KR930006942B1 - Method for producing of prostaglandin - Google Patents
Method for producing of prostaglandin Download PDFInfo
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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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- Prior art keywords
- tetrahydropyran
- yloxy
- group
- hydroxy
- formula
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- 150000003180 prostaglandins Chemical class 0.000 title claims description 5
- 238000004519 manufacturing process Methods 0.000 title description 2
- -1 1-ethoxy-1-ethyl Chemical group 0.000 claims abstract description 38
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims abstract description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims abstract description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims abstract 2
- 125000004665 trialkylsilyl group Chemical group 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 3
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 abstract description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 abstract 2
- 238000007239 Wittig reaction Methods 0.000 abstract 1
- 230000000767 anti-ulcer Effects 0.000 abstract 1
- 230000001590 oxidative effect Effects 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 58
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 37
- 239000000243 solution Substances 0.000 description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 239000002904 solvent Substances 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- BOFNAOHMSHEKQL-UHFFFAOYSA-N heptylcyclopentane Chemical compound CCCCCCCC1CCCC1 BOFNAOHMSHEKQL-UHFFFAOYSA-N 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 6
- WZXLHTGRNRKWOY-UHFFFAOYSA-N 2-cyclopentyloxyoxane Chemical compound C1CCCC1OC1OCCCC1 WZXLHTGRNRKWOY-UHFFFAOYSA-N 0.000 description 5
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UXOGUUJCKQYQKU-UHFFFAOYSA-N [3-(oxan-2-yloxy)cyclopentyl]methanol Chemical compound C1C(CO)CCC1OC1OCCCC1 UXOGUUJCKQYQKU-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- WJVHECBCMNCKGN-UHFFFAOYSA-M (3-hydroxy-3-methylheptyl)-triphenylphosphanium iodide Chemical compound [I-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCC(C)(O)CCCC)C1=CC=CC=C1 WJVHECBCMNCKGN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000498 cooling water Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- ISCGGGVEXDAQCX-UHFFFAOYSA-N 1-iodo-3-methylheptan-3-ol Chemical compound CCCCC(C)(O)CCI ISCGGGVEXDAQCX-UHFFFAOYSA-N 0.000 description 2
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- PZASAAIJIFDWSB-CKPDSHCKSA-N 8-[(1S)-1-[8-(trifluoromethyl)-7-[4-(trifluoromethyl)cyclohexyl]oxynaphthalen-2-yl]ethyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid Chemical compound FC(F)(F)C=1C2=CC([C@@H](N3C4CCC3CC(C4)C(O)=O)C)=CC=C2C=CC=1OC1CCC(C(F)(F)F)CC1 PZASAAIJIFDWSB-CKPDSHCKSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 229940117975 chromium trioxide Drugs 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- RYIOLWQRQXDECZ-UHFFFAOYSA-N phosphinous acid Chemical class PO RYIOLWQRQXDECZ-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- KNJQJOPDTKDGLE-UHFFFAOYSA-M 5-hydroxypentyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCCCO)C1=CC=CC=C1 KNJQJOPDTKDGLE-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- UXFYCPBPDSDURL-UHFFFAOYSA-N ethyl 3-hydroxy-3-methylpentanoate Chemical compound CCOC(=O)CC(C)(O)CC UXFYCPBPDSDURL-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- POXSDSRWVJZWCN-UHFFFAOYSA-N triphenylphosphanium;iodide Chemical compound I.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 POXSDSRWVJZWCN-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Classifications
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
Description
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.
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-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) 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.
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-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 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.
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).
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).
