CN1055921C - 20位改性的维生素d系列衍生物,其制备方法和其药剂 - Google Patents
20位改性的维生素d系列衍生物,其制备方法和其药剂 Download PDFInfo
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- CN1055921C CN1055921C CN93107406A CN93107406A CN1055921C CN 1055921 C CN1055921 C CN 1055921C CN 93107406 A CN93107406 A CN 93107406A CN 93107406 A CN93107406 A CN 93107406A CN 1055921 C CN1055921 C CN 1055921C
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- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 101710146873 Receptor-binding protein Proteins 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- RQPCXPDUSNVHSU-UHFFFAOYSA-N [O].[K] Chemical compound [O].[K] RQPCXPDUSNVHSU-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001262 acyl bromides Chemical class 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- RGVBVVVFSXWUIM-UHFFFAOYSA-M bromo(dimethyl)sulfanium;bromide Chemical compound [Br-].C[S+](C)Br RGVBVVVFSXWUIM-UHFFFAOYSA-M 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001609 comparable effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- BNSOYWDFFBDEFB-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O BNSOYWDFFBDEFB-UHFFFAOYSA-L 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 238000000247 postprecipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 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
- 230000005855 radiation Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 1
- 229940071536 silver acetate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- JXAZAUKOWVKTLO-UHFFFAOYSA-L sodium pyrosulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OS([O-])(=O)=O JXAZAUKOWVKTLO-UHFFFAOYSA-L 0.000 description 1
- HELHAJAZNSDZJO-UHFFFAOYSA-L sodium tartrate Chemical compound [Na+].[Na+].[O-]C(=O)C(O)C(O)C([O-])=O HELHAJAZNSDZJO-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 150000003527 tetrahydropyrans Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 1
- IPSRAFUHLHIWAR-UHFFFAOYSA-N zinc;ethane Chemical group [Zn+2].[CH2-]C.[CH2-]C IPSRAFUHLHIWAR-UHFFFAOYSA-N 0.000 description 1
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
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Abstract
本发明涉及20-位改性的式(Ⅰ)维生素D-衍生物,式中X,Y,Z,R1,R2和R3如说明书所述,其制备方法及其作为为皮肤过量增生疾病治疗剂的应用。
Description
其中Y各为氢或1~9碳烷酰基或芳酰基;Z为氢,羟基或1~9碳烷酰基;X各为氢或两个X共同为环外亚甲基;R1和R2分别为氢,1~4碳烷基,共同为亚甲基或与季碳原子20共同成为环丙基单元,其中两个X为亚甲基时,R1和R2不是甲基;R3各为甲基、乙基或丙基或与叔碳原子共同形成环丙或环戊基环;L为
,其中A为氧,而B为亚烷基-(CH2)n-,其中n=1,2,3,4,5或6并且任何亚甲基可被氧原子代替或L为
其中D为第20和第22碳原子之间的直接键,亚甲基或1,2-乙烯二基桥键,其为E-双键构型,E和F分别为氢或共同为第二键,其中构成E-双键构型,而G为直接键或亚烷基-(CH2)n-,其中n=1,2,3,4,5或6,任何亚甲基可被氧原子代替并且各亚甲基可被羟基或卤原子(氟,氯,溴)取代。
可作Y和Z的酰基或酰氧基尤其衍生自饱和羧酸或苯甲酸。
烷基R3可为甲基,乙基或丙基并且可为与叔碳原子共同形成的环丙或环戊环。
特别优选化合物为:
(5Z,7E)-(1S,3R)-26,27-二甲基-23-氧杂-9,10-断胆甾-5,7,10(19),20-四烯-1,3,25-三醇,
(5Z,7E)-(1S,3R)-26,27-二乙基-23-氧杂-9,10-断胆甾-5,7,10(19),20-四烯-1,3,25-三醇,
(7E)-(1R,3R)-20,26,27-三甲基-23-氧杂-19-降-9,10-断胆甾-5,7-二烯-1,3,25-三醇,
(5Z,7E)-(1S,3R)-26,27-二甲基-20,21-亚甲基-23-氧杂-9,10-断胆甾-5,7,10(19)-三烯-1,3,25-三醇,
(5Z,7E)-(1S,3R)-23-氧杂-9,10-断胆甾-5,7,10(19),20-四烯-1,3,25-三醇,
(5Z,7E)-(1S,3R)-24-(3-羟基-3-甲基丁基)-23-氧杂-9,10-断胆-5,7,10(19),20-四烯-1,3-二醇,
(5Z,7E)-(1S,3R)-24-(3-乙基-3-羟戊基)-23-氧杂-9,10-断胆-5,7,10(19),20-四烯-1,3-二醇,
(5Z,7E)-(1S,3R)-26,27-二乙基-20,21-亚甲基-23-氧杂-9,10-断胆甾-5,7,10(19)-三烯-1,3,25-三醇,
(7E)-(1R,3R)-23-氧杂-19-降-9,10-断胆甾-5,7,20-三烯-1,3,25-三醇
(5Z,7E)-(1S,3R)-20,21-亚甲基-23-氧杂-9,10-断胆甾-5,7,10(19)-三烯-1,325-三醇,
(5Z,7E)-(1S,3R)-24-(3-羟基-3-甲基丁基)-20,21-亚甲基-23-氧杂-9,10-断胆-5,7,10(19)-三烯-1,3-二醇,
(5Z,7E)-(1S,3R)-24-(3-乙基-3-羟戊基)-20,21-亚甲基-23-氧杂-9,10-断胆-5,7,10(19)-三烯-1,3-二醇,
(7E)-(1R,3R)-20-甲基-19-降-23-氧杂-9,10-断胆甾-5,7-二烯-1,3,25-三醇,
(7E)-(1R,3R)-26,27-二乙基-20-甲基-19-降-23-氧杂-9,10-断胆甾-5,7-二烯-1,3,25-三醇,
(7E)-(1R,3R)-24-(3-羟基-3-甲基丁基)-20-甲基-19-降-23-氧杂-9,10-断胆-5,7-二烯-1,3-二醇,
(7E)-(1R,3R)-24-(3-乙基-3-羟戊基)-20-甲基-19-降-23-氧杂-9,10-断胆-5,7-二烯-1,3-二醇
(7E)-(1R,3R)-26,27-二甲基-19-降-23-氧杂-9,10-断胆甾-5,7,20-三烯-1,3,25-三醇,
(7E)-(1R,3R)-26,27-二乙基-19-降-23-氧杂-9,10-断胆甾-5,7,20-三烯-1,3,25-三醇,
(7E)-(1R,3R)-24-(3-羟基-3-甲基丁基)-19-降-23-氧杂-9,10-断胆-5,7,20-三烯-1,3-二醇,
(7E)-(1R,3R)-24-(3-乙基-3-羟戊基)-19-降-23-氧杂-9,10-断胆-5,7,20-三烯-1,3-二醇,
(5Z,7E,22E)-(1S,3R)-24-(2-羟基-2-甲基丙氧基)-9,10-断胆-5,7,10(19),20,22-五烯-1,3-二醇,
(5Z,7E,22E)-(1S,3R)-24-(2-乙基-2-羟丁氧基)-9,10-断胆-5,7,10(19),20,22-五烯-1,3-二醇,
(7E,22E)-(1R,3R)-24-(2-羟基-2-甲基丙氧基)-19-降-9,10-断胆-5,7,20,22-四烯-1,3-二醇,
(7E,22E)-(1R,3R)-24-(2-乙基-2-羟丁氧基)-19-降-9,10-断胆-5,7,20,22-四烯-1,3-二醇。
天然维生素D2和D3(见通式Vit.D)本身无生物活性,可先在肝中于25一位或在肾中于1一位羟基化后转化为其生物活性代谢物,维生素D2和D3的作用在于稳定血浆-Ca++和血浆-磷酸盐水平,可阻止血浆-Ca++水平下降。
麦角骨化醇:Ra=Rb=H,Rc=CH3 维生素D2
双键C-22/23
胆钙化〔甾〕醇:Ra=Rb=Rc=H 维生素D3
25-羟基胆钙化〔甾〕醇:Ra=Rc=H,Rb=OH
1a-羟基胆钙化〔甾〕醇:Ra=OH,Rb=Rc=H
1a-二羟基胆钙化〔甾〕醇:Ra=Rb=OH,Rc=H钙三醇
除了对钙和磷酸盐代谢是有显著作用外,维生素D2和D3及其衍生物还是有阻止细胞增生和细胞分化作用(H.F.De Luca,TheMetabolism and Function of Vitamin D inBiochemistry of Steroid Honmones,Hrsg.H.L.J.Makin,2nd Edition,Blackwell ScientificPublications 1984,S.71-116)。
维生素D应用中有过量问题(高钙血)。
24-位羟基化1α-胆钙化〔甾〕醇已见于DE-A-2526981,其毒性低于相应的非羟基化1α-胆钙化〔甾〕醇,羟基化化合物可选择性活化肠内钙吸收并且骨吸收作用弱于1α-胆钙化〔甾〕醇。
国际专利申请WO87/00834所述24-羟基维生素D类似物可用于治疗不正常细胞增生和/或细胞分化引起的人和动物障碍。
对于多种1,25-二羟基同型维生素D衍生物,有关骨吸收作用和HL-60细胞分化性能的分离最近已由Deluca报到,其中外骨吸收作用为体内钙活动的直接参数。
本发明化合物的维生素D活性可由钙三醇受体试验确定,其中可用取自小猪肠的专一性受体蛋进行(M.C.Dame,E.A.Pierce,H.F.Deluca,Proc.Natl.Acad.Sci.USA82,7825(1985))。
含受体结合蛋白在试管中于4℃有和没有试验物质存在下用反应体积为0.270ml的3H-钙三醇(5×10-10mol/l)保持2小时,为将游离的和结合受体的钙三醇分离可进行木炭-葡聚糖吸收,其中各试管中加250ml木炭-葡聚糖悬浮液并4℃保持20分钟后试样在10000×g下4℃离心分离5分钟,上层清液倾析出来并平衡1小时后在Picofluor 15TM中用β-计数器测定。
用不同浓度的试验物质以及对比物质(未标示钙三醇)在恒定浓度的参考物质(3H-钙三醇)情况下所得竞争曲线相互关联起来而得出竞争因子(KF)。
为确定各种钙三醇衍生物的急性高钙血作用,可进行以下试验。
参考物质(溶剂培养基),对比物质(1,25(OH)2-D3=钙三醇)和试验物质作用可通过在10只天然鼠(140-170g)组中皮下一次注射来进行试验,该试验期间鼠关在特殊的笼中以确定水和矿物质的排泄,两次收集尿样(16h和22h)。口服钙剂(6.5%α-羟丙基纤维素中0.1mM钙,5ml/只动物)以补充因取消饲料而缺少的钙吸入量,试验结束时断头杀死各动物并且为确定血清钙质而使其失血,而为了体内进行初级过筛临床检查,可试验各标准剂量(200μg/kg),选定物质的结果可通过剂量-作用关系而保证得到。
高钙血作用体现在与参考物质比较而提高的血清钙水平值。
物质组和参考组间及试验物质和对比物质间的显著差别可用适宜统计方法保证得到,结果以剂量关系DR(DR=可比作用下试验物质剂量/对比物质剂量的因子)给出。
钙三醇类似物的分化刺激作用必要时可定量得到。
定量收集方法在文献中已知(Mangelsdorf,D.J.etal.,J.Cell.Biol.98;391-398(1984)),其中体外用钙三醇治疗人白血病细胞(PromyelozytenzellinieHL 60),诱发这些细胞分化成巨噬细胞。
HL60-细胞用组织培养基(RPMI-10%胎儿牛犊血清)37℃在5%CO2空气气氛中培养。
试验中细胞离心分离后在无酚红的组织培养基中制成浓度为2.0×105个细胞/ml的悬浮液,再将试验物质溶于乙醇并用无酚红组织培养基稀释到要求浓度,然后将稀释液与细胞悬浮液以1∶10的比例混合并将100ml这种加有试验物质的细胞悬浮液吸移到96孔板凹槽内而参考细胞悬浮液中类似加溶剂。
在5%CO2空气气氛中37℃保持96小时后向96孔板凹槽内的细胞悬浮液中吸移入100ml NBT-TPA液(Nitrobl-autetrazolium(NBT)加料终浓度1mg/ml,Tetradecanoylphorbolmyristat-13-acetat(TPA)加料终浓度2×10-7mol/l)。
在37℃和5%CO2空气气氛中保持2小时,由于细胞内氧自由基释放而得以由TPA刺激,在分化成巨噬细胞的细胞中NBT还原成不溶性甲。
反应结束时从96孔板凹槽中吸出物料并加甲醇使粘附细胞固定后干燥,为使形成的细胞内甲晶体溶解而在各凹槽中吸移入100μl氢氧化钾(2val/l)和100μl二甲基甲酰胺并超声波辐射1分钟,而甲浓度由光谱测定法在650nm下测定。
HL60-细胞分化成巨噬细胞的诱导参数为形成的甲浓度,该结果有时也以上述剂量关系DR给出。
钙三醇受体试验以及HL60-细胞诱导分化剂量关系和高钙组剂量关系测定结果总结如下:
(5Z,7E)-(1S,3R)-24-(3-乙基-3-羟戊基)-23-氧杂-9,10-断胆-5,7,10(19),20-四烯-1,3-二醇(16)
(5Z,7E)-(1S,3R)-26,27-二乙基-20,21-亚甲基-23-氧杂-9,10-断胆甾-5,7,10(19)-三烯-1,3,25-三醇(21)
(7E)-(1R,3R)-20,26,27-三甲基-19-降-23-氧杂-9,10-断胆甾-5,7-二烯-1,3,25-三醇(40)
(7E)-(1R,3R)-24-(3-乙基-3-羟戊基)-19-降-23-氧杂-9,10-断胆-5,7,20-三烯-1,3-二醇(87)
(5Z,7E,22E)-(1S,3R)-24-(2-羟基-2-甲基丙氧基)-9,10-断胆-5,7,10(19),20,22-五烯-1,3-二醇(92)
(5Z,7E,22E)-(1S,3R)-24-(2-乙基-2-羟丁氧基)-9,10-断胆-5,7,10(19),20,22-五烯-1,3-二醇(93)
对比化合物:钙三醇
选定化合物的生物数据:化合物 KF(受体) DR(HL60) DR(高钙血)钙三醇 1 1 116 1.6 0.3 3021 2.2 10 10040 1.5 0.2 587 6.3 1 10092 8.3 1.5 10093 2.2 1 100
