KR930006942B1 - Method for producing of prostaglandin - Google Patents

Method for producing of prostaglandin Download PDF

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KR930006942B1
KR930006942B1 KR1019900010844A KR900010844A KR930006942B1 KR 930006942 B1 KR930006942 B1 KR 930006942B1 KR 1019900010844 A KR1019900010844 A KR 1019900010844A KR 900010844 A KR900010844 A KR 900010844A KR 930006942 B1 KR930006942 B1 KR 930006942B1
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tetrahydropyran
yloxy
group
hydroxy
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KR920002534A (en
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박호군
이기정
이용섭
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한국과학기술연구원
박원희
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof

Abstract

A method for preparing 16-hydroxy-16-methyl prostaglandin E derivs. of formula (I) comprises (a) reacting a cpd. of formula (II) and a cpd. of formula (III) (wittig reaction); (b) protecting the 16- position OH gp. with tetrahydropyranyl gp. and removing the 9- position trialkylsilyl gp.; and (c) oxidizing it and removing the 1- and 6-position protecting gp. In the formulas, R1= t-butyl dimethyl silyl; R2= t-butyl dimethyl silyl, tetrahydropyran-2-yl or 1-ethoxy-1-ethyl; R3= tetrahydropyran-2-yl or 1-ethoxy-1-ethyl; X= hydroxymethyl or methoxy carbonyl. The cpds. (I) have an antiulcer activity.

Description

16-하이드록시-16메칠PGE계 프로스타글란딘 유도체의 제조방법Method for preparing 16-hydroxy-16methyl PGE-based prostaglandin derivative

본 발명은 다음 일반식 (I)로 표시되는 16-하이드록시-16- 메칠 PGE계 프로스타글란딘 유도체를 C-16에피입체화합물 상태로 제조하는 방법에 관한 것이다.The present invention relates to a method for producing a 16-hydroxy-16-methyl PGE-based prostaglandin derivative represented by the following general formula (I) in a C-16 epidimeric compound state.

Figure kpo00001
Figure kpo00001

상기식에서 X는 하이드록시메칠기 또는 메록시카르 보닐기이다.In the formula, X is a hydroxymethyl group or a hydroxycarbonyl group.

자연계에 존재하는 프로스타글란딘 화합물들중 PGE계통의 화합물들이 위산 분비를 억제한다는 사실은 1967년에 이미 밝혀졌으나 자연계에서 얻어지는 프로스타글란딘 화합물들은 체내에서 신진대사가 너무 빠르고, 여러가지 부작용을 유발시키며, 화학적으로 너무 불안정하여 위궤양 치료제로 사용하기 어려웠다.그러나, 프로스타 글란댄 E계통의 화합물들이 C-15 하이드록시기를 C-16위치로 옮기고, 다시 C-16위치에 메칠기를 도입한 상기 일반식 (I)의 프로스타글란딘 유도체들은 부작용이 현저하게 감소되었을 뿐만 아니라, 안정성이 뛰어나 위, 십이지장궤양에 탁월한 제약적 성질이 있음이 밝혀졌다. (참조 :Drugs of the Future, 1989, 14, 294 ; Drugs of the Future 1988, 13, 3). 이들에 대한 종래의 합성방법은 라세믹 혼합물인 메칠 7-(3-테트라하이드로피란-2-일옥시-5-옥소시클로펜트-1-엔)헵타노에이트, 혹은 7-(1-(1-에톡시)에톡시)-5-옥소시클로펜트-1-엔에 알케닐 유기금속시약을 부가하여 C-16위치가 에피입체화학적 배열을 가진 라세믹 혼합물 상태의 16-하이드록시-16-메칠프로스타글란딘 유도체들을 합성하였다. (예 : European Patent 0.133, 450, U.S. Patent 4, 275, 224)Of the prostaglandin compounds present in nature, PGE-based compounds inhibit gastric acid secretion, which was discovered in 1967, but the prostaglandin compounds obtained in nature are too fast for metabolism in the body, cause various side effects, and are chemically unstable. However, prostaglandin E-based compounds transfer C-15 hydroxyl groups to the C-16 position and then introduce a methyl group to the C-16 position. Derivatives have been found to not only significantly reduce side effects, but also have excellent stability in gastric and duodenal ulcers due to their excellent stability. (Drugs of the Future, 1989, 14, 294; Drugs of the Future 1988, 13, 3). Conventional synthetic methods for these include methyl 7- (3-tetrahydropyran-2-yloxy-5-oxocyclopent-1-ene) heptanoate, or racemic mixture, 7- (1- (1- Addition of an alkenyl organometallic reagent to ethoxy) ethoxy) -5-oxocyclopent-1-ene with 16-hydroxy-16-methylprostaglandin in racemic mixture with C-16 position epidermal chemical arrangement Derivatives were synthesized. (E.g. European Patent 0.133, 450, U.S. Patent 4, 275, 224)

본 발명에서는 광학적으로 순수한 다음일반식 (II)의

Figure kpo00002
-하이드록시 포스포니움 염을 사용하여 트란스-올레핀을 선택적으로 얻을 수 있는 빗티히 반응에 의하여 알케닐 측쇄를 도입하였으며, 이때 얻어지는 화합물들은 종래의 합성방법에서 얻어지는 라세믹 혼합물이 아닌 광학이성체 상태의 C-16 에피입체 화합물이다.In the present invention, the optically pure formula (II)
Figure kpo00002
Alkenyl side chains were introduced by a Wittich reaction in which trans-olefins can be selectively obtained using a hydroxy phosphonium salt, wherein the obtained compounds are in an optical isomeric state, not racemic mixtures obtained by conventional synthetic methods. C-16 epidimeric compound.

따라서 본 발명에서는 최초로 라세믹 혼합물 상태가 아닌 상태의 상기화합물들을 제조하였다.Therefore, in the present invention, the compounds were prepared for the first time in a racemic mixture.

Figure kpo00003
Figure kpo00003

상기식에서 R1은 t-부칠디메칠실릴기이며, R2은 t-부칠디메칠실릴기, 테트라하이드로피란 -2-일기, 1-에톡시-1-에칠기이며, R3는 테트라하이드로피란-2-일기, 1-에톡시-1-에칠기이다.Wherein R 1 is a t-butyldimethylsilyl group, R 2 is a t-butyldimethylsilyl group, a tetrahydropyran-2-yl group, a 1-ethoxy-1-ethyl group, and R 3 is a tetrahydropyran -2-yl group and 1-ethoxy-1-ethoxy group.

빗티히 반응에 의한 트란스-올레핀의 합성은 여러문현 (예 : J. Org.Chem., 43,790(1978), J.Am.Chem.Soc,102,6580(1980), Tetrahedron Lett., 26,311(1985)등)에 수록되어 있으나, 이들 문헌에서는 트란스-올레핀의 합성에 목적을 두거나, 서로 다른 목적화합물의 합성에 목적을 두고 있으며 16-하이드록시-16-메칠 프로스타글란딘 유도체의 합성에 이용된 예는 없었다. 따라서 본 발명은 프로스타글란딘 유도체의 트란스-알케닐 측쇄의 도입에 있어서 위에서 열거한 문헌들에 이론적인 근거를 두고 있다. 즉

Figure kpo00004
-하이드록시 포스포니움염 (III)에 리튬브로마이드를 함유하고 있는 n-부칠리튬을 가하여 얻는 다음일반식의 일리드용액(IV)에 알데하이드를 가한후, 다시 리튬브로마이드를 함유하고 있는 n-부칠리튬을 가하여 트란스 올레핀의 구조를 갖는 알케닐측쇄를 도입하였다.The synthesis of trans-olefins by the Wittich reaction has been described in several expressions (e.g. J. Org. Chem., 43,790 (1978), J. Am. Chem. Soc, 102,6580 (1980), Tetrahedron Lett., 26,311 (1985). Although these publications are intended to be used for the synthesis of trans-olefins or for the synthesis of different target compounds, these documents have not been used for the synthesis of 16-hydroxy-16-methyl prostaglandin derivatives. . The present invention is therefore theoretically based on the documents listed above in the introduction of trans-alkenyl side chains of prostaglandin derivatives. In other words
Figure kpo00004
After adding aldehyde to the lylide solution (IV) of the following general formula obtained by adding n-buty lithium containing lithium bromide to hydroxy phosphonium salt (III), n-buty lithium containing lithium bromide again Was added to introduce an alkenyl side chain having the structure of trans olefin.

