CN110551166A - 一种胆酸衍生物及其制备方法和应用 - Google Patents
一种胆酸衍生物及其制备方法和应用 Download PDFInfo
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- CN110551166A CN110551166A CN201810549644.4A CN201810549644A CN110551166A CN 110551166 A CN110551166 A CN 110551166A CN 201810549644 A CN201810549644 A CN 201810549644A CN 110551166 A CN110551166 A CN 110551166A
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- cholic acid
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- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical class C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 title claims abstract description 69
- 239000002812 cholic acid derivative Substances 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 189
- 238000006243 chemical reaction Methods 0.000 claims abstract description 151
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 85
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 82
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 81
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 39
- 239000003814 drug Substances 0.000 claims abstract description 22
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 208000035150 Hypercholesterolemia Diseases 0.000 claims abstract description 18
- 238000005886 esterification reaction Methods 0.000 claims abstract description 16
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 15
- 238000005893 bromination reaction Methods 0.000 claims abstract description 15
- 230000003647 oxidation Effects 0.000 claims abstract description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 12
- 208000006575 hypertriglyceridemia Diseases 0.000 claims abstract description 11
- 238000006192 iodination reaction Methods 0.000 claims abstract description 11
- 238000006467 substitution reaction Methods 0.000 claims abstract description 11
- 238000007256 debromination reaction Methods 0.000 claims abstract description 10
- 230000009467 reduction Effects 0.000 claims abstract description 9
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 8
- 230000031709 bromination Effects 0.000 claims abstract description 6
- 230000032050 esterification Effects 0.000 claims abstract description 6
- 238000001727 in vivo Methods 0.000 claims abstract 2
- 230000026045 iodination Effects 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 93
- -1 Ethyl Chemical group 0.000 claims description 45
- 238000006722 reduction reaction Methods 0.000 claims description 42
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims description 28
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims description 28
- 229960004844 lovastatin Drugs 0.000 claims description 28
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 238000003747 Grignard reaction Methods 0.000 claims description 22
- 238000011282 treatment Methods 0.000 claims description 22
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 21
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 claims description 19
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 18
- 239000007858 starting material Substances 0.000 claims description 18
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 claims description 16
- 238000006266 etherification reaction Methods 0.000 claims description 16
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 claims description 15
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 claims description 15
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 15
- 229940125833 compound 23 Drugs 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 229940125844 compound 46 Drugs 0.000 claims description 14
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 13
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 claims description 13
- 238000006460 hydrolysis reaction Methods 0.000 claims description 13
- 150000003626 triacylglycerols Chemical class 0.000 claims description 13
- 229940126657 Compound 17 Drugs 0.000 claims description 12
- 238000005984 hydrogenation reaction Methods 0.000 claims description 12
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 claims description 11
- 238000007239 Wittig reaction Methods 0.000 claims description 11
- 229940127113 compound 57 Drugs 0.000 claims description 11
- 229940125904 compound 1 Drugs 0.000 claims description 10
- 238000010511 deprotection reaction Methods 0.000 claims description 10
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 claims description 9
- SMEROWZSTRWXGI-UHFFFAOYSA-N Lithocholsaeure Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 SMEROWZSTRWXGI-UHFFFAOYSA-N 0.000 claims description 8
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 claims description 8
- 150000003138 primary alcohols Chemical group 0.000 claims description 8
- 150000003509 tertiary alcohols Chemical class 0.000 claims description 8
- 125000004185 ester group Chemical group 0.000 claims description 6
