KR100562771B1

KR100562771B1 - Preparation method of the diacid compound which can be used for the stereoselective synthesis of 13-cis-retinoic acid and all-trans-retinoic acid

Info

Publication number: KR100562771B1
Application number: KR1020030098676A
Authority: KR
Inventors: 구상호; 전혜선
Original assignee: 구상호
Priority date: 2003-12-29
Filing date: 2003-12-29
Publication date: 2006-03-20
Also published as: KR20050067675A

Abstract

본 발명은 화학식 1의 13-씨스-레티노익 애씨드와 화학식 2의 올-트렌스-레티노익 애씨드의 입체 선택적인 합성 방법을 제공한다. 쥴리아의 설폰화학을 이용하여 레티놀 및 카로틴 화합물의 합성에 효율적으로 사용되는 C15 설폰(화합물 [F])을 이용하여 C5 할로알릴릭 디에스테르(화합물 [G])와의 결합으로 C20 설폰 디에스테르(화합물 [H])를 얻은 다음, 이를 염기로 처리하여 에스테르의 가수분해와 동시에 디하이드로설폰화(dehydrosulfonation) 반응을 진행하여 화학식 3의 C20 디애씨드 화합물을 얻게된다. 화학식 3의 디애씨드 화합물은 2,6-루티딘 또는 피리딘과의 반응으로 각각 입체선택적으로 화학식 1의 13-씨스-레티노익 애씨드와 화학식 2의 올-트랜스-레티노익 애씨드를 제공하게 된다.The present invention provides methods for stereoselective synthesis of 13-cis-retinoic acid of formula (1) and all-trans-retinoic acid of formula (2). C20 sulfone diester (compound [G]) in combination with C5 haloallylic diester (compound [G]) using C15 sulfone (compound [F]), which is efficiently used for the synthesis of retinol and carotene compounds using Julia's sulfone chemistry [H]) is then treated with a base to undergo hydrolysis of the ester and dehydrosulfonation reaction to obtain C20 diacid compound of Chemical Formula 3. The diacid compound of formula 3 is reacted with 2,6-lutidine or pyridine to stereoselectively provide 13-cis-retinoic acid of formula 1 and all-trans-retinoic acid of formula 2, respectively.

13-씨스-레티노익 애씨드, 올-트랜스-레티노익 애씨드, 쥴리아 설폰화학13-Sea-Retinoic Acid, All-Trans-Retinoic Acid, Julia Sulfon Chemistry

Description

(Preparation method of the diacid compound which can be used for the stereoselective synthesis of 13-cis-retinoic acid, 13-cis-retinoic acid and all-trans-retinoic acid) and all-trans-retinoic acid}

본 발명은 레티놀 계통 화합물의 제조방법에 관한 것으로, 보다 상세하기로는, 13-씨스-레티노익 애씨드 및 올-트랜스-레티노익 애씨드(retinoic acid)의 입체 선택적인 합성 방법에 관한 것이다.The present invention relates to a method for preparing a retinol family compound, and more particularly, to a stereoselective method for synthesizing 13-cis-retinoic acid and all-trans-retinoic acid.

비타민 A로 널리 알려져 있는 레티놀은 고등동물에 있어서 조직의 생장 및 분화, 시각작용, 노화 방지 등의 효능을 보이는 필수 영양소이며, 최근에는 미백효과 및 주름살 방지의 목적으로 기능성 화장품의 원료로도 사용되고 있다. 레티놀의 산화물인 올-트랜스-레티노익 애씨드는 트레티노인(tretinoin)이라는 이름으로도 알려져 있으며, 여드름, 기미, 주근깨를 비롯하여 광범위 피부질환의 치료에 널리 쓰이고 있다. 특히 13번 탄소 위치가 씨스 형태의 이중결합으로 되어 있는 레티노익 애씨드를 이소트레티노인(isotretinoin)이라 부르는데, 트레티노인 보다 효능이 훨씬 뛰어난 것으로 알려져 있다. 이와 같이 기능적으로 그리고 경제적으로 중요한 레티노익 애씨드의 효율적인 합성법 개발에 대하여 많은 연구가 진행되어 왔으며, 특히, 고가인 13-씨스-레티노익 애씨드를 입체 선택적으로 합성하려는 시도가 계속 진행되고 있다.Retinol, widely known as vitamin A, is an essential nutrient that shows the effects of tissue growth, differentiation, visual action, and anti-aging in higher animals. Recently, it has been used as a raw material of functional cosmetics for the purpose of whitening and wrinkle prevention. . Retinol oxide, an all-trans-retinoic acid, is also known as tretinoin and is widely used for the treatment of a wide range of skin diseases, including acne, blemishes, and freckles. In particular, the retinoic acid whose carbon number 13 is a double bond of the Sea form is called isotretinoin, and is known to be much more effective than tretinoin. Much research has been conducted on the development of an efficient synthesis method of such functionally and economically important retinoic acid, and in particular, attempts to stereo-selectively synthesize an expensive 13-CS-Retinoic acid are ongoing.

화학식 1의 13-씨스-레티노익 애씨드를 입체 선택적으로 합성하는 방법으로는 하기 반응식 1에서 나타낸 바와 같이, 호프만-라로쉬(Hoffmann-La Roche)에서 개발한 것으로, 화합물 [A]의 C15 비티히 염(Wittig salt)과 화합물 [B]의 하이드록시부탄올라이드(hydroxybutanolide)와의 비티히 (Wittig) 반응을 이용한 방법이 있다(미국 특허 4,556,518). A method for stereoselectively synthesizing the 13-cis-retinoic acid acid of Formula 1 was developed by Hoffmann-La Roche, as shown in Scheme 1 below, and the C15 biti salt of Compound [A]. (Wittig) reaction of (Wittig salt) with hydroxybutanolide of compound [B] (US Pat. No. 4,556,518).

상기 반응식 1의 비티히 반응을 이용한 방법은, 화합물 [A]로 표기되어지는 C15 비티히 염의 제조가 까다롭다는 단점과 비티히 반응 후에 생성되는 부산물(byproduct)인 포스핀옥사이드(phosphine oxide)의 제거가 용이하지 못하다는 단점 외에도, 비티히 반응의 결과 11번 탄소에 씨스 구조를 갖는 11-씨스-13-씨스-레티노익 애씨드가 주된 생성물로 얻어지게 된다. 따라서, 상기 비티히 반응을 통하여 13-씨스-레티노익 애씨드를 얻기 위해서, 금속 촉매를 이용하여 이중결합의 아이소머화(isomerization) 반응을 진행하여야 하며, 이 때 13번 위치의 이중결합 은 건드리지 않은 채 11번 위치의 씨스 이중결합만을 트랜스로 바꾸어야 하는 어려운 점이 있다.The method using the Wittich reaction of Scheme 1 is difficult to prepare a C15 Wittich salt, which is represented by the compound [A], and of the phosphine oxide which is a byproduct produced after the Wittich reaction. In addition to the disadvantages of not easy removal, the Wittich reaction results in 11-cis-13-cis-retinoic acid having a cis structure on carbon 11 as the main product. Therefore, in order to obtain 13-cis-retinoic acid through the Wittich reaction, an isomerization reaction of a double bond must be performed using a metal catalyst, and the double bond at position 13 is not touched. There is a difficulty in converting only the double sheath of position 11 to trans.