通过降低高钙血危险,本发明物质可以优选公式用于制备过量增生疾病的治疗药剂,如皮肤过量增生病(牛皮癣)和恶性肿瘤(白血病,肠癌和乳腺癌)以及痤疮(J.Invest.Dermatol.,Vol.92,No.3,1989),本发明化合物也可用于治疗和预防免疫系统失衡疾病,如自身免疫疾病,包括糖尿病和移植过程中的排斥现象(WO-A-91/00855)。在本发明特别优选的方案中可在治疗前明确所涉及器官中的钙三醇受体。
而且出人意料地发现,通过大鼠、小鼠和海豚皮肤上局部应用来发明化合物可增加皮肤潮红并加大表皮层厚度,其中皮肤潮红的增加可通过提高由色彩测定仪定量测得的皮肤表面红色值而达到,以典型方式间隔24小时3次用药(剂量0.003%)可使红色值提高约1.5倍,而表皮层厚度的加大可用组织切法定量测得,表面层增生细胞(皮肤周期的S-阶段细胞)数目可经导流血细胞计数法测得,其提高因子一般约6。
本发明化合物的这些性解可用药物制剂在萎缩皮肤上显示出来,如在皮肤自然变化过程中,由于光照增强或用糖〔肾上腺〕皮质激素治疗造成的药物诱发皮肤萎缩,会出现早期皮肤变异。
因此,本发明还涉及药物制剂,其中含至少一种式(I)化合物以及药用载体。
这些化合物可在药用溶剂中配制成溶液或在适宜药用溶剂或载体中配制成乳液,悬浮液或分散液或用固体载体按已知方式配制成丸,片或胶囊,而局部用药时这些化合物优选配制成乳膏或软膏或宜于局部应用的常规剂型,而且各些配分还可含其它非毒性药用助剂如稳定剂,抗氧化剂,粘合剂,色素,乳化剂或矫味剂。这些化合物优选服用方式可为注射或静脉输注适宜无菌溶液或经营养途径口服或以乳膏,软膏,洗剂或宜经皮用药的膏剂局部应用,如见于EP-A0387077。
日服用剂量0.1-1000μg/人/天,优选1.0-500μg/人/天。
本发明化合物可按已知“钙三醇”制剂用于治疗牛皮癣的用药方式给药。
此外,本发明还涉及式(I)化合物在药剂制备过程中的应用。
式(I)化合物,特别是其制备过程中必须的初始化合物可用新方法制得,本发明也涉及这些化合物的制备方法。
该化合物制备所用初始物料为式VII已知化合物(见WO90/09991,Leo Pharmaceutical Products)其中Q为烷基-或芳基-取代的甲硅烷基。
Me3S+I-或Me3S+(O)I-类型试剂用碱如叔丁醇钾(KOtBu),NaH或KH脱质子可制得Schwefelyliden,再用其反应可得式VIII化合物,其中C-20上的立体化学结构不必是单一的。
用碱如二异丙氨化锂(LDA),二乙氨化锂(LiNEt2),双(三甲基甲硅烷基)氨化锂(LiN(TMS)2)或异丙醇铝(Al(OiPr)3重排环氧化物VIII可得烯丙醇IX,该化合物可灵活转化成式(I)化合物。
为合成式(I′)中R1和R2共同为亚甲基,L为
且A为氧的化合物,可将式IX化合物用式X化合物醚化其中L为离去基如Br,I,CH3C6H4SO2O;B为亚烷基-(CH2)n-,其中n=1,2或3;R为1-8碳直链或支链烷基以及R4和R5可各为OR基或R4和R5共同为氧,从而得到式XI化合物。
在其羰基上加式XII亲核试剂
R3-M (XII)其中R3为1-5碳直链或支链烷基且M为MgHal(Hal=Cl,Br,I)或碱金属原子(Li,Na,K),从而形成式XIII化合物其中Z′为羟基。
甲硅烷基分离后自由羟基必要时部分或全部用链烷酰氯,-溴或-酸酐或苯甲酰氯酯化,其中烷酰基部分含1-9碳。
例如可在所谓的“三重线增敏剂”存在下经紫外光照射而将式XIII化合物转化成式XIV化合物,其中本发明为此可用蒽,然后将5,6-双键的Pi-键分开,A-环绕5,6-单键转180℃并重新形成5,6-双键即可再次得到5,6-双键立体异构体。
然后脱除已有的羟基保护基,如用氟化四正丁铵进行并且必要时用相应酰卤(酰氯,酰溴)或酸酐按常见方法将自由羟基部分或全部酯化。
为合成式I′中R1和R2与季碳原子20共同为环丙基且L为的化合物,烯丙醇IX先类似于式XIII化合物与式XIV化合物的反应经光化学法异构化成式XV化合物后与I-CH2-Zn-I类型的金属有机试剂反应(Simmons-Smith反应)而形成式XVI化合物,其中用Zn/Cu,Zn/Ag或Et2Zn(二乙基锌)与CH2I2反应制成金属有机试剂。
初始物料可用文献中已知的式XX醛(H.H.Inhoffen etal.Chem.Ber.91,780(1958),Chem.Ber.92,1772(1959))。其中P为氢,1-9碳烷酰基,四氢吡喃基或四氢呋喃基,烷基-或芳基-取代或烷基-和芳基-取代(混合取代)甲硅烷基,其烷酰基优选来自直链或支链饱和羧酸,优选为乙酰基或新戍酰基,而甲硅烷基尤其可举出叔丁基二甲基甲硅烷基,三甲基甲硅烷基,叔丁基二苯基甲硅烷基或三苯基甲硅烷基。
为合成式I″中R1和R2各为亚甲基的化合物,可用碱如NaH,KH,二异丙氨化锂(LDA)或叔丁醇钾(KOtBu)脱质子并与亲电子试剂CH3X(X=Cl,Br,I,CH3C6H4SO2O)反应而形成式XXI化合物。
用还原剂如NaBH4,NaBH4/CeCl3,LiAlH4或氟化二异丁铝将式XXI化合物中的羰基还原得式XXII化合物,再用前述式X化合物醚化而得式XXIII化合物。
在式XXIII化合物的羰基上加式XII亲核试剂而得式XXIV化合物,其中Z′为羟基。
式XXIV化合物中必要时存在的保护基脱除后得式XXV化合物,其中酰基保护基情况下在碱性条件(K2CO3/甲醇,KOH或NaOH/甲醇)下进行,在甲硅烷基保护基情况下用氟化物试剂(氟化四丁铵,HF,HF/吡啶)进行并在四氢吡喃或四氢呋喃醚保护基情况下用酸催化(对甲苯磺酸,PPTS,离子交换剂)进行,其仲羟基用氧化剂(PCC,PDC,Collins反应剂,BaMnO4)氧化并且其叔羟基Z′可被保护而成为例如甲硅烷基醚,如三甲基甲硅烷基醚,其中生成式XXVI化合物其中Z″为甲硅烷氧基,如三甲基甲硅烷氧基,四氢吡喃基或四氢呋喃基。
通过与用碱如正丁基锂(BuLi)或二异丙氨化锂(LDA)产生的文献中已知的膦氧化物XXVII(H.F.Deluca,TetrahedronLett.32,7663(1991))的阴离子反应,其中Q为烷基-或芳基-取代的甲硅烷基,从而得到式XXVIII化合物,其保护基Q和Z″可如上述脱除并必要时使自由羟基酰化。
从而形成式XXXI化合物,其中R1和R2和P如以上定义。
如上所述仅将式XXXIV酮与文献中已知的式XXVII膦氧化物偶联即可得式XXXV化合物,其保护基可如上述脱除并且其自由羟基必要时可酰化。为合成式I′中L为D为20和22碳间的直接键,E和F为E-双键且G为CH2-O-CH2单元的化合物,可用氧化剂(二氧化锰,氯铬酸吡啶鎓,锰酸钡)将式XV醇氧化成式XXXVI醛,氧化剂亦可用重铬酸吡啶鎓。
用碱(NaH,KH,二异丙氨化锂,叔丁醇钾)脱质子化产生的式XXXVII膦酸盐阴离子进行Wadsworth-Emmons反应,
(RO)2P(O)-CH2-COOR′ (XXXVII)其中R和R′分别为1-9碳直链或支链烷基或苯基,从而产生式XXXVIII化合物,其酯基可用还原剂(NaBH4,NaBH4/CeCl3,LiAlH4,氢化二异丁铝〔DIBAH〕)还原成式XXXIX醇。
在其羰基上加上述式R3-M(XII)亲核试剂可生成式XLI化合物,其中B,Q和Z′定义和分解性如上述。
本发明尤其涉及以下中间化合物:
(5E,7E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-20-亚甲基-9,10-断孕甾-5,7,10(19)-三烯-21-醇,
(5Z,7E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-20-亚甲基-9,10-断孕甾-5,7,10(19)-三烯-21-醇,
〔1S-(1,3aβ,4α,7aα)〕-1-〔4-(乙酰氧基)-7a-甲基八氢-1H-茚-1-基〕乙酮(ethanon),
〔1R(1α,3aβ,4α,7aα)〕-4-〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-7a-甲基-β-亚甲基八氢-1H-茚-1-乙醇。
以下实施例详述本发明。
实施例
1.(5E,7E)-(1S,3R,20R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-20,21-桥氧-20-甲基-9,10-断孕甾-5,7,10(19)-三烯(2)
氩气下将3.1g(3.84mmol)(5E,7E)-(1S,3R)-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-9,10-断孕甾-5,7,10(19)-三烯-20-酮(1)(双TBDMS醚,见WO 90/09991,Leo PharmaceuticalProducts)溶于70ml N,N-二甲基甲酰胺(DMF)后加入1.06g(5.2mmol)碘化三甲基锍,冷至0℃后分批加入0.51g(5.2mmol)叔丁醇钾,0℃15分钟后加饱和氯化钠液,用乙酸乙酯萃取后有机相用氯化钠液多次洗涤,硫酸钠干燥并分出溶剂后经硅胶(己烷/乙酸乙酯)提纯剩余物而得2.2g无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,58ppm(s,3H,H-18);0,89u.0,94(2xs,je9H,Si-t-Butyl);1,32(s,3H,H-21);2,31u 2,50(2xd,J=5Hz,je 1H,H-22u H-22’);4,19(m,1H,H-3);4,59(t,J=5,5Hz,1H,H-1);4,70u.4,82(2xs,je 1H,H-19u.H-19’);5,57u.6,31(2xd,J=11Hz,je1H,H-6 u.H-7);7,12-7,68(m,20H,Si-Phenyl)[Es wird durchgngig dieSteroid-Nummerierung verwendet]
2.(5E,7E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-20-亚甲基-9,10-断孕甾-5,7,10(19)-三烯-21-醇(3)
氩气下将0.28g(3.8mmol)二乙胺溶于35ml乙醚并0℃加入2.4ml(3.8mmol)正丁基锂液(己烷中1.6M),该温度下30分钟后滴加0.72g(0.88mmol)(2)的5ml乙醚液并0℃搅拌1小时后室温搅拌1小时,再加氯化钠液,用乙酸乙酯萃取后有机相用氯化钠液洗涤,硫酸钠干燥后剩余物浓缩并用硅胶色谱(己烷/乙酸乙酯)提纯而得360mg无色泡沫状题示化合物以及280mg初始物料。1H-NMR(CDCl3):δ=0,45ppm(s,3H,H-18);0,99u.1,00(2xs,je 9H,Si-t-Butyl);4,08u4,17(2xd,J=14,5Hz,je 1H,H-22u.H-22’);4,29(m,1H,H-3);4,65(m,1H,H-1);4,75u.4,90(2xs,je 1H,H-19u.H-19’);5,03u.5,23(2xs,je1H,H-21u.H-21’);5,67u.6,39(2xd,J=11Hz,je1H,H-6u.H-7);7,20-7,62(m,20H,Si-Phenyl)
3.(5E,7E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-23-氧杂-9,10-断胆-5,7,10(19),20-四烯-24-羧酸-1,1-二甲基乙基酯(4)
将800mg(0.97mmol)(3)加入3ml甲苯中并氩气下加入4.6.ml氢氧化钠水溶液(25%),1.45g(7.4mmol)溴乙酸叔丁酯和22mg硫酸氢四丁铵,室温搅拌过夜后将混合物倒入氯化钠液中,乙酸乙酯萃取,用氯化钠液洗涤有机相,硫酸钠干燥并分出溶剂后硅胶(己烷/乙酸乙酯)提纯粗产品而得640mg无色泡沫状题示化合物。
1H-NMR(CDCl3):δ=0,43ppm(s,3H,H-18);0,96u.0,98(2xs,je 9H,Si-t-Butyl);1,50(s,9H,t-Butylester);3,98(s,2H,H-24);4,02(sbr,2H,H-22);4,29(m,1H,H-3);4,63(m,1H,H-1);4,72u.4,89(2xs,je 1H,H-19u.H-19’),5,07u.5,23(2xs,je 1H,H-21u.H-21’);5,65u.6,39(2xd,J=11Hz,je 1H,H-6u.H-7);7,24-7,65(m,20H,Si-Phenyl)IR(KBr):ν=1750cm-1
4.(5E,7E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-23-氧杂-9,10-断胆甾-5,7,10(19),20-四烯-25-醇(5)
在5ml乙醚中用90mg(3.7mmol)镁屑和522mg(3.7mmol)碘甲烷制成格利雅试剂,0℃仅加350mg(0.37mmol)(4)的2ml四氢呋喃(THF)溶液并室温搅拌1小时后用氯化铵液水解,用乙酸乙酯萃取水相,用氯化钠液洗涤有机相并用硫酸钠干燥,分出溶剂后硅胶色谱(己烷/乙酸乙酯)提纯剩余物而得125mg无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,43ppm(s,3H,H-18);0,98(s,18H,Si-t-Butyl);1,20(s,6H,H-26uH-27);3,21(d,J=9,5Hz,1H,H-24);3,28(d,J=9,5Hz,1H,H-24’);3,94(d,J=12,5Hz,1H,H-22);4,01(d,J=12,5Hz,1H,H-22’);4,30(m,1H,H-3);4,53(m,1H,H-1);4,69u.4,89(2xs,je 1H,H-19u.H-19’);5,02u.5,20(2xs,je 1H,H-21u.H-21’);5,67u.6,41(2xd,J=11Hz,je 1H,H-6u.H-7);7,25-7,65(m,20H,Si-Phenyl)
5.(5E,7E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-26,27-二甲基-23-氧杂-9,10-断胆甾-5,7,10(19),20-四烯-25-醇(6)
在5ml THF中氩气下用350mg(3.2mmol)溴乙烷和78mg(3.2mmol)镁屑制成格利雅试剂并同于4与310mg(0.33mmol)(4)反应而得270mg无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,46ppm(s,3H,H-18);0,90(t,J=7Hz,6H,H-28 u.H-29);0,96u.0,98(2xs,je 9H,Si-t-Butyl);1,56(q,J=7Hz,4H,H-26u.H-27);3,27u.3,32(2xd,J=10Hz,je 1H,H-24u.H-24’);3,92u.4,01(2xd,J=13Hz,je 1H,H-22u.H-22’);4,29(m,1H,H-3);4,64(m,1H,H-1);4,73u.4,90(2xs,je 1H,H-19u.H-19’);5,03u.5,20(2xs,je 1H,H-21u.H-21’);5,65u.6,39(2xd,J=11Hz,je 1H,H-6u.H-7);7,24-7,64(m,20H,Si-Phenyl)
6.(5E,7E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-26,27-二乙基-23-氧杂-9,10-断胆甾-5,7,10(19),20-四烯-25-醇(7)
在5ml THF中氩气下用390mg(3.2mmol)1-溴丙烷和78mg(3.2mmol)镁屑制成格利雅试剂并同于4与310mg(0.33mmol)(4)反应而得265mg无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,44ppm(s,3H,H-18);0,92(t,J=7Hz,6H,H-30u.H-31);0,96u.0,98(2xs,je 9H,Si-t-Butyl);3,24u.3,30(2xd,J=11Hz,je 1H,H-24u.H-24’);3,91u.4,00(2xd,J=13Hz,je 1H,H-22u.H-22’);4,29(m,1H,H-3);4,63(m,1H,H-1);4,73u.4,90(2xs,je 1H,H-19u.H-19’);5,02u.5,20(2xs,je 1H,H-21u.H-21’);5,65u.6,39(2xd,J=11Hz,je 1H,H-6u.H-7);7,23-7,63(m,20H,Si-Phenyl)