Figure kpo00005
Figure kpo00005

또한 포스포니움염(III)이 분자내 하이드록 시기를 가지고 있으므로 리튬브로마이드를 함유하지 않은 n-부칠리튬을 가하여도 반응중에 리튬이오다이드가 생성되며, 하이드록시기 또한 분자내에서 염기로 작용할 수 있으므로, 이 경우에도 트란스-알케닐 측쇄를 손쉽게 얻을 수 있다.In addition, since phosphonium salt (III) has an intramolecular hydroxyl time, lithium iodide is formed during the reaction even when n-buty lithium without lithium bromide is added, and the hydroxyl group can also act as a base in the molecule. In this case, therefore, the trans-alkenyl side chain can be easily obtained.

상경리반식 (II)화합물은 일반식(I) 을 출발물질로 하여 빗티히 반응에 의해서 프로스타글란딘의 윗가지를 도입하여 일반식(2)의 화합물을 얻고, 이 일반식(2)의 화합물을 이미다졸과 디메칠포름 아미드의 존재하에 t-부칠디메칠실릴클로라이드와 반응시켜 일반식(3)의 화합물을 얻고, 이 일반식(3)의 화합물을 수소화시켜 일반식(4)의 화합물을 얻고, 이 일반식(4)의 화합물을 삼산화크롬과 같은 산화제로 산화하여 일반식(II)화합물을 제조한다.The commercially available compound (II) has a compound of the formula (2) obtained by introducing a prostaglandin upper branch by a Wittich reaction using the formula (I) as a starting material, and the compound of the formula (2) Reacting with t-butyldimethylsilyl chloride in the presence of dozol and dimethylformamide to obtain a compound of formula (3), hydrogenating the compound of formula (3) to obtain a compound of formula (4), The compound of formula (4) is oxidized with an oxidizing agent such as chromium trioxide to prepare a compound of formula (II).

Figure kpo00006
Figure kpo00006

일반식(II)의 화합물을 상기일반식(III)의 화합물을 사용하여 상술한 트랜스 선택적인 빗티히 반응에 의하여 트랜스알케닐 측쇄를 도입하여 일반식(5)의 화합물을 얻고, 이 일반식(5)의 화합물의 하이드록시기를 테트라하이드로피라닐기로 보호하여 일반식(6)의 화합물을 얻고, 이 일반식(6)의 화합물에서 t-부칠디메칠실릴기를 제거하여 일반식(7)의 화합물을 얻고, 이 일반식(7)의 화합물을 산화시켜 일반식(8)의 화합물을 얻고 이 일반식(8)의 화합물을 초산용액으로 가수분해하여 일반식(I)의 목적화합물을 얻는다.Transalkenyl side chains were introduced by the trans-selective Bittich reaction described above using the compound of formula (III) to obtain a compound of formula (5). The hydroxy group of the compound of 5) was protected by tetrahydropyranyl group to obtain the compound of formula (6), and the t-butylmethylsilyl group was removed from the compound of formula (6) to remove the compound of formula (7). The compound of formula (7) was oxidized to obtain a compound of formula (8), and the compound of formula (8) was hydrolyzed with an acetic acid solution to obtain the target compound of formula (I).

Figure kpo00007
Figure kpo00007

이하 실시예에 의하여 본 발명을 자세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail with reference to the following examples.

실시예 1Example 1

3

Figure kpo00008
-벤질옥시메칠-2
Figure kpo00009
-(7-하이드록시헵트-2-엔일)-4
Figure kpo00010
-(테트라하이드로피란-2-일옥시)시클로펜트-1
Figure kpo00011
-올 (2a)3
Figure kpo00008
Benzyloxymethyl-2
Figure kpo00009
-(7-hydroxyhept-2-enyl) -4
Figure kpo00010
-(Tetrahydropyran-2-yloxy) cyclopent-1
Figure kpo00011
-All (2a)

건조된 7ml의 테트라하이드로푸란에 1.98g(4.62mmol)의 (5-하이드록시펜틸) 트리페닐포스 포니움 브로마이드를 녹이고 질소분위기하에서 0℃로 냉각한 후 5.8ml (9.28mmol)의 n-부칠리튬 (1.6몰농도)을 천천히 가하였다. 반응온도를 상온으로 올리고 15분간 교반한후, 이용액을 4

Figure kpo00012
-벤질옥시메칠-2-하이드록시-5
Figure kpo00013
-(테트라하이드로피란-2-일옥시)-3, 3a
Figure kpo00014
, 4
Figure kpo00015
, 5
Figure kpo00016
, 6a-헥사하이드로-2H-시클로펜타(b)푸란((1)740mg, 2.2mmol)을 전조된 5ml의 테트라하이드로푸란에 용해한 용액에 천천히 가하고 30분간 교반하였다. 반응혼합물에 에테르와 물을 차례로 가한후 에테르층을 분리하여 물로 씻고, 무수 황산마그네슘으로 건조한 후, 감압에서 용매를 제거하였다. 잔사를 실리카겔 컬럼상에서 에칠에테르내의 20%헥산으로 용출하여 680mg의 표제화합물을 얻었다.1.98 g (4.62 mmol) of (5-hydroxypentyl) triphenylphosphonium bromide was dissolved in dried 7 ml tetrahydrofuran, cooled to 0 ° C. under nitrogen atmosphere, and then 5.8 ml (9.28 mmol) of n-butylithium. (1.6 molarity) was added slowly. After raising the reaction temperature to room temperature and stirring for 15 minutes, the used solution was added to 4
Figure kpo00012
Benzyloxymethyl-2-hydroxy-5
Figure kpo00013
-(Tetrahydropyran-2-yloxy) -3, 3a
Figure kpo00014
, 4
Figure kpo00015
, 5
Figure kpo00016
, 6a-hexahydro-2H-cyclopenta (b) furan ((1) 740 mg, 2.2 mmol) was slowly added to a solution dissolved in the prepared 5 ml tetrahydrofuran and stirred for 30 minutes. Ether and water were sequentially added to the reaction mixture, the ether layer was separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was eluted with 20% hexane in ethyl ether on a silica gel column to give 680 mg of the title compound.

NMR (CDCl3) : δ7.43 (s, 5H), 5.3-5.67 (m, 2H), 4.73 (br, s, 1H), 4.57 (s, 2H)NMR (CDCl 3 ): δ 7.43 (s, 5H), 5.3-5.67 (m, 2H), 4.73 (br, s, 1H), 4.57 (s, 2H)

실시예 1bExample 1b

3

Figure kpo00017
-벤질옥시메칠-4
Figure kpo00018
-(테트라하이드로피란-2-일옥시)-2
Figure kpo00019
-((7-테트라하이드로피란-2-일옥시)헵트-2-엔일)시클로펜트-1
Figure kpo00020
-올 (2b)3
Figure kpo00017
Benzyloxymethyl-4
Figure kpo00018
-(Tetrahydropyran-2-yloxy) -2
Figure kpo00019
-((7-tetrahydropyran-2-yloxy) hept-2-enyl) cyclopent-1
Figure kpo00020
-All (2b)

4

Figure kpo00021
-벤질옥시메칠-2-하이드록시 5
Figure kpo00022
-(테트라하이드로피란-2-일옥시)-3, 3a, 4
Figure kpo00023
, 5
Figure kpo00024
,6,6a-헥사하이드로-2H-시클로펜타 (b)푸란과 (5-테트라하이드로피란-2-일옥시)트리페닐포스포니움 이오다이드를 사용하여 실시예 1a와 같은 방법으로 표제화합물을 얻었다.4
Figure kpo00021
-Benzyloxymethyl-2-hydroxy 5
Figure kpo00022
-(Tetrahydropyran-2-yloxy) -3, 3a, 4
Figure kpo00023
, 5
Figure kpo00024
The title compound was prepared in the same manner as in Example 1a using 6,6a-hexahydro-2H-cyclopenta (b) furan and (5-tetrahydropyran-2-yloxy) triphenylphosphonium iodide. Got it.