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-벤질옥시메칠-2-(7-하이드록시헵트-2-엔일)-4-(테트라하이드로피란-2-일옥시)시클로펜트-1-올 (2a)3 Benzyloxymethyl-2 -(7-hydroxyhept-2-enyl) -4 -(Tetrahydropyran-2-yloxy) cyclopent-1 -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-벤질옥시메칠-2-하이드록시-5-(테트라하이드로피란-2-일옥시)-3, 3a, 4, 5, 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 Benzyloxymethyl-2-hydroxy-5 -(Tetrahydropyran-2-yloxy) -3, 3a , 4 , 5 , 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-벤질옥시메칠-4-(테트라하이드로피란-2-일옥시)-2-((7-테트라하이드로피란-2-일옥시)헵트-2-엔일)시클로펜트-1-올 (2b)3 Benzyloxymethyl-4 -(Tetrahydropyran-2-yloxy) -2 -((7-tetrahydropyran-2-yloxy) hept-2-enyl) cyclopent-1 -All (2b)
4-벤질옥시메칠-2-하이드록시 5-(테트라하이드로피란-2-일옥시)-3, 3a, 4, 5,6,6a-헥사하이드로-2H-시클로펜타 (b)푸란과 (5-테트라하이드로피란-2-일옥시)트리페닐포스포니움 이오다이드를 사용하여 실시예 1a와 같은 방법으로 표제화합물을 얻었다.4 -Benzyloxymethyl-2-hydroxy 5 -(Tetrahydropyran-2-yloxy) -3, 3a, 4 , 5 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-벤질옥시메칠-1-(t-부틸디메칠실릴옥시)-2-(7-t-부칠디메칠실릴옥시헵트-2-엔일)-4-(테트라하이드로피란-2-일옥시) 시크로펜탄(3a) 건조된 3ml의 디메칠포름아미드에 610mg (1.457mmol)의 3-벤질옥시메칠-2-(7-하이드록시헵트-2-엔일)-4-(테트라하이드로피란-2-일옥시) 시클로펜트-1-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 Benzyloxymethyl-1 -(t-butyldimethylsilyloxy) -2 -(7-t-butylmethylsilyloxyhept-2-enyl) -4 -(Tetrahydropyran-2-yloxy) cyclopentane (3a) in 3 ml of dimethylformamide dried 610 mg (1.457 mmol) of 3 Benzyloxymethyl-2 -(7-hydroxyhept-2-enyl) -4 -(Tetrahydropyran-2-yloxy) cyclopent-1 -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-벤질옥시메칠-1-(t-부칠디메칠실릴옥시)-4-(테트라하이드로피란3 Benzyloxymethyl-1 -(t-butylmethylsilyloxy) -4 Tetrahydropyran
-2-일옥시)-2-(테트라하이드로피란-2-일옥시)헵트-2-엔일)시클로펜탄(3b)2-yloxy) -2 -(Tetrahydropyran-2-yloxy) hept-2-enyl) cyclopentane (3b)
3-벤질옥시메칠-4-(테트라하이드로피란-2-일옥시)-2-(7-테트라하이드로피란-2-일옥시헵트-2-엔일) 시클로펜트-1올(2b)로부터 실시예 2a와 같은 방법으로 표제화합물을 얻었다.3 Benzyloxymethyl-4 -(Tetrahydropyran-2-yloxy) -2 -(7-tetrahydropyran-2-yloxyhept-2-enyl) cyclopent-1 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-(t-부칠디메칠실릴옥시)-2-(7t-부칠디메칠실릴옥시헵틸)-3-하이드록시메칠-4-(테트라하이드로피란-2-일옥시)시클로펜탄(4a) 15ml의 무수에탄올 내의 5% 식초산 용액에 546mg(0.84mmol)의 3β-벤질옥시메칠-1α-(t-부칠디메칠실릴옥시)-4-(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 -(t-butylmethylsilyloxy) -2 -(7t-Butyldimethylsilyloxyheptyl) -3 Hydroxymethyl-4 -(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 -(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-(t-부칠디메칠실릴옥시)-3-하이드록시메칠-4-(테트라하이드로피란-2-일옥시)-2-(테트라하이드로피란-일옥시)헵틸시클로펜탄(4b) 3-벤질옥시메칠-1-(t-부칠디메칠실릴옥시)-4-(테트라하이드로피란-2-일옥시)-2-일옥시)-2-(테트라하이드로피란-2-일옥시)헵틸) 시클로펜탄(3b)으로부터 실시예 3a와 같은 방법으로 표제화합물을 얻었다.One -(t-butyldimethylsilyloxy) -3 Hydroxymethyl-4 -(Tetrahydropyran-2-yloxy) -2 -(Tetrahydropyran-yloxy) heptylcyclopentane (4b) 