7.(5Z,7E)-(1S,3R)-23-氧杂-9,10-断胆甾-5,7,10(19),20-四烯-1,3,25-三醇(8)
在Pyrex-Tauchreaktor中将125mg(0.14mmol)(5),25mg蒽和5μl三乙胺溶于80ml甲苯中并在氮气氛中用高压水银灯(Philips HPK 125)照射15分钟,浓缩后将剩余物溶于20ml THF中,加2.1ml氟化四丁铵液(THF中1M)并60℃氩气下搅拌1小时后将反应混合物搅拌加入饱和碳酸氢钠液,用乙酸乙酯萃取,硫酸钠干燥并分出溶剂,再用硅胶色谱(己烷/乙酸乙酯)多次提纯而得25mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,40ppm(s,3H,H-18);1,12(s,6H,H-26u.H-27);3,12(d,J=9.5Hz,1H,H-24);3,18(d,J=9,5Hz,1H,H-24’);3,83(d,J=14Hz,1H,H-22);3,92(d,J=14Hz,1H,H-22’);4,08(m,1H,H-3);4,31(m,1H,H-1);4,89(s,2H,H-19u.H-21);5,10(s,1H,H-21’);5,25(s,1H,H-19’);5,98u.6,29(2xd,J=11Hz,Je 1H,H-6u.H-7)
8.(5Z,7E)-(1S,3R)-26,27-二甲基-23-氧杂-9,10-断胆甾-5,7,10(19),20-四烯-1,3,25-三醇(9)
类似于7用270mg(0.29mmol)(6)反应并相应提纯后得41mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,49ppm(s,3H,H-18);0,88u.0,90(2xt,J=7Hz,je 3H,H-28u.H-29);1,51(q,J=7Hz,4H,H-26u.H-27);3,22u.3,30(2xd,J=9,5Hz,je 1H,H-24u.H-24’);3,90u.3,98(2xd,J=14Hz,je 1H,H-22u.H-22’);4,18(m,1H,H-3);4,39(m,1H,H-1);4,98(s,2H,H-19u.H-21);5,18(s,1H,H-21’);5,30(s,1H,H-19’);6,05u.6,38(2xd,J=11Hz,je 1H,H-6u.H-7)
9.(5Z,7E)-(1S,3R)-26,27-二乙基-23-氧杂-9,10-断胆甾-5,7,10(19),20-四烯-1,3,25-三醇(10)
类似于7用265mg(0.24mmol)(7)反应并相应提纯后得38mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,48ppm(s,3H,H-18);0,90(t,J=7Hz,6H,H-30u.H-31);3,22u.3,28(2xd,J=9,5Hz,H-24u.H-24’);3,89u.3,98(2xd,J=14Hz,H-22u.H-22’);4,18(m,1H,H-3);4,39(m 1H,H-1);4,98(s,2H,H-19u.H-21);5,17(s,1H,H-21’);5,30(s,1H,H-19’);6,04u.6,38(2xd,J=11Hz,je 1H,H-6u.H-7)
10.(5Z,7E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-20-亚甲基-9,10-断孕甾-5,7,10(19)-三烯-21-醇(11)
将500mg(0.61mmol)(3)溶于80ml甲苯中,与80mg(0.44mmol)蒽和15μl三乙胺反应并在7所述装置中照射18分钟,处理并提纯而得450mg无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,43ppm(s,3H,H-18);0,95u.1,00(2xs,je 9H,Si-t-Butyl);4,05u.4,15(2xd,J=14,5Hz,je 1H,H-22u.H-22’);4,25(m,1H,H-3);4,55(m,1H,H-1);4,83(s,1H,H-19);5,00(s,1H,H-21);5,08(s,1H,H-19’);5,21(s,1H,H-21’);6,02u.6,10(2xd,J=11Hz,je 1H,H-6u.H-7);7,15-7,68(m,20H,Si-Phenyl)
11.3-〔(5Z,7E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-23-氧杂-9,10-断胆-5,7,10(19),20-四烯-24-基〕丙酸甲酯(12)
将500mg(0.61mmol)(11)溶于1ml甲苯中并与2.8ml苛性钠水溶液(25%),12mg硫酸氢四丁铵和681mg(1.83mmol)4-溴原丁酸三甲酯并室温搅拌过夜后倒入氯化钠液中,用乙酸乙酯萃取,用氯化钠液洗涤有机相,硫酸钠干燥后分出溶剂,色谱提纯而得180mg无色泡沫状题示化合物以及130mg未反应离析物。1H-NMR(CDCl3):δ=0.42ppm(s,3H,H-18);0,92u.1,00(2xs,je 9H,Si-t-Butyl);2,47(t,J=7Hz,2H,H-26);3,70(s,3H,COOMe);3,46(m,2H,H-24);3,91(s,2H,H-22);4,24(m,1H,H-3);4,55(m,1H,H-1);4,83(s,1H,H-19);4,98(s,1H,H-21);5,08(s,1H,H-19’);5,17(s,1H,H-21’);6,03u.6,10(2xd,J=11Hz,je 1H,H-6u.H-7);7,22-7,70(m,20H,Si-Phenyl)
12.(5Z,7E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-24-(3-羟基-3-甲基丁基-23-氧杂-9,10-断胆-5,7,10(19),20-四烯(13)
在5ml乙醚中用185mg(1.3mmol)碘甲烷和31mg(1.3mmol)镁屑制成格利雅试剂并同于4与120mg(0.13mmol)(12)反应而得60mg无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,42ppm(s,3H,H-18);0,91u.1,00(2xs,je 9H,Si-t-Butyl);1,23(s,6H,H-28u.H-29);3,48(m,2H,H-24);3,92(s,2H,H-22);4,24(m,1H,H-3);4,54(m,1H,H-3);4,83(s,1H,H-19);5,00(s,1H,H-21);5,09(s,1H,H-19’);5,19(s,1H,H-21’);6,01u.6,09(2xd,J=11Hz,H-6u.H-7);7,22-7,68(m,20H,Si-Phenyl)
13.(5Z,7E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-24-(3-乙基-3-羟戊基)-23-氧杂-9,10-断胆-5,7,10(19),20-四烯(14)
在5ml THF中用142mg(1.3mmol)溴乙烷和31mg(1.3mmol)镁屑制成格利雅试剂并同于4与120mg(0.13mmol)(12)反应而得70mg无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,42ppm(s,3H,H-18);0,88(t,J=7Hz,6H,H-30u,H-31);0,92u.1,00(2xs,je 9H,Si-t-Butyl);1,49(q,J=7Hz,H-28u.H-29);3,46(m,2H,H-24);3,91(s,2H,H-22);4,24(m,1H,H-3);4,54(m,1H,H-1);4,82(s,1H,H-19);4,98(s,1H,H-21);5,08(s,1H,H-19’);5,18(s,1H,H-21’);6,01u.6,09(2xd,J=11Hz,H-6u.H-7);7,23-7,69(m,20H,Si-Phenyl)
14.(5Z,7E)-(1S,3R)-24-(3-羟基-3-甲基丁基)-23-氧杂-9,10-断胆-5,7,10(19),20-四烯-1,3-二醇(15)
将57mg(0.062mmol)(13)溶于5ml THF中并加0.67ml氟化四丁铵液(THF中1M)后60℃搅拌1小时,再加氯化钠液后用乙酸乙酯萃取,用氯化钠液洗涤有机相,硫酸钠干燥并分出溶剂,硅胶色谱(己烷/乙酸乙酯)多次提纯而得9mg无色泡沫状题示化合物1H-NMR(CD2Cl2):δ=0,47ppm(s,3H,H-18);1,19(s,6H,H-28u.H-29);3,42(m,2H,H-24);3,89(s,2H,H-22);4,18(m,1H,H-3);4,39(m,1H,H-1);4,97(s,2H,H-19u.H-21);5,17(s,1H,H-19’);5,30(s,1H,H-21’);6,05u.6,29(2xd,J=11Hz,je 1H,H-6u.H-7)
15.(5Z,7E)-(1S,3R)-24-(3-乙基-3-羟戊基)-23-氧杂-9,10-断胆-5,7,10(19),20-四烯-1,3-二醇(16)
类似于14将67mg(0.07mmol)(14)与0.76ml氟化四丁铵液在5ml THF中反应后提纯而得11mg无色泡沫状题示化合物。
1H-NMR(CD2Cl2):δ=0,47ppm(s,3H,H-18);0,84(t,J=7Hz,6H,H-30u.H-31);1,47(q,J=7Hz,H-28u.H.29);3,40(m,2H,H-24);3,89(m,2H,H-22);4,18(m,1H,H-3);4,39(m,1H,H-1);4,97(s,2H,H-19u.H-21);5,16(s,1H,H-19’);5,30(s,1H,H-21’);6,04u.6,38(2xd,J=11Hz,H-6u.H-7)
16.(5Z,7E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-20,21-亚甲基-9,10-断孕甾-5,7,10(19)-三烯-20-甲醇(17)
用锌粉和乙酸银类似于J.M.Conia et al.(Synthesis549(1972))制成锌/银试剂,氩气下仅将98mg(1.5mmol)试剂加入5ml乙醚中并缓慢滴加268mg(1mmol)二碘甲烷后将反应液稍为煮沸,室温搅拌30分钟并加入200mg(0.24mmol)(11)的5ml乙醚液,室温再搅拌1小时后加0.2ml吡啶,滤除产生的沉淀后用乙酸乙酯稀释滤液,有机相用碳酸氢钠和氯化钠液洗涤,硫酸钠干燥并分出溶剂,剩余物经硅胶色谱(己烷/乙酸乙酯)提纯而得65mg无色泡沫状题示化合物。
1H-NMR(CDCl3):δ=0,20ppm(m,1H,Cyclopropyl);0,34(m,2H,Cyclopropyl);0,55(s,3H,H-18);0,66(m,1H,Cyclopropyl);0,92u.0,99(2xs,je 9H,Si-t-Butyl);3,04u.3,92(2xdbr,J=10,5Hz,je1H,H-22u.H-22’);4,23(m,1H,H-3);4,54(m,1H,H-1);4,82u.5,09(2xs,je 1H,H-19u.H-19’);5,98u.6,10(2xd,J=11Hz,je 1H,H-6u.H-7);7,22-7,68(m,20H,Si-Phenyl)
17.(5Z,7E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-20,21-亚甲基-23-氧杂-9,10-断胆-5,7,10(19)-三烯-24-羧酸-1,1-二甲基乙基酯(18)
类似于3在1ml甲苯中将130mg(17)与0.16g(0.81mmol)溴乙酸叔丁酯,0.7ml氢氧化钠水溶液和3mg硫酸氢四丁铵反应后提纯而得80mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,28-0,42ppm(m,3H,Cyclopropyl);0,53(s,3H,H-18);0,62(m,1H,Cyclopropyl);0,90u.0,98(2xs,je 9H,Si-t-Butyl);1,50(s,9H,t-Butylester);2,99(dbr,J=10,5Hz,1H,H-22);3,72(d,J=10Hz,1H,H-24);3,90(dbr,J=10,5Hz,1H,H-22’);3,90(d,J=10Hz,1H,H-24’);4,25(m,1H,H-3);4,55(m,1H,H-1);4,82u.5,08(2xs,je 1H,H-19u.H-19’);5,99u.6,12(2xd,J=11Hz,je 1H,H-6u.H-7);7,28-7,68(m,20H,Si-Phenyl)
18.(5Z,7E)-(1S,3R)-20,21-亚甲基-23-氧杂-9,10-断胆甾-5,7,10(19)-三烯-1,3,25-三醇(19)
在5ml乙醚中用170mg(1.2mmol)碘甲烷和30mg(1.2mmol)镁屑制成格利雅试剂并同于4与120mg(0.13mmol)(18)反应,所得粗产物同于14直接与1.1ml氟化四丁铵的THF液反应并色谱提纯而得14mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,14-0,30ppm(m,3H,Cyclopropyl);0,54(s,3H,H-18);1,02(m,1H,Cyclopropyl);1,18(s,6H,H-26u.H-27);2,82(d,J=10Hz,1H,H-22);3,05(d,J=9,5Hz,1H,H-24);3,17(d,J=9,5Hz,1H,H-24’);3,68(d,J=10Hz,1H,H-22’);4,09(m,1H,H-3);4,30(m,1H,H-1);4,88u.5,21(2xs,je 1H,H-19u.H-19’);5,91u.6,28(2xd,J=11Hz,je 1H,H-6u.H-7)
19.(5Z,7E)-(1S,3R)-26,27-二甲基-20,21-亚甲基-23-氧杂-9,10-断胆甾-5,7,10(19)-三烯-1,3,25-三醇(20)
用19.4mg(0.8mmol)镁屑和88mg(0.8mmol)溴乙烷制成格利雅试剂并同于4与80mg(0.1mmol)(18)反应,所得粗产物溶于5ml THF并同于14与0.85ml氟化四丁铵的THF液反应后经硅胶色谱(己烷/乙酸乙酯)多次提纯而得22mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,21-0,40ppm(m,3H,Cyclopropyl);0,52(s,3H,H-18);0,85(t,J=7Hz,6H,H-28u.H-29);0,89(m,1H,Cyclopropyl);1,49(q,J=7Hz,4H,H-26u.H-27);2,88(dbr,J=10,5Hz,1H,H-22);3,17(d,J=10Hz,1H,H-24);3,26(d,J=10Hz,1H,H-24’);3,72(dbr,J=10,5Hz,1H,H-22’);4,17(m,1H,H-3);4,39(m,1H,H-1);4,97u.5,29(2xs,je 1H,H-19u.H-19’);6,00u.6,38(2xd,J=11Hz,je 1H,H-6u.H-7)
20.(5Z,7E)-(1S,3R)-26,27-;乙基-20,21-亚甲基-23-氧杂-9,10-断胆甾-5,7,10(19)-三烯-1,3,25-三醇(21)