NMR (CDCl3) : δ7.32 (s,5H), 5.25-5.62 (m,2H), 4.69 (br, s, 1H), 4.57 (br,s,1H), 4.51(d, 2H), 4.27(m,1H), 4.11(m, 1H)NMR (CDCl 3 ): δ7.32 (s, 5H), 5.25-5.62 (m, 2H), 4.69 (br, s, 1H), 4.57 (br, s, 1H), 4.51 (d, 2H), 4.27 (m, 1H), 4.11 (m, 1H)

실시예 2aExample 2a

3

Figure kpo00025
-벤질옥시메칠-1
Figure kpo00026
-(t-부틸디메칠실릴옥시)-2
Figure kpo00027
-(7-t-부칠디메칠실릴옥시헵트-2-엔일)-4
Figure kpo00028
-(테트라하이드로피란-2-일옥시) 시크로펜탄(3a) 건조된 3ml의 디메칠포름아미드에 610mg (1.457mmol)의 3
Figure kpo00029
-벤질옥시메칠-2
Figure kpo00030
-(7-하이드록시헵트-2-엔일)-4
Figure kpo00031
-(테트라하이드로피란-2-일옥시) 시클로펜트-1
Figure kpo00032
-올(2a)과 1.10g(7.2285mmol)의 t-부틸디메칠실릴클로라이드와 1.98g(29.1mmol)의 이미다졸을 가하고 상온에서 15시간동안 교반하였다. 반응혼합물을 15ml의 물로 희석한후, 에칠에테르내의 50%펜탄용액으로 추출하였다. 물층을 펜탄으로 2번에 걸쳐 추출한후 모두합친 유기용액을 물과 포화소금물로 씻어주었다. 유지층을 무수 황산마그네슘으로 건조하고 감압에서 용매를 증발시킨후 실리카 켈컬럼상에서 헥산내의 10%에칠아세테이트로 용출하여 890mg의 표제화합물을 얻었다.3
Figure kpo00025
Benzyloxymethyl-1
Figure kpo00026
-(t-butyldimethylsilyloxy) -2
Figure kpo00027
-(7-t-butylmethylsilyloxyhept-2-enyl) -4
Figure kpo00028
-(Tetrahydropyran-2-yloxy) cyclopentane (3a) in 3 ml of dimethylformamide dried 610 mg (1.457 mmol) of 3
Figure kpo00029
Benzyloxymethyl-2
Figure kpo00030
-(7-hydroxyhept-2-enyl) -4
Figure kpo00031
-(Tetrahydropyran-2-yloxy) cyclopent-1
Figure kpo00032
-Ol (2a), 1.10 g (7.2285 mmol) of t-butyl dimethylsilyl chloride, and 1.98 g (29.1 mmol) of imidazole were added and stirred at room temperature for 15 hours. The reaction mixture was diluted with 15 ml of water and extracted with 50% pentane solution in ethyl ether. The water layer was extracted twice with pentane, and the combined organic solutions were washed with water and saturated brine. The oily layer was dried over anhydrous magnesium sulfate, the solvent was evaporated at reduced pressure, and eluted with 10% ethyl acetate in hexane on silica kel column to obtain 890 mg of the title compound.

NMR(CDCl3) : δ7.32(m, 5H), 5.23-5.43(m, 2H), 4.64(m, 1H), 4.57(m, 1H), 4.51(d, 2H), 4.13(m, 1H), 0.90(s, 9H), 0.08(s, 6H)NMR (CDCl 3 ): δ 7.32 (m, 5H), 5.23-5.43 (m, 2H), 4.64 (m, 1H), 4.57 (m, 1H), 4.51 (d, 2H), 4.13 (m, 1H) ), 0.90 (s, 9H), 0.08 (s, 6H)

실시예 2bExample 2b

3

Figure kpo00033
-벤질옥시메칠-1
Figure kpo00034
-(t-부칠디메칠실릴옥시)-4
Figure kpo00035
-(테트라하이드로피란3
Figure kpo00033
Benzyloxymethyl-1
Figure kpo00034
-(t-butylmethylsilyloxy) -4
Figure kpo00035
Tetrahydropyran

-2-일옥시)-2

Figure kpo00036
-(테트라하이드로피란-2-일옥시)헵트-2-엔일)시클로펜탄(3b)2-yloxy) -2
Figure kpo00036
-(Tetrahydropyran-2-yloxy) hept-2-enyl) cyclopentane (3b)

3

Figure kpo00037
-벤질옥시메칠-4
Figure kpo00038
-(테트라하이드로피란-2-일옥시)-2
Figure kpo00039
-(7-테트라하이드로피란-2-일옥시헵트-2-엔일) 시클로펜트-1
Figure kpo00040
올(2b)로부터 실시예 2a와 같은 방법으로 표제화합물을 얻었다.3
Figure kpo00037
Benzyloxymethyl-4
Figure kpo00038
-(Tetrahydropyran-2-yloxy) -2
Figure kpo00039
-(7-tetrahydropyran-2-yloxyhept-2-enyl) cyclopent-1
Figure kpo00040
The title compound was obtained in the same manner as in Example 2a from Ol (2b).

NMR(CDCl3) : δ7.32(m, 5H), 5.23-5.43(m, 2H), 4.64(m, 1H), 4.57(m, 1H), 4.51(d, 2H), 4.13(m, 1H), 0.90(s, 9H), 0.08(s, 6H)NMR (CDCl 3 ): δ 7.32 (m, 5H), 5.23-5.43 (m, 2H), 4.64 (m, 1H), 4.57 (m, 1H), 4.51 (d, 2H), 4.13 (m, 1H) ), 0.90 (s, 9H), 0.08 (s, 6H)

실시예 3aExample 3a

1

Figure kpo00041
-(t-부칠디메칠실릴옥시)-2
Figure kpo00042
-(7t-부칠디메칠실릴옥시헵틸)-3
Figure kpo00043
-하이드록시메칠-4
Figure kpo00044
-(테트라하이드로피란-2-일옥시)시클로펜탄(4a) 15ml의 무수에탄올 내의 5% 식초산 용액에 546mg(0.84mmol)의 3β-벤질옥시메칠-1α-(t-부칠디메칠실릴옥시)-4
Figure kpo00045
-(테트랄하이드로피란-2-일옥시)-2α((테트라하이드로피란-2-일옥시)헵틸) 시클로펜탄(3a)과 109mg의 탄소내의 5% 팔라듐을 가한후 상압의 수소 대기하에서 실온에서 38시간 동안 교반하였다. 반응 혼합물을 Celite-545통하여 여과하고 메칠렌클로라이드로 여러차례 씻어주었다. 모두 합친 용매를 감압에서 제거하고 실리카 겔 컬럼상에서 헥산내의 25%에칠아세테이트 용액으로 용출하여 427mg의 표제화합물을 얻었다.One
Figure kpo00041
-(t-butylmethylsilyloxy) -2
Figure kpo00042
-(7t-Butyldimethylsilyloxyheptyl) -3
Figure kpo00043
Hydroxymethyl-4
Figure kpo00044
-(Tetrahydropyran-2-yloxy) cyclopentane (4a) 546 mg (0.84 mmol) of 3β-benzyloxymethyl-1α- (t-butyldimethylsilyloxy) in a 5% vinegar solution in 15 ml of anhydrous ethanol -4
Figure kpo00045
-(Tetrahydropyran-2-yloxy) -2α ((tetrahydropyran-2-yloxy) heptyl) cyclopentane (3a) and 5% palladium in 109 mg of carbon were added and then at room temperature under atmospheric hydrogen atmosphere. Stir for 38 hours. The reaction mixture was filtered through Celite-545 and washed several times with methylene chloride. The combined solvents were removed under reduced pressure and eluted with a 25% ethyl acetate solution in hexane on a silica gel column to give 427 mg of the title compound.

IR(neat) : 3420IR (neat): 3420

실시예 3bExample 3b

1

Figure kpo00046
-(t-부칠디메칠실릴옥시)-3
Figure kpo00047
-하이드록시메칠-4
Figure kpo00048
-(테트라하이드로피란-2-일옥시)-2
Figure kpo00049
-(테트라하이드로피란-일옥시)헵틸시클로펜탄(4b) 3
Figure kpo00050
-벤질옥시메칠-1
Figure kpo00051
-(t-부칠디메칠실릴옥시)-4
Figure kpo00052
-(테트라하이드로피란-2-일옥시)-2-일옥시)-2-(테트라하이드로피란-2-일옥시)헵틸) 시클로펜탄(3b)으로부터 실시예 3a와 같은 방법으로 표제화합물을 얻었다.One
Figure kpo00046
-(t-butyldimethylsilyloxy) -3
Figure kpo00047
Hydroxymethyl-4
Figure kpo00048
-(Tetrahydropyran-2-yloxy) -2
Figure kpo00049
-(Tetrahydropyran-yloxy) heptylcyclopentane (4b) 3
Figure kpo00050
Benzyloxymethyl-1
Figure kpo00051
-(t-butylmethylsilyloxy) -4
Figure kpo00052
The title compound was obtained in the same manner as in Example 3a from-(tetrahydropyran-2-yloxy) -2-yloxy) -2- (tetrahydropyran-2-yloxy) heptyl) cyclopentane (3b).