3 Benzyloxymethyl-1 -(t-butylmethylsilyloxy) -4 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-(t-부칠디메칠실릴옥시)-2-(7-t-부칠디메칠실릴옥시헵틸-3-포르밀-4-(테트라하이드로피란-2-일옥시) 시클로펜탄(IIa)One -(t-butylmethylsilyloxy) -2 -(7-t-butylmethylsilyloxyheptyl-3 Formyl-4 -(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-(t-부칠디메칠실릴옥시)-2-(7-t-부칠디메칠실릴옥시헵틸)-3하이드록시메칠-4-(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 -(t-butylmethylsilyloxy) -2 -(7-t-butylmethylsilyloxyheptyl) -3 Hydroxymethyl-4 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-(t-부칠디메칠실릴옥시)-3-포르밀-4-(테트라하이드로피란-2-일옥시)-2-(7-테트라하이드로피란-2-일옥시) 헵틸시클로펜탄(IIb) 1-(t-부칠디메칠실릴옥시)-3-하이드록시메칠-4-(테트라하이드로피란-2-일옥시)-2-(테트라하이드로피란-2-일옥시)헵틸시크로펜탄(4b)으로부터 실시예 4a와 같은 방법으로 표제 화합물을 얻었다.One -(t-butyldimethylsilyloxy) -3 Formyl-4 -(Tetrahydropyran-2-yloxy) -2 -(7-tetrahydropyran-2-yloxy) heptylcyclopentane (IIb) 1 -(t-butyldimethylsilyloxy) -3 Hydroxymethyl-4 -(Tetrahydropyran-2-yloxy) -2 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--(t-부칠디메칠실릴옥시)-2-(7-t-부칠디메칠실릴옥시헵틸)-3-[(RS)-E-3-하이드록시-3-메칠-1-옥테닐]-4-(테트라하이드로피란-2-일옥시)시클로펜탄(5a)One- -(t-butylmethylsilyloxy) -2 -(7-t-butylmethylsilyloxyheptyl) -3 -[(RS) -E-3-hydroxy-3-methyl-1-octenyl] -4 -(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-(t-부칠디메칠실릴옥시)-3-포르밀-4-(테트라하이드로피란-2-일옥시)-2-(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 -(t-butyldimethylsilyloxy) -3 Formyl-4 -(Tetrahydropyran-2-yloxy) -2 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-(t-부칠디메칠실릴옥시)-3-포르밀-4-(테트라하이드로피란-2-일옥시)-2-(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 -(t-butyldimethylsilyloxy) -3 Formyl-4 -(Tetrahydropyran-2-yloxy) -2 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-[(RS)-(E)-3-하이드록시-3-메칠-1-옥테닐)-4-(테트라하이드로피란-2-일옥시)-2-(7-테트라하이드로피란-2-일옥시)헵틸시클로펜탄(5b)1- (t-butyldimethylsilyloxy) -3 -[(RS)-(E) -3-hydroxy-3-methyl-1-octenyl) -4 -(Tetrahydropyran-2-yloxy) -2 -(7-tetrahydropyran-2-yloxy) heptylcyclopentane (5b)
1-(t-부칠디메칠실릴옥시)-3-포르밀-4-(테트라하이드로피란-2-일옥시)-2-(7-테트라하이드로피란-2-일옥시)헵틸시클로펜탄(IIb)으로 부터 실시예 10a와 같은 방법으로 표제화합물을 얻었다.One -(t-butyldimethylsilyloxy) -3 Formyl-4 -(Tetrahydropyran-2-yloxy) -2 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-(t-부칠디메칠실릴옥시)3--포르밀-4-(테트라하이드로피란-2-일옥시)-2-(7-테트라하이드로피란-2-일옥시)헵틸시클로펜탄으로부터 실시예 10b와 같은 방법으로 실시예 10c의 표제화합물을 얻었다.One -(t-butyldimethylsilyloxy) 3- Formyl-4 -(Tetrahydropyran-2-yloxy) -2 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-(t-부칠디메칠실릴옥시)-2-(7-t-부칠디메칠실릴옥시헵틸)-3[(RS)-(E)-3-메칠-3-(테트라하이드로피란-2-일옥시)-1-옥테닐]-4-(테트라하이드로피란-2-일옥시)시클로펜탄(6a)One -(t-butylmethylsilyloxy) -2 -(7-t-butylmethylsilyloxyheptyl) -3 [(RS)-(E) -3-Methyl-3- (tetrahydropyran-2-yloxy) -1-octenyl] -4 (Tetrahydropyran-2-yloxy) cyclopentane (6a)