在5ml THF中用163mg(1.3mmol)1-溴丙烷和32mg(1.3mmol)镁屑制成格利雅试剂并同于4与125mg(0.13mmol)(18)反应,所得粗产物同于14与0.72ml氟化四丁铵液在5ml THF中反应并多次色谱提纯而得26mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,20-0,37ppm(m,3H,Cyclopropyl);0,90(t,J=7Hz,6H,H-30u.H-31);1,08(m,1H,Cyclopropyl);2,87(d,J=10Hz,1H,H-22);3,13(d,J=9,5Hz,1H,H-24);3,23(d,J=9,5Hz,1H,H-24’);3,70(d,J=10Hz,1H,H-22’);4,17(m,1H,H-3);4,37(m,1H,H-1);4,93u.5,28(2xs,je 1H,H-19u.H-19’);5,98u.6,35(2xd,J=11Hz,je 1H,H-6u.H-7)
21.3-〔(5Z,7E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-20,21-亚甲基-23-氧杂-9,10-断胆-5,7,10(19)-三烯-24-基〕丙酸甲酯(22)
400mg(0.48mmol)(17),2.2ml苛性钠水溶液(25%),10mg硫酸氢四丁铵和536mg(1.44mmol)4-溴原丁酸三甲酯在1ml甲苯中同于11反应,提纯而得100mg无色泡沫状题示化合物以及310mg初始物料。1H-NMR(CDCl3):δ=0,18-0,35ppm(m,3H,Cyclopropyl);0,47(s,3H,H-18);0,.53(m,1H,Cyclopropyl);0,88u.0,97(2xs,je 9H,Si-t-Butyl);2,37(t,J=7Hz,2H,H-26);2,74(d,J=10,5Hz,1H,H-22);3,35(m,2H,H-24);3,60(s,3H,COOMe);3,62(d,J=10,5Hz,1H,H-22’);4,17(m,1H,H-3);4,48(m,1H,H-1);4,76u.5,02(2xs,je1H,H-19u.H-19’);5,90u.6.02(2xd,J=11Hz,je 1H,H-6u.H-7);7,20-7,60(m,20H,Si-Phenyl)
22.(5Z,7E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-24-(3-乙基-3-羟戊基)-20,21-亚甲基-23-氧杂-9,10-断胆-5,7,10(19)-三烯(23)
在5mlTHF中用305mg(2.8mmol)溴乙烷和68mg(2.8mmol)镁屑制成格利雅试剂并同于4与145mg(0.15mmol)(22)反应而得103mg无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,28-0,45ppm(m,3H,Cyclopropyl);0,52(s,3H,H-18);0,61(m,1H,Cyclopropyl);0,88(t,J=7Hz,6H,H-30u.H-31);0,90u.0,99(2xs,je 9H,Si-t-Butyl);2,86(d,J=10Hz,1H,H-22);3,39(m,2H,H-24);3,70(d,J=10Hz,1H,H-22’);4,23(m,1H,H-3);4,54(t,J=6Hz,1H,H-1);4,82u.5,09(2xs,je 1H,H-19u.H-19’);5,98u,6,09(2xd,J=11Hz,je 1H,H-6u.H-7);7,22-7,68(m,20H,Si-Phenyl)
23.(5Z,7E)-(1S,3R)-24-(3-乙基-3-羟戊基)-20,21-亚甲基-23-氧杂-9,10-断胆-5,7,10(19)-三烯-1,3-二醇(24)
在5ml THF中同于11将100mg(0.1mmol)(23)与1ml氟化四丁铵反应并提纯而得21mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,10-0,29ppm(m,3H,Cyclopropyl);0,51(s,3H,H-18);0,78(t,J=7Hz,H-30u.H-31);1,01(m,1H,Cyclopropyl);1,38(q,J=7Hz,4H,H-28u.H-29);2,78(d,J=10Hz,1H,H-22);3,28(m,2H,H-24);3,58(d,J=10Hz,1H,H-22’);4,09(m,1H,H-3);4,30(m,1H,H-1);4,88u.5,22(2xs,je 1H,H-19);5,91u.6,29(2xd,J=11Hz,je 1H,H-6u.H-7)
24.〔1S-(1α,3aβ,4α,7aα)〕-4-(乙酰氧基)八氢-α,α,7a-三甲基-1H-茚-1-乙醛(25)
在120ml THF中用900mg(30mmol)氢化钠(80%)制成悬浮液并氢气下0℃滴入6.3g(25mmol)〔1R-〔1α(S*),3aβ,4α,7aα〕〕-4-(乙酰氧基)-α,7a-二甲基八氢-1H-茚-1-乙醛(H.H.Inhoffen etal.Chem.Ber.91,780(1958),Chem.Ber.92,1772(1959))的60ml THF液,30分钟后再滴加19.65g(75mmol)甲基碘并50℃搅拌6小时,冷却后将反应混合物倒入氯化钠液中,用乙酸乙酯萃取,有机相用氯化钠液洗涤后硫酸钠干燥并分出溶剂,剩余物经硅胶色谱(己烷/乙酸乙酯)提纯而得3.2g无色油状题示化合物。1H-NMR(CDCl3):δ=0,82ppm(s,3H,H-18);1,05u 1,08(2xs,je 3H,H-21uC-20-Methyl);1,99(s,3H,OAc);5,09(m,1H,H-8);9,60(s,1H,H-22)IR(Film):ν=1725,1710cm-1
25.〔1S-(1α,3aβ,4α,7aα)〕-4-(乙酰氧基)八氢-β,β,7a-三甲基-1H-茚-1-乙醇(26)
将350mg(1.3mmol)(25)溶于5ml THF和5ml甲醇中并加入193mg(1.4mmol)三氯化铈七水合物,0℃分批加入仅46mg(1.2mmol)硼氢化钠并再搅拌1小时,然后用氯化钠液水解,用乙酸乙酯萃取,有机相用氯化钠液洗涤后用硫酸钠干燥并浓缩,剩余物经硅胶色谱(己烷/乙酸乙酯)提纯而得285mg无色油状题示化合物。
1H-NMR(CDCl3):δ=0,90ppm(s,3H,H-18);1,00u.1,01(2xs,je 3H,H-21u.C-20-Methyl);2,05(s,3H,OAc);3,29u.3,37(2xd,J=10,5Hz,je 1H,H-22u.H-22’);5,16(m,1H,H-8)IR(Film):ν=1725cm-1
26.〔1S-(1α,3aβ,4α,7aα)〕-1,1-二甲基乙基-〔2-〔4-(乙酰氧基)-7a-甲基八氢-1H-茚-1-基〕-2-甲基丙氧基〕乙酸酯(27)
将3.04g(11.3mmol)(26)溶于40ml甲苯中,氩气下加11.9(61.3mmol)溴乙酸叔丁酯,33.9ml氢氧化钠水溶液(25%)和172mg硫酸氢四丁铵,室温搅拌48小时后倒入氯化钠液,用乙酸乙酯萃取后,有机相用氯化钠液洗涤后用硫酸钠干燥并分出溶剂,剩余物用硅胶色谱(己烷/乙酸乙酯)提纯而得1.1g无色油状题示化合物以及1.93g初始物料。1H-NMR(CDCl3):δ=0,88ppm(s,3H,H-18);0,93u.0,99(2xs,je 3H,H-21u.C-20-Methyl);1,41(s,9H,t-Butylester);1,99(s,3H,OAc);3,03u.3,20(2xd,J=9Hz,je1H,H-22u.H-22’);3,82u.3,90(2xd,J=16Hz,je 1H,H-24u.H-24’);5,09(m,1H,H-8)
27.〔1S-(1α,3aβ,4α,7aα)〕-1-〔1,1-二甲基-2-(2-乙基-2-羟丁氧基)乙基〕-7a-甲基八氢-1H-茚-4-醇(28)
在20ml THF中用10.8g(100mmol)溴乙烷和928mg(88mmol)镁屑制成格利雅试剂并0℃加1.1g(2.8mmol)(27)的39ml THF溶液,室温搅拌1小时后将反应混合物倒入饱和氯化铵液中,用乙酸乙酯萃取后有机相用氯化钠液洗涤,用硫酸钠干燥并蒸出溶剂后粗产物经硅胶色谱(己烷/乙酸乙酯)提纯而得995mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,88ppm(s,3H,H-18);0,90(t,J=7Hz,6H,H-28u.H-29);1,00u.1,07(2xs,je 3H,H-21u.C-20-Methyl);1,51(q,J=7Hz,4H,H-26u.H-27);3,11u.3,16(2xd,J=9,5Hz,je 1H,H-22u.H-22’);3,21u.3,27(2xd,J=9,5Hz,je 1H,H-24u.H-24’);4,09(m,1H,H-8)
28.〔1S-(1α,3aβ,4α,7aα)〕-1-〔1,1-二甲基-2-(2-羟基-2-甲基丙氧基)乙基〕-7a-甲基八氢-1H-茚-4-醇(29)
在20ml乙醚中用2.04g(14.4mmol)碘甲烷和350mg(14.4mmol)镁屑制成格利雅试剂并同于27与690mg(1.8mmol)(27)反应而得410mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,87ppm(s,1H,H-18);0,94u.1,00(2xs,je 3H,H-21u.C-20-Methyl);1,15(s,3H,H-26u.H-27);2,31(sbr,1H,OH);3,09(s,2H,H-22);3,11(d,J=9,5Hz,1H,H-24);3,18(d,J=9,5Hz,1H,H-24’);4,02(m,1H,H-8)
29.〔1S-(1α,3aβ,4α,7aα)〕-1-〔1,1-二甲基-2-(2-羟基-2-丙基戊氧基)乙基〕-7a-甲基八氢-1H-茚-4-醇(30)
在20ml THF中用1.97g(14.4mmol)1-溴丙烷和350mg(14.4mmol)镁屑制成格利雅试剂并同于27与690mg(1.8mmol)(27)反应而得630mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,82ppm(s,3H,H-18);0,84(t,J=7Hz,6H,H-30u.H-31);0,93u.0,98(2xs,je 3H,H-21u.C-20-Methyl);2,29(t,J=6Hz,1H,OH);3,07(s,2H,H-22);3,12(d,J=9,5Hz,1H,H-24);3,18(d,J=9,5Hz,1H,H-24’);4,01(m,1H,H-8)
30.〔1S-(1α,3aβ,7aα)〕-1-〔1,1-二甲基-2-(2-乙基-2-羟丁氧基)乙基〕-7a-甲基八氢-4H-茚-4-酮(31)
氩气下将890mg(2.8mmol)(28)的10ml二氯甲烷液滴入1.41g(6.6mmol)氯铬酸吡啶鎓的50ml二氯甲烷悬浮液中,室温2小时后用乙醚稀释,用Celite多次过滤后分出溶剂,剩余物用硅胶色谱(己烷/乙酸乙酯)提纯而得696mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,72ppm(s,3H,H-18);0,90(t,J=7Hz,6H,H-28u.H-29);0,92u.1,02(2xs,je 3H,H-21u.C-20-Methyl);1,52(q,J=7Hz,4H,H-26u.H-27);3,18(s,2H,H-22);3,22u.3,28(2xd,J=9,5Hz,je 1H,H-24u.H-24’)
31.〔1S-(1α,3aβ,7aα)〕-1-〔1,1-二甲基-2-(2-羟基-2-甲基丙氧基)乙基〕-7a-甲基八氢-4H-茚-4-酮(32)
在20ml二氯甲烷中同于30将410mg(1.37mmol)(29)与379mg(1.76mmol)氯铬酸吡啶鎓反应而得273mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,76ppm(s,3H,H-18);0,88u.0,97(2xs,je 1H,H-21uC-20-Methyl);1,15(s,6H,H-26u.H-27);2,36(dd,J=10,5,7,5Hz,1H,H-14);3,12(s,2H,H-22);3.12(d.J=9,5Hz.1H.H-24);3.19(d.J=9.5Hz,1H.H-24’)
32.〔1S-(1α,3aβ,7aα)〕-1-〔1,1-二甲基-2-(2-羟基-2-丙基戊氧基)乙基〕-7a-甲基八氢-4H-茚-4-酮(33)
在20ml二氯甲烷中同于30将640mg(1.83mmol)(30)与503mg(2.34mmol)氯铬酸吡啶鎓反应而得386mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,75ppm(s,3H,H-18);0,86(t,J=7Hz,6H,H-30u.H-31);0,86u.0,95(2xs,je 3H,H-21u.C-20-Methyl);2,35(dd,J=10,5,7,5Hz,1H,H-14);3,08(s,2H,H-22);3,13(d,J=9,5,2H,H-22);3,18(d,J=9,5Hz,1H,H-22’)
33.〔1S-(1α,3aβ,7aα)〕-1-〔1,1-二甲基-2-〔2-乙基-2-〔(三甲基甲硅烷基)氧代〕丁氧基〕乙基〕-7a-甲基八氢-4H-茚-4-酮(34)
氩气下将696mg(2.1mmol)(31),571mg(8.4mmol)咪唑和456mg(4.2mmol)三甲基氯硅烷溶于10mlDMF中并室温搅拌过夜,然后加氯化钠液,用乙酸乙酯萃取,有机相用氯化钠液洗涤,用硫酸钠干燥并分出溶剂后剩余物经硅胶色谱(己烷/乙酸乙酯)提纯而得766mg无色油状题示化合物。1H-NMR(CD2Cl2):δ=0,10ppm(s,9H,SiMe3);0,70(s,3H,H-18);0,82(t,J=7Hz,6H,H-28u.H-29);0,91u.1,03(2xs,je 3H,H-21u.C-20-Methyl);1,53(q,J=7Hz,4H,H-26u.H-27);3,05u.3,13(2xd,J=9Hz,je 1H,H-22u.H-22’);3,20u.3,24(2xd,J=9,5Hz,je 1H,H-24u.H-24’)
34.〔1S-(1α,3aβ,7aα)〕-1-〔1,1-二甲基-2-〔2-甲基-2-〔(三甲基甲硅烷基)氧代〕丙氧基〕乙基〕-7a-甲基八氢-4H-茚-4-酮(35)
在30ml乙醚中同于33将270mg(0.92mmol)(32)与300mg(2.76mmol)三甲基氯硅烷,248mg(3.59mmol)咪唑和0.37ml吡啶反应而得272mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,11ppm(s,9H,SiMe3);0,72(s,3H,H-18);0,91u.1,02(2xs,je 3H,H-21u.C-20-Methyl);1,23(s,6H,H-26u.H-27);2,41(dd,J=10,5,7,5Hz,1H,H-14);3,11(d,J=9,5Hz,1H,H-22);3,14(2xd,J=9,5Hz,je 1H,H-22’u.H-24);3,19(d,J=9,5Hz,1H,H-24’)
35.〔1S-(1α,3aβ,7aα)〕-1-〔1,1-二甲基-2-〔2-丙基-2-〔(三甲基甲硅烷基)氧代〕戊氧基〕乙基〕-7a-甲基八氢-4H-茚-4-酮(36)
在30ml乙醚中同于33将383mg(1.10mmol)(33)与358mg(3.30mmol)三甲基氯硅烷,296mg(4.29mmol)咪唑和0.44ml吡啶反应而得386mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,11ppm(s,9H,SiMe3);0,73(5,3H,H-18);0,90(t,J=7Hz,6H,H-30u.H-31);0,91u.1,03(2xs,je 3H,H-21u.C-20-Methyl);2,42(dd,J=10,5,7,5Hz,1H,H-14);2,92u.3,00(2xd,J=9,5Hz,je 1H,H-22u.H-22’);3,08u.3,12(2xd,J=9,5Hz,je1H,H-24u.H-24’)