NMR(CDC1) : δ4.97(m, 1H). 4.10(m,1H), 0.88(s,9H), 0.06(s, 6H)NMR (CDC1): δ 4.97 (m, 1H). 4.10 (m, 1H), 0.88 (s, 9H), 0.06 (s, 6H)

실시예 4aExample 4a

1

Figure kpo00053
-(t-부칠디메칠실릴옥시)-2
Figure kpo00054
-(7-t-부칠디메칠실릴옥시헵틸-3
Figure kpo00055
-포르밀-4
Figure kpo00056
-(테트라하이드로피란-2-일옥시) 시클로펜탄(IIa)One
Figure kpo00053
-(t-butylmethylsilyloxy) -2
Figure kpo00054
-(7-t-butylmethylsilyloxyheptyl-3
Figure kpo00055
Formyl-4
Figure kpo00056
-(Tetrahydropyran-2-yloxy) cyclopentane (IIa)

18ml의 건조된 메칠렌클로라이드에 0.92ml의 피리딘을 가한후 568mg(5mmol, 68)의 크로미움 트리옥사이드를 한번에 모두 가하고 15분간 교반하였다. 529mg(0.94mmol)의 1

Figure kpo00057
-(t-부칠디메칠실릴옥시)-2
Figure kpo00058
-(7-t-부칠디메칠실릴옥시헵틸)-3
Figure kpo00059
하이드록시메칠-4
Figure kpo00060
-(테트라하이드로피란-2-일옥시) 시클로펜탄(4a)을 5ml의 메칠렌클로라이드에 녹인 용액을 한번에 모두 가하고 30분동안 교반하였다. 반응 혼합물에 에테르를 가한후 Celite-545를 통하여 여과하고 에트르로 여러차례 씻어 주었다. 모두 합친 에테르 용액을 감압에서 농축한 후 3cm길이의 실리카겔 컬럼상에서 여과하고 에테르로 여러차례 씻어주었다. 모두합친 에테르용액을 감압에서 제거하여 527mg의 표제 화합물을 수득하였다.0.92 ml of pyridine was added to 18 ml of dried methylene chloride, and then 568 mg (5 mmol, 68) of chromium trioxide was added all at once and stirred for 15 minutes. 529 mg (0.94 mmol) 1
Figure kpo00057
-(t-butylmethylsilyloxy) -2
Figure kpo00058
-(7-t-butylmethylsilyloxyheptyl) -3
Figure kpo00059
Hydroxymethyl-4
Figure kpo00060
A solution of (tetrahydropyran-2-yloxy) cyclopentane (4a) in 5 ml of methylene chloride was added all at once and stirred for 30 minutes. Ether was added to the reaction mixture, which was then filtered through Celite-545 and washed several times with ether. The combined ether solutions were concentrated at reduced pressure, filtered over a 3 cm long silica gel column and washed several times with ether. The combined ether solutions were removed at reduced pressure to afford 527 mg of the title compound.

NMR(CDC13) : δ9.6-9.83(m, 1H), 4.5(br,s,1H), 0.8(s, 18H), 0.03(s, 12H)NMR (CDC1 3 ): δ9.6-9.83 (m, 1H), 4.5 (br, s, 1H), 0.8 (s, 18H), 0.03 (s, 12H)

실시예 4bExample 4b

1

Figure kpo00061
-(t-부칠디메칠실릴옥시)-3
Figure kpo00062
-포르밀-4
Figure kpo00063
-(테트라하이드로피란-2-일옥시)-2
Figure kpo00064
-(7-테트라하이드로피란-2-일옥시) 헵틸시클로펜탄(IIb) 1
Figure kpo00065
-(t-부칠디메칠실릴옥시)-3
Figure kpo00066
-하이드록시메칠-4
Figure kpo00067
-(테트라하이드로피란-2-일옥시)-2
Figure kpo00068
-(테트라하이드로피란-2-일옥시)헵틸시크로펜탄(4b)으로부터 실시예 4a와 같은 방법으로 표제 화합물을 얻었다.One
Figure kpo00061
-(t-butyldimethylsilyloxy) -3
Figure kpo00062
Formyl-4
Figure kpo00063
-(Tetrahydropyran-2-yloxy) -2
Figure kpo00064
-(7-tetrahydropyran-2-yloxy) heptylcyclopentane (IIb) 1
Figure kpo00065
-(t-butyldimethylsilyloxy) -3
Figure kpo00066
Hydroxymethyl-4
Figure kpo00067
-(Tetrahydropyran-2-yloxy) -2
Figure kpo00068
The title compound was obtained in the same manner as Example 4a from-(tetrahydropyran-2-yloxy) heptylcyclopentane (4b).

NMR(CDC13) : δ9.76(dd, 1H, J-11.8Hz, 8.8Hz), 4.58(m, 2H), 4.16(m,1H)NMR (CDC1 3 ): δ9.76 (dd, 1H, J-11.8Hz, 8.8Hz), 4.58 (m, 2H), 4.16 (m, 1H)

실시예 5Example 5

에칠 3-하이드록시-3-메칠펜타노에이트 3.9g의 아연분말을 40ml의 벤젠에 가하고 온도를 80℃로 유지하면서 5g(49.9mmol)의 2-헥사논과 10g(59.88mmol)의 에칠 브로모아세테이트의 혼합물을 30분동안 천천히 가하였다. 반응 혼합물을 1시간 동안 환류시킨 후 상온으로 온도를 낮추고 10%염산 용액을 가하였다. 반응 혼합물을 에테르로 추출한후, 무수 황산마그네슘으로 건조시키고 용매를 감압에서 증발시켰다. 잔사를 실리카겔 컬럼상에서 헥산내의 20%에칠 아세테이트 용액으로 용출하여 7.2g의 표제화합물을 얻었다.3.9 g of zinc 3-hydroxy-3-methylpentanoate was added to 40 ml of benzene and 5 g (49.9 mmol) of 2-hexanone and 10 g (59.88 mmol) of ethyl bromoacetate while maintaining the temperature at 80 ° C. Was added slowly for 30 minutes. The reaction mixture was refluxed for 1 hour, and then cooled to room temperature and 10% hydrochloric acid solution was added thereto. The reaction mixture was extracted with ether, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was eluted with a 20% ethyl acetate solution in hexane on a silica gel column to give 7.2 g of the title compound.

NMR(CDC13) : δ4.20(q,2H), 3.60(s, 1H), 2.45(s, 2H), 1.30(t, 3H)NMR (CDC1 3 ): δ 4.20 (q, 2H), 3.60 (s, 1H), 2.45 (s, 2H), 1.30 (t, 3H)

실시예 6Example 6

3-하이드록시-3-메칠헵트-1-올 건조된 5ml의 에테르에 0.2g(5.3mmol)의 리튬 알루미늄 하이드라이드를 0℃의 온도에서 가하고 0.5g(2.65mmol)의 에칠 3-하이드록시-3-메칠펜타 노에이트를 2ml의에테르에 녹인 용액을 천천히 가하였다. 0℃에서 6시간 동안 교반한후 1ml의 물과 2ml의 10% 수산화나트륨용액을 차례로 가하였다. 반응혼합물을 Celite-545를 통하여 여과하고 에테르로 여러차례 씻어 주었다. 모두 합친 에테르 용액을 포화 소금물로 씻어주고 무수 황산마그네슘으로 건조시킨 후 용매를 감압에서 증발시켰다. 잔사를 실리카겔 컬럼상에서 에칠 아세테이트내의 33%헥산용액으로 용출하여 370mg의 표제화합물을 얻었다.3-hydroxy-3-methylhept-1-ol To a dried 5 ml ether was added 0.2 g (5.3 mmol) of lithium aluminum hydride at a temperature of 0 ° C. and 0.5 g (2.65 mmol) of ethyl 3-hydroxy- A solution of 3-methylpentanonoate in 2 ml of ether was slowly added. After stirring at 0 ° C. for 6 hours, 1 ml of water and 2 ml of 10% sodium hydroxide solution were added sequentially. The reaction mixture was filtered through Celite-545 and washed several times with ether. The combined ether solutions were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was eluted with 33% hexane solution in ethyl acetate on a silica gel column to give 370 mg of the title compound.