13-씨스-레티노익-애씨드 및 올-트랜스-레티노익 애씨드를 입체 선택적으로 합성하는 비교적 효율적인 방법으로, 화합물 [C]로 표기되는 C15 알데히드와 화합물 [D]로 표기되는 이소프로필리덴 말로내이트(isopropylidene malonate)와의 스토베(Stobbe) 형태의 결합 반응으로 화합물 [E]로 표기되는 C20 디애씨드 하프-에스테르(diacid half-ester)를 형성하고, 이를 가수분해하여 화학식 3으로 표기되는 C20 디애씨드(diacid) 화합물을 얻은 다음, 2,6-루티딘(2,6-lutidine)과 반응하여 화학식 1의 13-씨스-레티노익 애씨드를, 피리딘(pyridine)과 반응하여 화학식 2의 올-트랜스-레티노익 애씨드를 각각 입체 선택적으로 합성하는 방법이 알려져 있다 (Tetrahedron Letters 1999, 40, 9235-9237). A relatively efficient method of stereoselectively synthesizing 13-cis-retinoic-acid and all-trans-retinoic acid, C15 aldehyde represented by compound [C] and isopropylidene malonite represented by compound [D] reaction of the Stobe form with (isopropylidene malonate) to form a C20 diacid half-ester represented by the compound [E], and hydrolyzed to form a C20 diacid represented by the formula (3). (diacid) compound, and then reacted with 2,6-lutidine to react the 13-cis-retinoic acid of formula 1 with pyridine to all-trans- Methods for stereoselectively synthesizing retinoic acids, respectively, are known ( Tetrahedron Letters 1999 , 40 , 9235-9237).

상기 반응식 2의 방법은 화학식 3의 디애씨드(diacid) 화합물로부터 처리하는 염기의 종류에 따라 각각 13-씨스 및 올-트랜스 구조의 레티노익 애씨드를 입체선택적으로 합성할 수 있는 매우 효율적인 방법이다. 하지만, 화학식 3의 디애씨드 화합물을 합성하기 위하여 사용하는 화합물 [C]의 합성이 베타-이오논(β-ionone)으로부터 4 단계의 비교적 긴 반응 단계를 필요로하고, 반응의 수율도 그다지 좋지 않다. 또한 화합물 [C]와 화합물 [D]의 스토베 커플링의 수율도 그리 좋지 않은 것으로 보고 되어있다. 따라서, 13-씨스-레티노익 애씨드 및 올-트랜스-레티노익 애씨드의 입체선택적인 합성을 위하여 상기 언급한 단점들을 극복하는 좀더 효율적이며, 경제적인 화학식 3의 C20 디애씨드 화합물의 합성법 개발이 필요하게 되었다.The method of Scheme 2 is a highly efficient method capable of stereoselectively synthesizing a retinoic acid of 13-seas and all-trans structure, respectively, depending on the type of base to be treated from the diacid compound of formula (3). However, the synthesis of compound [C] used to synthesize the diacid compound of formula 3 requires 4 relatively long reaction steps from beta-ionone, and the yield of the reaction is not so good. . It is also reported that the yields of the Stobbe coupling of compound [C] and compound [D] are not so good. Thus, there is a need for the development of more efficient and economical synthesis of C20 diacid compounds of Formula 3 that overcomes the above-mentioned disadvantages for the stereoselective synthesis of 13-cis-retinoic acid and all-trans-retinoic acid. It became.

본 발명이 이루고자 하는 기술적 과제는, 화학식 1과 화학식 2의 13-씨스-레티노익 애씨드 및 올-트랜스-레티노익 애씨드의 입체선택적 합성에 효율적으로 사용되는 화학식 3의 C20 디애씨드(diacid)를 합성하는데 있어서, 상술한 문제점들을 극복하는 효율적이며, 경제적인 합성법을 제공하는 것이다.The technical problem to be achieved by the present invention is the synthesis of C20 diacids of the formula (3) which is efficiently used for the stereoselective synthesis of 13-cis-retinoic acid and all-trans-retinoic acid of the formula (1) and (2) In providing an efficient and economical synthesis method that overcomes the above-mentioned problems.

본 발명의 기술적 과제는, (1) C15 설폰 화합물 [F]에 염기를 처리하여 디프로톤화(deprotonation) 시킨 다음, 이를 할로알릴릭 디에스테르(haloallylic diester) 화합물 [G]와 반응시켜 C20 설폰 디에스테르(sulfone diester) 화합물 [H]를 얻는 단계; 및 (2) 상기 C20 설폰 디에스테르 화합물 [H]에 염기를 처리하여 에스테르기의 가수분해와 동시에 디하이드로설폰화(dehydrosulfonation) 반응을 진행하는 것을 특징으로 하는 화학식 3의 C20 디애씨드(diacid) 화합물의 제조방법에 의해 이루어진다 (반응식 3).Technical problem of the present invention is (1) C15 sulfone compound [F] is treated with a base to deprotonation (deprotonation), and then reacted with a haloallylic diester compound [G] to C20 sulfone di Obtaining a sulfone diester compound [H]; And (2) C20 sulfone diester compound [H] by treating a base with hydrolysis of the ester group and simultaneously carrying out a dehydrosulfonation reaction (dehydrosulfonation). It is made by the method of preparation (Scheme 3).

화학식 3의 C20 디애씨드 화합물은 상술한 바와 같이 화학식 1의 13-씨스-레티노익 애씨드와 화학식 2의 올-트랜스-레티노익 애씨드의 입체선택적 합성에 효율적으로 사용될 수 있다.As described above, the C20 diacid compound of Formula 3 may be efficiently used for the stereoselective synthesis of the 13-cis-retinoic acid of Formula 1 and the all-trans-retinoic acid of Formula 2.