36.(7E)-(1R,3R)-1,3-双〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-20,26,27-三甲基-25-〔(三甲基甲硅烷基)氧代〕-19-降-23-氧杂-9,10-断胆甾-5,7-二烯(37)
将200mg(0.35mmol)(3R-反式)-〔2-〔3,5-双〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕亚环己基〕乙基〕二苯基膦氧化物〔H.F.Deluca et al.Tetrahedron Lett.32,7663(1991))溶于10mlTHF中并氩气下冷至-70℃,然后仅滴加0.21ml(0.36mmol)正丁基锂液(己烷中1.6M),5分钟后滴入277mg(0.7mmol)(34)的4ml THF液并于该温度下搅拌30分钟,之后用酒石酸钾-钠/碳酸氢钾液水解,用乙酸乙酯萃取,有机相用氯化钠液洗涤,用硫酸钠干燥并分出溶剂,剩余物经硅胶色谱(己烷/乙酸乙酯)提纯而得80mg无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,00ppm(s,12H,SiMe2);0,07(s,9H,SiMe3);0,58(s,3H,H-18);0,80(t,J=7Hz,6H,H-28u.H-29);0,82(s,18H,Si-t-Butyl);0,88u.0,98(2xs,je 3H,H-21u.C-20-Methyl);2,98u.3,08(2xd,J=9Hz,je 1H,H-22u.H-22’);3,12u.3,18(2xd,J=9,5Hz,je 1H,H-24u.H-24’);4,02(m,2H,H-1u.H-3);5,76u.6,12(2xd,J=11Hz,je 1H,H-6u.H-7)
37.(7E)-(1R,3R)-1,3-双〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-20-甲基-25-〔(三甲基甲硅烷基)氧代〕-19-降-23-氧杂-9,10-断胆甾-5,7-二烯(38)
类似于36用61mg(0.16mmol)(33)反应而得75mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,04,0,05,0,11ppm(3xs,21H,SiMe);0,62(s,3H,H-18);0,87u.0,88(2xs,je 9H,Si-t-Butyl);0,90u.1,01(2xs,je 3H,H-21u.C-20-Methyl);1,22(s,6H,H-26u.H-27);3,10(d,J=9,5Hz,H-22);3,12(d,J=9,5Hz,1H,H-24);3,17(d,J=9,5Hz,1H,H-22’);3,18(d,J=9,5Hz,1H,H-24’);4,08(m,2H,H-1u.H-3);5,80 u.6,18(2xd,J=11Hz,je 1H,H-6u.H-7)
38.(7E)-(1R,3R)-1,3-双〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-26,27-二乙基-20-甲基-25-〔(三甲基甲硅烷基)氧代〕-19-降-23-氧杂-9,10-断胆甾-5,7-二烯(39)
类似于36用126g(0.30mmol)(35)反应而得193mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,04,0,05,0,10ppm(3xs,21H,SiMe);0,62(s,3H,H-18);0,88(t,J=7Hz,6H,H-30u.H-31);0,87(2xs,je 9H,Si-t-butyl);0,92u.1,02(2xs,je 3H,H-21u.C-20-Methyl);3,03u.3,12(2xd,J=9,5Hz,je 1H,H-22);3,18u.3,21(2xd,J=9,5Hz,je 1H,H-24);4,08(m,2H,H-1u-H-3);5,81u.6,18(2xd,J=11Hz,je 1H,H-6u-H-7)
39.(7E)-(1R,3R)-20,26,27-三甲基-19-降-23-氧杂-9,10-断胆甾-5,7-二烯-1,3,25-三醇(40)
将80mg(0.106mmol)(37)溶于12ml THF中并氩气下加183mg(0.58mmol)氟化四丁铵后55℃搅拌2小时,然后加入氯化钠液,用乙酸乙酯萃取,有机相用氯化钠液洗涤,用硫酸钠干燥并分出溶剂,剩余物经硅胶色谱(己烷/乙酸乙酯)提纯而得24mg题示化合物无色晶体。1H-NMR(CD2Cl2):δ=0,63ppm(s,3H,H-18);0,85(t,J=7Hz,6H,H-28u.H-29);0,93u.1,00(2xs,je 3H,H-21u.C-20-Methyl);1,49(q,J=7Hz,4H,H-26u.H-27);3,15u.3,17(2xd,J=9Hz,je 1H,H-22u.H-22’);3,22u.3,27(2xd,J=9,5Hz,je 1H,H-24u.H-24’);3,98u.4,07(2xm,je 1H,H-1u.H-3);5,85u.6,28(d,J=11Hz,je 1H,H-6u.H-7)UV(MeOH):λmax=251nm,Fp:155℃
40.(7E)-(1R,3R)-20-甲基-19-降-23氧杂-9,10-断胆甾-5,7-二烯-1,3,25-三醇(41)
在5ml THF中同于39将72mg(0.10mmol)(38)与234mg(0.75mmol)氟化四丁铵反应并提纯而得29mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,57ppm(s,3H,H-18);0,87u.0,94(2xs,je 3H,H-21u.C-20-Methyl);1,10(s,6H,H-26u.H-27);3,09(d,J=9,5Hz,1H,H-24);3,10(s,2H,H-22);3,13(d,J=9,5Hz,1H,H-24’);3,91u.3,99(2xm,je 1H,H-1u.H-3);5,77u.6,20(d,J=11Hz,je 1H,H-6u.H-7)
41.(7E)-(1R,3R)-26,27-二乙基-20-甲基-19-降-23-氧杂-9,10-断胆甾-5,7-二烯-1,3,25-三醇(42)
在12ml THF中同于39将190mg(0.24mmol)(39)与571mg(1.83mmol)氟化四丁铵反应并提纯而得87mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,57ppm(s,3H,H-18);0,84(t,J=7Hz,6H,H-30u.H-31);0,85u.0,92(2xs,je 3H,H-21u.C-20-Methyl);3,08(s,2H,H-22);3,11(d,J=9,5Hz,1H,H-24);3,17(d,J=9,5Hz,1H,H-24’);3,91u.3,99(2xm,je 1H,H-1u.H-3);5,77u.6,20(2xd,J=11Hz,je 1H,H-6u.H-7)
42.〔1S-(1α,3aβ,4α,7aα)〕-4-〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕八氢-α,α,7a-三甲基-1H-茚-乙醛(43)
在130ml THF中同于24将9.2g(28.34mmol)〔1R-〔1α(S*),3aβ,4α,7aα〕〕-α,7a-二甲基-4-〔〔二甲基-(1,1-二甲基乙基)甲硅烷基〕氧代〕八氢-1H-茚-1-乙醛(W.G.D.auben et al.Tetranedron Lett.30,6m(1989)与1.02g(34.05mmol)氢化钠(80%)和12.07g(85.03mmol)碘甲烷反应而得7.89g无色油状题示化合物。1H-NMR(CDCl3):δ=0,01ppm(2xs,je 3H,SiMe);0,88(s,9H,Si-t-Butyl);0,98(s,3H,H-18);1,09u.1,12(2xs,je 3H,H-21u.C-20-Methyl);4,01(m,1H,H-8);9,68(s,1H,H-22)
43.〔1S-(1α,3aβ,4α,7aα)〕-4-〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕八氢-β,β,7a-三甲基-1H-茚-1-乙醇(44)
在27ml THF/27ml甲醇中同于25将3.5g(10.33mmol)(43)与1.53g(11.1mmol)三氯化铈七水合物和365mg(9.53mmol)硼氢化钠反应而得2.36g无色油状题示化合物。1H-NMR(CDCl3):δ=0,01ppm(2xs,je 3H,SiMe);0,89(s,9H,Si-t-Butyl);0,89(s,3H,H-18);0,99u.1,05(2xs,je 3H,H-21u.H-20-Methyl);1,60(t,J=5Hz,1H,OH);3,30(dd,J=11,5,5Hz,1H,H-22);3,36(dd,J=11,5Hz,1H,H-22’);4,00(m,1H,H-8)
44.〔1S-(1α,3aβ,4α,7aα)〕-4-〔2-〔4-〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-7a-甲基八氢-1H-茚-1-基〕-2-甲基丙氧基〕丁酸甲酯(45)
在9.3ml苛性钠溶液(25%)和3ml甲苯中同于11将2.36g(6.93mmol)(44)与6.3g(27.7mmol)4-溴原丁酸三甲酯和366mg硫酸氢四丁铵反应而得3.14g无色油状题示化合物。1H-NMR(CDCl3):δ=0,01ppm(2xs,je 3H,SiMe);0,89(s,9H,Si-t-Butyl);0,89(s,3H,H-18);0,98u.1,03(2xs,je 3H,H-21u.C-20-Methyl);2,41(t,J=7Hz,2H,H-26);3,03(d ,J=9Hz,1H,H-22);3,10(d,J=9Hz,1H,H-22’);3,38(t,J=7Hz,2H,H-24);3,70(s,3H,COOMe);4,00(m,1H,H-8)
45.〔1S-(1α,3aβ,4α,7aα)〕-5-〔2-〔4-〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-7a-甲基八氢-1H-茚-1-基〕-2-甲基丙氧基〕-2-甲基-2-戊醇(46)
在10ml乙醚中用1.21g(8.5mmol)碘甲烷和206mg(8.5mmol)镁屑制成格利雅试剂并同于27与750mg(1.7mmol)(45)反应而得453mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,02ppm(2xs,je 3H,SiMe);0,89(s,9H,Si-t-Butyl);0,92(s,3H,H-18);1,00u.1,04(2xs,je 3H,H-21u.C-20-Me);1,22(s,6H,H-28u.H-29);3,09(d,J=9,5Hz,1H,H-22);3,18(d,J=9,5Hz,1H,H-22’);3,42(t,J=7Hz,2H,H-24);4,00(m,1H,H-8)
46.〔1S-(1α,3aβ,4α,7aα)〕-1-〔2-〔4-〔〔二甲基(1,1-甲基乙基)甲硅烷基〕氧代〕-7a-甲基八氢-1H-茚-1-基〕-2-甲基丙氧基〕-4-乙基-4-己醇(47)
在20ml THF中用935mg(8.5mmol)溴乙烷和206mg(8.5mmol)镁屑制成格利雅试剂并同于27与750mg(1.7mmol)(45)反应而得412mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,01ppm(2xs,je 3H,SiMe);0,88(t,J=7Hz,6H,H-30u.H-31);0,89(s,9H,Si-t-Butyl);0,90(s,3H,H-18);1,00u.1,04(2xs,je 3H,H-21u.C-20-Methyl);1,48(q,J=7Hz,4H,H-28u.H-29);3,07(d,J=9,5Hz,1H,H-22);3,14(d,J=9,5Hz,1H,H-22’);3,40(t,J=7Hz,2H,H-24);3,99(m,1H,H-8)
47.〔1α-(1α,3aβ,4α,7aα)〕-1-〔1,1-二甲基-〔2-(4-羟基-4-甲基戊氧基)乙基〕-7a-甲基八氢-1H-茚-4-醇(48)
在8.2ml THF/乙腈(1∶1)中将400mg(0.91mmol)(46)与4.1ml氢氟酸(40%)室温搅拌30分钟后用苛性钠稀溶液中和,用乙酸乙酯萃取,有机相用氯化钠液洗涤并用硫酸钠干燥,分出溶剂后的剩余物色谱提纯而得266mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,84ppm(s,3H,H-18);0,92u.1,00(2xs,je 3H,H-21u.C-20-Methyl);1,17(s,6H,H-28u.H-29);3,01u.3.09(2xd,J=9,5Hz,je 1H,H-22u.H-22’);3,36(t,J=7Hz,2H,H-24);4,00(m,1H,H-8)
48.〔1S-(1α,3aβ,4α,7aα)〕-1-〔1,1-二甲基-〔2-(4-乙基-4-羟己氧基)乙基〕-7a-甲基八氢-1H-茚-4-醇(49)
在7.8ml THF/乙腈(1∶1)同于47将412mg(0.87mmol)(47)与3.9ml氢氟酸(40%)反应而得251mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,80ppm(t,J=7Hz,6H,H-30u.H-31);0,82(s,3H,H-18);0,93u.0,99(2xs,je 3H,H-21u.C-20-Methyl);1,42(q,J=7Hz,4H,H-28u.H-29);3,00u.3,08(2xd,J=9,5Hz,je 1H,H-22u.H-22’);3,33(t,J=7Hz,2H,H-24);4,00(m,1H,H-8)
49.〔1S-(1α,3aβ,7aα)〕-1-〔1,1-二甲基-〔2-(4-羟基-4-甲基戊氧基)乙基〕-7a-甲基八氢-4H-茚-4-酮(50)
在16ml二氯甲烷中同于30将260mg(0.80mmol)(48)与240mg(1.12mmol)氯铬酸吡啶鎓反应而得201mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,69ppm(s,3H,H-18);0,88u.1,01(2xs,je 3H,H-21u.C-20-Methyl);1,22(s,6H,H-28u.H-29);2,42(dd,J=10,5,7,5Hz,1H,H-14);3,07u.3,13(2xd,J=9,5Hz,je 1H,H-22u.H-22’);3,39(t,J=7Hz,2H,H-24)
50.〔1S-〔1α,3aβ,7aα)〕-1-〔1,1-二甲基-〔2-(4-乙基-4-羟己氧基)乙基〕-7a-甲基八氢-4H-茚-4-酮(51)
在16ml二氯甲烷中同于30将251mg(0.71mmol)(49)与212mg(0.99mmol)氯铬酸吡啶鎓反应而得183mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,70ppm(s,3H,H-18);0,86(t,J=7Hz,6H,H-30u.H-31);0,90u.1,01(2xs,je 3H,H-21u.H-20-Methyl);1,48(q,J=7Hz,4H,H-28u.H-29);2,42(dd,J=10,5,7,5Hz,1H,H-14);3,08u.3,15(2xd,J=9,5Hz,je 1H,H-22u.H-22’);3,40(t,J=7Hz,2H,H-24)