NMR(CDCl3) : δ3.86(t-2H), 1.79(t, 2H), 1.23(s, 3H)NMR (CDCl 3 ): δ 3.86 (t-2H), 1.79 (t, 2H), 1.23 (s, 3H)

IR (neat) : 2780-3020, 2980-3700IR (neat): 2780-3020, 2980-3700

실시예 7Example 7

3-하이드록시-3-메칠-1-p-톨루엔술포닐옥시헵탄3-hydroxy-3-methyl-1-p-toluenesulfonyloxyheptane

7.3g(49.9mmol)의 에칠 3-하이드록시-3-메칠 펜타노에이트를 50ml의 피리딘에 녹이고 0℃로 냉각시킨후 11g(57.4mmol)의 p-톨루엔술포닐 클로라이드를 가하고 4시간 동안 교반하였다. 반응온도를 상온으로 서서히 올린후 다시 4시간동안 교반하였다. 반응혼합물에 얼음물을 가하고 에테르로 추출하였다. 에테르층을 1N-황산용액으로 2회에 걸쳐 씻어준후 중탄산나트륨용액과 포화소금물로 씻어주었다. 유기층을 무수황산 마그네슘으로 건조한 후, 용매를 감압에서 제거하여 12.25g의 표제화합물을 얻었다.7.3 g (49.9 mmol) of ethyl 3-hydroxy-3-methylpentanoate was dissolved in 50 ml of pyridine and cooled to 0 ° C., then 11 g (57.4 mmol) of p-toluenesulfonyl chloride were added and stirred for 4 hours. . The reaction temperature was slowly raised to room temperature and then stirred for another 4 hours. Ice water was added to the reaction mixture, which was then extracted with ether. The ether layer was washed twice with 1N-sulfuric acid solution and then with sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to obtain 12.25 g of the title compound.

NMR(CDCl3)δ: 7.33-7.96(m, 4H), 4.25(t, 2H), 2.45(s, 3H), 1.67(s, 1H)NMR (CDCl 3 ) δ: 7.33-7.96 (m, 4H), 4.25 (t, 2H), 2.45 (s, 3H), 1.67 (s, 1H)

실시예 8Example 8

3-하이드록시-1-이오도-3-메칠헵탄3-hydroxy-1-iodo-3-methylheptane

0.1g(0.50mmol)의 하이드록시-3-메칠-1-톨루엔 술포닐옥시헵탄과 0.15g(1.0mmol)의 쏘듐 이오다이드를 10ml의 아세톤에 녹이고 2시간 동안 환류시켰다. 온도를 상온으로 낮춘후 5ml의 물을 가하고 에테르로 추출하였다. 에테르층을 중탄산 나트륨 용액 및 포화소금물로 씻어주고 무수 황산 마그네슘으로 건조한 후 용매를 감압에서 증발시켰다. 잔사를 실리카겔 컬럼상에서 헥산내의 20% 에칠아세테이트 용액으로 용출하여 0.11g의 표제화합물을 얻었다.0.1 g (0.50 mmol) of hydroxy-3-methyl-1-toluene sulfonyloxyheptane and 0.15 g (1.0 mmol) of sodium iodide were dissolved in 10 ml of acetone and refluxed for 2 hours. After the temperature was lowered to room temperature, 5 ml of water was added and extracted with ether. The ether layer was washed with sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was eluted with a 20% ethyl acetate solution in hexane on a silica gel column to give 0.11 g of the title compound.

NMR(CDCl3)δ: 3.10-3.45(m, 2H)NMR (CDCl 3 ) δ: 3.10-3.45 (m, 2H)

IR(neat) : 2730-2980, 3050-3600IR (neat): 2730-2980, 3050-3600

실시예 9Example 9

(3-하이드록시-3-메칠헵틸)트리페닐포스포니움 이오다이드(3-hydroxy-3-methylheptyl) triphenylphosphonium iodide

2g(7.8mmol)의 3-하이드록시-1-이오도-3-메칠 헵탄과 5g(19mmol)의 트리페닐포스핀을 5ml의 벤젠에 가하고 60℃에서 55시간동안 교반하였다. 반응 혼합물을 상온으로 냉각시킨후 메칠렌클로라이드와 에칠 아세테이트로 재결정하여 1.97g의 표제화합물을 얻었다.2 g (7.8 mmol) of 3-hydroxy-1-iodo-3-methyl heptane and 5 g (19 mmol) of triphenylphosphine were added to 5 ml of benzene and stirred at 60 ° C. for 55 hours. The reaction mixture was cooled to room temperature and recrystallized with methylene chloride and ethyl acetate to obtain 1.97 g of the title compound.

NMR(CDCl3)δ: 7.69-7.90(m, 15H), 3.62(m, 2H), 0.82(t, 3H)NMR (CDCl 3 ) δ: 7.69-7.90 (m, 15H), 3.62 (m, 2H), 0.82 (t, 3H)

실시예 10aExample 10a

1-

Figure kpo00069
-(t-부칠디메칠실릴옥시)-2
Figure kpo00070
-(7-t-부칠디메칠실릴옥시헵틸)-3
Figure kpo00071
-[(RS)-E-3-하이드록시-3-메칠-1-옥테닐]-4
Figure kpo00072
-(테트라하이드로피란-2-일옥시)시클로펜탄(5a)One-
Figure kpo00069
-(t-butylmethylsilyloxy) -2
Figure kpo00070
-(7-t-butylmethylsilyloxyheptyl) -3
Figure kpo00071
-[(RS) -E-3-hydroxy-3-methyl-1-octenyl] -4
Figure kpo00072
-(Tetrahydropyran-2-yloxy) cyclopentane (5a)

질소대기권에서 5ml의 건조된 테트라하이드로푸란에 164mg(0.316mmol)의 (3-하이드록시-3-메칠헵틸)트리페닐포스포니움 이오다이드를 녹이고 5mg의 리튬브로마이드가 녹아있는 1.4ml의 n-부칠리튬용액(0.5M, 헥산/테트라하이드로푸란=10 : 22)을 상온에서 천천히 가하고 30분동안 교반하였다. 이때 얻어지는 붉은색의 용액의 온도를 -78℃로 낮추고 125mg(0.225mmol)1ml 1

Figure kpo00073
-(t-부칠디메칠실릴옥시)-3
Figure kpo00074
-포르밀-4
Figure kpo00075
-(테트라하이드로피란-2-일옥시)-2
Figure kpo00076
-(7-테트라하이드로피란-2-일옥시)헵틸시클로펜탄(11a)을 1ml의 테트라하이드푸란에 녹인 용액을 5분동안 가하였다. 반응온도를 1시간 동안 서서히 상온으로 올린후 2시간동안 교반하였다. 반응혼합물을 5ml의 냉각수에 부은후 에테르로 3회에 걸쳐 추출하였다. 에테르층을 무수 황산마그네슘으로 건조시키고 용매를 감압에서 증발시킨후 실리카겔 컬럼상에서 헥산내의 25% 에칠 아세테이트로 용출하여 92mg의 표제화합물을 얻었다.In a nitrogen atmosphere, 1.4 ml of n- is dissolved in 164 mg (0.316 mmol) of (3-hydroxy-3-methylheptyl) triphenylphosphonium iodide in 5 ml of dried tetrahydrofuran and 5 mg of lithium bromide is dissolved. Butylithium solution (0.5M, hexane / tetrahydrofuran = 10: 22) was added slowly at room temperature and stirred for 30 minutes. At this time, lower the temperature of the red solution to -78 ℃ and 125mg (0.225mmol) 1ml 1
Figure kpo00073
-(t-butyldimethylsilyloxy) -3
Figure kpo00074
Formyl-4
Figure kpo00075
-(Tetrahydropyran-2-yloxy) -2
Figure kpo00076
A solution of-(7-tetrahydropyran-2-yloxy) heptylcyclopentane (11a) in 1 ml of tetrahydrofuran was added for 5 minutes. The reaction temperature was slowly raised to room temperature for 1 hour and then stirred for 2 hours. The reaction mixture was poured into 5 ml of cooling water and extracted three times with ether. The ether layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and eluted with 25% ethyl acetate in hexane on a silica gel column to obtain 92 mg of the title compound.