상기 식중, X는 -Cl, -Br, -I로부터, R은 탄소수 1에서 10사이의 알킬기로 이루어진 군으로부터 각각 선택된다.Wherein X is selected from -Cl, -Br, -I, and R is each selected from the group consisting of alkyl groups having 1 to 10 carbon atoms.

상기 (1) 단계에서, C15 설폰 화합물 [F]는 베타-이오논(β-ionone)으로부터 2 단계의 짧은 반응으로 효율적으로 합성될 수 있으며, 화합물 [F]의 디프로톤화(deprotonation) 반응은 -80℃~-20℃의 온도에서 염기를 적가하는 것이 필요하며, 이 때, 염기로는 n-BuLi, s-BuLi, t-BuLi, PhLi, NaH, KH, NaNH₂, 리튬 디아이소프로필아마이드 (lithium diisopropylamide), 리튬 헥사메틸디살라자이드 (lithium hexamethyldisilazide), 쏘디움 헥사메틸디살라자이드 (sodium hexamethyldisilazide), t-BuOK, EtOK, MeOK, EtONa, MeONa 등을 이용한다. 한편, C5 할로알릴릭 디에스테르 화합물 [G]의 합성은 이소프로필리덴 말로내이트(isopropylidene malonate)로부터 알릴릭 할로겐화 반응에 의해 효율적으로 진행될 수 있고(Helvetica Chimica Acta 1966, 49, 1937-1950), 이소프로필리덴 말로내이트는 디알킬 말로내이트(dialkyl malonate)와 아세톤(acetone)의 루이스 산(Lewis acid)을 이용한 결합반응을 통해 합성될 수 있음이 보고되어 있다(독일 특허 4237897). 상기 화합물 [F]와 화합물 [G]의 줄리아 방식에 의한 결합 반응은 매우 효율적으로, 그리고 높은 수율로 진행된다.In step (1), the C15 sulfone compound [F] can be efficiently synthesized from beta-ionone in two short reactions, and the deprotonation reaction of compound [F] is It is necessary to dropwise add a base at a temperature of -80 ° C to -20 ° C, wherein base is n -BuLi, s -BuLi, t -BuLi, PhLi, NaH, KH, NaNH ₂ , lithium diisopropylamide (lithium diisopropylamide), lithium hexamethyldisilazide, sodium hexamethyldisilazide, t- BuOK, EtOK, MeOK, EtONa, MeONa and the like. On the other hand, the synthesis of the C5 haloallylic diester compound [G] can be efficiently carried out by an allyl halide reaction from isopropylidene malonate ( Helvetica Chimica Acta 1966 , 49 , 1937-1950), It is reported that isopropylidene malonite can be synthesized through a coupling reaction using dialkyl malonate and Lewis acid of acetone (German Patent 4237897). The coupling reaction of the compound [F] with the compound [G] by the Julia mode proceeds very efficiently and with high yield.

상기 (2) 단계의 가수분해 반응은, KOH, NaOH 등의 염기를 적가하여 MeOH, EtOH, i-PrOH 등의 알콜 용매에서 진행하는 것이 바람직하며, 이러한 조건에서, 디하이드로설폰화(dehydrosulfonation) 반응도 동시에 진행되어 화학식 3으로 표기되는 C20 디애씨드(diacid) 화합물을 얻을 수 있게 된다.The hydrolysis reaction of step (2) is preferably carried out in an alcohol solvent such as MeOH, EtOH, i- PrOH by dropwise addition of a base such as KOH, NaOH, and under such conditions, the degree of dehydrosulfonation reaction It proceeds at the same time to obtain a C20 diacid compound represented by the formula (3).

이하, 본 발명을 합성 예를 들어 상세히 설명하기로 하되, 본 발명이 하기 합성예로만 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by way of synthesis examples, but the present invention is not limited to the following synthesis examples.

합성예 1. 2-(2-브로모-1-메틸-에틸리덴)-말로닉 애씨드 디에틸 에스테르(화합물 [G])Synthesis Example 1. 2- (2-Bromo-1-methyl-ethylidene) -malonic acid diethyl ester (Compound [G])

디에틸 말로내이트 4.6 ㎖(30.0 mmol)을 아세톤 10 ㎖와 아세틱 안하이드라이드 10 ㎖에 용해하고 FeCl₃ 0.5 g(3.0 mmol)을 더한다. 상기 혼합물을 6시간 동안 용매를 환류시키며 가열한 뒤 실온으로 식히고, 디에틸에테르로 묽힌 다음, 물로 세척한다. 유기층을 무수 Na₂SO₄를 이용하여 수분을 제거하고, 거른 다음, 감압하에 농축한 뒤, 실리카겔 컬럼크로마토그라피의 방법으로 정제하여 2-이소프로필리덴-말로닉 애씨드 디에틸에스테르 4.83 g(24.2 mmol)을 80%의 수율로 얻을 수 있었다.4.6 mL (30.0 mmol) of diethyl malonite is dissolved in 10 mL of acetone and 10 mL of acetic anhydride, and 0.5 g (3.0 mmol) of FeCl ₃ is added. The mixture is heated under reflux for 6 hours, cooled to room temperature, diluted with diethyl ether and washed with water. The organic layer was removed with water using anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 4.83 g (24.2 mmol) of 2-isopropylidene-malonic acid diethyl ester. ) Was obtained in a yield of 80%.

¹H NMR (300 MHz, CDCl₃) δ 1.29 (6H, t, J = 7.1 Hz), 2.07 (6H, s), 4.24 (4H, t, J = 7.1 Hz) ppm. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.29 (6H, t, J = 7.1 Hz), 2.07 (6H, s), 4.24 (4H, t, J = 7.1 Hz) ppm.

¹³C NMR (75.5 MHz, CDCl₃) δ 14.0, 23.0, 60.7, 124.6, 154.9, 165.6 ppm. ¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 14.0, 23.0, 60.7, 124.6, 154.9, 165.6 ppm.