- 150000003333 secondary alcohols Chemical class 0.000 claims description 6
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims description 6
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims description 5
- 150000002170 ethers Chemical class 0.000 claims description 5
- 229960002855 simvastatin Drugs 0.000 claims description 5
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 4
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical class COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 4
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims description 4
- 229960005370 atorvastatin Drugs 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 4
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- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims description 4
- SZNYYWIUQFZLLT-UHFFFAOYSA-N 2-methyl-1-(2-methylpropoxy)propane Chemical compound CC(C)COCC(C)C SZNYYWIUQFZLLT-UHFFFAOYSA-N 0.000 claims description 3
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- A—HUMAN NECESSITIES
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- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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Abstract
本发明公开了一种如式(I)所示的胆酸衍生物及其制备方法,通过酯化、氧化、溴代、脱溴、4,4‑二甲基化、C‑7氧化、还原、TBSCl保护、碘代、氰基取代、Wittig、格氏、脱TBS保护等反应制备得到目标产物胆酸衍生物。本发明还提供了该类胆酸衍生物在抑制胆固醇合成和降低体内胆固醇和甘油三酯水平方面的应用,可以用于制备预防和治疗高胆固醇血症,高甘油三酯,动脉粥样硬化等疾病的药物,具有良好的应用前景。
Description
技术领域
本发明属于医药及其制备和应用技术领域,具体涉及一种胆酸衍生物及其制备方法和应用。
背景技术
高胆固醇血症是危害人们身体健康的严重疾病之一,是脑卒中、冠心病、心肌梗死、心脏猝死的独立而重要危险因素。高胆固醇血症对身体的损害是隐匿、逐渐、进行性和全身性的,它的直接损害是加速全身动脉粥样硬化。因为全身的重要器官都要依靠动脉供血、供氧,一旦动脉被粥样斑块堵塞,就会造成严重的后果。动脉硬化引起的肾功能衰竭等,也与高胆固醇血症密切相关。此外,高胆固醇血症也是促进高血压、糖耐量异常、糖尿病的一个重要危险因素。
他汀类药物是目前应用最为广泛的血脂调节药物,也是目前降低内源性胆固醇合成中最有效的药物,临床应用显示该类药物能有效的调整胆固醇和甘油三酯水平(即降脂效应),对各种类型的高血脂症均有一定的疗效(Maron,D.J.Circulation,2000,101(2),207-213)。目前每天大约有1000万人服用此类药物。美国的两位专家曾把他汀类药物称为抗动脉粥样硬化治疗的基石药物。美国心脏病学杂志主编Roberts WC认为:他汀类药物对动脉粥样硬化的疗效,如同青霉素治疗感染性疾病,对冠心病病人,要充分使用他汀类药物(Roberts,W.C.Am.J.Cardiol.,1996,78(3),377-378);美国Cleveland Clinic中心心脏病学专家Eric Topol认为:针对动脉粥样硬化疾病,他汀类药物在减少死亡率、降低心脏病和卒中发病率方面已超越所有其他类药物(Topol,E.J.N.Engl.J.Med.,2004,350(15),1562-1564.)。这充分说明了他汀类药物在临床应用上发挥了举足轻重的作用。
目前市场上常用的他汀类药物有阿托伐他汀(atorvastatin、立普妥)、辛伐他汀(simvastatin、舒降之)、洛伐他汀(lovastatin、美降之)、普伐他汀(pravastatin、普拉固)、氟伐他汀(fluvastatin、来适可)、西立伐他汀(cerivastatin、拜斯亭)等(陈明卫,杨明功。实用糖尿病杂志,2005,1(4),13-15.)。(如下所示)
但是,不能忽略的是,他汀类药物都有一些严重的副作用,其中最为常见的是肝脏损害和肌病(肌肉痛、肌炎及横纹肌溶解等),其他表现还有胃肠不适、头痛、睡眠障碍、周围神经病变等。如2001年的“拜斯亭”事件,因服用西伐他汀而死于横纹肌溶解和并发症肾衰竭的患者达到了几十例(Farmer,J.A.Lancet,2001,358(9291),1383-1385.),这一事件也使得人们对于他汀类药物安全性的关注达到前所未有的程度。在时隔两年之后的2003年,阿斯利康(AstraZenca)公司的“超级他汀”瑞舒伐伐他汀(Rosuvastatin,商品名:Crestor)刚刚正式上市,就在《柳叶刀》杂志上引发了一场关于其安全性的论战(Editoria1.Lancet,2003,362(9393),1341.),充分说明了他汀类药物的安全性已经受到学术界和全社会的关注。因此迫切需要开发高效、高安全性的降胆固醇药物。
石胆酸是人体肠内经细菌代谢产生的甾体化合物,具有众多药理活性,如:如:抑制20S蛋白酶体中的类似胰凝乳蛋白酶的活性(Dang,Z.etc.Bioorg.Med.Chem.lett.,2011,21(7),1926-1928.);能够选择性抑制哺乳类DNA聚合酶的活性(Mizushina,Y.etc.Biochemistry.,2004,43(33),10669-10677.);可以选择性杀死癌细胞(如脑肿瘤和乳腺癌中的癌细胞),亦可以抑制肿瘤生长(Goldberg,A.A.etc.Oncotarget.,2011,2(10),761-782.)等。
石胆酸(3α-羟基-5β-胆烷酸)结构
本发明以天然产物石胆酸为起始原料,设计、合成了一系列结构新颖、能显著降低体内胆固醇和甘油三酯水平的化合物,适用于制备预防和治疗高胆固醇血症,高甘油三酯血症,动脉粥样硬化等疾病的药物。
发明内容
本发明在寻找新型预防和治疗高胆固醇血症药物的研究过程中,设计合成了一种胆酸衍生物,其结构如式(I)所示:
其中,n选自自然数,R选自酯基、羧酸、伯醇、取代仲醇、取代叔醇、取代醚等。
其中,所述自然数为1,2,3,4,5……。
优选地,所述自然数为2,3,4,5。
其中,所述酯基包括甲酯乙酯正丙酯异丙酯正丁酯异丁酯叔丁酯烯丙酯丙炔酯苯酯苄酯等。
优选地,所述酯基包括甲酯
其中,所述羧酸为
其中,所述伯醇为
其中,所述取代仲醇包括甲基仲醇乙基仲醇正丙基仲醇异丙基仲醇正丁基仲醇异丁基仲醇叔丁基仲醇烯丙基仲醇丙炔基仲醇苯基仲醇苄基仲醇等;
优选地,所述取代仲醇包括甲基仲醇乙基仲醇烯丙基仲醇
其中,所述取代叔醇包括二甲基叔醇二乙基叔醇二正丙基叔醇二异丙基叔醇二正丁基叔醇二异丁基叔醇二烯丙基叔醇二丙炔基叔醇二苯基叔醇二苄基叔醇等;
优选地,所述取代叔醇包括二甲基叔醇二乙基叔醇二烯丙基叔醇
其中,所述取代醚包括甲基醚乙基醚正丙基醚异丙基醚正丁基醚异丁基醚叔丁基醚烯丙基醚丙炔基醚苯基醚苄基醚等。
优选地,所述取代醚为甲基醚
本发明还提出了一种胆酸衍生物的制备方法,以石胆酸(Lithocholic acid)为起始原料,经过酯化、TBSCl保护、还原、碘代、氰基取代、脱TBS及氰基醇解等反应得到化合物6;然后以化合物1或6为起始原料,经过氧化、溴代、脱溴,4,4-二甲基化,酯化、C-7位氧化、还原等反应得到化合物13或36;所述制备方法如路线(1)所示:
具体地,所述方法包括以下步骤:
a:酯化反应
将石胆酸Lithocholic acid溶于有机溶剂中,加入酯化反应所用的试剂,室温反应,得到化合物1。
步骤a中,所述有机溶剂选自甲醇、四氢呋喃和甲醇混合溶剂等中任意的一种或多种;优选地,为甲醇。
步骤a中,所述酯化反应所用的试剂为二氯亚砜、浓硫酸、对甲苯磺酸等中任意的一种或多种;优选地,为二氯亚砜。
步骤a中,所述酯化反应所用的试剂的作用为促进酯化反应。
步骤a中,所述石胆酸(Lithocholic acid)与酯化反应所用的试剂的摩尔比为1:(1~10);优选地,为1:4。
步骤a中,所述酯化反应的温度为25~70℃;优选地,为25℃。
步骤a中,所述酯化反应的时间为5~24h;优选地,为5h。
b:TBSCl保护反应
将化合物1溶于有机溶剂中,加入TBSCl保护反应所用的试剂、碱,进行TBSCl保护反应,得到化合物2。
步骤b中,所述有机溶剂选自DMF、二氯甲烷、三氯甲烷、四氯化碳等中任意的一种或多种;优选地,为DMF。
步骤b中,所述TBSCl保护反应所用的试剂为TBSCl。
步骤b中,所述碱为咪唑、三乙胺、二异丙基乙基胺等中任意的一种或多种;优选地,为咪唑。
步骤b中,所述TBSCl保护反应所用的试剂的作用为保护3,7-位羟基。
步骤b中,所述TBSCl保护反应所用的碱作为活化剂和缚酸剂使用。
步骤b中,所述化合物1与TBSCl保护反应所用的试剂、碱的摩尔比为1:(2~3):(4~6);优选地,为1:2.5:5。
步骤b中,所述TBSCl保护反应的温度为25~150℃;优选地,为80℃。
步骤b中,所述TBSCl保护反应的时间为4~10h;优选地,为6h。
c:还原反应
将化合物2溶于有机溶剂中,加入还原反应所用的试剂,进行还原反应,得到化合物3。
步骤c中,所述有机溶剂选自四氢呋喃、乙醚、甲醇、乙醇等中任意的一种或多种;优选地,为四氢呋喃。
步骤c中,所述还原反应所用的试剂为LiAlH4、NaBH4、红铝、二异丁基氢化铝等中任意的一种或多种;优选地,为LiAlH4。
步骤c中,所述还原反应的试剂的作用为还原D-环侧链的酯为伯醇。
步骤c中,所述化合物2与还原反应的试剂的摩尔比为1:(1~2);优选地,为1:2。
步骤c中,所述还原反应的温度为25~65℃;优选地,为25℃。
步骤c中,所述还原反应的时间为12~24h;优选地,为24h。
d:碘代反应
将化合物3溶于有机溶剂中,加入碘代反应的试剂、催化剂和缚酸剂,进行碘代反应,得到化合物4。
步骤d中,所述有机溶剂选自甲苯、二氯甲烷、四氢呋喃、乙醚、乙腈等中任意的一种或多种;优选地,为甲苯。