74mg(0.11mmol)의 1-(t-부칠디메칠실릴옥시)-2-(7-t-부칠디메칠실릴옥시헵틸)-3-[(RS)-(E)-3-하이드록시-3-메칠-1-옥테닐]-4-(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 -(t-butylmethylsilyloxy) -2 -(7-t-butylmethylsilyloxyheptyl) -3 -[(RS)-(E) -3-hydroxy-3-methyl-1-octenyl] -4 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-(t-부칠디메칠실릴옥시)-3-[(RS)-(E)-3-메칠-3-(테트라하이드로피란-2-일옥시)-1-옥테닐]-4-(테트라하이드로피란-2-일옥시)-2-(7-테트라하이드로피란-2-일옥시)헵틸시클로펜탄(6b)One -(t-butyldimethylsilyloxy) -3 -[(RS)-(E) -3-methyl-3- (tetrahydropyran-2-yloxy) -1-octenyl] -4 -(Tetrahydropyran-2-yloxy) -2 -(7-tetrahydropyran-2-yloxy) heptylcyclopentane (6b)
1-(t-부칠디메칠실릴옥시)-3-[(RS)-(E)-3-하이드록시-3-메칠-1-옥테닐]-4-(테트라하이드로피란-2-일옥시)-2-(7-테트라하이드로피란-2-일옥시)헵틸시클로펜탄(5b)으로부터 실시예 11a와 같은 방법으로 표제화합물을 얻었다.1- (t-butyldimethylsilyloxy) -3 -[(RS)-(E) -3-hydroxy-3-methyl-1-octenyl] -4 -(Tetrahydropyran-2-yloxy) -2 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-하이드록시-2-(7-하이드록시-1-헵틸)-3[(RS)-(E)-메칠-3-(테트라하이드로피란-2-일옥시)-1-옥테닐]-4-(테트라하이드로피란-2-일옥시)시클로펜탄(7a)One Hydroxy-2 -(7-hydroxy-1-heptyl) -3 [(RS)-(E) -Methyl-3- (tetrahydropyran-2-yloxy) -1-octenyl] -4 -(Tetrahydropyran-2-yloxy) cyclopentane (7a)
105mg(0.14mmol)의 1-(t-부칠디메칠실릴옥시)-2-(7-t-부칠디메칠실릴옥시헵틸)-3-[(RS)-(E)-3-메칠-3-(테트라하이드로피란-2-일옥시)-1-옥테닐]-4-(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 -(t-butylmethylsilyloxy) -2 -(7-t-butylmethylsilyloxyheptyl) -3 -[(RS)-(E) -3-methyl-3- (tetrahydropyran-2-yloxy) -1-octenyl] -4 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-하이드록시-3-[(RS)-(E)-3-메칠-3-3-(테트라하이드로피란-2-일옥시)-1-옥테닐]-4-(테트라하이드로피란-2-일옥시)-2-(7-테트라하이드로피란-2-일옥시)-1-헵틸)시클로펜탄(7b)One Hydroxy-3 -[(RS)-(E) -3-methyl-3-3- (tetrahydropyran-2-yloxy) -1-octenyl] -4 -(Tetrahydropyran-2-yloxy) -2 -(7-tetrahydropyran-2-yloxy) -1-heptyl) cyclopentane (7b)
1-(t-부틸디메칠실릴옥시)-3-[(RS)-(E)-3-메칠-3(테트라하이드로피란-2-일옥시)-1-옥테닐]-4-(테트라하이드로피란-2-일옥시)-2-(7-(테트라하이드로피란-2-일옥시)헵틸시클로펜탄(7b)으로 부터 실시예 12a와 같은 방법으로 표제화합물을 얻었다.One -(t-butyldimethylsilyloxy) -3 -[(RS)-(E) -3-Methyl-3 (tetrahydropyran-2-yloxy) -1-octenyl] -4 -(Tetrahydropyran-2-yloxy) -2 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-(7-하이드록시-1-헵틸)-3-[(RS)-(E)-메칠-3-(테트라하이드로피란-2-일옥시)-1-옥테닐]-4-(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 -(7-hydroxy-1-heptyl) -3 -[(RS)-(E) -Methyl-3- (tetrahydropyran-2-yloxy) -1-octenyl] -4 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-하이드록시-3-[(RS)-(E)-3-메칠-3-(테트라하이드로피란-2-일옥시)-1-옥테닐]-4-(테트라하이드로피란-2-일옥시)-2-(7-테트라하이드로피란-2-일옥시)-1-헵틸)시클로펜탄(7b)으로 부터 실시예 13a와 같은 방법으로 표제화합물을 얻었다.One Hydroxy-3 -[(RS)-(E) -3-methyl-3- (tetrahydropyran-2-yloxy) -1-octenyl] -4 -(Tetrahydropyran-2-yloxy) -2 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
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