상기 2-이소프로필리덴-말로닉 애씨드 디에틸에스테르 1.3 g(6.47 mmol)을 CCl₄ 20 ㎖에 용해한 뒤, N-브로모쑥신이미드(N-bromosuccinimide, NBS) 1.4 g(7.76 mmol)과 AIBN 소량을 더한다. 상기 혼합물을 200 와트의 할로겐 램프를 비추면서 5시간 동안 용매를 환류시키며 가열한 뒤 실온으로 식힌다. 상기 반응 혼합물을 필터 페이퍼로 걸러 쑥신이미드를 제거하고, 여액은 감압하에 농축한 뒤, 실리카겔 컬럼크로마토그래피의 방법으로 정제하여 2-(2-브로모-1-메틸-에틸리덴)-말로닉 애씨드 디에틸 에스테르(화합물 [G]) 1.27 g(4.57 mmol)을 71%의 수율로 얻을 수 있었다.The 2-isopropylidene-words Nick Acid diethyl ester 1.3 g (6.47 mmol) of CCl ₄ after dissolved in 20 ㎖, N-bromo mossuk god imide (N -bromosuccinimide, NBS) 1.4 g (7.76 mmol) and a small amount of AIBN Add. The mixture is heated with reflux of solvent for 5 hours while illuminating a 200 watt halogen lamp and cooled to room temperature. The reaction mixture was filtered through filter paper to remove succinimide, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2- (2-bromo-1-methyl-ethylidene) -malonic. 1.27 g (4.57 mmol) of the acid diethyl ester (Compound [G]) were obtained in a yield of 71%.

¹H NMR (300 MHz, CDCl₃) δ 1.31 (3H, t, J = 7.1 Hz), 1.31 (3H, t, J = 7.1 Hz), 2.15 (3H, s), 4.27 (2H, q, J = 7.1 Hz), 4.27 (2H, q, J = 7.1 Hz), 4.31 (2H, s) ppm. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.31 (3H, t, J = 7.1 Hz), 1.31 (3H, t, J = 7.1 Hz), 2.15 (3H, s), 4.27 (2H, q, J = 7.1 Hz), 4.27 (2H, q, J = 7.1 Hz), 4.31 (2H, s) ppm.

¹³C NMR (75.5 MHz, CDCl₃) δ 13.9, 13.9, 20.0, 31.4, 61.3, 61.4, 126.9, 150.4, 163.9, 165.1 ppm. ¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 13.9, 13.9, 20.0, 31.4, 61.3, 61.4, 126.9, 150.4, 163.9, 165.1 ppm.

합성예 2. 2-(2-브로모-1-메틸-에틸리덴)-말로닉 애씨드 디아이소프로필 에 스테르(화합물 [G])Synthesis Example 2. 2- (2-Bromo-1-methyl-ethylidene) -malonic acid diisopropyl ester (Compound [G])

디아이소프로필 말로내이트 5.76 ㎖(30.0 mmol)을 아세톤 10 ㎖와 아세틱 안하이드라이드 10 ㎖에 용해하고 FeCl₃ 0.5 g(3.0 mmol)을 더한다. 상기 혼합물을 11시간 동안 용매를 환류시키며 가열한 뒤 실온으로 식히고, 디에틸에테르로 묽힌 다음, 물로 세척한다. 유기층을 무수 Na₂SO₄를 이용하여 수분을 제거하고, 거른 다음, 감압하에 농축한 뒤, 실리카겔 컬럼크로마토그라피의 방법으로 정제하여 2-이소프로필리덴-말로닉 애씨드 디아이소프로필 에스테르 4.83 g(24.2 mmol)을 78%의 수율로 얻을 수 있었다.5.76 mL (30.0 mmol) of diisopropyl malonite is dissolved in 10 mL of acetone and 10 mL of acetic anhydride, and 0.5 g (3.0 mmol) of FeCl ₃ is added. The mixture is heated under reflux for 11 hours, cooled to room temperature, diluted with diethyl ether and washed with water. The organic layer was dehydrated using anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 4.83 g (24.2 of 2-isopropylidene-malonic acid diisopropyl ester). mmol) was obtained in a yield of 78%.

¹H NMR (300 MHz, CDCl₃) δ 1.27 (12H, d, J = 6.2 Hz), 2.06 (6H, s), 5.11 (2H, heptet, J = 6.2 Hz) ppm. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.27 (12H, d, J = 6.2 Hz), 2.06 (6H, s), 5.11 (2H, heptet, J = 6.2 Hz) ppm.

¹³C NMR (75.5 MHz, CDCl₃) δ 21.7, 22.9, 68.2, 125.3, 154.1, 165.2 ppm. ¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 21.7, 22.9, 68.2, 125.3, 154.1, 165.2 ppm.

상기 2-이소프로필리덴-말로닉 애씨드 디아이소프로필 에스테르 2.0 g(8.76 mmol)을 CCl₄ 20 ㎖에 용해한 뒤, NBS 1.87 g(10.5 mmol)과 AIBN 소량을 더한다. 상기 혼합물을 200 와트의 할로겐 램프를 비추면서 5시간 동안 용매를 환류시키며 가열한 뒤 실온으로 식힌다. 상기 반응 혼합물을 필터 페이퍼로 걸러 쑥신이미드를 제거하고, 여액은 감압하에 농축한 뒤, 실리카겔 컬럼크로마토그래피의 방법으로 정제하여 2-(2-브로모-1-메틸-에틸리덴)-말로닉 애씨드 디아이소프로필 에스테르(화합물 [G]) 1.95 g(6.36 mmol)을 73%의 수율로 얻을 수 있었다.After dissolving 2.0 g (8.76 mmol) of the 2-isopropylidene-malonic acid diisopropyl ester in 20 ml of CCl ₄ , 1.87 g (10.5 mmol) of NBS and a small amount of AIBN are added thereto. The mixture is heated with reflux of solvent for 5 hours while illuminating a 200 watt halogen lamp and cooled to room temperature. The reaction mixture was filtered through filter paper to remove succinimide, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2- (2-bromo-1-methyl-ethylidene) -malonic. 1.95 g (6.36 mmol) of the acid diisopropyl ester (Compound [G]) were obtained in a yield of 73%.

¹H NMR (300 MHz, CDCl₃) δ 1.29 (12H, d, J = 6.3 Hz), 2.14 (3H, s), 4.31 (2H, s), 5.14 (1H, heptet, J = 6.3 Hz), 5.15 (1H, heptet, J = 6.3 Hz) ppm. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.29 (12H, d, J = 6.3 Hz), 2.14 (3H, s), 4.31 (2H, s), 5.14 (1H, heptet, J = 6.3 Hz), 5.15 (1H, heptet, J = 6.3 Hz) ppm.

¹³C NMR (75.5 MHz, CDCl₃) δ 19.8, 21.6, 31.6, 69.0, 69.1, 127.6, 149.6, 163.5, 164.6 ppm. ¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 19.8, 21.6, 31.6, 69.0, 69.1, 127.6, 149.6, 163.5, 164.6 ppm.

IR (KBr) 2983, 1717, 1637, 1456, 1255 cm^-1.IR (KBr) 2983, 1717, 1637, 1456, 1255 cm ^-1 .