步骤d中,所述碘代反应所用的试剂为I2、N-碘代丁二酰亚胺等中任意的一种或多种;优选地,为I2。
步骤d中,所述催化剂和缚酸剂分别为PPh3和咪唑。
步骤d中,所述碘代反应所用的试剂的作用为取代化合物3的D-环侧链上伯醇上的羟基。
步骤d中,所述碘代反应所用的催化剂和缚酸剂的作用为促进碘代反应。
步骤d中,所述化合物3与碘代反应所用的试剂、催化剂和缚酸剂的摩尔比为1:(2~5):(2~5):(5~10);优选地,为1:5:5:10。
步骤d中,所述碘代反应的温度为25~50℃;优选地,为25℃。
步骤d中,所述碘代反应的时间为2~5h;优选地,为2h。
e:氰基取代反应
将化合物4溶于有机溶剂中,加入氰基取代反应所用的试剂,加热进行氰基取代反应,得到化合物5。
步骤e中,所述有机溶剂选自四氢呋喃、DMSO、DMF、乙腈、H2O、N-甲基吡咯烷酮(NMP)、CH3OH、甲苯等中任意的一种或多种;优选地,为四氢呋喃和DMSO。
步骤e中,所述氰基取代反应所用的试剂为氰化亚铜(CuCN)、氰化钠、氰化钾等中任意的一种或多种;优选地,为氰化钠。
步骤e中,所述氰基取代反应所用的试剂的作用为取代D-环侧链上的碘。
步骤e中,所述化合物4与氰基取代反应所用的试剂的摩尔比为1:(2~4);优选地,为1:3。
步骤e中,所述氰基取代反应的温度为25~60℃;优选地,为60℃。
步骤e中,所述氰基取代反应的时间为4~6h;优选地,为6h。
f:脱TBS及氰基醇解反应
将化合物5溶于有机溶剂中,加入脱TBS及氰基醇解反应所用的试剂,加热进行反应,得到化合物6。
步骤f中,所述有机溶剂选自甲醇、二氧六环、四氢呋喃等中任意的一种或多种;优选地,为甲醇。
步骤f中,所述脱TBS及氰基醇解反应所用的试剂为HCL/MeOH溶液、HCL/EtOH溶液等中任意的一种或多种;优选地,为HCL/MeOH溶液。
步骤f中,所述试剂HCL/MeOH溶液的作用为促进脱TBS及氰基醇解反应。
步骤f中,所述脱TBS及氰基醇解反应的温度为25~65℃;优选地,为65℃。
步骤f中,所述脱TBS及氰基醇解反应的时间为1~2h;优选地,为1h。
g:氧化反应
将化合物1或6溶于有机溶剂中,加入氧化反应的氧化剂,进行氧化反应,得到化合物7或30。
步骤g中,所述有机溶剂选自二氯甲烷、DMSO、四氢呋喃、丙酮等中任意的一种或多种;优选地,为二氯甲烷。
步骤g中,所述氧化反应的氧化剂为PCC、PDC、IBX等中任意的一种或多种;优选地,为PCC。
步骤g中,所述氧化反应的氧化剂的作用为氧化羟基。
步骤g中,所述化合物1或6与氧化反应的氧化剂的摩尔比为1:(1~2);优选地,为1:2。
步骤g中,所述氧化反应的温度为25~40℃;优选地,为25℃。
步骤g中,所述氧化反应的时间为12~16h;优选地,为12h。
h:溴代反应
将化合物7或30溶于有机溶剂中,加入溴代反应的溴代试剂、催化剂,进行溴代反应,得到化合物8或31。
步骤h中,所述有机溶剂选自二氯甲烷、三氯甲烷、四氯化碳、四氢呋喃、甲醇、乙酸等中任意的一种或多种;优选地,为二氯甲烷。
步骤h中,所述溴代反应的溴代试剂为Br2、NBS、过溴化吡啶氢溴酸盐、二溴海因等中任意的一种或多种;优选地,为Br2。
步骤h中,所述溴代反应的催化剂为乙酸。
步骤h中,所述溴代反应的溴代试剂的作用为溴代羰基的α位。
步骤h中,所述化合物7或30与溴代反应的试剂的摩尔比为1:(1~1.5);优选地,为1:1。
步骤h中,所述溴代反应的温度为25~40℃;优选地,为25℃。
步骤h中,所述溴代反应的时间为0.5~3h;优选地,为1h。
i:脱溴反应
将化合物8或31溶于有机溶剂中,加入脱溴反应的试剂,加热进行脱溴反应,得到化合物9或32。
步骤i中,所述有机溶剂选自DMF、甲醇、三氯甲烷等中任意的一种或多种;优选地,为DMF。
步骤i中,所述脱溴反应的试剂为吡啶、K2CO3、Li2CO3/LiBr·H2O等中任意的一种或多种;优选地,为Li2CO3/LiBr·H2O。
步骤i中,所述化合物8或31与脱溴试剂的摩尔比为1:(1~2);优选地,为1:2。
步骤i中,所述脱溴反应的温度为25~153℃;优选地,为90℃。
步骤i中,所述脱溴反应的时间为1~10h;优选地,为10h。
j:4,4-二甲基化反应
将化合物9或32溶于有机溶剂中,加入甲基化反应所用的试剂、碱,进行甲基化反应,得到化合物10或33。
步骤j中,所述有机溶剂选自t-BuOH、苯、四氯化碳、四氢呋喃等中任意的一种或多种;优选地,为t-BuOH。
步骤j中,所述甲基化反应所用的碱为t-BuOK、KOC(Et)Me2等中任意的一种或多种;优选地,为t-BuOK。
步骤j中,所述甲基化反应所用的试剂为CH3Cl、CH3Br、CH3I等中任意的一种或多种;优选地,为CH3I。
步骤j中,所述甲基化反应所用的碱的作用为拔掉4,4-位上的氢。
步骤j中,所述甲基化反应所用的试剂的作用是提供甲基。
步骤j中,所述化合物9或32与甲基化试剂的摩尔比为1:(2~10);优选地,为1:10。
步骤j中,所述化合物9或32与甲基化反应所用碱的摩尔比为1:(2~4);优选地,为1:4。
步骤j中,所述4,4-二甲基化反应所用的温度为25~60℃;优选地,为25℃。
步骤j中,所述4,4-二甲基化反应所用的时间为12~24h;优选地,为24h。
k:酯化反应
步骤k酯化反应的合成方法类似于步骤a酯化反应的合成方法。化合物10或33经酯化反应得到化合物11或34。
l:C-7氧化反应
将化合物11或34溶于有机溶剂中,加入氧化反应的试剂、催化剂,加热进行氧化反应,得到化合物12或35。
步骤l中,所述有机溶剂选自丙酮、甲苯、二氯甲烷等中任意的一种或多种;优选地,为丙酮。
步骤l中,所述催化剂为NHPI和乙酸。
步骤l中,所述氧化反应的试剂为重铬酸钠、t-BuOOH、CrO3等中任意的一种或多种;优选地,为重铬酸钠。
步骤l中,所述氧化反应所用的试剂的作用是氧化C-7。
步骤l中,所述氧化反应所用的催化剂的作用是促进C-7位氧化。
步骤l中,所述化合物11或34与氧化反应的试剂的摩尔比为1:(1~1.5);优选地,为1:1.05。
步骤l中,所述氧化反应的温度为25~60℃;优选地,为50℃。
步骤l中,所述氧化反应的时间为2~10h;优选地,为6h。
m:还原反应
将化合物12或35溶于有机溶剂中,加入还原反应的试剂,进行还原反应,得到产物13或36。
步骤m中,所述有机溶剂选自甲醇、乙醇、四氢呋喃等中任意的一种或多种;优选地,为甲醇。
步骤m中,所述还原反应的试剂为NaBH4、KBH4等;优选地,为NaBH4。
步骤m中,所述还原反应所用的试剂的作用为还原化合物Q11上3,7-位羰基。
步骤m中,所述化合物12和35与还原反应的试剂的摩尔比为1:(2~4);优选地,为1:4。
步骤m中,所述还原反应的温度为25~60℃;优选地,为25℃。
步骤m中,所述还原反应的时间为12~24h;优选地,为24h。
本发明还提供了一种胆酸衍生物的制备方法,以化合物13或36为起始原料,经过水解反应得到产物14或37;或经过LiAlH4还原反应得到产物15或38;或经过TBSCl保护、还原、甲醚化和脱TBS保护反应得到产物19或42;所述制备方法如路线(2)所示:
具体地,所述方法包含以下步骤:
a:水解反应
将化合物13或36溶于有机溶剂中,在4M NaOH溶液的作用下发生水解反应,得到产物14或37。
其中,所述有机溶剂选自甲醇、乙醇、DMSO、DMF、四氢呋喃、水等中任意的一种或多种;优选地,为甲醇。
其中,所述4M NaOH溶液的作用为促进水解反应。
其中,所述化合物13或36与NaOH的摩尔比为1:(1~60);优选地,为1:60。
其中,所述水解反应的温度为25~60℃;优选地,为25℃。
其中,所述水解反应的时间为12~24h;优选地,为24h。
b:LiAlH4还原反应
化合物15或38的合成类似于路线(1)中化合物2的还原方法。
c:TBSCl保护反应
化合物16或39的合成类似于路线(1)中化合物1的TBSCl保护方法。
d:还原反应
化合物17或40的合成类似于路线(1)中化合物2的还原方法。
e:甲醚化反应
将化合物17或40溶于有机溶剂中,加入甲醚化反应的试剂、碱,加热进行甲醚化反应,得到化合物18或41。
步骤e中,所述有机溶剂选自无水乙醚、无水四氢呋喃、丙酮、乙腈、无水DMF等中任意的一种或多种;优选地,为无水四氢呋喃。
步骤e中,所述甲醚化反应的试剂为CH3I、(CH3)2SO4;优选地,为CH3I。
步骤e中,所述碱为NaH。
步骤e中,所述碱的作用为促进甲醚化反应。
步骤e中,所述甲醚化反应的作用是将化合物Q29上D-环侧链的伯醇转化为甲醚。
步骤e中,所述化合物17或40与碱、甲醚化反应的试剂的摩尔比为1:(1~10):(1~10);优选地,为1:10:10。
步骤e中,所述甲醚化反应的温度为25~65℃;优选地,为25℃。
步骤e中,所述甲醚化反应的时间为12~24h;优选地,为24h。
f:脱TBS保护反应
将化合物18或41溶于有机溶剂中,加入脱TBS保护反应的试剂,加热回流进行脱TBS保护反应,得到化合物19或42。
步骤f中,所述有机溶剂选自四氢呋喃、水、甲醇、乙醇等中任意的一种或多种;优选地,为四氢呋喃。
步骤f中,所述脱TBS保护反应的试剂为1M HCl、BF3·Et2O、TMSOTF、四丁基氟化铵(TBAF)等中任意的一种或多种;优选地,为四丁基氟化铵(TBAF)。
步骤f中,所述脱TBS保护反应的作用是脱除化合物18或41C-3、C-7上的TBS保护基为羟基。
步骤f中,所述化合物18或41与脱TBS保护反应的试剂的摩尔比为1:(4~10);优选地,为1:6。
步骤f中,所述脱TBS保护反应的温度为25~70℃;优选地,为70℃。
步骤f中,所述脱TBS保护反应的时间为12~24h;优选地,为24h。
本发明还提供了一种胆酸衍生物的制备方法,其特征在于,以化合物13或36为起始原料,与CH3MgCl、C2H5MgCl或CH2=CHCH2MgCl分别发生格氏反应得到产物20-22或43-45;所述制备方法如路线(3)所示:
其中,所述有机溶剂选自无水乙醚、无数四氢呋喃、甲苯、苯等中任意的一种或多种;优选地,为无水四氢呋喃。
其中,所述CH3MgCl、C2H5MgCl、CH2=CHCH2MgCl的作用为与化合物13或36的甲酯进行格氏反应。
其中,所述格氏反应的温度为25~60℃;优选地,为25℃。
其中,所述格氏反应的时间为0.5~2h;优选地,为1h。
本发明还提供了一种胆酸衍生物的制备方法,以化合物17或40为起始原料,经过IBX氧化得到化合物23或46;再经过与CH3MgCl、C2H5MgCl或CH2=CHCH2MgCl分别发生格氏反应得到化合物24-26或47-49;然后再经过脱TBS保护基得到产物27-29或50-52;所述制备方法如路线(4)所示:
a:IBX氧化反应
将化合物17或40溶于有机溶剂中,加入IBX氧化反应的试剂,加热进行IBX氧化反应,得到化合物23或46。
步骤a中,所述有机溶剂选自DMSO、甲苯、四氢呋喃等中任意的一种或多种;优选地,为DMSO。
步骤a中,所述IBX氧化反应的试剂为IBX、PCC、DDQ、PDC等中任意的一种或多种;优选地,为IBX。
步骤a中,所述IBX氧化反应的试剂的作用为氧化化合物17或40上D-环侧链的羟基。