NMR(CDCl3)δ: 5.45(m, 1H), 5.36(dd, J=15Hz, 1H), 4.51, 4.69(br, sa, 1H), 4.05(m, 1H), 3.82(m, 2H), 3.54(t, 2H), 3.39(m, 1H), 0.84(s, 21H), 0.00(s, 12H)NMR (CDCl 3 ) δ: 5.45 (m, 1H), 5.36 (dd, J = 15 Hz, 1H), 4.51, 4.69 (br, sa, 1H), 4.05 (m, 1H), 3.82 (m, 2H), 3.54 (t, 2H), 3.39 (m, 1H), 0.84 (s, 21H), 0.00 (s, 12H)

실시예 10bExample 10b

질소대기권에서 1ml의 테트라하이드로푸란에 80mg(0.154mmol)의 (3-하이드록시-3-메칠헵틸)트리페닐포스포니움 이오다이드를 녹인후 210μl의 n-부칠리튬용액(헥산내의 1.6M농도)을 상온에서 5분동안 가하였다. 상온에서 30분동안 교반한후 온도를 -78℃로 낮추고 43mg(0.077mmol)의 1

Figure kpo00077
-(t-부칠디메칠실릴옥시)-3
Figure kpo00078
-포르밀-4
Figure kpo00079
-(테트라하이드로피란-2-일옥시)-2
Figure kpo00080
-(7-테트라하이드로피란-2-일옥시)헵틸시크로펜탄(IIa)을 0.4ml의 테트라하이드로푸란에 녹인 용액을 가하고 5분동안 교반하였다. 반응 혼합물에 에테르를 가한후 냉각수로 씻어주었다. 물층을 에테르로 2회에 걸쳐 씻어준후, 모두 합친 에테르 용액을 무수 황산마그네슘으로 건조시키고 감압에서 용매를 증발시킨 후 실리카겔 컬럼상에서 헥산내의 25% 에칠 아세테트용액으로 용출하여 실시예 10a의 표제화합물과 동일한 화합물을 33mg 얻었다.Dissolve 80 mg (0.154 mmol) of (3-hydroxy-3-methylheptyl) triphenylphosphonium iodide in 1 ml of tetrahydrofuran in a nitrogen atmosphere, and then add 210 μl of n-butylithium solution (1.6 M concentration in hexane). ) Was added at room temperature for 5 minutes. After 30 minutes of stirring at room temperature, the temperature was lowered to -78 ° C and 43 mg (0.077 mmol) of 1
Figure kpo00077
-(t-butyldimethylsilyloxy) -3
Figure kpo00078
Formyl-4
Figure kpo00079
-(Tetrahydropyran-2-yloxy) -2
Figure kpo00080
A solution of (7-tetrahydropyran-2-yloxy) heptylcyclopentane (IIa) in 0.4 ml of tetrahydrofuran was added and stirred for 5 minutes. Ether was added to the reaction mixture, followed by washing with cooling water. The aqueous layer was washed twice with ether, and the combined ether solutions were dried over anhydrous magnesium sulfate, the solvent was evaporated at reduced pressure, and then eluted with 25% ethyl acetate solution in hexane on a silica gel column to obtain the title compound of Example 10a. 33 mg of the same compound was obtained.

실시예 10cExample 10c

1-(t-부칠디메칠실릴옥시)-3

Figure kpo00081
-[(RS)-(E)-3-하이드록시-3-메칠-1-옥테닐)-4
Figure kpo00082
-(테트라하이드로피란-2-일옥시)-2
Figure kpo00083
-(7-테트라하이드로피란-2-일옥시)헵틸시클로펜탄(5b)1- (t-butyldimethylsilyloxy) -3
Figure kpo00081
-[(RS)-(E) -3-hydroxy-3-methyl-1-octenyl) -4
Figure kpo00082
-(Tetrahydropyran-2-yloxy) -2
Figure kpo00083
-(7-tetrahydropyran-2-yloxy) heptylcyclopentane (5b)

1

Figure kpo00084
-(t-부칠디메칠실릴옥시)-3
Figure kpo00085
-포르밀-4
Figure kpo00086
-(테트라하이드로피란-2-일옥시)-2
Figure kpo00087
-(7-테트라하이드로피란-2-일옥시)헵틸시클로펜탄(IIb)으로 부터 실시예 10a와 같은 방법으로 표제화합물을 얻었다.One
Figure kpo00084
-(t-butyldimethylsilyloxy) -3
Figure kpo00085
Formyl-4
Figure kpo00086
-(Tetrahydropyran-2-yloxy) -2
Figure kpo00087
The title compound was obtained in the same manner as in Example 10a from-(7-tetrahydropyran-2-yloxy) heptylcyclopentane (IIb).

NMR(CDCl3)δ: 5.43-5.50(m, 1H), 5.24-5.36(m, 1H), 4.75(br, s, 1H), 4.57(br, s, 1H), 4.10(br, s, 1H)NMR (CDCl 3 ) δ: 5.43-5.50 (m, 1H), 5.24-5.36 (m, 1H), 4.75 (br, s, 1H), 4.57 (br, s, 1H), 4.10 (br, s, 1H )

실시예 10dExample 10d

1

Figure kpo00088
-(t-부칠디메칠실릴옥시)3-
Figure kpo00089
-포르밀-4
Figure kpo00090
-(테트라하이드로피란-2-일옥시)-2
Figure kpo00091
-(7-테트라하이드로피란-2-일옥시)헵틸시클로펜탄으로부터 실시예 10b와 같은 방법으로 실시예 10c의 표제화합물을 얻었다.One
Figure kpo00088
-(t-butyldimethylsilyloxy) 3-
Figure kpo00089
Formyl-4
Figure kpo00090
-(Tetrahydropyran-2-yloxy) -2
Figure kpo00091
The title compound of Example 10c was obtained by the same method as Example 10b from-(7-tetrahydropyran-2-yloxy) heptylcyclopentane.

실시예 11aExample 11a

1

Figure kpo00092
-(t-부칠디메칠실릴옥시)-2
Figure kpo00093
-(7-t-부칠디메칠실릴옥시헵틸)-3
Figure kpo00094
[(RS)-(E)-3-메칠-3-(테트라하이드로피란-2-일옥시)-1-옥테닐]-4
Figure kpo00095
-(테트라하이드로피란-2-일옥시)시클로펜탄(6a)One
Figure kpo00092
-(t-butylmethylsilyloxy) -2
Figure kpo00093
-(7-t-butylmethylsilyloxyheptyl) -3
Figure kpo00094
[(RS)-(E) -3-Methyl-3- (tetrahydropyran-2-yloxy) -1-octenyl] -4
Figure kpo00095
(Tetrahydropyran-2-yloxy) cyclopentane (6a)

74mg(0.11mmol)의 1

Figure kpo00096
-(t-부칠디메칠실릴옥시)-2
Figure kpo00097
-(7-t-부칠디메칠실릴옥시헵틸)-3
Figure kpo00098
-[(RS)-(E)-3-하이드록시-3-메칠-1-옥테닐]-4
Figure kpo00099
-(테트라하이드로피란-2-일옥시)시클로펜탄(5a)을 1.5ml의 메칠렌클로라이드에 희석한후 18mg(0.07mmol)의 피리디니움 p-톨루엔술포네이트와 90μl(0.98mmol)의 디하이드로피란을 가하였다. 상온에서 12시간 동안 교반한 후 90μl(0.98mmol)의 디하이드로피란을 다시 가하고 6시간동안 교반한후 10ml의 중탄산나트륨 용액을 가하고 메칠렌클로라이드로 3회에 걸쳐 추출하였다. 모두 합친 유기층을 포화 소금물로 씻어주고, 무수황산마그네슘으로 건조 시킨 후 용매를 감압에서 제거하였다. 잔사를 실리카겔 컬럼상에서 헥사내의 10% 에칠아세테이트 용액으로 용출하여 70mg의 표제화합물을 얻었다.74 mg (0.11 mmol) of 1
Figure kpo00096
-(t-butylmethylsilyloxy) -2
Figure kpo00097
-(7-t-butylmethylsilyloxyheptyl) -3
Figure kpo00098
-[(RS)-(E) -3-hydroxy-3-methyl-1-octenyl] -4
Figure kpo00099
Dilute (tetrahydropyran-2-yloxy) cyclopentane (5a) with 1.5 ml of methylene chloride and then 18 mg (0.07 mmol) of pyridinium p-toluenesulfonate and 90 μl (0.98 mmol) of dihydro Piran was added. After stirring at room temperature for 12 hours, 90 μl (0.98 mmol) of dihydropyran was added again, stirred for 6 hours, and then 10 ml of sodium bicarbonate solution was added and extracted three times with methylene chloride. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was eluted with a 10% ethyl acetate solution in hexa on a silica gel column to give 70 mg of the title compound.