합성예 3. 2-[3-벤젠설포닐-1,5-디메틸-7-(2,6,6,-트리메틸-1-싸이클로핵센-1-닐)-4,6-헵타디에닐리덴]말로닉 애씨드 디에틸 에스테르(화합물 [H])Synthesis Example 3. 2- [3-benzenesulfonyl-1,5-dimethyl-7- (2,6,6, -trimethyl-1-cyclonucenen-1-yl) -4,6-heptadienylidene] Malonic Acid Diethyl Ester (Compound [H])

C15 설폰 화합물 [F] 1.0 g(2.9 mmol)을 THF 30 ㎖에 녹이고 아르곤으로 충진시킨 다음 -78 ℃에서 1.6 M n-BuLi 핵산용액 2.0 ㎖(3.20 mmol)을 적가한다. 상기 혼합물을 30분간 교반한 후, 상기 온도에서 2-(2-브로모-1-메틸-에틸리덴)-말로닉 애씨드 디에틸 에스테르(화합물 [G]) 1.1 g(3.77 mmol)을 THF 에 묽혀 천천히 가한 다음, 30 분간 교반하고 실온으로 온도를 올려 1시간 더 교반한다. 상기 반응 혼합물에 1 M HCl 50 ㎖를 가하여 반응을 종결시키고, 디에틸에테르로 추출한 다음, 물로 세척한다. 유기층을 무수 Na₂SO₄를 이용하여 수분을 제거하고, 거른 다음, 감압하에 농축한 뒤, 실리카겔 컬럼크로마토그라피의 방법으로 정제하여 2-[3-벤젠설포닐-1,5-디메틸-7-(2,6,6,-트리메틸-1-싸이클로핵센-1-닐)-4,6-헵타디에닐리덴]말로닉 애씨드 디에틸 에스테르(화합물 [H]) 1.16 g(2.1 mmol)을 74%의 수율로 얻 을 수 있었다.1.0 g (2.9 mmol) of C15 sulfone compound [F] was dissolved in 30 mL of THF, charged with argon, and 2.0 mL (3.20 mmol) of 1.6 M n -BuLi nucleic acid solution was added dropwise at -78 ° C. After stirring the mixture for 30 minutes, 1.1 g (3.77 mmol) of 2- (2-bromo-1-methyl-ethylidene) -malonic acid diethyl ester (Compound [G]) was diluted in THF at this temperature. Add slowly, stir for 30 minutes, raise temperature to room temperature and stir for 1 hour more. 50 ml of 1 M HCl was added to the reaction mixture to terminate the reaction, extracted with diethyl ether and washed with water. The organic layer was removed with water using anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and purified by silica gel column chromatography for 2- [3-benzenesulfonyl-1,5-dimethyl-7- 74% of 1.16 g (2.1 mmol) of (2,6,6, -trimethyl-1-cyclonucenen-1-yl) -4,6-heptadienylidene] malonic acid diethyl ester (Compound [H]) Yield was obtained.

¹H NMR (300 MHz, CDCl₃) δ 0.96 (3H, s), 0.97 (3H, s), 1.25 (3H, t, J = 7.1 Hz), 1.29 (3H, t, J = 7.1 Hz), 1.29 (3H, d, J = 1.3 Hz), 1.43~1.47 (2H, m), 1.56~1.62 (2H, m), 1.65 (3H, s), 1.97~2.03 (2H, m), 2.01 (3H, s), 2.87 (1H, dd, J = 12.7, 11.0 Hz), 3.23 (1H, dd, J = 12.7, 3.9 Hz), 4.21 (2H, q, J = 7.2 Hz), 4.23 (2H, dq, J _q = 7.1, J _d = 2.4 Hz), 4.32 (1H, ddd, J = 11.0, 10.8, 3.9 Hz), 5.21 (1H, d, J = 10.8 Hz), 5.95 (1H, A of ABq, J _AB = 16.2 Hz), 5.99 (1H, B of ABq, J _AB = 16.2 Hz), 7.46~7.53 (2H, m), 7.58~7.65 (1H, m), 7.80~7.86 (2H, m) ppm. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.96 (3H, s), 0.97 (3H, s), 1.25 (3H, t, J = 7.1 Hz), 1.29 (3H, t, J = 7.1 Hz), 1.29 (3H, d, J = 1.3 Hz), 1.43-1.47 (2H, m), 1.56-1.62 (2H, m), 1.65 (3H, s), 1.97-2.03 (2H, m), 2.01 (3H, s ), 2.87 (1H, dd, J = 12.7, 11.0 Hz), 3.23 (1H, dd, J = 12.7, 3.9 Hz), 4.21 (2H, q, J = 7.2 Hz), 4.23 (2H, dq, J _q = 7.1, J _d = 2.4 Hz), 4.32 (1H, ddd, J = 11.0, 10.8, 3.9 Hz), 5.21 (1H, d, J = 10.8 Hz), 5.95 (1H, A of ABq, J _AB = 16.2 Hz), 5.99 (1H, B of ABq, J _AB = 16.2 Hz), 7.46-7.53 (2H, m), 7.58-7.85 (1H, m), 7.80-7.86 (2H, m) ppm.

¹³C NMR (75.5 MHz, CDCl₃) δ 12.3, 13.9, 14.0, 19.2, 21.5, 21.8, 28.8(2), 32.8, 34.1, 34.2, 39.4, 61.0, 61.2, 63.7, 120.1, 127.4, 128.6, 128.7(2), 129.3(2), 129.6, 133.6, 135.8, 137.2, 137.4, 142.6, 152.4, 164.9, 165.0 ppm. ¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 12.3, 13.9, 14.0, 19.2, 21.5, 21.8, 28.8 (2), 32.8, 34.1, 34.2, 39.4, 61.0, 61.2, 63.7, 120.1, 127.4, 128.6, 128.7 ( 2), 129.3 (2), 129.6, 133.6, 135.8, 137.2, 137.4, 142.6, 152.4, 164.9, 165.0 ppm.

IR (KBr) 2934, 1722, 1636, 1447, 1306, 1244 cm^-1.IR (KBr) 2934, 1722, 1636, 1447, 1306, 1244 cm ^-1 .

High Resolution Mass (FAB⁺) calcd for C₂₅H₃₇O₄ (C ₃₁H₄₂O₆S - C₆H₅SO₂) 401.2692, found 401.2700.High Resolution Mass (FAB ⁺ ) calcd for C ₂₅ H ₃₇ O ₄ (C ₃₁ H ₄₂ O ₆ S-C ₆ H ₅ SO ₂ ) 401.2692, found 401.2700.