步骤a中,所述化合物17或40与IBX氧化反应的试剂的摩尔比为1:(1~2);优选地,为1:2。
步骤a中,所述IBX氧化反应的温度为25~50℃;优选地,为50℃。
步骤a中,所述IBX氧化反应的时间为3~5h;优选地,为3h。
b:格氏反应
步骤b所述格氏反应类似于路线(3)中制备化合物20-22或43-45的格氏反应方法。
c:脱TBS保护基反应
步骤c所述脱TBS保护基反应类似于路线(2)中制备化合物18或41的脱TBS保护基方法。
本发明还提供了一种胆酸衍生物的制备方法,其特征在于,以化合物23或46为起始原料,经过Wittig反应、加氢还原反应得到化合物54或75;化合物54经水解和脱TBS保护等反应得到产物56;或以化合物54或75为起始原料,经过还原反应得到化合物57或76,然后经过脱保护反应得到产物60或77;或化合物57经甲醚化和脱TBS保护反应得到产物59;所述制备方法如路线(5)所示:
a:Wittig反应
将化合物23或46溶于有机溶剂中,加入Wittig试剂,回流进行Wittig反应,得到化合物53或74。
步骤a中,所述有机溶剂选自甲苯、四氢呋喃、二氯甲烷、石油醚、苯等中任意的一种或多种;优选地,为甲苯。
步骤a中,所述Wittig反应所用的试剂为Ph3P=CHCOOCH2CH3。
步骤a中,所述Wittig反应的试剂的作用为在化合物23或46的D-环侧链上进行碳链的延长。
步骤a中,所述化合物23或46与Wittig反应的试剂的摩尔比为1:(1~3);优选地,为1:2。
步骤a中,所述Wittig反应的温度为25~110℃;优选地,为110℃。
步骤a中,所述Wittig反应的时间为4~6h;优选地,为6h。
b:加氢还原反应
将化合物53或74溶于有机溶剂中,加入加氢还原的试剂、催化剂,进行加氢还原反应,得到化合物54或75。
步骤b中,所述有机溶剂选自甲醇、乙醇、异丙醇、四氢呋喃、乙酸乙酯、乙酸、二氧六环、DMF、DMSO等中任意的一种或多种;优选地,为甲醇。
步骤b中,所述催化剂为10%Pd/C。
步骤b中,所述加氢还原反应的试剂为氢气。
步骤b中,所述加氢还原反应的试剂的作用为还原化合物53或74上D-环侧链上的双键。
步骤b中,所述加氢还原反应所用的催化剂的作用为促进加氢还原反应。
步骤b中,所述化合物53或74与加氢还原反应所用的催化剂的质量比为1:(0.1~1);优选地,为1:0.2。
步骤b中,所述加氢还原反应的温度为25~60℃;优选地,为25℃。
步骤b中,所述加氢还原反应的时间为12~24h;优选地,为24h。
c:水解反应
将化合物54溶于有机溶剂中,加入水解反应的试剂、碱,进行水解反应,得到化合物55。
步骤c中,所述有机溶剂选自甲醇、乙醇、DMSO、DMF、四氢呋喃、水等中任意的一种或多种;优选地,为甲醇或四氢呋喃。
步骤c中,所述碱为碳酸钾、碳酸钠、氢氧化钠、氢氧化钾等中任意的一种或多种;优选地,为碳酸钾。
步骤c中,所述水解反应的作用为将化合物54上D-环侧链上的酯基水解为羧基。
步骤c中,所述化合物54与碱的摩尔比为1:(1~1.5);优选地,为1:1.3。
步骤c中,所述水解反应的温度为25~60℃;优选地,为25℃。
步骤c中,所述水解反应的时间为12~24h;优选地,为24h。
d:脱TBS保护反应
步骤d所述脱TBS保护反应类似于路线(2)中制备化合物18或41的脱TBS保护反应。
e:还原反应
步骤e所述还原反应类似于路线(1)中制备化合物2的还原反应。
f:甲醚化反应
步骤f所述甲醚化反应类似于路线(2)中制备化合物17或40的甲醚化反应。
g:脱TBS保护反应
步骤g所述脱TBS保护反应类似于路线(2)中制备化合物18或41的脱TBS保护反应。
h:脱TBS保护反应
步骤h所述脱TBS保护反应类似于路线(2)中制备化合物18或41的脱TBS保护反应。
本发明还提供了一种胆酸衍生物的制备方法,其特征在于,以化合物54或75为起始原料,与CH3MgCl、C2H5MgCl或CH2=CHCH2MgCl分别发生格氏反应,然后进行脱TBS保护反应得到化合物64-66或81-83;所述制备方法如路线(6)所示:
a:格氏反应
步骤a所述格氏反应类似于路线(3)中制备化合物20-22或43-45的格氏方法。
b:脱TBS保护反应
步骤b所述脱TBS保护反应类似于路线(2)中制备化合物18或41的脱TBS保护方法。
本发明还提供了一种胆酸衍生物的制备方法,其特征在于,以化合物57或76为起始原料,经过IBX氧化、与CH3MgCl、C2H5MgCl或CH2=CHCH2MgCl分别发生格氏反应,然后进行脱TBS保护反应得到化合物71-73或88-90;所述制备方法如路线(7)所示:
a:IBX氧化反应
步骤a所述IBX氧化反应类似于路线(4)中制备化合物23或46的IBX氧化方法。
b:格氏反应
步骤b所述格氏反应类似于路线(3)中制备化合物20-22或43-45的格氏反应方法。
c:脱TBS保护
步骤c所述脱TBS保护反应类似于路线(2)中制备化合物18或41的脱TBS保护反应的方法。
本发明制备方法中,上述反应通过薄板层析法跟踪测定反应的进度,反应完毕后采用的后处理方法包括浓缩、萃取、柱层析分离等,最终产物以核磁共振谱来验证。
本发明制备方法中,重点是对D-环侧链的长度及官能团的类型进行结构修饰。针对D-环侧链的长度进行改造,主要是通过NaCN在D-环侧链上增加一个碳原子的长度以及通过Wittig反应在D-环侧链上增加两个碳原子的长度来实现的,此方法操作简单,反应效果好,收率高。针对D-环侧链上官能团的类型进行改造,主要是引入羧酸、伯醇、仲醇、叔醇及醚来实现的,此方法操作简便,反应效果好。
本发明还提供了由上述制备方法得到的式(I)所示的胆酸衍生物。
本发明还提供了式(I)所示的胆酸衍生物在降低体内胆固醇和甘油三酯方面的应用。
本发明还提供了式(I)所示的胆酸衍生物在制备预防和治疗高胆固醇血症,高甘油三酯血症和动脉粥样硬化药物中的应用。
本发明还提供了式(I)所示的胆酸衍生物在制备预防和治疗高胆固醇血症,高甘油三酯血症,动脉粥样硬化药物中与他汀类药物的联合应用。
其中,所述他汀类药物包括洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、瑞舒伐他汀等。
本发明还提供了式(I)所示的胆酸衍生物在胆固醇依赖的细胞生长实验中的应用,表明胆酸衍生物能够有效抑制细胞胆固醇的合成。
本发明还提供了式(I)所示的胆酸衍生物在与治疗心血管系统疾病的里程碑的药物洛伐他汀单独和联合使用方面的应用,提示胆酸衍生物能够显著的降低体内血清和肝脏中胆固醇的含量,且与他汀类药物联用时进一步降低胆固醇水平,表明胆酸衍生物单独使用,尤其与他汀类药物联合使用有利于预防和治疗高胆固醇血症和动脉粥样硬化。
本发明还提供了式(I)所示的胆酸衍生物在与洛伐他汀单独和联合使用方面的应用,提示胆酸衍生物单独使用时能够显著的降低体内血清和肝脏中甘油三酯的含量,与他汀类药物联用时有进一步降低甘油三酯水平的趋势,表明胆酸衍生物单独使用,尤其与他汀类药物联合使用有利于预防和治疗高甘油三酯血症。
本发明的有益效果在于,本发明设计、合成了一系列胆酸衍生物。本发明的反应条件温和、单元反应操作简单、合成方法简便。制备得到的胆酸衍生物能显著抑制胆固醇合成和降低体内胆固醇的含量,可以用于制备预防和治疗高胆固醇血症,高甘油三酯血症,动脉粥样硬化等疾病的药物,具有良好的应用前景。另外,制备得到的胆酸衍生物单独使用时能够显著的降低体内血清和肝脏中甘油三酯的含量,与他汀类药物连用时有进一步降低甘油三酯水平的趋势,从而更有利于预防和治疗高甘油三酯血症。
附图说明
图1为实施例中胆酸衍生物抑制细胞胆固醇合成降低胆固醇含量的柱状图。
图2为部分胆酸衍生物在胆固醇依赖的细胞生长实验中的测试结果图。
图3为活性最好的化合物与洛伐他汀单独和联合使用时降低血液和肝脏中脂类水平的活性结果图:
图3A所示化合物45和洛伐他汀单独给药后,显著降低血清中的总胆固醇水平,且二者效果相当;化合物45和洛伐他汀联用时,比二者单独使用时更进一步降低血清中的总胆固醇水平;
图3B所示化合物45和洛伐他汀单独给药后,显著降低血清中的甘油三酯水平,二者效果相当;化合物45和洛伐他汀联用时,有降低血清中的甘油三酯的趋势;
图3C所示化合物45和洛伐他汀单独给药后,显著降低肝脏中的总胆固醇含量,效果相当;二者联用时,进一步降低肝脏中总胆固醇的含量;
图3D所示化合物45和洛伐他汀单独给药后,显著降低肝脏中的甘油三酯含量,效果相当;化合物45和洛伐他汀联用时,有降低肝脏中甘油三酯的趋势。
具体实施方式
结合以下具体实施例和附图,对本发明作进一步的详细说明。实施发明的过程、条件、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。
下述实施例中化合物结构由核磁共振仪测定;试剂主要由上海国药化学试剂公司提供;产品纯化主要通过柱色谱,硅胶(200-300目)由青岛海洋化工厂生产。
实施例1 化合物13和36的制备
化合物Lithocholic acid(3.76g,10mmol)溶解在无水甲醇(150mL)中,0℃下逐滴滴加SOCl2(4.76g,2.9mL,40mmol),滴加完毕后,自然升至室温后继续搅拌5h。TLC检测完全反应后,浓缩反应液,然后加入乙酸乙酯(250mL)溶解残留物,有机相依次用饱和NaHCO3溶液(3×50mL),饱和NaCl溶液(3×50mL)洗涤,无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=3:1)纯化,得到白色固体化合物1(3.88g,99%)。1H NMR(500MHz,CDCl3)δ3.67(s,3H),3.59-3.65(m,1H),2.30-2.40(m,1H),2.20-2.26(m,1H),1.93-1.99(m,1H),1.74-1.90(m,5H),1.63-1.73(m,2H),1.57-1.60(m,1H),1.48-1.54(m,1H),1.23-1.44(m,11H),1.02-1.17(m,5H),0.92(s,3H),0.91(d,J=6.8Hz,3H),0.64(s,3H).
化合物1(8.69g,22.25mmol)溶于无水DMF(30mL)中,在冰水浴和氮气保护下,向反应体系中加入咪唑(7.57g,111.25mmol),然后分批向反应体系中缓慢加入TBSCl(8.38g,55.63mmol),加料完毕后撤去冰水浴,自然升温至80℃左右反应6h。TLC检测完全反应后,冷却至室温,将反应体系缓慢倒入冰水(40mL)中,乙酸乙酯(3×80mL)萃取,合并有机相,依次用H2O(5×50mL),饱和NaCl溶液(3×40mL)洗涤,无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=20:1)纯化,得到白色固体化合物2(9.66g,86%)。1H NMR(500MHz,CDCl3)δ3.66(s,3H),3.54-3.62(m,1H),2.30-2.40(m,1H),2.16-2.27(m,1H),1.91-1.99(m,1H),1.71-1.89(m,5H),1.51-1.63(m,3H),1.31-1.48(m,9H),1.19-1.29(m,3H),1.01-1.17(m,5H),0.88-0.93(m,15H),0.63(s,3H),0.06(s,6H).