51.〔1S-(1α,3aβ,7aα)〕-1-〔1,1-二甲基-〔2-〔4-甲基-〔(三甲基甲硅烷基)氧代〕戊氧基〕乙基〕-7a-甲基八氢-4H-茚-4-酮(52)
在15ml乙醚中同于33将201mg(0.62mmol)(50)与205mg(1.86mmol)三甲基氯硅烷,167mg(2.42mmol)咪唑和0.25ml吡啶反应而得194mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,1lppm(s,9H,SiMe3);0,82(s,3H,H-18);0,90u.1,01(2xs,je 3H,H-21u.C-20-Methyl);1,22(s,6H,H-29u.H-30);2,43(dd,J=10,5,7,5Hz,1H,H-14);3,07u.3,12(2xd,J=9,5Hz,je 1H,H-22);3,37(t,J=7Hz,2H,H-24)
52.〔1S-(1α,3aβ,7aα)〕-1-〔1,1-二甲基-〔2-〔4-乙基-4-〔(三甲基甲硅烷基)氧代〕己氧基〕乙基〕-7a-甲基八氢-4H-茚-4-酮(53)
在15ml乙醚中同于33将183mg(0.52mmol)(51)与171mg(1.56mmol)三甲基氯硅烷,140mg(2.03mmol)咪唑和0.21ml吡啶反应而得178mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,10ppm(s,9H,SiMe3);0,70(s,3H,H-18);0,82(t,J=7Hz,6H,H-30u.H-31);0,91u.1,00(2xs,je 3H,H-21u.C-20-Methyl);2,42(dd,J=10,5,7,5Hz,1H,H-14);3,05u.3,11(2xd,J=9,5Hz,je 1H,H-22);3,35(t,J=7Hz,2H,H-24)
53.(7E)-(1R,3R)-1,3-双〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-20-甲基-24-〔3-甲基-3-〔(三甲基甲硅烷基)氧代〕丁基〕-19-降-23-氧杂-9,10-断胆-5,7-二烯(54)
类似于36用100mg(0.25mmol)(52)反应而得130mg无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,01u.0,08ppm(2xs,21H,SiMe3u.SiMe);0,58(s,3H,H-18);0,82(s,18H,Si-t-Butyl);0,86u.0,97(2xs,je 3H,H-21u.C-20-Methyl);1,18(s,6H,H-28u.H-29);3,01u.3,09(2xd,J=9,5Hz,je 1H,H-22u.H-22’);3,32(t,J=7Hz,2H,H-24);4,03(m,2H,H-1u.H-3);5,76u.6,12(2xd,J=11Hz,je 1H,H-6u.H-7)
54.(7E)-(1R,3R)-1,3-双〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-20-甲基-24-〔3-乙基-3-〔(三甲基甲硅烷基)氧代〕戊基〕-19-降-23-氧杂-9,10-断胆-5,7-二烯(55)
类似于36用100mg(0.24mmol)(53)反应而得111mg无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,02u.0,10ppm(2xs,21H,SiMe3u.SiMe);0,56(s,3H,H-18);0,79(t,J=7Hz,6H,H-30u.H-31);0,83(s,18H,Si-t-Butyl);0,85u.0,95(2xs,je 3H,H-21u.C-20-Methyl);3,02u.3,08(2xd,J=9,5Hz,je 1H,H-22u.H-22’);3,26(t,J=7Hz,2H,H-24);3,99(m,2H,H-1u.H-3);5,70u.6,07(2xd,J=11Hz,je 1H,H-6u.H-7)
55.(7E)-(1R,3R)-24-(3-羟基-3-甲基丁基)-20-甲基-19-降-23-氧杂-9,10-断胆-5,7-二烯-1,3-二醇(56)
在10ml THF中同于39将125mg(0.17mmol)(54)与424mg(1.36mmol)氟化四丁铵反应而得56mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,55ppm(s,3H,H-18);0,82u.0,90(2xs,je 3H,H-21u.C-20-Methyl);1,10(s,6H,H-28u.H-29);3,00u.3,08(2xd,J=9,5Hz,je 1H,H-22u.H-22’);3,30(t,J=7Hz,2H,H-24);3,91u.3,98(2xm,je 1H,H-1u.H-3);5,77u.6,20(2xd,J=11Hz,je 1H,H-6u.H-7)
56.(7E)-(1R,3R)-24-(3-乙基-3-羟戊基)-20-甲基-19-降-23-氧杂-9,10-断胆-5,7-二烯-1,3-二醇(57)
在10ml THF中同于39将106mg(0.14mmol)(55)与340mg(1.09mmol)氟化四丁铵反应而得57mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,54ppm(s,3H,H-18);0,77(t,J=7Hz,6H,H-30u.H-31);0,81u0,90(2xs,je 3H,H-21u.C-20-Methyl);1,38(q,J=7Hz,4H,H-28u.H-29);3,00u.3,08(2xd,J=9,5Hz,je 1H,H-22u.H-22’);3,30(t,J=7Hz,2H,H-24);3,91u.3,98(2xm,je 1H,H-1u.H-3);5,77u.6,20(2xd,J=11Hz,je 1H,H-6u.H-7)
57.〔1S-(1α,3aβ,4α,7aα)〕-1-〔4-(乙酰氧基)-7a-甲基八氢-1H-茚-1-基〕乙酮(ethanon)(58)
将19.2g(76.1mmol)〔1R-〔1α(S*),3aβ,4α,7aα〕〕-4-(乙酰氧基)-α,7a-二甲基八氢-1H-茚-1-乙醛(见24)溶于1000ml DMF中并加7.59g(66.5mmol)1,4-二氮双环〔2.2.2〕辛烷1.14g(5.7mmol)乙酸酮(II)-水合物和909mg(5.7mmol)2,2′-联吡啶后加热到70℃并同时导入氧气,24小时后倒入氯化钠液中,用乙酸乙酯萃取,用氯化钠液洗涤,硫酸钠干燥并分出溶剂剩余物经硅胶色谱(己烷/乙酸乙酯)提纯而得12.75g无色油状题示化合物。1H-NMR(CDCl3):δ=0,83ppm(s,3H,H-18);2,03(s,3H,H-21);2,12(s,3H,OAc);2,50(t,J=9,5Hz,1H,H-17);5,19(m,1H,H-8)
58.〔1S-(1α,3aβ,4α,7aα)〕-7a-甲基-1-(2-甲基-2-环氧乙烷基)八氢-1H-茚-4-酮(59)
将12.75g(53.5mmol)(58)溶于400mlDMF中并加入15.2g(86mmol)碘化三甲基锍,冷至0℃后分批加入29.8g(267mmol)叔丁氧钾,室温搅拌24小时后加入氯化钠液,用乙酸乙酯萃取,有机相用氯化钠液洗涤,硫酸钠干燥并分出溶剂后粗产物经硅胶色谱(己烷/乙酸乙酯作洗涤剂)提纯而得7.91g无色油状题示化合物。1H-NMR(CDCl3):δ=1,00ppm(s,3H,H-18);1,30(s,3H,H-21);2,25(d,J=5Hz,1H,H-22);2,43(d,J=5Hz,1H,H-22’);4,02(m,1H,H-8)
59.〔1S-(1α,3aβ,4α,7aα)〕-4-〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-7a-甲基-1-(2-甲基-2-环氧乙烷基)八氢-1H-茚(60)
向7.91g(37.6mmol)(59)的200ml DMF液中加10.19g(150mmol)咪唑和11.25g(75mmol)叔丁基二甲基甲硅烷基氯并室温搅拌过夜,然后倒入氯化钠液中,用乙酸乙酯萃取,有机相用氯化钠液洗涤,用硫酸钠干燥并分出溶剂后剩余物溶于50ml乙醚中并0℃滴入二乙基氨化锂液中〔2.77g(37.8mmol)二乙胺,24.28ml正丁基锂液(己烷中1.6M)〕,再室温搅拌24小时,加氯化钠液,用乙酸乙酯萃取,有机相用氯化钠液洗涤,硫酸钠干燥并分出溶剂后色谱提纯而得8.64g无色油状题示化合物。1H-NMR(CDCl3):δ=0,01u.0,10ppm(2xs,je 3H,SiMe);0,88(s,9H,Si-t-Butyl);0,90(s,3H,H-18);1,36(s,3H,H-21);2,31(d,J=5Hz,H-22);2,50(d,J=5Hz,H-22’);4,00(m,1H,H-8)
60.〔1S-(1α,3aβ,4α,7aα)〕-4-〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-7a-甲基-β-亚甲基八氢-1H-茚-1-乙醇(61)
将8.46g(26.06mmol)(60)溶于500ml甲苯中并加10.8g(53.2mmol)异丙醇铝后120℃搅拌过夜,冷却后加水/异丙醇,过滤后滤液浓缩,剩余物经硅胶色谱(己烷/乙酸乙酯)提纯而得7.56g题示化合物。1H-NMR(CDCl3):δ=0,01u.0,02ppm(2xs,je 3H,SiMe);0,80(s,3H,H-18);0,89(s,9H,Si-t-Butyl);2,05(t,J=9,5Hz,1H,H-17);4,00(dbr,J=15Hz,1H,H-22);4,02(m,1H,H-8);4,10(dd,J=15,5Hz,1H,H-22’);4,92u.5,20(2xs,je 1H,H-21)
61.〔1S-〔1α,3aβ,4α,7aα〕〕-1,1-二甲基乙基-2-〔4-〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-7a-甲基八氢-1H-茚-1-基〕-2-丙烯氧基〕乙酸酯(62)
在18ml甲苯中同于3将2g(6.16mmol)与27.6ml苛性钠溶液(25%),129mg硫酸氢四丁铵和5.96g(30.55mmol)溴乙酸叔丁酯而得2.67g无色油状题示化合物。1H-NMR(CDCl3):δ=0,01ppm(2xs,je 3H,SiMe);0,80(s,3H,H-18);0,90(s,9H,Si-t-Butyl);1,50(s,9H,t-Butylester);3,93(s,2H,H-24);3,98(s,2H,H-22);4,02(m,1H,H-8);4,98u.5,22(2xs,je 1H,H-21)
62.〔1S-〔1α,3aβ,4α,7aα〕〕-3-〔〔〔2-〔4-〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-7a-甲基八氢-1H-茚-1-基〕-2-丙烯基〕氧代〕甲基〕-3-戊醇(63)
在30ml THF中用1.34g(12.32mmol)溴乙烷和300mg(12.3mmol)镁屑制成格利雅试剂并同于4与2.67g(6.24mmol)(62)反应而得2.58g无色油状题示化合物,不经提纯而用于进一步反应。
63.〔1S-〔1α,3aβ,4α,7aα〕〕-1-〔2-〔4-〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-7a-甲基八氢-1H-茚-1-基〕-2-丙烯氧基〕-2-甲基-2-丙醇(64)
在100ml乙醚中用2.52g(21.3mmol)碘甲烷和517mg(21.3mmol)镁屑制成格利雅试剂并同于4与3.4g(7.7mmol)(62)反应而得2.65g题示化合物。1H-NMR(CDCl3):δ=0,01ppm(2xs,je 3H,SiMe);0,80(s,3H,H-18);0,88(s,9H,Si-t-Butyl);1,21(s,6H,H-26u.H-27);3,19u.3,25(2xd,J=9Hz,je 1H,H-24u.H-24’);3,89u.3,96(2xd,J=13Hz,je 1H,H-22u.H-22’);4,01(m,1H,H-8);4,93u.5,18(2xs,je1H,H-21u.H-21’)
64.〔1S-〔1α,3aβ,4α,7aα〕〕-1-〔2-(2-乙基-2-羟丁氧基)-1-亚甲基乙基〕-7a-甲基八氢-1H-茚-4-醇(65)
将2.58g(6.07mmol)(63)溶于60ml THF中,加12.4ml HF/吡啶(70%)并室温搅拌3天后倒入硫酸氢钠液,用乙酸乙酯萃取,有机相用碳酸氢钠液和氯化钠液洗涤并用硫酸钠干燥,分出溶剂后色谱提纯而得750mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,78ppm(s,3H,H-18);0,81(t,J=7Hz,6H,H-28u.H-29);1,48(q,J=7Hz,4H,H-26u.H-27);3,17u.3,23(2xd,J=9Hz,je 1H,H-24u.H-24’);3,81u.3,90(2xd,J=12,5Hz,je 1H,H-22u.H-22’);4,03(m,1H,H-8);4,89u.5,14(2xs,je 1H,H-21u.H-21’)
65.〔1S-〔1α,3aβ,4α,7aα〕〕-1-〔2-(2-羟基-2-甲基丙氧基)-1-亚甲基乙基〕-7a-甲基八氢-1H-茚-4-醇(66)
在38ml乙腈和30ml THF中将2g(5mmol)(64)与30ml HF(40%)反应并室温搅拌3小时后小心加入碳酸氢钠液,用乙酸乙酯萃取,用氯化钠液洗涤并用硫酸钠干燥,分出溶剂后色谱提纯而得1.25g无色油状题示化合物。1H-NMR(CDCl3):δ=0,85ppm(s,3H,H-18);1,22(s,6H,H-26u.H-27);3,21u.3,28(2xd,J=9Hz,je 1H,H-24u.H-24’);3,91u.3,98(2xd,J=13Hz,je 1H,H-22u.H-22’);4,10(m,1H,H-8);4,97u.5,22(2xs,je 1H,H-21u.H-21’)
66.〔1S-〔1α,3aβ,7aα〕〕-1-〔2-(2-乙基-2-羟丁氧基)-1-亚甲基乙基〕-7a-甲基八氢-4H-茚-4-酮(67)
在50ml二氯甲烷中同于30将720mg(2.40mmol)(65)与755mg(3.51mmol)氯铬酸吡啶鎓反应而得522mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,52ppm(s,3H,H-18);0,80(t,J=7Hz,6H,H-28u.H-29);1,21(s,1H,OH);1,48(q,J=7Hz,4H,H-26u.H-27);3,18u.3,23(2xd,J=9,5Hz,je 1H,H-24u.H-24’);3,84u.3,95(2xd,J=13Hz,je 1H,H-22u.H-22’);4,96u.5,16(2xs,je 1H,H-21u.H-21’)
67.〔1S-〔1α,3aβ,7aα〕〕-1-〔2-(2-羟基-2-甲基丙氧基)-1-亚甲基乙基〕-7a-甲基八氢-4H-茚-4-酮(68)
在40ml二氯甲烷中同于30将600mg(2.12mmol)(66)与645mg(3mmol)氯铬酸吡啶鎓反应而得439mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,58ppm(s,3H,H-18);1,22(s,6H,H-26u.H-27);2,57(dd,J=10,5,7,5Hz,1H,H-14);3,22u.3,28(2xd,J=9Hz,je 1H,H-24u.H-24’);3,95u.4,04(2xd,J=13Hz,je 1H,H-22u.H-22’);5,02u.5,23(2xs,je 1H,H-21u.H-21’)
68.〔1S-〔1α,3aβ,7aα〕〕-1-〔2-〔〔2-乙基-2-〔(三甲基甲硅烷基)氧代〕丁氧基〕-1-亚甲基乙基〕-7a-甲基八氢-4H-茚-4-酮(69)