합성예 4. 2-[3-벤젠설포닐-1,5-디메틸-7-(2,6,6,-트리메틸-1-싸이클로핵센- 1-닐)-4,6-헵타디에닐리덴]말로닉 애씨드 디아이소프로필 에스테르(화합물 [H])Synthesis Example 4. 2- [3-Benzenesulfonyl-1,5-dimethyl-7- (2,6,6, -trimethyl-1-cyclonuxene-1-yl) -4,6-heptadienylidene] Malonic Acid Diisopropyl Ester (Compound [H])

C15 설폰 화합물 [F] 2.0 g(5.8 mmol)을 THF 30 ㎖에 녹이고 아르곤으로 충진시킨 다음 -78 ℃에서 1.6 M n-BuLi 핵산용액 4.0 ㎖(6.40 mmol)을 적가한다. 상기 혼합물을 30분간 교반한 후, 상기 온도에서 2-(2-브로모-1-메틸-에틸리덴)-말로닉 애씨드 디아이소프로필 에스테르(화합물 [G]) 2.14 g(7.0 mmol)을 THF 에 묽혀 천천히 가한 다음, 1 시간 동안 교반한다. 상기 반응 혼합물에 1 M HCl 50 ㎖를 가하여 반응을 종결시키고, 디에틸에테르로 추출한 다음, 물로 세척한다. 유기층을 무수 Na₂SO₄를 이용하여 수분을 제거하고, 거른 다음, 감압하에 농축한 뒤, 실리카겔 컬럼크로마토그라피의 방법으로 정제하여 2-[3-벤젠설포닐-1,5-디메틸-7-(2,6,6,-트리메틸-1-싸이클로핵센-1-닐)-4,6-헵타디에닐리덴]말로닉 애씨드 디아이소프로필 에스테르(화합물 [H]) 2.12 g(3.8 mmol)을 64%의 수율로 얻을 수 있었다.2.0 g (5.8 mmol) of C15 sulfone compound [F] was dissolved in 30 mL of THF, charged with argon, and 4.0 mL (6.40 mmol) of 1.6 M n -BuLi nucleic acid solution was added dropwise at -78 ° C. After stirring the mixture for 30 minutes, 2.14 g (7.0 mmol) of 2- (2-bromo-1-methyl-ethylidene) -malonic acid diisopropyl ester (Compound [G]) was added to THF at this temperature. Dilute slowly and add for 1 hour. 50 ml of 1 M HCl was added to the reaction mixture to terminate the reaction, extracted with diethyl ether and washed with water. The organic layer was removed with water using anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and purified by silica gel column chromatography for 2- [3-benzenesulfonyl-1,5-dimethyl-7- 2.12 g (3.8 mmol) of (2,6,6, -trimethyl-1-cyclonucenen-1-yl) -4,6-heptadienylidene] malonic acid diisopropyl ester (Compound [H]) 64 Yield in% yield.

¹H NMR (300 MHz, CDCl₃) δ 0.92 (3H, s), 0.94 (3H, s), 1.19 (6H, d, J = 6.2 Hz), 1.22 (3H, d, J = 5.5 Hz), 1.24 (3H, d, J = 5.9 Hz), 1.26 (3H, d, J = 0.7 Hz), 1.38~1.43 (2H, m), 1.52~1.60 (2H, m), 1.61 (3H, s), 1.92~1.99 (2H, m), 1.95 (3H, s), 2.82 (1H, dd, J = 12.6, 11.3 Hz), 3.19 (1H, dd, J = 12.6, 3.8 Hz), 4.29 (1H, ddd, J = 11.3, 10.8, 3.8 Hz), 5.02 (1H, heptet, J = 6.2 Hz), 5.07 (1H, heptet, J = 6.2 Hz), 5.19 (1H, d, J = 10.8 Hz), 5.92 (1H, A of ABq, J _AB = 16.3 Hz), 5.95 (1H, B of ABq, J _AB = 16.3 Hz), 7.43~7.60 (3H, m), 7.78~7.81 (2H, m) ppm. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.92 (3H, s), 0.94 (3H, s), 1.19 (6H, d, J = 6.2 Hz), 1.22 (3H, d, J = 5.5 Hz), 1.24 (3H, d, J = 5.9 Hz), 1.26 (3H, d, J = 0.7 Hz), 1.38-1.43 (2H, m), 1.52-1.60 (2H, m), 1.61 (3H, s), 1.92- 1.99 (2H, m), 1.95 (3H, s), 2.82 (1H, dd, J = 12.6, 11.3 Hz), 3.19 (1H, dd, J = 12.6, 3.8 Hz), 4.29 (1H, ddd, J = 11.3, 10.8, 3.8 Hz), 5.02 (1H, heptet, J = 6.2 Hz), 5.07 (1H, heptet, J = 6.2 Hz), 5.19 (1H, d, J = 10.8 Hz), 5.92 (1H, A of ABq, J _AB = 16.3 Hz), 5.95 (1H, B of ABq, J _AB = 16.3 Hz), 7.43-7.60 (3H, m), 7.78-7.81 (2H, m) ppm.

¹³C NMR (75.5 MHz, CDCl₃) δ 12.3, 19.1, 21.5, 21.6, 21.6, 21.6, 21.7, 28.8(2), 32.8, 34.1, 39.4, 63.6, 68.5, 68.8, 120.0, 128.0, 128.5, 128.7(2), 129.3(2), 129.6, 133.6, 135.9, 137.2, 137.4, 142.5, 151.5, 164.5, 164.5 ppm. ¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 12.3, 19.1, 21.5, 21.6, 21.6, 21.6, 21.7, 28.8 (2), 32.8, 34.1, 39.4, 63.6, 68.5, 68.8, 120.0, 128.0, 128.5, 128.7 ( 2), 129.3 (2), 129.6, 133.6, 135.9, 137.2, 137.4, 142.5, 151.5, 164.5, 164.5 ppm.

IR (KBr) 2931, 1717, 1636, 1307, 1251 cm^-1.IR (KBr) 2931, 1717, 1636, 1307, 1251 cm ^-1 .