化合物2(5.05g,10mmol)溶于无水THF(50mL)中,在冰水浴和氮气保护下,向反应体系中分批缓慢加入LiAlH4(759mg,20mmol),加料完毕后撤去冰水浴在室温下反应24h。TLC检测完全反应后,在冰盐浴下,向反应体系中分批慢慢的加入Na2SO4·10H2O,直至反应体系中无气泡产生,且体系呈现白色,分层为止,抽滤出固体,浓缩滤液,硅胶柱层析(PE:EA=5:1),得到白色固体化合物3(4.58g,96%)。1H NMR(500MHz,CDCl3)δ3.50-3.68(m,3H),1.92-1.99(m,1H),1.72-1.87(m,4H),1.59-1.69(m,1H),1.51-1.57(m,2H),1.31-1.49(m,10H),1.18-1.28(m,4H),1.00-1.16(m,6H),0.92(d,J=6.5Hz,3H),0.89(s,12H),0.64(s,3H),0.06(s,6H).
将I2(21.85g,86mmol)溶于无水甲苯(250mL)中,完全溶解后依次向反应体系中加入PPh3(22.55g,86mmol)和咪唑(11.71g,172mmol),加料完毕后在室温下搅拌2h。然后将化合物3(8.2g,17.2mmol)分批加入到反应体系中继续反应1h。TLC检测反应完全后,抽滤出不溶物,滤液在50℃的水浴上浓缩,硅胶柱层析(PE:EA=25:1),得到白色固体化合物4(9.89g,98%)。1H NMR(500MHz,CDCl3)δ3.53-3.62(m,1H),3.08-3.24(m,2H),1.91-1.97(m,1H),1.67-1.91(m,6H),1.52-1.59(m,2H),1.31-1.48(m,9H),1.20-1.29(m,3H),1.00-1.20(m,7H),0.88-0.92(m,15H),0.63(s,3H),0.06(s,6H).
化合物4(13.49g,22.9mmol)溶于THF(40mL)和DMSO(60mL)的混合溶剂中,完全溶解后向反应体系中加入NaCN(3.37g,68.7mmol),加料完毕后自然升温至60℃左右反应6h。TLC检测反应完全后,冷却至室温将反应体系缓慢倒入H2O(50mL)中,乙酸乙酯(3×100mL)萃取,合并有机相依次用H2O(5×50mL)、饱和NaCl溶液(3×50mL)洗涤,无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=20:1)纯化,得到白色固体化合物5(10.79g,97%)。1H NMR(500MHz,CDCl3)δ3.53-3.64(m,1H),2.24-2.37(m,2H),1.90-1.98(m,1H),1.68-1.87(m,5H),1.47-1.59(m,5H),1.31-1.47(m,8H),1.16-1.28(m,4H),1.01-1.16(m,5H),0.92(d,J=6.6Hz,3H),0.90(s,3H),0.89(s,9H),0.64(s,3H),0.06(s,6H).
化合物5(4.86g,10mmol)溶于饱和的HCl/MeOH溶液(20mL),加料完毕后自然升温回流1h。TLC检测完全反应后,浓缩反应液,用乙酸乙酯(200mL)溶解残留物,有机相依次用饱和NaHCO3溶液(3×50mL)、饱和NaCl溶液(3×50mL)洗涤,无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=3:1)纯化,得到白色固体化合物6(4.01g,99%)。1H NMR(500MHz,CDCl3)δ3.65(s,3H),3.57-3.64(m,1H),2.19-2.33(m,2H),1.92-1.98(m,1H),1.62-1.88(m,6H),1.43-1.57(m,3H),1.28-1.43(m,8H),1.17-1.28(m,3H),1.00-1.16(m,6H),0.93-1.00(m,1H),0.91(d,J=6.2Hz,3H),0.90(s,3H),0.62(s,3H).
化合物1(3.88g,10mmol)溶解于DCM(120mL)中,加入PCC(4.32g,20mmol),室温搅拌12h。TLC检测完全反应后,深褐色反应液经过硅藻土过滤,滤饼用DCM洗涤,母液浓缩得棕黄色固体,加入乙酸乙酯(200mL)将其溶解,饱和亚硫酸氢钠水溶液洗涤至有机层无色,然后用饱和NaCl溶液(3×50mL)洗涤,有机层用无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=7:1)纯化,得到白色固体化合物7(3.56g,92.3%)。1H NMR(500MHz,CDCl3)δ3.67(s,3H),2.70(t,J=14.2Hz,1H),2.29-2.40(m,2H),2.20-2.26(m,1H),2.13-2.20(m,1H),1.99-2.06(m,3H),1.76-1.92(m,4H),1.57-1.63(m,1H),1.28-1.54(m,10H),1.19-1.24(m,1H),1.05-1.16(m,4H),1.02(s,3H),0.92(d,J=6.5Hz,3H),0.68(s,3H).
化合物30的合成类似于化合物7的合成方法,化合物6(7.2g,17.8mmol)经PCC氧化和后处理得到白色的固体化合物30(6.74g,94%)。1H NMR(500MHz,CDCl3)δ3.67(s,3H),2.65-2.74(m,1H),2.20-2.38(m,3H),2.12-2.19(m,1H),1.99-2.07(m,3H),1.77-1.93(m,3H),1.65-1.77(m,1H),1.56-1.61(m,1H),1.33-1.54(m,9H),1.03-1.29(m,8H),1.02(s,3H),0.93(d,J=6.6Hz,3H),0.68(s,3H).
化合物7(3.56g,9.2mmol)溶解在DCM(150mL)和HOAc(20mL)中,0℃下缓慢滴加溴的醋酸溶液(Br2(1.62g,0.5mL,10.1mmol)溶解在HOAc(10mL)中),30min滴加完毕后,将反应液自然升至室温后继续搅拌30min。TLC检测完全反应后,有机相依次用H2O(3×50mL)洗涤,饱和NaHCO3溶液(3×50mL)洗涤,饱和NaCl溶液(3×50mL)洗涤,有机层用无水Na2SO4干燥,浓缩,得淡黄色油状粘稠液体化合物8,未经纯化直接用于下一步反应。
化合物8溶解在无水DMF(60mL)中,加入Li2CO3(2.72g,36.8mmol)和LiBr·H2O(1.93g,18.4mmol),加料完毕后升温至90℃左右后反应6h。TLC检测完全反应后,冷却至室温,过滤出固体,滤饼用乙酸乙酯洗涤,然后加入乙酸乙酯(200mL)稀释反应液,有机相依次用H2O(6×50mL)洗涤,饱和NaCl溶液(3×50mL)洗涤,有机层用无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=6:1),得到白色固体化合物9(1.83g,48%)。1H NMR(500MHz,CDCl3)δ5.72(s,1H),3.67(s,3H),2.30-2.46(m,4H),2.18-2.30(m,2H),1.98-2.06(m,2H),1.75-1.93(m,3H),1.65-1.73(m,1H),1.57-1.63(m,1H),1.48-1.56(m,2H),1.38-1.47(m,2H),1.23-1.37(m,3H),1.18(s,3H),1.15-1.17(m,1H),1.07-1.14(m,2H),0.97-1.07(m,2H),0.92(d,J=6.5Hz,3H),0.71(s,3H).
化合物31的合成类似于化合物8的合成方法,化合物30(6.19g,15.4mmol)经溴代和后处理得到淡黄色油状粘稠液体化合物31,未经纯化直接用于下一步反应。
化合物32的合成类似于化合物9的合成方法,化合物31经脱除反应和后处理得到白色固体化合物32(3.08g,50%)。1H NMR(500MHz,CDCl3)δ5.72(s,1H),3.67(s,3H),2.21-2.46(m,6H),1.97-2.06(m,2H),1.80-1.90(m,2H),1.65-1.76(m,2H),1.59-1.64(m,1H),1.47-1.56(m,3H),1.34-1.48(m,3H),1.21-1.34(m,2H),1.18(s,3H),0.97-1.17(m,6H),0.93(d,J=6.5Hz,3H),0.71(s,3H).
化合物9(1.83g,4.7mmol)溶解在无水叔丁醇(30mL)中,氮气保护下分批加入叔丁醇钾(2.13g,19.0mmol),室温下搅拌30min,待反应液澄清后,再向反应体系中缓慢滴加碘甲烷(6.76g,3.0mL,47.0mmol)。滴加完毕后,室温搅拌24h。TLC检测完全反应后,将反应液慢慢地倒入冰水(50mL)中,用1M HCl调节溶液的pH至5左右,然后用乙酸乙酯萃取(3×50mL),合并有机相,依次用H2O(3×50mL)洗涤,饱和NaCl溶液(3×50mL)洗涤,无水Na2SO4干燥,浓缩。再将混合物溶解在无水甲醇(30mL)中,0℃下逐滴滴加SOCl2(2.2g,1.4mL,19mmol),滴加完毕后继续搅拌10h。浓缩反应液,加入乙酸乙酯(50mL)溶解残留物,有机相依次用饱和NaHCO3溶液(3×50mL)洗涤,饱和NaCl溶液(3×50mL)洗涤,无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=25:1),可得白色粉末状固体化合物11(0.98g,50%)。1H NMR(400MHz,CDCl3)δ5.56(dd,J=2.0,4.8Hz,1H),3.67(s,3H),2.43-2.63(m,2H),2.32-2.42(m,1H),2.18-2.28(m,1H),2.06-2.15(m,1H),1.98-2.05(m,2H),1.75-1.94(m,2H),1.65-1.72(m,1H),1.29-1.62(m,8H),1.23(s,6H),1.00-1.20(m,5H),0.93(d,J=6.4Hz,3H),0.85(s,3H),0.69(s,3H).
化合物34的合成类似于化合物11的合成方法,化合物32(7.3g,18.2mmol)经C-4甲基化和后处理得白色粉末状固体化合物34(7.03g,60%)。1H NMR(500MHz,CDCl3)δ5.55(dd,J=2.4,5.1Hz,1H),3.67(s,3H),2.41-2.60(m,2H),2.20-2.36(m,2H),2.06-2.14(m,1H),1.98-2.05(m,2H),1.80-1.89(m,1H),1.59-1.74(m,3H),1.46-1.56(m,3H),1.34-1.45(m,3H),1.24-1.30(m,2H),1.23(s,6H),1.15-1.21(m,1H),0.98-1.14(m,5H),0.94(d,J=6.5Hz,3H),0.85(s,3H),0.68(s,3H).
