2.38-2.33 , 2.23-215 (1H, m), 1.91-1.82 (2H, m), 1.07 (9H, s), 0.93 (9H, s), 0.83 (9 H, m).

실시예Example 15: 화학식 19의 화합물의 제조 15: Preparation of compound of formula 19

(Z)-[2-{(3R,4R,5R)-3,5-비스(tert-부틸디메틸실라닐옥시)-2-메틸렌-4-(3-(tert-부틸디페닐실라닐옥시)프로폭시)시클로헥실리덴}디페닐포스핀 옥사이드(17) (5.1 g)을 테트라히드로퓨란(50 ml)에 희석하고, 반응물의 온도를 -65 ℃ 이하로 냉각하였다. n-부틸리튬(2.3 ml, 2.5 M in 헥산)을 -65 ℃ 이하에서 적가하고, 등 온도에서 약 1 시간 동안 교반하였다. (1R,3aR,7aR)-7a-메틸-1-((R)-6-메틸-6-(트리메틸실릴옥시)헵탄-2-일)헥사히드로-1H-인덴-4(2H)-온(18) (1.0 g)을 테트라히드로퓨란(10 ml)에 희석하여 적가하고, 실온으로 서서히 승온하였다. 반응의 진행을 박층 크로마토그래피 (헥산 : 에틸아세테이트 = 10 : 1)에 의해 관측하였다. 반응 완료 후, 5% 염화암모늄 수용액(50 ml), 에틸아세테이트(50 ml)를 가하여 10 분 동안 교반하였다. 유기층을 분리하여 무수황산나트륨 중에 건조하고 진공 중에 농축하여 혼합물을 수득하였다. 실리카겔을 사용한 칼럼 크로마토그래피 (헥산 : 에틸아세테이트 = 30 : 1 내지 20 : 1)로 정제하여 순수한 ((1R,2R,3R,Z)-2-(3-(tert-부틸디페닐실릴옥시)프로폭시)-5-((E)-2-((1R,3aS,7aR)-7a-메틸-1-((R)-6-메틸-6-(트리메틸실릴옥시)헵탄-2-일)디히드로-1H-인덴-4(2H,5H,6H,7H,7aH)-일리덴)에틸리덴)-4-메틸렌시클로헥산-1,3-디일)비스(옥시)비스(tert-부틸디메틸실란) (19) (2.3 g, 86%)를 수득하였다.Butyldimethylsilanyloxy) -2-methylene-4- (3- (tert-butyldiphenylsilanyloxy) -2,5- Propoxy) cyclohexylidene} diphenylphosphine oxide (17) (5.1 g) was diluted in tetrahydrofuran (50 ml) and the temperature of the reaction was cooled to -65 캜 or lower. n-Butyl lithium (2.3 ml, 2.5 M in hexane) was added dropwise at -65 DEG C or lower, and the mixture was stirred at the same temperature for about 1 hour. (1R, 3aR, 7aR) -7a-methyl-1 - ((R) -6-methyl-6- (trimethylsilyloxy) heptan-2-yl) hexahydro- 18) (1.0 g) was added dropwise to tetrahydrofuran (10 ml), and the temperature was gradually raised to room temperature. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 10: 1). After completion of the reaction, a 5% aqueous solution of ammonium chloride (50 ml) and ethyl acetate (50 ml) were added, and the mixture was stirred for 10 minutes. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to give a mixture. ((1R, 2R, 3R, Z) -2- (3- (tert-butyldiphenylsilyloxy) propyl) piperazine was obtained by purifying by column chromatography using silica gel (hexane: ethyl acetate = 30: 1 to 20: (R) -6-methyl-6- (trimethylsilyloxy) heptan-2-yl) dihydroxy) -5 - ((E) -2 - ((1R, 3aS, 7aR) (Methyl) cyclohexane-1,3-diyl) bis (oxy) bis (tert-butyldimethylsilane) (19) (2.3 g, 86%).

¹H NMR (300 MHz, CDCl₃) : δ 7.666-7.637 (4H, m), 7.437-7.329 (6H, m), 6.223 (1H, d, J = 11.4 Hz), 5.994 (1H, d, J = 11.1 Hz), 5.240-5.236 (1H, m), 4.958 (1H, d, J = 2.1 Hz), 4.183-4.085 (2H, m), 3.800-3.644 (4H, m), 3.230-3.202 (1H, m), 2.831-2.795 (1H, m), 2.480-2.410 (1H, m), 2.235-2.133 (1H, m), 2.043-1.214 (14H, m), 1.185 (6H, s), 1.039 (12H, s), 0.971-0.848 (27H, m ), 0.600-0.523 (9H, m), 0.062-0.036 (12H, m).
^{1 H NMR (300 MHz, CDCl} 3): δ 7.666-7.637 (4H, m), 7.437-7.329 (6H, m), 6.223 (1H, d, J = 11.4 Hz), 5.994 (1H, d, J = 11.1 Hz), 5.240-5.236 (1H, m), 4.958 (1H, d, J = 2.1 Hz), 4.183-4.085 (2H, m), 3.800-3.644 (4H, m), 3.230-3.202 (1H, m ), 2.831-2.795 (1H, m), 2.480-2.410 (1H, m), 2.235-2.133 (1H, m), 2.043-1.214 (14H, m), 1.185 ), 0.971-0.848 (27H, m), 0.600-0.523 (9H, m), 0.062-0.036 (12H, m).