在50ml乙醚中同于33将522mg(1.75mmol)(67)与554mg(5.1mmol)三甲基氯硅烷,459mg(6.63mmol)咪唑和0.7ml吡啶反应而得343mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,01ppm(s,9H,SiMe3);0,48(s,3H,H-18);0,77(t,J=7Hz,6H,H-28u.H-29);3,11u.3,18(2xd,J=9,5Hz,je 1H,H-24u.H-24’);3,75u.3,87(2xd,J=13Hz,je1H,H-22u.H-22’);4,91u.5,16(2xs,je 1H,H-21u.H-21’)
69.〔1S-〔1α,3aβ,7aα〕〕-7a-甲基-1-〔2-〔〔2-甲基-2-〔(三甲基甲硅烷基)氧代〕丙氧基〕-1-亚甲基乙基〕八氢-4H-茚-4-酮(70)
在50ml乙醚中同于33将420mg(1.5mmol)(68)与325mg(3mmol)三甲基氯硅烷。408mg(6mmol)咪唑和0.6ml吡啶反应而得445mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,10ppm(s,9H,SiMe3);0,58(s,3H,H-18);1,25(s,6H,H-26u.H-27);2,57(dd,J=10,5,7,5Hz,1H,H-14);3,18u.3,22(2xd,J=9Hz,je 1H,H-24u.H-24’);3,92u.4,00(2xd,J=13Hz,je 1H,H-22u.H-22’);5,01u.5,24(2xs,je 1H,H-21u.H-21’)
70.(7E)-(1R,3R)-1,3-双〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-26,27-二甲基-25-(三甲基甲硅烷基)氧代-19-降-23-氧杂-9,10-断胆甾-5,7,20-三烯(71)
类似于36用300mg(0.81mmol)(69)反应而得508mg无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,06u.0.09ppm(2xs,12Hu.9H,SiMe);0,47(s,3H,H-18);0,83u.0,84(2xs,je 9H,Si-t-Butyl);0,85(t,J=7Hz,6H,H-28u.H-29);1,52(q,J=7Hz,4H,H-26u.H-27);3,20u.3,27(2xd,J=9,5Hz,je 1H,H-24u.H-24’);3,84u.3,91(2xd,J=13Hz,je1H,H-22u.H-22’);4,09(m,2H,H-1u.H-3);4,97u.5,20(2xs,je 1H,H-21u.H-21’);5,83u.6,18(2xd,J=11Hz,je 1H,H-6u.H-7)
71.(7E)-(1R,3R)-1,3-双〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-25-(三甲基甲硅烷基)氧代-19-降-23-氧杂-9,10-断胆甾-5,7,20-三烯(72)
类似于36用352mg(1mmol)(70)反应而得50mg无色泡沫状题示化合物,直接用于下一步反应。
72.(7E)-(1R,3R)-26,27-二甲基-19-降-23-氧杂-9,10-断胆甾-5,7,20-三烯-1,3,25-三醇(73)
在45ml THF中同于39将500mg(0.68mmol)(71)与1.70g(5.44mmol)氟化四丁铵反应而得217mg无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,40ppm(s,3H,H-18);0,82(t,J=7Hz,6H,H-28u.H-29);1,48(q,J=7Hz,4H,H-26u.H-27);3,18u.3,23(2xd,J=9Hz,je 1H,H-24u.H-24’);3,84u.3,92(2xd,J=13Hz,je 1H,H-22u.H-22’);3,99u.4,06(2xm,je 1H,H-1u.H-3);4,92u.5,11(2xs,je 1H,H-21u.H-21’);5,81u.6,24(2xd,J=11Hz,je 1H,H-6u.H-7)
73.(7E)-(1R,3R)-19-降-23-氧杂-9,10-断胆甾-5,7,20-三烯-1,3,25-三醇(74)
在10ml THF中同于39将50mg(0.07mmol)(72)与121mg(0.385mmol)氟化四丁铵反应而得22.5mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,40ppm(s,3H,H-18);1,10(s,6H,H-26u.H-27);3,12u.3,18(2xd,J=9Hz,je 1H,H-24u.H-24’);3,85u.3,92(2xd,J=13Hz,je 1H,H-22u.H-22’);3,93u.4,00(2xm,je 1H,H-1u.H-3);4,91u.5,10(2xs,je 1H,H-21u.H-21’);5,70u.6,20(2xd,J=11Hz,je 1H,H-6u.H-7)
74.〔1S-〔1α,3aβ,4α,7aα〕〕-4-〔2-〔4-〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-7a-甲基八氢-1H-茚-1-基〕-2-丙烯氧基〕丁酸甲酯(75)
类似于11将2.30g(7.09mmol)(61)与′6.45g(28.4mmol)4-溴原丁酸三甲酯,9.5ml苛性钠溶液(50%)和375mg硫酸氢四丁铵反应而得2.31g无色油状题示化合物。1H-NMR(CDCl3):δ=0,01ppm(2xs,je 3H,SiMe);0,80(s,3H,H-18);0,89(s,9H,Si-t-Butyl);2,42(t,J=6,5Hz,2H,H-26);3,40(t,J=6,5Hz,2H,H-24);3,68(s,3H,COOMe);3,85(s,2H,H-22);4,01(m,1H,H-8);4,92u.5,18(2xs,je 1H,H-21u.H-21’)
75.〔1S-〔1α,3aβ,4α,7aα〕〕-1-〔2-〔4-〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-7a-甲基八氢-1H-茚-1-基〕-2-丙烯氧基〕-4-甲基-4-戊醇(76)
在15ml乙醚中用1.15g(8.1mmol)碘甲烷和196mg(8.1mmol)镁屑制成格利雅试剂并用于4与1.15g(2.7mmol)(75)反应而得934mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,01ppm(2xs,je 3H,SiMe);0,80(s,3H,H-18);0,88(s,9H,Si-t-Butyl);1,21(s,6H,H-28u.H-29);3,42(m,2H,H-24);3,88(s,2H,H-22);4,01(m,1H,H-8);4,92u.5,18(2xs,je 1H,H-21u.H-21’)
76.〔1S-〔1α,3aβ,4α,7aα〕〕-1-〔2-〔4-〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-7a-甲基八氢-1H-茚-1-基〕-2-丙烯氧基〕-4-乙基-4-己醇(77)
在15ml THF中用882mg(8.1mmol)溴乙烷和196mg(8.1mmol)镁屑制成格利雅试剂并同于4与1.15g(2.7mmol)(75)反应而得734mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,01ppm(2xs,je 3H,SiMe);0,80(s,3H,H-18);0,88(t,J=7Hz,6H,H-30u.H-31);0,89(s,9H,Si-t-Butyl);1,48(q,J=7Hz,4H,H-28u.H-29);3,42(m,2H,H-24);3,88(s,2H,H-22);4,02(m,1H,H-8);4,93u.5,20(2xs,je 1H,H-21u.H-21’)
77.〔1S-〔1α,3aβ,4α,7aα〕〕-1-〔2-(4-羟基-4-甲基戊氧基)-1-亚甲基乙基〕-7a-甲基八氢-1H-茚-4-醇(78)
在30ml THF中同于64将580mg(1.37mmol)(76)与4.41ml HF/吡啶(70%)反应而得156mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,78ppm(s,3H,H-18);1,18(s,6H,H-28u.H-29);3,48(m,2H,H-24);3,82(s,2H,H-22);4,03(m,1H,H-8);4,89u.5,15(2xs,je 1H,H-21u.H-21’)
78.〔1S-〔1α,3aβ,4α,7aα〕〕-1-〔2-(4-乙基-4-羟己氧基)-1-亚甲基乙基〕-7a-甲基八氢-1H-茚-4-醇(79)
在35ml THF中同于64将734mg(1.62mmol)(77)与5.22ml HF/吡啶(70%)反应而得200mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,77ppm(s,3H,H-18);0,78(t,J=7Hz,6H,H-30u.H-31);1,40(q,J=7Hz,4H,H-28u.H-29);3,34(m,2H,H-24);3,70(s,2H,H-22);4,03(m,1H,H-8);4,88u.5,14(2xs,je 1H,H-21u.H-21’)
79.〔1S-〔1α,3aβ,7aα〕〕-1-〔2-(4-羟基-4-甲基戊氧基)-1-亚甲基乙基〕-7a-甲基八氢-4H-茚-4-酮(80)
在10ml二氯甲烷中同于29将150mg(0.48mmol)(78)与144mg(0.67mmol)氯铬酸吡啶鎓反应而得124mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,58ppm(s,3H,H-18);1,23(s,6H,H-28u.H-29);2,57(dd,J=10,5,7,5Hz,1H,H-14);3,42u.3,50(2xdt,J=9,7Hz,je 1H,H-24u.H-24’);3,90u.3,97(2xd,J=12,5Hz,je 1H H-22u.H-22’);5,02u.5,24(2xs,je 1H,H-21u.H-21’)
80.〔1S-〔1α,3aβ,7aα〕〕-1-〔2-(4-乙基-4-羟己氧基)-1-亚甲基乙基〕-7a-甲基八氢-4H-茚-4-酮(81)
在10ml二氯甲烷中同于30将200mg(0.59mmol)(79)与177mg(0.83ml)氯铬酸吡啶鎓反应而得145mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,58ppm(s,3H,H-18);0,88(t,J=7Hz,6H,H-30u.H-31);1,50(q,J=7Hz,4H,H-28u.H-29);2,58(dd,J=10,5,7,5Hz,1H,H-14);3,40u.3,48(2xdt,J=9,7Hz,je 1H,H-24u.H-24’);3,89u.3,96(d,J=12,5Hz,je 1H,H-22u.H-22’);5,01u.5,23(2xs,je 1H,H-21u.H-21’)
81.〔1S-〔1α,3aβ,7aα〕〕-1-〔2-〔4-甲基-4-〔(三甲基甲硅烷基)氧代〕戊氧基〕-1-亚甲基乙基〕-7a-甲基八氢-4H-茚-4-酮(82)
在10ml乙醚中同于33将120mg(0.39mmol)(80)与127mg(1.17mmol)三甲基氯硅烷。105mg(1.52mmol)咪唑和0.16ml吡啶反应而得119mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,10ppm(s,9H,SiMe3);0,58(s,3H,H-18);1,12(s,6H,H-28u.H-29);2,57(dd,J=10,5,7,5Hz,1H,H-14);3,38u.3,43(2xdt,J=9,7Hz,je 1H,H-24u.H-24’);3,88u.3,96(2xd,J=12,5Hz,je 1H,H-22u.H-22’);5,01u.5,23(2xs,je 1H,H-21u.H-21’)
82.〔1S-〔1α,3aβ,7aα〕〕-1-〔2-〔4-乙基-4-〔(三甲基甲硅烷基)氧代〕己氧基〕-1-亚甲基乙基〕-7a-甲基八氢-4H-茚-4-酮(83)
在10ml乙醚中同于33将140mg(0.42mmol)(81)与136mg(1.26mmol)三甲基氯硅烷,113mg(1.64mmol)咪唑和0.17ml吡啶反应而得136mg无色油状题示化合物。1H-NMR(CDCl3):δ=0,01ppm(s,9H,MeSi);0,49(s,3H,H-18);0,71(t,J=7Hz,6H,H-30u.H-31);1,39(q,J=7Hz,4H,H-28u.H-29);2,47(dd,J=10,5,7,5Hz,1H,H-14);3,26u.3,33(2xdt,J=9,7Hz,je 1H,H-24u.H-24’);3,79u.3,87(2xd,J=12,5Hz,je 1H,H-22U.H-22’);4,91u.5,14(2xs,je 1H,H-21u.H-21’)
83.(7E)-(1R,3R)-1,3-双〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-24-〔3-甲基-3-〔(三甲基甲硅烷基)氧代〕丁基〕-19-降-23-氧杂-9,10-断胆-5,7,20-三烯(84)
类似于36用110mg(0.29mmol)(82)反应而得125mg无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,01u.0,07ppm(2xs,12Hu.9H,SiMe);0,41(s,3H,H-18);0,79u.0,80(2xs,Si-t-Butyl);1,18(s,6H,H-28u.H-29);3,37(m,2H,H-24);3,88(s,2H,H-22);4,04(m,2H,H-1u.H-3);4,93u.5,15(2xs,je 1H,H-21u.H-21’);5,79u.6,12(d,J=11Hz,je 1H,H-6u.H-7)
84.(7E)-(1R,3R)-1,3-双〔〔二甲基(1,1-二甲基乙基)甲硅烷基〕氧代〕-24-〔3-乙基-3-〔(三甲基甲硅烷基)氧代〕戊基〕-19-降-23-氧杂-9,10-断胆-5,7,20-三烯(85)
类似于36用126mg(0.31mmol)(83)反应而得150mg无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,01u.0,05ppm(2xs,12Hu.9H,SiMe);0,38(s,3H,H-18);0,79u.0,80(2xs,je 9H,Si-t-Butyl);0,83(t,J=7Hz,6H,H-30u.H-31);1,38(q,J=7Hz,4H,H-28u.H-29);3,30(m,2H,H-24);3,81(s,2H,H-22);4,00(m,2H,H-1u.H-3);4,89u.5,10(2xs,je 1H,H-21u.H-21’);5,74u.6,08(2xd,J=11Hz,je 1H,H-6u.H-7)
85.(7E)-(1R,3R)-24-(3-羟基-3-甲基丁基)-19-降-23-氧杂-9,10-断胆-5,7,20-三烯-1,3-二醇(86)
在10ml THF中同于39将110mg(0.15mmol)(84)与374mg(1.2mmol)氟化四丁铵反应而得53mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,38ppm(s,3H,H-18);1,12(s,6H,H-28u.H-29);3,33(m,2H,H-24);3,81(s,2H,H-22);3,91u.3,98(2xm,je 1H,H-1u.H.3);4,90u.5,10(2xs,je 1H,H-21u.H-21’);5,80u.6,21(2xd,J=11Hz,je 1H,H-6u.H-7)