化合物11(30mg,0.073mmol)溶于丙酮(10mL)中,向反应体系中加入NHPI(23mg,0.14mmol)和冰醋酸(17.3μL),完全溶解后,再向反应体系中加入Na2Cr2O7.2H2O(23mg,0.077mmol),加料完毕后自然升温至50℃左右,保温24h。TLC检测完全反应后,冷却至室温,抽滤出固体,将滤液浓缩,用DCM(30mL)溶解残留物再次过滤出固体,滤液依次用饱和NaHCO3溶液(3×10mL)洗涤,饱和NaCl溶液(3×10mL)洗涤,无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=5:1)纯化,得到白色固体化合物12(28mg,89.1%)。1H NMR(500MHz,CDCl3)δ5.91(s,1H),3.67(s,3H),2.54-2.69(m,2H),2.32-2.45(m,2H),2.19-2.31(m,2H),2.10-2.17(m,1H),2.02-2.08(m,1H),1.91-1.99(m,1H),1.77-1.87(m,2H),1.57-1.65(m,2H),1.49-1.57(m,1H),1.39-1.48(m,1H),1.32(s,6H),1.28-1.39(m,4H),1.14-1.21(m,1H),1.08-1.14(m,1H),1.07(s,3H),0.94(d,J=6.5Hz,3H),0.70(s,3H).
化合物35的合成类似于化合物12的合成方法,化合物34(3.35g,7.8mmol)经在C-7引入一个羰基和后处理得到白色固体化合物35(2.94g,85%)。1H NMR(500MHz,CDCl3):δ5.89(s,1H),3.66(s,3H),2.56-2.62(m,2H),2.32-2.42(m,1H),2.24-2.31(m,3H),2.10-2.14(m,1H),2.00-2.08(m,1H),1.83-1.90(m,1H),1.77-1.82(m,1H),1.60-1.75(m,2H),1.45-1.55(m,2H),1.32-1.42(m,3H),1.30(s,6H),1.24-1.29(m,3H),1.06-1.17(m,3H),1.06(s,3H),0.94(d,J=7.0Hz,3H),0.68(s,3H).
化合物12(393mg,0.912mmol)溶于无水甲醇(40mL)中,完全溶解后向反应体系中分批加入NaBH4(138mg,3.648mmol),加料完毕后在室温下搅拌过夜。TLC检测完全反应后,将反应液浓缩,加入H2O(20mL),用乙酸乙酯(3×30mL)萃取,合并有机相,有机层用饱和NaCl溶液(3×30mL)洗涤,无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=3:1)纯化,得到白色固体化合物13(316mg,80%)。1H NMR(500MHz,CDCl3)δ5.52(d,J=3.0Hz,1H),3.90(dd,J=2.9,7.9Hz,1H),3.67(s,3H),3.26(dd,J=4.7,10.7Hz,1H),2.31-2.41(m,1H),2.18-2.27(m,1H),1.97-2.03(m,1H),1.88-1.96(m,1H),1.70-1.86(m,5H),1.30-1.53(m,10H),1.18(s,3H),1.14(s,3H),1.08-1.12(m,2H),1.10(s,3H),0.93(d,J=6.5Hz,3H),0.69(s,3H).13C NMR(125MHz,CDCl3)δ174.71,153.31,123.65,77.09,73.97,56.18,55.09,51.47,49.78,42.70,41.45,40.28,39.41,36.85,36.24,35.28,31.02,30.99,28.36,27.25,27.06,26.08,23.31,21.31,20.65,18.30,11.75.ESI-HRMS(m/z)[M+Na]+:calcd forC27H44NaO4 455.3132;found 455.3170.
化合物36的合成类似于化合物13的合成方法,化合物35(1.86g,4.2mmol)经还原反应和后处理得到白色固体化合物36(1.52g,81%)。1H NMR(500MHz,CDCl3)δ5.52(d,J=2.8Hz,1H),3.90(dd,J=2.5,7.6Hz,1H),3.67(s,3H),3.26(dd,J=4.7,11.2Hz,1H),2.20-2.35(m,2H),1.96-2.04(m,1H),1.84-1.93(m,1H),1.66-1.84(m,5H),1.25-1.54(m,11H),1.18(s,3H),1.14(s,3H),1.10(s,3H),1.08-1.13(m,3H),0.94(d,J=6.5Hz,3H),0.69(s,3H).13C NMR(125MHz,CDCl3)δ174.32,153.30,123.66,77.07,73.98,56.20,55.08,51.43,49.81,42.66,41.45,40.27,39.41,36.85,36.24,35.41,35.38,34.47,28.42,27.25,27.07,26.10,23.32,21.47,21.31,20.65,18.60,11.73.ESI-HRMS(m/z)[M+Na]+:calcdfor C28H46NaO4 469.3288;found 469.3274.
实施例2 化合物14、37、15、38、19和42的制备
化合物13(56mg,0.13mmol)溶于无水甲醇(10mL)中,完全溶解后向反应体系中加入4M NaOH溶液(2mL),体系立即变混浊,加料完毕后在室温下搅拌24h。TLC检测完全反应后,将反应液进行浓缩,然后向残留物中加入H2O(10mL),再用1M盐酸调溶液的pH为3左右,有大量的白色固体析出,抽滤出白色固体,然后用无水甲醇将白色固体物质溶解,无水Na2SO4干燥,浓缩,硅胶柱层析(DCM:MeOH=20:1)纯化,得到白色固体化合物14(52mg,95%)。1H NMR(500MHz,DMSO-d6)δ11.94(brs,1H),5.36(d,J=2.7Hz,1H),4.50-4.56(m,1H),4.15-4.20(m,1H),3.58-3.64(m,1H),2.97-3.04(m,1H),2.17-2.27(m,1H),2.04-2.14(m,1H),1.89-1.96(m,1H),1.72-1.81(m,2H),1.57-1.71(m,4H),1.50-1.56(m,1H),1.38-1.46(m,2H),1.28-1.38(m,6H),1.14-1.28(m,3H),1.06(s,6H),0.97(s,3H),0.87(d,J=6.5Hz,3H),0.62(s,3H).13C NMR(100MHz,DMSO-d6)δ174.89,150.89,125.02,75.20,72.03,56.21,54.82,49.54,42.12,40.97,39.05,36.23,35.99,34.83,30.73,28.98,27.92,27.26,27.08,25.80,23.65,22.06,20.83,20.32,18.20,11.63.ESI-HRMS(m/z)[M+Na]+:calcd for C26H42NaO4441.2975;found 441.2999.
化合物37的合成类似于化合物14的合成方法,化合物36(58mg,0.13mmol)经水解反应和后处理得到白色固体化合物37(52mg,93%)。1H NMR(500MHz,DMSO-d6)δ11.94(brs,1H),5.36(d,J=2.8Hz,1H),4.47-4.55(m,1H),4.13-4.18(m,1H),3.57-3.66(m,1H),2.96-3.06(m,1H),2.08-2.23(m,2H),1.89-1.96(m,1H),1.71-1.82(m,2H),1.50-1.68(m,4H),1.26-1.46(m,8H),1.15-1.25(m,1H),0.99-1.12(m,5H),1.06(s,3H),1.05(s,3H),0.98(s,3H),0.89(d,J=6.4Hz,3H),0.63(s,3H).13C NMR(125MHz,DMSO-d6)δ174.50,150.91,125.07,75.22,72.07,56.28,54.89,49.59,48.60,43.24,42.13,41.01,36.27,36.03,35.02,34.94,34.08,28.06,27.30,27.13,25.83,23.69,21.06,20.88,20.37,18.55,11.65.ESI-HRMS(m/z)[M+Na]+:calcd for C27H44NaO4 455.3132;found 455.3172.
化合物13(65mg,0.15mmol)溶于无水THF(20mL)中,在冰水浴和氮气保护下,向反应体系中缓慢分批加入LiAlH4(29mg,0.75mmol),加料完毕后撤去冰水浴在室温下反应24h。TLC检测完全反应后,在冰盐浴下,向反应体系中分批慢慢的加入Na2SO4·10H2O,直至反应体系中无气泡产生,且体系呈现白色、分层为止,抽滤出固体,浓缩滤液,硅胶柱层析(DCM:MeOH=25:1),得到白色固体化合物15(57mg,94%)。1H NMR(500MHz,DMSO-d6)δ5.37(d,J=2.3Hz,1H),4.40-4.48(m,1H),4.24(t,J=5.1Hz,1H),4.05-4.10(m,1H),3.59-3.65(m,1H),3.31-3.39(m,2H),2.98-3.05(m,1H),1.90-1.98(m,1H),1.72-1.82(m,2H),1.58-1.66(m,2H),1.51-1.57(m,1H),1.15-1.50(m,12H),1.04(s,6H),1.00-1.04(m,3H),0.98(s,3H),0.89(d,J=6.4Hz,3H),0.64(s,3H).13C NMR(125MHz,DMSO-d6)δ150.79,124.93,75.13,71.96,61.19,56.18,55.03,49.53,42.01,40.88,39.08,36.16,35.93,34.97,31.72,29.08,28.83,27.93,27.16,27.01,25.68,23.51,20.75,20.25,18.54,11.55.ESI-HRMS(m/z)[M+Na]+:calcd for C26H44NaO3 427.3183;found 427.3181.