NMR(CDCl3)δ: 5.23-5.61(m, 2H), 4.60, 4.69(두개의 br, s, 2H), 4.14, 3.50(m,2H), 3.95(m, 4H), 3.61(t, J=6.6Hz, 2H)NMR (CDCl 3 ) δ: 5.23-5.61 (m, 2H), 4.60, 4.69 (two br, s, 2H), 4.14, 3.50 (m, 2H), 3.95 (m, 4H), 3.61 (t, J = 6.6 Hz, 2H)

IR(neat) : 2930, 2857, 1740IR (neat): 2930, 2857, 1740

실시예 11bExample 11b

1

Figure kpo00100
-(t-부칠디메칠실릴옥시)-3
Figure kpo00101
-[(RS)-(E)-3-메칠-3-(테트라하이드로피란-2-일옥시)-1-옥테닐]-4
Figure kpo00102
-(테트라하이드로피란-2-일옥시)-2
Figure kpo00103
-(7-테트라하이드로피란-2-일옥시)헵틸시클로펜탄(6b)One
Figure kpo00100
-(t-butyldimethylsilyloxy) -3
Figure kpo00101
-[(RS)-(E) -3-methyl-3- (tetrahydropyran-2-yloxy) -1-octenyl] -4
Figure kpo00102
-(Tetrahydropyran-2-yloxy) -2
Figure kpo00103
-(7-tetrahydropyran-2-yloxy) heptylcyclopentane (6b)

1-(t-부칠디메칠실릴옥시)-3

Figure kpo00104
-[(RS)-(E)-3-하이드록시-3-메칠-1-옥테닐]-4
Figure kpo00105
-(테트라하이드로피란-2-일옥시)-2
Figure kpo00106
-(7-테트라하이드로피란-2-일옥시)헵틸시클로펜탄(5b)으로부터 실시예 11a와 같은 방법으로 표제화합물을 얻었다.1- (t-butyldimethylsilyloxy) -3
Figure kpo00104
-[(RS)-(E) -3-hydroxy-3-methyl-1-octenyl] -4
Figure kpo00105
-(Tetrahydropyran-2-yloxy) -2
Figure kpo00106
The title compound was obtained in the same manner as in Example 11a from-(7-tetrahydropyran-2-yloxy) heptylcyclopentane (5b).

NMR(CDCL3)δ: 5.24-5.87(m, 2H), 4.75(br, s, 1H), 4.64(br, s,1H), 4.57(br, s, 1H), 9.10(m, 1H), 0.88(s, 9H), 0.03(s, 6H)NMR (CDCL 3 ) δ: 5.24-5.87 (m, 2H), 4.75 (br, s, 1H), 4.64 (br, s, 1H), 4.57 (br, s, 1H), 9.10 (m, 1H), 0.88 (s, 9H), 0.03 (s, 6H)

실시예 12aExample 12a

1

Figure kpo00107
-하이드록시-2
Figure kpo00108
-(7-하이드록시-1-헵틸)-3
Figure kpo00109
[(RS)-(E)-메칠-3-(테트라하이드로피란-2-일옥시)-1-옥테닐]-4
Figure kpo00110
-(테트라하이드로피란-2-일옥시)시클로펜탄(7a)One
Figure kpo00107
Hydroxy-2
Figure kpo00108
-(7-hydroxy-1-heptyl) -3
Figure kpo00109
[(RS)-(E) -Methyl-3- (tetrahydropyran-2-yloxy) -1-octenyl] -4
Figure kpo00110
-(Tetrahydropyran-2-yloxy) cyclopentane (7a)

105mg(0.14mmol)의 1

Figure kpo00111
-(t-부칠디메칠실릴옥시)-2
Figure kpo00112
-(7-t-부칠디메칠실릴옥시헵틸)-3
Figure kpo00113
-[(RS)-(E)-3-메칠-3-(테트라하이드로피란-2-일옥시)-1-옥테닐]-4
Figure kpo00114
-(테트라하이드로피란-2-일옥시)시클로펜탄(6a)을 2ml의 테트라하이드로푸란으로 희석한후 860μl(0.86mmol)의 테트라부칠암모니움 플루오라이드용액(테트라하이드로푸란내의 1M용액)을 가하고 14시간 동안 교반하였다. 500μl(0.5mmol)의 테트라부칠암모니움 플루오라이드 용액을 다시 가하고 26시간 동안 교반한 후, 에테르로 희석하였다. 반응혼합물로 씻어준 다음 물층을 2회에 걸쳐 에테르로 추출하였다. 모두 합친 유기용액을 포화소금물로 씻어준 후 무수황산 마그네슘으로 건조시키고, 용매를 감압에서 증발시켰다. 잔사를 실리카 겔 컬럼상에서 헥산내의 50% 에칠 아세테이트로 용출하여 65mg의 표제화합물을 얻었다.105 mg (0.14 mmol) of 1
Figure kpo00111
-(t-butylmethylsilyloxy) -2
Figure kpo00112
-(7-t-butylmethylsilyloxyheptyl) -3
Figure kpo00113
-[(RS)-(E) -3-methyl-3- (tetrahydropyran-2-yloxy) -1-octenyl] -4
Figure kpo00114
Dilute (tetrahydropyran-2-yloxy) cyclopentane (6a) with 2 ml of tetrahydrofuran and add 860 μl (0.86 mmol) of tetrabutylammonium fluoride solution (1M solution in tetrahydrofuran). Stir for hours. 500 μl (0.5 mmol) of tetrabutylammonium fluoride solution was added again, stirred for 26 hours, and diluted with ether. After washing with the reaction mixture, the water layer was extracted twice with ether. The combined organic solution was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was eluted with 50% ethyl acetate in hexanes on a silica gel column to give 65 mg of the title compound.

NMR(CDCl3)δ: 5.2-5.7(m, 2H), 4.75, 4.67(두개의 br, s, 2H), 4.13, 3.47(m, 2H), 3.92(m, 4H), 3.63(t, J=6.5Hz, 2H), 1.16(s, 3H), 0.89(t, 3H)NMR (CDCl 3 ) δ: 5.2-5.7 (m, 2H), 4.75, 4.67 (two br, s, 2H), 4.13, 3.47 (m, 2H), 3.92 (m, 4H), 3.63 (t, J = 6.5 Hz, 2H), 1.16 (s, 3H), 0.89 (t, 3H)

실시예 12bExample 12b

1

Figure kpo00115
-하이드록시-3
Figure kpo00116
-[(RS)-(E)-3-메칠-3-3-(테트라하이드로피란-2-일옥시)-1-옥테닐]-4
Figure kpo00117
-(테트라하이드로피란-2-일옥시)-2
Figure kpo00118
-(7-테트라하이드로피란-2-일옥시)-1-헵틸)시클로펜탄(7b)One
Figure kpo00115
Hydroxy-3
Figure kpo00116
-[(RS)-(E) -3-methyl-3-3- (tetrahydropyran-2-yloxy) -1-octenyl] -4
Figure kpo00117
-(Tetrahydropyran-2-yloxy) -2
Figure kpo00118
-(7-tetrahydropyran-2-yloxy) -1-heptyl) cyclopentane (7b)

1

Figure kpo00119
-(t-부틸디메칠실릴옥시)-3
Figure kpo00120
-[(RS)-(E)-3-메칠-3(테트라하이드로피란-2-일옥시)-1-옥테닐]-4
Figure kpo00121
-(테트라하이드로피란-2-일옥시)-2
Figure kpo00122
-(7-(테트라하이드로피란-2-일옥시)헵틸시클로펜탄(7b)으로 부터 실시예 12a와 같은 방법으로 표제화합물을 얻었다.One
Figure kpo00119
-(t-butyldimethylsilyloxy) -3
Figure kpo00120
-[(RS)-(E) -3-Methyl-3 (tetrahydropyran-2-yloxy) -1-octenyl] -4
Figure kpo00121
-(Tetrahydropyran-2-yloxy) -2
Figure kpo00122
The title compound was obtained in the same manner as in Example 12a from-(7- (tetrahydropyran-2-yloxy) heptylcyclopentane (7b).