합성예 5. 2-[1,5-디메틸-7-(2,6,6,-트리메틸-1-싸이클로핵센-1-닐)-2,4,6-헵타트리에닐리덴]말로닉 애씨드(화학식 3)Synthesis Example 5. 2- [1,5-dimethyl-7- (2,6,6, -trimethyl-1-cyclocyclosensenyl-yl) -2,4,6-heptatrienylidene] malonic acid (Formula 3)

3-벤젠설포닐-1,5-디메틸-7-(2,6,6,-트리메틸-1-싸이클로핵센-1-닐)-4,6-헵타디에닐리덴]말로닉 애씨드 디에틸 에스테르(화합물 [H]) 1.7 g(3.13 mmol)을 i-PrOH 30 ㎖에 녹인 후 KOH 0.88 g(15.7 mmol)을 가한다. 상기 혼합물을 실온에서 27시간 동안 교반한 뒤, 3 M HCl 수용액 50 ㎖를 가하여 pH를 1로 맞춘다. 반응혼합물을 에틸 아세테이트로 추출한 뒤, 유기층을 무수 Na₂SO₄를 이용하여 수분을 제거하고, 거른 다음, 감압하에 농축한 결과물을 CHCl₃로 재결정하여 2-[1,5-디메틸-7-(2,6,6,-트리메틸-1-싸이클로핵센-1-닐)-2,4,6-헵타트리에닐리덴]말로닉 애씨드(화학식 3) 0.99 g(1.82 mmol)을 58%의 수율로 얻을 수 있었다.3-benzenesulfonyl-1,5-dimethyl-7- (2,6,6, -trimethyl-1-cyclocyclosen-1-yl) -4,6-heptadienylidene] malonic acid diethyl ester ( 1.7 g (3.13 mmol) of Compound [H]) was dissolved in 30 mL of i- PrOH, and 0.88 g (15.7 mmol) of KOH was added thereto. The mixture is stirred at room temperature for 27 hours, and then 50 ml of 3 M HCl aqueous solution is added to adjust the pH to 1. After the reaction mixture was extracted with ethyl acetate, the organic layer was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The resultant was recrystallized with CHCl ₃ to obtain 2- [1,5-dimethyl-7- ( 0.99 g (1.82 mmol) of 2,6,6, -trimethyl-1-cyclonucleone-1-yl) -2,4,6-heptatrienylidene] malonic acid (Formula 3) in 58% yield Could get

¹H NMR (300 MHz, CD₃OD) δ 1.03 (6H, s), 1.46~1.52 (2H, m), 1.59~1.69 (2H, m), 1.71 (3H, s), 2.00~2.08 (2H, m), 2.02 (3H, s), 2.24 (3H, s), 6.16 (1H, A of ABq, J _AB = 16.1 Hz), 6.19 (1H, d, J = 11.0 Hz), 6.34 (1H, B of ABq, J _AB = 16.1 Hz), 7.08 (1H, A of ABq, J _AB = 15.0 Hz), 7.21 (1H, d of B of ABq, J _AB = 15.0, J _d = 11.0 Hz) ppm. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.03 (6H, s), 1.46-1.52 (2H, m), 1.59-1.69 (2H, m), 1.71 (3H, s), 2.00-2.08 (2H, m), 2.02 (3H, s), 2.24 (3H, s), 6.16 (1H, A of ABq, J _AB = 16.1 Hz), 6.19 (1H, d, J = 11.0 Hz), 6.34 (1H, B of ABq, J _AB = 16.1 Hz), 7.08 (1H, A of ABq, J _AB = 15.0 Hz), 7.21 (1H, d of B of ABq, J _AB = 15.0, J _d = 11.0 Hz) ppm.

¹³C NMR (75.5 MHz, CD₃OD) δ 12.9, 16.1, 20.3, 22.0, 29.4(2), 34.0, 35.3, 40.8, 126.5, 130.2, 131.0, 131.1(2), 134.7, 138.9, 139.0, 141.9, 149.3, 169.2, 169.6 ppm. ¹³ C NMR (75.5 MHz, CD ₃ OD) δ 12.9, 16.1, 20.3, 22.0, 29.4 (2), 34.0, 35.3, 40.8, 126.5, 130.2, 131.0, 131.1 (2), 134.7, 138.9, 139.0, 141.9, 149.3, 169.2, 169.6 ppm.

합성예 6. 13-씨스-레티노익 애씨드(화학식 1)Synthesis Example 6. 13-CS-Retinoic Acid (Formula 1)

2-[1,5-디메틸-7-(2,6,6,-트리메틸-1-싸이클로핵센-1-닐)-2,4,6-헵타트리에닐리덴]말로닉 애씨드(화학식 3) 0.3 g(0.86 mmol)을 2,6-루티딘 10 ㎖에 녹인 뒤, 2시간 동안 용매를 환류시키며 가열한 다음 실온으로 식힌다. 반응 혼합물에서 2,6-루티딘을 증류하여 제거한 뒤, 3 M HCl 수용액 20 ㎖를 가하여 pH를 1로 맞춘다. 반응혼합물을 디에틸에테르로 추출한 뒤, 유기층을 무수 Na₂SO₄를 이용하여 수분을 제거하고, 거른 다음, 감압하에 농축한 뒤, 실리카겔 컬럼크로마토그라피의 방법으로 정제하여 13-씨스-레티노익 애씨드(화학식 1) 0.16 g(0.54 mmol)을 63% 수율로 얻을 수 있었다.2- [1,5-dimethyl-7- (2,6,6, -trimethyl-1-cyclonucenen-1-yl) -2,4,6-heptatrienylidene] malonic acid (Formula 3) 0.3 g (0.86 mmol) is dissolved in 10 ml of 2,6-lutidine, and the solvent is heated to reflux for 2 hours and then cooled to room temperature. After distilling off 2,6-lutidine from the reaction mixture, 20 ml of 3 M HCl aqueous solution is added to adjust the pH to 1. The reaction mixture was extracted with diethyl ether, the organic layer was dried with anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, purified by silica gel column chromatography, and purified by 13-CS-Retinoic acid. 0.16 g (0.54 mmol) was obtained in a 63% yield.

¹H NMR (300 MHz, CDCl₃) δ 1.02 (6H, s), 1.42~1.49 (2H, m), 1.56~1.65 (2H, m), 1.71 (3H, s), 1.97~2.05 (2H, m), 1.99 (3H, s), 2.09 (3H, s), 5.65 (1H, s), 6.18 (1H, A of ABq, J _AB = 16.2 Hz), 6.27 (1H, d, J = 11.4 Hz), 6.29 (1H, B of ABq, J _AB = 16.2 Hz), 7.03 (1H, dd, J = 15.2, 11.4 Hz), 7.75 (1H, d, J = 15.2 Hz), 12.20 (1H, br s) ppm. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.02 (6H, s), 1.42-1.49 (2H, m), 1.56-1.65 (2H, m), 1.71 (3H, s), 1.97-2.05 (2H, m ), 1.99 (3H, s), 2.09 (3H, s), 5.65 (1H, s), 6.18 (1H, A of ABq, J _AB = 16.2 Hz), 6.27 (1H, d, J = 11.4 Hz), 6.29 (1H, B of ABq, J _AB = 16.2 Hz), 7.03 (1H, dd, J = 15.2, 11.4 Hz), 7.75 (1H, d, J = 15.2 Hz), 12.20 (1H, br s) ppm.