실시예Example 16: 16: 엘더칼시톨의Elder Calcitol 제조 Produce

((1R,2R,3R,Z)-2-(3-(tert-부틸디페닐실릴옥시)프로폭시)-5-((E)-2-((1R,3aS,7aR)-7a-메틸-1-((R)-6-메틸-6-(트리메틸실릴옥시)헵탄-2-일)디히드로-1H-인덴-4(2H,5H,6H,7H,7aH)-일리덴)에틸리덴)-4-메틸레시클로헥산-1,3-디일)비스(옥시)비스(tert-부틸디메틸실란) (19) (2.3 g)을 디클로로메탄 : 메탄올의 혼합용액(1 : 1, 34.5 ml)에 희석하고, p-톨루엔설포닉산(0.4 g)을 가하여 약 5 내지 6 시간 동안 교반하였다. 반응의 진행을 박층 크로마토그래피 (디클로로메탄 : 메탄올 = 10 : 1)에 의해 관측하였다. 반응 완료 후, 포화중조수(30 ml)을 가하여 반응을 종료시키고, 메틸렌클로라이드(40 ml)을 가하여 10 분 동안 교반하였다. 유기층을 분리하여 무수황산나트륨 중에 건조하고 진공 중에 농축하여 혼합물을 수득하였다. 실리카겔을 사용한 칼럼 크로마토그래피 (디클로로메탄 : 메탄올 = 10 : 1)로 정제하여 순도 98% 이상인 엘더칼시톨(1) (1.0 g, 88%)을 수득하였다.((1R, 2R, 3R, Z) -2- (3- (tert-butyldiphenylsilyloxy) propoxy) -5- (2H, 5H, 6H, 7H, 7aH) -ylidene) ethylidene) -1H-indene- Butyl ester (2.3 g) was dissolved in a mixed solution (1: 1, 34.5 ml) of dichloromethane: methanol, , And p-toluenesulfonic acid (0.4 g) was added thereto, followed by stirring for about 5 to 6 hours. The progress of the reaction was observed by thin layer chromatography (dichloromethane: methanol = 10: 1). After completion of the reaction, saturated aqueous sodium bicarbonate (30 ml) was added to terminate the reaction, and methylene chloride (40 ml) was added and the mixture was stirred for 10 minutes. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to give a mixture. The residue was purified by column chromatography using silica gel (dichloromethane: methanol = 10: 1) to obtain eldercalcitol (1) having a purity of 98% or more (1.0 g, 88%).

¹H NMR (300 MHz, CDCl₃) : δ 6.353 (1H, d, J = 11.07 Hz), 6.043 (1H, d, J = 11.07 Hz), 5.496 (1H, t, 1.98 Hz), 5.076 (1H, t, J =1.98 Hz), 4.313 (1H, d, J = 8.16 Hz), 4.254 (1H, s), 3.949-3.880 (1H, m), 3.8314 (2H, s), 3.752-3.682 (1H, m), 3.273-3.234 (1H, dd, J = 9.06 Hz, J = 2.8 Hz), 2.828-2.2782 (1H, m), 2.538 (1H, dd, J = 14.49 Hz, J = 3.96 Hz), 2.435-2.387 (1H, m), 2.007-1.259 (16H, m), 1.212 (6H, s), 1.130-1.002 (1H, m), 0.935 (3H, d, J = 6.27 Hz), 0.547 (3H, s). ¹ H NMR (300 MHz, CDCl ₃ ):? 6.353 (IH, d, J = 11.07 Hz), 6.043 (IH, d, J = 11.07 Hz), 5.496 t, J = 1.98 Hz), 4.313 (1H, d, J = 8.16 Hz), 4.254 (1H, s), 3.949-3.880 (1H, m), 3.8314 (2H, s), 3.752-3.682 (1H, m ), 3.273-3.234 (IH, dd, J = 9.06 Hz, J = 2.8 Hz), 2.828-2.2782 (IH, m), 2.538 (IH, dd, J = 14.49 Hz, J = 3.96 Hz) (1H, m), 2.007-1.259 (16H, m), 1.212 (6H, s), 1.130-1.002 (1H, m), 0.935 (3H, d, J = 6.27 Hz), 0.547 (3H, s).