化合物38的合成类似于化合物15的合成方法,化合物36经过还原和后处理得到白色的固体化合物38(48mg,92%)。1H NMR(500MHz,DMSO-d6)δ5.36(d,J=2.8Hz,1H),4.49-4.54(m,1H),4.32(t,J=5.1Hz,1H),4.14-4.18(m,1H),3.58-3.64(m,1H),3.34-3.39(m,2H),2.96-3.04(m,1H),1.89-1.96(m,1H),1.72-1.81(m,2H),1.57-1.67(m,2H),1.49-1.57(m,1H),1.25-1.45(m,10H),1.07-1.24(m,4H),1.06(s,6H),0.99-1.03(m,3H),0.97(s,3H),0.89(d,J=6.4Hz,3H),0.63(s,3H).13C NMR(125MHz,DMSO-d6):δ150.81,124.97,75.14,71.98,60.69,56.22,54.97,49.53,42.05,40.92,39.14,38.97,36.18,35.95,35.34,35.14,32.97,28.02,27.20,27.05,25.73,23.57,21.87,20.78,20.28,18.53,11.57.ESI-HRMS(m/z)[M+Na]+:calcd for C27H46NaO3 441.3339;found 441.3333.
化合物13(1.5g,3.467mmol)溶于无水DMF(20mL)中,冰水浴和氮气保护下,向反应体系中依次加入咪唑(7.1g,104.01mmol)、TBSCl(7.8g,52mmol),加料完毕后撤去冰水浴,自然升温至80℃左右搅拌3h。TLC检测完全反应后,将反应体系缓慢倒入冰水(50mL)中,用乙酸乙酯(3×60mL)萃取,合并有机相依次用H2O(5×40mL)、饱和NaCl溶液(3×40mL)洗涤,无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=20:1)纯化,得到白色固体化合物16(2.1g,93.7%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.2Hz,1H),3.99(dd,J=3.2,7.5Hz,1H),3.66(s,3H),3.21(dd,J=4.1,11.4Hz,1H),2.30-2.39(m,1H),2.17-2.27(m,1H),1.93-1.99(m,1H),1.70-1.89(m,4H),1.62-1.69(m,1H),1.24-1.56(m,10H),1.12(s,3H),1.07(s,3H),1.05-1.09(m,3H),1.05(s,3H),0.85-0.93(m,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物39的合成类似于化合物16的合成,化合物36(0.86g,1.93mmol)经C-3、C-7羟基双保护和后处理得到白色固体化合物39(1.20g,92%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.1Hz,1H),3.99(dd,J=3.1,7.5Hz,1H),3.67(s,3H),3.21(dd,J=4.1,11.5Hz,1H),2.20-2.33(m,2H),1.93-2.00(m,1H),1.77-1.86(m,1H),1.63-1.77(m,4H),1.43-1.58(m,4H),1.31-1.43(m,5H),1.20-1.29(m,2H),1.12(s,3H),1.08(s,3H),1.05(s,3H),1.07–0.98(m,4H),0.93(d,J=6.5Hz,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物16(866mg,1.31mmol)溶于无水THF(20mL)中,冰水浴和氮气保护下,向反应体系中分批加入LiAlH4(497mg,13.1mmol),加料完毕后,撤去冰水浴自然升至室温反应24h。TLC检测完全反应后,冰盐浴下向反应体系中分批慢慢的加入Na2SO4·10H2O,直至反应体系中无气泡产生为止,且体系呈现白色,分层,抽滤出固体,浓缩滤液,硅胶柱层析(PE:EA=5:1),得到白色固体化合物17(181mg,92%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.2Hz,1H),4.00(dd,J=3.1,7.6Hz,1H),3.57-3.66(m,2H),3.21(dd,J=4.1,11.5Hz,1H),1.95-2.01(m,1H),1.78-1.88(m,1H),1.70-1.78(m,2H),1.61-1.69(m,2H),1.49-1.57(m,2H),1.20-1.49(m,10H),1.12(s,3H),1.07(s,3H),1.11–1.06(m,3H),1.05(s,3H),0.93(d,J=6.5Hz,3H),0.89(s,9H),0.88(s,9H),0.68(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物40的合成类似于化合物17的合成方法,化合物39(843mg,1.25mmol)经过还原和后处理得到白色的固体化合物40(744mg,92%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=2.4Hz,1H),3.99(dd,J=2.5,7.4Hz,1H),3.60-3.68(m,2H),3.21(dd,J=3.6,11.2Hz,1H),1.94-2.01(m,1H),1.78-1.87(m,1H),1.69-1.78(m,2H),1.62-1.69(m,1H),1.31-1.56(m,10H),1.19-1.30(m,4H),1.12(s,3H),1.08(s,3H),1.05(s,3H),1.02-1.09(m,4H),0.92(d,J=6.5Hz,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
氮气保护下,将60%NaH(64mg,1.6mmol)溶于无水THF(5mL)中,0℃左右向反应体系中慢慢滴加化合物17的THF溶液(化合物2-29(100mg,0.16mmol)溶于无水THF(5mL)中),滴加完毕后反应0.5h。然后向反应体系中缓慢滴入CH3I(0.1mL,1.6mmol),滴加完毕后撤去冰水浴自然升至室温下反应24h。TLC检测完全反应后,将反应液倒入冰水中(5mL),乙酸乙酯(3×30mL)萃取,合并有机相用饱和NaCl溶液(3×20mL)洗涤,无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=20:1)纯化,得到白色固体化合物18(94mg,91%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.1Hz,1H),4.00(dd,J=3.1,7.5Hz,1H),3.36(t,J=6.7Hz,2H),3.33(s,3H),3.22(dd,J=4.0,11.5Hz,1H),1.96-1.99(m,1H),1.83-1.93(m,1H),1.70-1.82(m,2H),1.64-1.67(m,2H),1.52-1.58(m,2H),1.34-1.48(m,7H),1.24-1.29(m,2H),1.02-1.11(m,4H),1.12(s,3H),1.08(s,3H),1.05(s,3H),0.93(d,J=6.5Hz,3H),0.90(s,9H),0.88(s,9H),0.68(s,3H),0.09(s,3H),0.08(s,3H),0.04(s,3H),0.02(s,3H).
化合物41的合成类似于化合物18的合成方法,化合物40(94mg,0.15mmol)经甲醚化和后处理得到白色固体化合物41(90mg,91%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.2Hz,1H),3.99(dd,J=3.2,7.5Hz,1H),3.37(t,J=6.6Hz,2H),3.34(s,3H),3.21(dd,J=4.2,11.6Hz,1H),1.94-2.01(m,1H),1.78-1.87(m,1H),1.69-1.78(m,2H),1.63-1.69(m,1H),1.43-1.57(m,5H),1.34-1.42(m,5H),1.16-1.28(m,3H),1.12(s,3H),1.07(s,3H),1.05(s,3H),1.00-1.10(m,5H),0.91(d,J=6.8Hz,3H),0.89(s,9H),0.88(s,9H),0.66(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物18(81mg,0.126mmol)溶于THF(10mL)中,完全溶解后向反应体系中加入TBAF(239mg,0.756mmol),升温回流24h。TLC检测完全反应后,浓缩反应液,向反应体系中加入饱和NH4Cl溶液(10mL),乙酸乙酯(3×30mL)萃取,合并有机相用饱和NaCl溶液(3×20mL)洗涤,无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=3:1)纯化,得到白色固体化合物19(48mg,90%)。1H NMR(500MHz,CDCl3)δ5.51(d,J=2.6Hz,1H),3.89(dd,J=2.5,7.8Hz,1H),3.34(t,J=6.7Hz,2H),3.32(s,3H),3.25(dd,J=4.6,10.9Hz,1H),1.98-2.01(m,1H),1.83-1.93(m,1H),1.60-1.82(m,7H),1.37-1.59(m,10H),1.21-1.32(m,2H),1.17(s,3H),1.13(s,3H),1.07(s,3H),0.92(d,J=6.4Hz,3H),0.68(s,3H).13C NMR(125MHz,CDCl3)δ153.29,123.67,77.07,73.99,73.44,58.48,56.21,55.30,49.82,42.66,41.45,40.28,39.44,36.86,36.26,35.54,32.18,28.47,27.26,27.07,26.16,26.11,23.33,21.31,20.66,18.65,11.76.ESI-HRMS(m/z)[M+Na]+:calcd for C27H46NaO3 441.3339;found 441.3324.
化合物42的合成类似于化合物19的合成方法,化合物41(82mg,0.124mmol)经反应和后处理得到白色固体化合物42(48mg,90%)。1H NMR(500MHz,CDCl3)δ5.52(d,J=3.0Hz,1H),3.90(dd,J=2.6,7.8Hz,1H),3.37(t,J=6.6Hz,2H),3.34(s,3H),3.26(dd,J=4.8,10.8Hz,1H),1.97-2.04(m,1H),1.84-1.94(m,1H),1.71-1.83(m,4H),1.35-1.61(m,12H),1.18(s,3H),1.14(s,3H),1.10(s,3H),1.04-1.13(m,5H),0.92(d,J=6.5Hz,3H),0.68(s,3H).13C NMR(125MHz,CDCl3):δ153.25,123.64,77.03,73.97,72.96,58.49,56.19,55.25,49.79,42.63,41.42,40.25,39.41,36.83,36.23,35.74,35.59,30.05,28.45,27.24,27.05,26.10,23.30,22.54,21.29,20.63,18.64,11.72.ESI-HRMS(m/z)[M+Na]+:calcdfor C28H48NaO3 455.3496;found 455.3486.