¹³C NMR (75.5 MHz, CDCl₃) δ 12.9, 19.2, 21.2, 21.7, 28.9(2), 33.1, 34.2, 39.6, 115.8, 128.8, 129.1, 130.2, 130.2, 133.0, 137.3, 137.6, 140.4, 153.6, 172.1 ppm. ¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 12.9, 19.2, 21.2, 21.7, 28.9 (2), 33.1, 34.2, 39.6, 115.8, 128.8, 129.1, 130.2, 130.2, 133.0, 137.3, 137.6, 140.4, 153.6, 172.1 ppm.

합성예 7. 올-트랜스-레티노익 애씨드(화학식 2)Synthesis Example 7 All-trans-Retinoic Acid (Formula 2)

2-[1,5-디메틸-7-(2,6,6,-트리메틸-1-싸이클로핵센-1-닐)-2,4,6-헵타트리에닐리덴]말로닉 애씨드(화학식 3) 0.26 g(0.75 mmol)에 CH₂Cl₂ 10 ㎖와 피리딘 0.12 ㎖(1.5 mmol)을 더하고, 실온에서 27시간 동안 교반한 다음, 3 M HCl 수용액 20 ㎖을 가하여 pH를 1로 맞춘다. 반응혼합물을 CH₂Cl₂로 추출한 뒤, 유기층을 무수 Na₂SO₄를 이용하여 수분을 제거하고, 거른 다음, 감압하에 농축한 뒤, 실리카겔 컬럼크로마토그라피의 방법으로 정제하여 올-트랜스-레티노익 애씨드(화학식 2) 0.15 g(0.5 mmol)을 67% 수율로 얻을 수 있었다.2- [1,5-dimethyl-7- (2,6,6, -trimethyl-1-cyclonucenen-1-yl) -2,4,6-heptatrienylidene] malonic acid (Formula 3) 10 ml of CH ₂ Cl ₂ and 0.12 ml (1.5 mmol) of pyridine are added to 0.26 g (0.75 mmol), stirred at room temperature for 27 hours, and then 20 ml of 3M HCl aqueous solution is added to adjust pH to 1. The reaction mixture was extracted with CH ₂ Cl ₂ , the organic layer was dried with anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, purified by silica gel column chromatography and all-trans-retinoic. 0.15 g (0.5 mmol) of the acid (Formula 2) was obtained in a 67% yield.

¹H NMR (300 MHz, CDCl₃) δ 1.01 (6H, s), 1.41~1.49 (2H, m), 1.55~1.65 (2H, m), 1.70 (3H, s), 1.94~2.04 (2H, m), 1.99 (3H, s), 2.35 (3H, s), 5.78 (1H, s), 6.14 (1H, A of ABq, J _AB = 16.2 Hz), 6.15 (1H, d, J = 11.4 Hz), 6.29 (1H, B of ABq, J _AB = 16.2 Hz), 6.31 (1H, d, J = 15.0 Hz), 7.04 (1H, dd, J = 15.0, 11.4 Hz), 12.20 (1H, br s) ppm. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.01 (6H, s), 1.41-1.49 (2H, m), 1.55-1.65 (2H, m), 1.70 (3H, s), 1.94-2.04 (2H, m ), 1.99 (3H, s), 2.35 (3H, s), 5.78 (1H, s), 6.14 (1H, A of ABq, J _AB = 16.2 Hz), 6.15 (1H, d, J = 11.4 Hz), 6.29 (1H, B of ABq, J _AB = 16.2 Hz), 6.31 (1H, d, J = 15.0 Hz), 7.04 (1H, dd, J = 15.0, 11.4 Hz), 12.20 (1H, br s) ppm.

¹³C NMR (75.5 MHz, CDCl₃) δ 12.9, 14.0, 19.2, 21.7, 28.9(2), 33.1, 34.2, 39.6, 117.8, 129.0, 129.4, 130.1, 131.8, 134.9, 137.2, 137.6, 140.2, 155.2, 172.7 ppm. ¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 12.9, 14.0, 19.2, 21.7, 28.9 (2), 33.1, 34.2, 39.6, 117.8, 129.0, 129.4, 130.1, 131.8, 134.9, 137.2, 137.6, 140.2, 155.2, 172.7 ppm.

이상에서 살펴본 바와 같이, 본 발명에 따르면, 화학식 1의 13-씨스-레티노익 애씨드 및 화학식 2의 올-트랜스-레티노익 애씨드를 각각 입체선택적으로 합성하는데 필요한 화학식 3의 C20 디애씨드(diacid) 화합물을, 기존의 방법을 이용한 경우보다 훨씬 짧은 반응의 단계로, 경제적이며, 효율적으로 제조하는 방법이 제공되며, 따라서 13-씨스-레티노익 애씨드와 올-트랜스-레티노익 애씨드를 각각 입체선택적이며 효율적으로 제조하는 방법이 제공된다.As described above, according to the present invention, the C20 diacid compound of Chemical Formula 3 required for stereoselectively synthesizing the 13-cis-retinoic acid of Chemical Formula 1 and the all-trans-retinoic acid of Chemical Formula 2, respectively In a much shorter reaction stage than using conventional methods, an economical and efficient method of manufacturing is provided, thus allowing stereoselective and efficient 13-CS-Retinoic acid and All-Trans-Retinoic acid, respectively. It is provided a method for producing.

Claims

(1) C15 sulfone compound [F] is subjected to deprotonation by treating with base, and then reacted with haloallylic diester compound [G] to give C20 sulfone diester compound [ H]; And

(2) C20 sulfone diester compound [H] of the C20 diacid compound of formula (3), characterized in that the dehydrosulfonation reaction is carried out simultaneously with the hydrolysis of the ester group by treating the base Manufacturing method.

Wherein X is selected from -Cl, -Br, -I, and R is each selected from the group consisting of alkyl groups having 1 to 10 carbon atoms.

The deprotonation reaction of step (1) is added dropwise to the base at a temperature of -80 ℃ ~ -20 ℃, where n -BuLi, s -BuLi, t -BuLi, PhLi, NaH, KH, NaNH ₂ , lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, t -BuOK, EtOK, MeOK, EtONa, MeONa, etc. The method characterized by using.

The method according to claim 1, wherein the hydrolysis and dehydro sulfonation reaction of step (2) is carried out in an alcohol solvent such as MeOH, EtOH, i- PrOH by dropwise addition of a base such as KOH or NaOH. .