Claims

(i) reacting a compound of formula (2) with p-anisaldehyde in the presence of an acid catalyst to obtain a compound of formula (3);
(ii) reducing the acetal group of the compound of formula (3) to obtain a compound of formula (4);
(iii) asymmetrically epoxidizing an allyl alcohol group of a compound of formula (4) to obtain a compound of formula (5);
(iv) reacting a compound of formula (5) with a compound of formula (6) in the presence of a base to obtain a compound of formula (7);
(v) reacting a compound of formula (7) with a compound of formula (8) to obtain a compound of formula (9);
(vi) protecting the secondary hydroxyl group of the compound of formula (9) to obtain a compound of formula (10);
(vii) selectively deprotecting the PMB group of the compound of formula (10) to obtain a compound of formula (11);
(viii) protecting the secondary hydroxyl group of the compound of formula (11) to obtain a compound of the formula (12);
(ix) selectively deprotecting the THP group of the compound of formula (12) to obtain a compound of formula (13);
(x) subjecting an acetylene group of the following formula (13) to a reduction reaction and reacting with iodine to obtain a compound of the following formula (14);
(xi) cyclizing the compound of formula (14) to obtain a compound of formula (15);
(xii) halogenating a compound of formula (15) to obtain a compound of formula (16);
(xiii) reacting a compound of formula (16) with diphenylphosphine and subjecting it to an oxidation reaction to obtain a compound of formula (17);
(xiv) reacting a compound of formula (17) with a compound of formula (18) to obtain a compound of formula (19); And
(xv) A process for producing an eldercalcitol represented by the following formula (1) comprising deprotecting a compound represented by the following formula (19)
(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

[Chemical Formula 9]

[Chemical formula 10]

(11)

[Chemical Formula 12]

[Chemical Formula 13]

[Chemical Formula 14]

[Chemical Formula 15]

[Chemical Formula 16]

[Chemical Formula 17]

[Chemical Formula 18]

[Chemical Formula 19]

[Chemical Formula 1]

In this formula,
PMP is p-methoxyphenyl,
PMB is p-methoxybenzyl,
TBDPS is tert-butyldiphenylsilyl,
TfO is trifluoromethane sulfonate,
THP is tetrahydro-2H-pyran-2-yl,
TBS is t-butyldimethylsilyl,
TMS is trimethylsilyl.

The process according to claim 1, wherein the acid catalyst in step (i) is p-toluenesulfonic acid.

The process according to claim 1, wherein the reduction reaction in step (ii) is carried out in the presence of diisobutyl aluminum hydride.

The process according to claim 1, wherein the asymmetric epoxidation reaction in step (iii) is carried out in the presence of titanium isopropoxide, (+) - diisopropyl tartrate and t-butyl hydroperoxide.

The process according to claim 1, wherein the temperature of the asymmetric epoxidation reaction in step (iii) is 0 to 30 占 폚.

2. The process according to claim 1 wherein in step (iv) the base is sodium hydride.

The process according to claim 1, wherein the reaction in step (v) is carried out in the presence of n-butyllithium and boron triflourodioethyl ether.

The process according to claim 1, wherein the protecting reaction in step (vi) is carried out by reacting the compound of formula (9) with t-butyldimethylsilyl chloride in the presence of a base.

The process according to claim 1, wherein the deprotection reaction in step (vii) is carried out using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

2. The process according to claim 1, wherein the protecting reaction in step (viii) is carried out by reacting the compound of formula (11) with t-butyldimethylsilyl chloride in the presence of a base.

The process according to claim 1, wherein the deprotection reaction in step (ix) is carried out in the presence of dimethylaluminum chloride.

The process according to claim 1, wherein the reduction reaction in step (x) is carried out in the presence of sodium bis (2-methoxyethoxy) aluminum hydride.

The process according to claim 1, wherein the cyclization reaction in step (xi) is carried out in the presence of a base and a palladium catalyst.

2. The process according to claim 1, wherein the halogenation reaction is carried out using N-chlorosuccinimide and dimethyl sulfide in step (xii).

The process according to claim 1, wherein the reaction with diphenylphosphine in step (xiii) is carried out in the presence of a base, and the oxidation reaction is carried out using hydrogen peroxide.

2. The process according to claim 1, wherein in step (xiv) the Wittig-oner reaction is carried out in the presence of a base.

3. The process according to claim 1, wherein the deprotection reaction in step (xv) is carried out in the presence of p-toluenesulfonic acid.

delete

(vi) protecting the secondary hydroxyl group of the compound of formula (9) to obtain a compound of formula (10);
(vii) selectively deprotecting the PMB group of the compound of formula (10) to obtain a compound of formula (11);
(viii) protecting the secondary hydroxyl group of the compound of formula (11) to obtain a compound of the formula (12);
(ix) selectively deprotecting the THP group of the compound of formula (12) to obtain a compound of formula (13);
(x) subjecting an acetylene group of the following formula (13) to a reduction reaction and reacting with iodine to obtain a compound of the following formula (14);
(xi) cyclizing the compound of formula (14) to obtain a compound of formula (15);
(xii) halogenating a compound of formula (15) to obtain a compound of formula (16); And
(xiii) a process for producing a compound represented by the following general formula (17), which comprises reacting a compound represented by the following general formula (16) with diphenylphosphine and subjecting the compound represented by the general formula
[Chemical Formula 9]