NMR(CDCl3) δ: 5.24-5.87(m, 2H), 4.74(br, s, 1H), 4.58(br, s, 1H)NMR (CDCl 3 ) δ: 5.24-5.87 (m, 2H), 4.74 (br, s, 1H), 4.58 (br, s, 1H)

실시예 13aExample 13a

16(RS)-15-데옥시-16-하이드록시-16-메칠-프로스타글란딘 E1메칠 에스테르16 (RS) -15-deoxy-16-hydroxy-16-methyl-prostaglandin E 1 methyl ester

33mg(0.06mmol)의 1a-하이드록시-2

Figure kpo00123
-(7-하이드록시-1-헵틸)-3
Figure kpo00124
-[(RS)-(E)-메칠-3-(테트라하이드로피란-2-일옥시)-1-옥테닐]-4
Figure kpo00125
-(테트라하이드로피란-2-일옥시)시클로펜탄(7a)을 2ml의 N,N-디메칠포름아미드에 희석한후 330mg(0.88mmol)의 피리디니움 디크로메이트를 가하고 상온에서 12시간 동안 교반하였다. 반응혼합물에 냉각수를 부운후 에테르로 3회에 걸쳐 추출하였다. 에테르층을 포화 소금물로 씻어주고 무수황산 마그네슘으로 건조시킨 후에 용매를 감압에서 증발시켰다. 잔사를 1ml의 에테르에 다시 희석시키고 디아조메탄 용액을 가한후 20분동안 교반하였다. 용매를 감압에서 증발시킨후 실리카겔 컬럼에서 헥산내의 25% 에칠 아세테이트 용액으로 용출하여 에테르를 전개 용매로 사용할 경우 R1가 0.8인 화합물을 16mg, Rf가 0.6인 화합물을 11mg 수득하였다. 이 두 화합물들을 식초산과 물과 테트라하이드로푸란이 20 : 10 : 3의 비율로 존재하는 혼합용액 1ml에 희석하고 이틀동안 교반하였다. 반응 용매를 진공에서 증발시키고 실리카 겔 컬럼상에서 헥산내의 50% 에칠 아세테이트 용액으로 용출하여 10mg의 표제화합물을 수득하였다.33 mg (0.06 mmol) of 1a-hydroxy-2
Figure kpo00123
-(7-hydroxy-1-heptyl) -3
Figure kpo00124
-[(RS)-(E) -Methyl-3- (tetrahydropyran-2-yloxy) -1-octenyl] -4
Figure kpo00125
Dilute (tetrahydropyran-2-yloxy) cyclopentane (7a) to 2 ml of N, N-dimethylformamide, add 330 mg (0.88 mmol) of pyridinium dichromate and stir at room temperature for 12 hours. It was. Cooling water was poured into the reaction mixture, followed by extraction three times with ether. The ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated at reduced pressure. The residue was diluted again in 1 ml of ether and diazomethane solution was added and stirred for 20 minutes. The solvent was evaporated under reduced pressure and eluted with a 25% ethyl acetate solution in hexane on a silica gel column to obtain 16 mg of a compound having R 1 of 0.8 and 11 mg of a compound having R f of 0.6 when ether was used as a developing solvent. These two compounds were diluted in 1 ml of a mixed solution in which vinegar acid, water, and tetrahydrofuran were present at a ratio of 20: 10: 3 and stirred for 2 days. The reaction solvent was evaporated in vacuo and eluted with a 50% ethyl acetate solution in hexanes on a silica gel column to afford 10 mg of the title compound.

NMR(CDCl3) δ: 5.72(m, 1H), 5.42(dd, J=15Hz, 1H), 4.02(m, 1H), 3.66(s, 3H), 1.80-2.77(m, 10H), 1.18(s, 3H), 0.93(t, J=6.6Hz, 3H)NMR (CDCl 3 ) δ: 5.72 (m, 1H), 5.42 (dd, J = 15 Hz, 1H), 4.02 (m, 1H), 3.66 (s, 3H), 1.80-2.77 (m, 10H), 1.18 ( s, 3H), 0.93 (t, J = 6.6 Hz, 3H)

IR(neat) : 3449, 2928, 1740, 1160, 973IR (neat): 3449, 2928, 1740, 1160, 973

실시예 13bExample 13b

1

Figure kpo00126
-하이드록시-3
Figure kpo00127
-[(RS)-(E)-3-메칠-3-(테트라하이드로피란-2-일옥시)-1-옥테닐]-4
Figure kpo00128
-(테트라하이드로피란-2-일옥시)-2
Figure kpo00129
-(7-테트라하이드로피란-2-일옥시)-1-헵틸)시클로펜탄(7b)으로 부터 실시예 13a와 같은 방법으로 표제화합물을 얻었다.One
Figure kpo00126
Hydroxy-3
Figure kpo00127
-[(RS)-(E) -3-methyl-3- (tetrahydropyran-2-yloxy) -1-octenyl] -4
Figure kpo00128
-(Tetrahydropyran-2-yloxy) -2
Figure kpo00129
The title compound was obtained in the same manner as in Example 13a from-(7-tetrahydropyran-2-yloxy) -1-heptyl) cyclopentane (7b).

NMR(CDCl3) δ: 5.20-5.80(m, 2H), 4.08(br, q, J=7.0Hz), 3.65(br, t,J=6.4Hz, 1H), 1.80-2.95(m, 9H), 1.08-1.80(m, 18H), 1.18(s, 3Hz), 0.92(br, t, J=6.4Hz, 3H)NMR (CDCl 3 ) δ: 5.20-5.80 (m, 2H), 4.08 (br, q, J = 7.0 Hz), 3.65 (br, t, J = 6.4 Hz, 1H), 1.80-2.95 (m, 9H) , 1.08-1.80 (m, 18H), 1.18 (s, 3 Hz), 0.92 (br, t, J = 6.4 Hz, 3H)

IR(neat) : 3200-3600, 2930, 2860, 1740, 1150, 970IR (neat): 3200-3600, 2930, 2860, 1740, 1150, 970

Claims (1)

다음 일반식(II)의 화합물과 다음 일반식(III)의 화합물을 빗티히 반응을 이용하여 반응시킨 다음 16위치의 하이드록시기를 테트라하이드로피라닐기로 보호하고 9위치의 트리알킬실릴기를 제거한후 산화시킨 다음 1 및 16위치의 보호기를 제거하는 16-하이드록시-16-메칠PGE계 프로스타 글란딘유도체의 제조방법.The following compound of formula (II) and the compound of formula (III) are reacted by using a Wittich reaction, and the hydroxy group at the 16 position is protected by tetrahydropyranyl group, the trialkylsilyl group at the 9 position is removed, and then oxidized. Method of producing a 16-hydroxy-16- methyl PGE-based prostaglandin derivative to remove the protecting groups in the 1 and 16 positions.
Figure kpo00130
Figure kpo00130
 상기식에서, R1은 t-부칠디메칠실릴기이고 ; R2는 t-부칠디메칠실릴기, 테트라하이드로피란-2-이기, 1-에톡시-1-에칠기이고 ; R3는 테트라하이드로피란-2-일기, 1-에톡시-1-에칠기이고 ; X는 하이드록시메칠기, 메톡시카르보닐기이고 ; 파상선은 에피입체 혼합물을 나타낸다.In the above formula, R 1 is a t-butyldimethylsilyl group; R 2 is a t-butyldimethylsilyl group, tetrahydropyran-2-group, and 1-ethoxy-1-ethyl group; R 3 is a tetrahydropyran-2-yl group and a 1-ethoxy-1-ethyl group; X is a hydroxymethyl group and a methoxycarbonyl group; The wavy line represents the epistere mixture.
KR1019900010844A 1990-07-18 1990-07-18 Method for producing of prostaglandin KR930006942B1 (en)

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