86.(7E)-(1R,3R)-24-(3-乙基-3-羟戊基)-19-降-23-氧杂-9,10-断胆-5,7,20-三烯-1,3-二醇(87)
在10ml THF中同于39将132mg(0.17mmol)(85)与424mg(1.36mmol)氟化四丁铵反应而得59mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,39ppm(s,3H,H-18);0,77(t,J=7Hz,6H,H-30u.H-31);1,38(q,J=7Hz,4H,H-28u.H-29);3,32(m,2H,H-24);3,80(s,2H,H-22);3,91u.3,98(2xm,je1H,H-1u.H-3);4,89u.5,09(2xs,je 1H,H-21u.H-21’);5,80u.6,21(2xd,J=11Hz,je1H,H-6u.H-7)
87.(5Z,7E)-(1S,3R)-1,3-双〔〔1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-20-甲酰基-9,10-断孕甾-5,7,10(19),20-四烯(88)
将2.8g(3.36mmol)(11)溶于100ml二氯甲烷中并加11.6g(133mmol)二氧化锰,室温搅拌1小时后经Celite吸滤,分出溶剂而得2.5g无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,35ppm(s,3H,H-18);0,92u.0,99(2xs,je 9H,Si-t-Butyl);4,23(m,1H,H-3);4,55(m,1H,H-1);4,83u.5,10(2xs,je 1H,H-19u.H-19’);6,02u.6,09(2xd,J=11Hz,je 1H,H-6u.H-7);6,11u.6,32(2xs,je 1H,H-21u.H-21’);7,23-7,69(m,20H,Si-Phenyl);9,58(s,1H,H-22)
88.(5Z,7E,22E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-9,10-断胆-5,7,10(19),20,22-五烯-24-酸甲酯(89)
将182mg(6mmol)氢化钠(80%)加入10mlTHF中并室温加825ml(4.8mmol)膦酸二甲基(甲氧羰基)甲基酯的20ml THF液,30分钟后滴加1.2g(1.5mmol)(88)并搅拌过夜,冰冷情况下仅滴入饱和氯化钠液,用乙酸乙酯萃取,有机相用氯化钠液洗涤,硫酸钠干燥后剩余物经硅胶色谱(己烷/乙酸乙酯作洗脱剂)提纯而得470mg无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,39ppm(s,3H,H-18);0,93u.0,99(2xs,je 9H,Si-t-Butyl);3,79(s,3H,COOMe);4,25(m,1H,H-3);4,57(m,1H,H-1);4,83u.5,10(2xs,je 1H,H-19u.H-19’);5,35u.5,55(2xs,je 1H,H-21u.H-21’);6,05(d,J=15,5Hz,1H,H-23);6,09u.6,20(2xd,J=11Hz,je 1H,H-6u.H-7);7,24-7,69(m,20H,Si-Phenyl)
89.(5Z,7E,22E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-9,10-断胆-5,7,10(19),20,22-五烯-24-醇(90)
将470mg(0.52mmol)(89)加入60mlTHF中并0℃加2.16ml DIBAH液(甲苯中1.3M),0℃搅拌1小时后用甲苯稀释,加0.1ml异丙醇和1.05ml水并室温搅拌30分钟,过滤分出溶剂后剩余物经硅胶色谱提纯而得450mg无色泡沫状题示物质。1H-NMR(CDCl3):δ=0,40ppm(s,3H,H-18);0,94u.0,99(2xs,je 9H,Si-t-Butyl);4,20(m,3H,H-3u.H-24);4,57(t,J=5,5Hz,1H,H-1);4,83(s,1H,H-19);5,00(s,1H,H-21);5,10(s,1H,H-19’);5,22(s,1H,H-21’);6,00(dt,J=16,5,5Hz,1H,H-23);6,01u.6,09 (2xd,J=11Hz,je 1H,H-6u.H-7);6,27(d,J=16Hz,1H,H-22);7,12-7,70(m,20H,Si-Phenyl)
90.〔(5Z,7E,22E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧代〕-9,10-断胆-5,7,10(19),20,22-五烯-24-氧代〕乙酸-1,1-二甲基乙基酯(91)
类似于3将450mg(0.53mmol)(90)与2.7ml苛性钠溶液(25%),11mg硫酸氢四丁铵和760mg(3.9mmol)溴乙酸叔丁酯反应而得340mg无色泡沫状题示化合物。1H-NMR(CDCl3):δ=0,40ppm(s,3H,H-18);0,94u.1,12(2xs,je 9H,Si-t-Butyl);1,28(s,9H,t-Butylester);3,98(s,2H,H-26);4,15(d,J=5,5Hz,2H,H-24);4,25(m,1H,H-3);4,56(m,1H,H-1);4,84(s,1H,H-19);5,01(s,1H,H-21);5,10(s,1H,H-19’);5,22(s,1H,H-21’);5,90(dt,J=15,5,5,5Hz,1H,H-23);6,28(d,J=15,5Hz,1H,H-22);6,03u.6,10(2xd,J=11Hz,je 1H,H-6u.H-7);7,24-7,70(m,20H,Si-Phenyl)
91.(5Z,7E,22E)-(1S,3R)-24-(2-羟基-2-甲基丙氧基)-9,10-断胆-5,7,10(19),20,22-五烯-1,3-二醇(92)
在5ml乙醚中用397mg(2.8mmol)碘甲烷和69mg(2.8mmol)镁屑制成格利雅试剂并同于4与340mg(0.35mmol)(91)反应而得210mg粗产物,将其溶于5mlTHF中并同于14与1ml氟化四丁铵液(THF中1M)反应,提纯分离后得60mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,42ppm(s,3H,H-18);1,20(s,6H,H-28u.H-29);3,25(s,2H,H-26);4,08(d,J=5,5Hz,2H,H-24);4,13(m,1H,H-3);4,38(m,1H,H-1);4,97(s,1H,H-19);5,00u.5,20(2xs,je 1H,H-21u.H-21’);5,30(s,1H,H-19’);5,90(dt,J=15,5,5,5Hz,1H,H-23);6,05u.6,35(2xd,J=11Hz,je 1H,H-6u.H-7);6,25(d,J=15,5Hz,1H,H-22)
92.(5Z,7E,22E)-(1S,3R)-24-(2-乙基-2-羟丁氧基)-9,10-断胆-5,7,10(19),20,22-五烯-1,3-二醇(93)
在5mlTHF中用136mg(125mmol)碘甲烷和30mg(1.25mmol)镁屑制成格利雅试剂并同于4与120mg(0.12mmol)(92)反应而得110mg粗产物,将其溶于5mlTHF中并同于14与1ml氟化四丁铵液(THF中1M)反应,提纯分离后得21mg无色泡沫状题示化合物。1H-NMR(CD2Cl2):δ=0,37ppm(s,3H,H-18);0,78(t,J=7Hz,6H,H-30u.H-31);1,40(q,J=7Hz,4H,H-28u.H-29);3.20(s,2H,H-26);3,97(d,J=5,5Hz,2H,H-24);4,10(m,1H,H-3);4,31(m,1H,H-1);4,89(s,1H,H-19);4,91u.5,12(2xs,je 1H,H-21u.H-21’);5,23(s,1H,H-19’);5,81(dt,J=15,5,5,5Hz,1H,H-24);5,98u.6,30(2xd,J=11Hz,je 1H,H-6u.H-7);6,18(d,J=15,5Hz,1H,H-22)
Claims (10)
其中Y各为氢或1~9碳烷酰基或芳酰基;Z为氢,羟基或1~9碳烷酰基;X各为氢或两个X共同为环外亚甲基;R1和R2分别为氢,1~4碳烷基,共同为亚甲基或与季碳原子20共同成为环丙基单元,其中两个X为亚甲基时,R1和R2不是甲基;R3各为直链或支链C1-C3烷基;L为-CH2-O-(CH2)n-,其中n=1,2,3,4,5或6或L为
其中D为第20和第22碳原子之间的直接键,亚甲基或1,2-乙烯二基桥键,其中E-双键构型,E和F分别为氢或共同为第二键,其中构成E-双键构型,而G为直接键或亚烷基-(CH2)n-,其中n=1,2,3,4,5或6,任何亚甲基可被氧原子代替并且各亚甲基可被羟基取代。
2.权利要求1的维生素D衍生物,其特征在于Y为氢或饱和烷羧酸烷酰基或苯甲酰基且Z为羟基或饱和烷羧酸烷酰氧基或苯甲酰氧基。
3.权利要求1的维生素D衍生物,其特征在于卤原子为氟、氯或溴。
4.权利要求1的维生素D衍生物,其特征在于两个Y为氢,Z为羟基。
6.权利要求1的维生素D衍生物,其为
(5Z,7E)-(1S,3R)-26,27-二甲基-23-氧杂-9,10-断胆甾-5,7,10(19),20-四烯-1,3,25-三醇,
(5Z,7E)-(1S,3R)-26,27-二乙基-23-氧杂-9,10-断胆甾-5,7,10(19),20-四烯-1,3,25-三醇,
(7E)-(1R,3R)-20,26,27-三甲基-23-氧杂-19-降-9,10-断胆甾-5,7-二烯-1,3,25-三醇,
(5Z,7E)-(1S,3R)-26,27-二甲基-20,21-亚甲基-23-氧杂-9,10-断胆甾-5,7,10(19)-三烯-1,3,25-三醇,
(5Z,7E)-(1S,3R)-23-氧杂-9,10-断胆甾-5,7,10(19),20-四烯-1,3,25-三醇,
(5Z,7E)-(1S,3R)-24-(3-羟基-3-甲基丁基)-23-氧杂-9,10-断胆-5,7,10(19),20-四烯-1,3-二醇,
(5Z,7E)-(1S,3R)-24-(3-乙基-3-羟戊基)-23-氧杂-9,10-断胆-5,7,10(19),20-四烯-1,3-二醇,
(5Z,7E)-(1S,3R)-26,27-二乙基-20,21-亚甲基-23-氧杂-9,10-断胆甾-5,7,10(19)-三烯-1,3,25-三醇,
(7E)-(1R,3R)-23-氧杂-19-降-9,10-断胆甾-5,7,20-三烯-1,3,25-三醇
(5Z,7E)-(1S,3R)-20,21-亚甲基-23-氧杂-9,10-断胆甾-5,7,10(19)-三烯-1,3,25-三醇,
(5Z,7E)-(1S,3R)-24-(3-羟基-3-甲基丁基)-20,21-亚甲基-23-氧杂-9,10-断胆-5,7,10(19)-三烯-1,3-二醇,
(5Z,7E)-(1S,3R)-24-(3-乙基-3-羟戊基)-20,21-亚甲基-23-氧杂-9,10-断胆-5,7,10(19)-三烯-1,3-二醇,
(7E)-(1R,3R)-20-甲基-19-降-23-氧杂-9,10-断胆甾-5,7-二烯-1,3,25-三醇,
(7E)-(1R,3R)-26,27-二乙基-20-甲基-19-降-23-氧杂-9,10-断胆甾-5,7-二烯-1,3,25-三醇,
(7E)-(1R,3R)-24-(3-羟基-3-甲基丁基)-20-甲基-19-降-23-氧杂-9,10-断胆-5,7-二烯-1,3-二醇,
(7E)-(1R,3R)-24-(3-乙基-3-羟戊基)-20-甲基-19-降-23-氧杂-9,10-断胆-5,7-二烯-1,3-二醇
(7E)-(1R,3R)-26,27-二甲基-19-降-23-氧杂-9,10-断胆甾-5,7,20-三烯-1,3,25-三醇,
(7E)-(1R,3R)-26,27-二乙基-19-降-23-氧杂-9,10-断胆甾-5,7,20-三烯-1,3,25-三醇,
(7E)-(1R,3R)-24-(3-羟基-3-甲基丁基)-19-降-23-氧杂-9,10-断胆-5,7,20-三烯-1,3-二醇,
(7E)-(1R,3R)-24-(3-乙基-3-羟戊基)-19-降-23-氧杂-9,10-断胆-5,7,20-三烯-1,3-二醇,
(5Z,7E,22E)-(1S,3R)-24-(2-羟基-2-甲基丙氧基)-9,10-断胆-5,7,10(19),20,22-五烯-1,3-二醇,
(5Z,7E,22E)-(1S,3R)-24-(2-乙基-2-羟丁氧基)-9,10-断胆-5,7,10(19),20,22-五烯-1,3-二醇,
(7E,22E)-(1R,3R)-24-(2-羟基-2-甲基丙氧基)-19-降-9,10-断胆-5,7,20,22-四烯-1,3-二醇,
(7E,22E)-(1R,3R)-24-(2-乙基-2-羟丁氧基)-19-降-9,10-断胆-5,7,20,22-四烯-1,3-二醇。
8.权利要求6的化合物为
(5E,7E)-(1S,3R)-1,3-双〔〔(1,1-二甲基乙基)二苯基甲硅烷基〕氧基〕-20-亚甲基-9,10-断孕甾-5,7,10(19)-三烯-21-醇,
(5Z,7E)-(1S,3R)-1,3-双〔〔(11,1-二甲基乙基)二苯基甲硅烷基〕氧基〕-20-亚甲基-9,10-断孕甾-5,7,10(19)-三烯-21-醇。
9.含至少一种式(I)化合物和药用载体的药物制剂。
10.式(I)化合物在药剂制备过程中的应用。
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DE4220757A DE4220757A1 (de) | 1992-06-24 | 1992-06-24 | Derivate in der Vitamin D-Reihe mit Modifikationen in der 20-Position, Verfahren zu ihrer Herstellung, Zwischenprodukte für dieses Verfahren, diese Derivate enthaltende pharmazeutische Präparate sowie deren Verwendung zur Herstellung von Arzneimitteln |
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ATE178596T1 (de) * | 1994-12-14 | 1999-04-15 | Duphar Int Res | Vitamin-d-derivate und verfahren zur herstellung dieser verbindungen |
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CA2303248A1 (en) | 1997-09-08 | 1999-03-18 | F. Hoffmann-La Roche Ag | 1,3-dihydroxy-20,20-dialkyl-vitamin d3 analogs |
DE19744127B4 (de) | 1997-10-01 | 2006-10-05 | Schering Ag | Neue Vitamin D-Derivate mit Cyclopropylringen in den Seitenketten, Verfahren und Zwischenprodukte zu ihrer Herstellung sowie ihre Verwendung zur Herstellung von Arzneimitteln |
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