实施例3 化合物20-22和43-45的制备
将化合物13(87mg,0.2mmol)溶于无水THF(12mL)中,在-10℃左右和氮气保护下,向反应体系中慢慢滴加CH3MgCl(1.0M,2mL)的THF溶液,滴加完毕,在自然升至室温后反应约0.5h。TLC检测完全反应后,在冰水浴下,向反应体系中慢慢滴加饱和的NH4Cl溶液,直至无气泡产生为止,抽滤出固体,滤液用乙酸乙酯(3×50mL)萃取,合并有机相用饱和NaCl溶液(3×30mL)洗涤,无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=1:1)纯化,得到白色固体化合物20(69mg,80%)。1H NMR(500MHz,DMSO-d6)δ5.35(d,J=2.3Hz,1H),4.51-4.54(m,1H),4.15-4.19(m,1H),4.02(s,1H),3.57-3.64(m,1H),2.96-3.05(m,1H),1.89-1.95(m,1H),1.72-1.82(m,2H),1.57-1.66(m,2H),1.49-1.57(m,1H),1.36-1.46(m,4H),1.27-1.36(m,4H),1.14-1.25(m,3H),1.02-1.07(m,4H),1.06(s,3H),1.05(s,3H),1.04(s,3H),1.03(s,3H),0.97(s,3H),0.88(d,J=6.2Hz,3H),0.62(s,3H).13C NMR(100MHz,CD3OD-d4+CDCl3)δ154.09,125.61,77.96,74.53,71.74,58.04,56.74,51.65,43.87,42.61,41.05,40.96,40.75,38.03,37.78,37.36,31.50,29.58,29.52,29.13,28.07,27.94,27.12,24.30,21.99,21.85,19.57,12.53.ESI-HRMS(m/z)[M+Na]+:calcd for C28H48NaO3 455.3496;found 455.3630.
化合物43的合成类似于化合物20的合成方法,化合物36经过甲基格氏反应和后处理得到白色的固体化合物43(57mg,79%)。1H NMR(500MHz,DMSO-d6)δ5.36(d,J=2.6Hz,1H),4.49-4.56(m,1H),4.14-4.20(m,1H),4.05(s,1H),3.53-3.66(m,1H),2.95-3.06(m,1H),1.90-1.97(m,1H),1.71-1.81(m,2H),1.57-1.68(m,2H),1.50-1.57(m,1H),1.10-1.45(m,13H),1.05(s,12H),0.94-1.02(m,4H),0.98(s,3H),0.90(d,J=6.3Hz,3H),0.63(s,3H).13C NMR(125MHz,DMSO-d6)δ150.89,125.05,75.21,72.06,68.78,56.30,55.17,49.60,47.83,44.16,42.14,41.00,39.17,36.29,36.26,36.04,35.33,29.39,29.21,28.17,27.28,27.12,25.83,23.68,20.86,20.38,20.36,18.64,11.67.ESI-HRMS(m/z)[M+Na]+:calcd for C29H50NaO3 469.3652;found469.3657.
将化合物13(87mg,0.2mmol)溶于无水THF(12mL)中,在0℃左右和氮气保护下,向反应体系中慢慢滴加CH3CH2MgCl(2.0M,1mL)的THF溶液,滴加完毕后在自然升至室温反应1h。TLC检测完全反应后,在冰水浴下,向反应体系中慢慢滴加饱和的NH4Cl溶液,直至无气泡产生为止,抽滤出固体,滤液用乙酸乙酯(3×50mL)萃取,合并有机相用饱和NaCl溶液(3×30mL)洗涤,无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=2:1)纯化,得到白色固体化合物21(78mg,85%)。1H NMR(400MHz,CD3OD-d4)δ5.49(d,J=3.2Hz,1H),3.78(dd,J=3.0,8.0Hz,1H),3.16(dd,J=4.2,11.8Hz,1H),2.00-2.05(m,1H),1.84-1.95(m,2H),1.80-1.83(m,1H),1.72–1.78(m,2H),1.62-1.69(m,1H),1.35–1.54(m,13H),1.28-1.33(m,5H),1.16(s,3H),1.14(s,3H),1.08(s,3H),0.96(d,J=6.5Hz,3H),0.82-0.87(m,6H),0.72(s,3H).13C NMR(100MHz,CDCl3+CD3OD-d4)δ156.61,128.12,80.48,78.23,77.06,60.55,59.28,54.15,46.42,45.15,43.48,43.28,40.57,40.31,40.13,37.61,34.53,34.17,33.08,32.25,30.60,30.50,29.67,26.86,24.54,24.41,22.23,15.09,10.90,10.80.ESI-HRMS(m/z)[M+Na]+:calcd for C30H52NaO3 483.3809;found 483.3803.
化合物44的合成类似于化合物21的合成方法,化合物36经乙基格氏反应和后处理得白色固体化合物44(85mg,81%)。1H NMR(500MHz,CDCl3)δ5.52(d,J=2.8Hz,1H),3.90(dd,J=2.4,7.8Hz,1H),3.26(dd,J=4.3,10.4Hz,1H),1.98–2.04(m,1H),1.84–1.93(m,1H),1.71–1.83(m,4H),1.44–1.49(m,7H),1.28–1.43(m,11H),1.18(s,3H),1.14(s,3H),1.10(s,3H),1.01–1.14(m,3H),0.93(d,J=6.5Hz,3H),0.84–0.88(m,6H),0.69(s,3H).13CNMR(125MHz,DMSO-d6)δ150.82,125.02,75.15,72.37,72.01,56.23,55.03,49.53,42.07,40.94,39.11,38.30,36.34,36.21,35.97,35.17,30.58,30.45,28.09,28.07,27.23,27.07,25.78,23.61,20.81,20.30,19.26,18.61,11.61,7.79,7.75.ESI-HRMS(m/z)[M+Na]+:calcd for C31H54NaO3 497.3965;found497.3948.
将化合物13(87mg,0.2mmol)溶于无水THF(12mL)中,在3~5℃和氮气保护下,向反应体系中慢慢滴加CH2=CHCH2MgCl(1.0M,2mL)的无水THF溶液,滴加完毕后自然升至室温反应大约0.5h。TLC检测完全反应后,在冰水浴下,向反应体系中慢慢滴加饱和NH4Cl溶液,直至无气泡产生为止,抽滤出固体,滤液用乙酸乙酯(3×50mL)萃取,合并有机相用饱和NaCl溶液(3×30mL)洗涤,无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=2:1)纯化,得到白色固体化合物22(84mg,86.5%)。1H NMR(500MHz,CDCl3)δ5.80-5.90(m,2H),5.52(d,J=3.0Hz,1H),5.08-5.17(m,4H),3.91(dd,J=3.0,7.9Hz,1H),3.26(dd,J=4.7,10.8Hz,1H),2.22(d,J=6.7Hz,4H),1.97-2.09(m,2H),1.87-1.97(m,1H),1.71-1.84(m,4H),1.35-1.57(m,11H),1.29-1.34(m,3H),1.18(s,3H),1.14(s,3H),1.10(s,3H),0.93(d,J=6.6Hz,3H),0.69(s,3H).13C NMR(125MHz,CDCl3)δ153.31,133.76(2C),123.69,118.59,118.52,73.98,73.62,56.23,55.12,49.83,43.78,43.56,42.66,41.45,40.27,39.43,36.86,36.27,36.02,35.38,29.66,29.24,28.52,27.25,27.09,26.13,23.34,21.30,20.66,18.81,11.74.ESI-HRMS(m/z)[M+Na]+:calcd for C32H52NaO3 507.3809;found 507.3822.
化合物45的合成类似于化合物22的合成方法,化合物36经反应和后处理得到白色固体化合物45(82mg,84%)。1H NMR(500MHz,CDCl3)δ5.80-5.90(m,2H),5.52(d,J=3.0Hz,1H),5.08-5.18(m,4H),3.91(dd,J=2.5,7.7Hz,1H),3.26(dd,J=4.7,10.7Hz,1H),2.18-2.28(m,4H),1.98-2.04(m,1H),1.83-1.92(m,1H),1.70-1.83(m,4H),1.23-1.55(m,17H),1.18(s,3H),1.14(s,3H),1.10(s,3H),0.93(d,J=6.5Hz,3H),0.69(s,3H).13C NMR(125MHz,CDCl3)δ153.30,133.80(2C),123.65,118.55(2C),77.08,74.01,73.52,56.19,55.31,49.81,43.77,43.65,42.67,41.44,40.29,39.61,39.43,36.86,36.41,36.24,35.59,28.49,27.26,27.06,26.12,23.31,21.31,20.65,19.69,18.72,11.75.ESI-HRMS(m/z)[M+Na]+:calcd for C33H54NaO3 521.3965;found 521.3993.
实施例4 化合物27-29和50-52的制备
化合物17(2.4g,3.75mmol)溶于DMSO(50mL)中,氮气保护下,向反应体系中加入IBX(2.1g,7.5mmol),加料完毕后自然升温至50℃左右反应3h。TLC检测完全反应后,将反应液冷却至室温,补加100mL的乙酸乙酯和100mL的H2O,抽滤出不溶物,分出EA相,水相再用乙酸乙酯(3×80mL)萃取,合并有机相用饱和NaCl溶液(3×50mL)洗涤,无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=25:1)纯化,得到白色固体化合物23(2.1g,88.6%)。1H NMR(500MHz,CDCl3)δ9.76(s,1H),5.49(d,J=3.0Hz,1H),4.00(dd,J=3.0,7.4Hz,1H),3.21(dd,J=4.1,11.5Hz,1H),2.40-2.50(m,1H),2.30-2.39(m,1H),1.93-2.01(m,1H),1.70-1.90(m,4H),1.62-1.68(m,1H),1.24-1.55(m,9H),1.12(s,3H),1.08(s,3H),1.06-1.11(m,2H),1.05(s,3H),1.02-1.06(m,2H),0.92(d,J=6.6Hz,3H),0.90(s,9H),0.88(s,9H),0.68(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物46的合成类似于化合物23的合成方法,化合物40(129mg,0.20mmol)经IBX氧化和后处理得到白色固体化合物46(112mg,87%)。1H NMR(500MHz,CDCl3)δ9.76(s,1H),5.49(d,J=3.2Hz,1H),3.99(dd,J=3.1,7.5Hz,1H),3.21(dd,J=4.2,11.5Hz,1H),2.32-2.46(m,2H),1.92-2.01(m,1H),1.78-1.86(m,1H),1.69-1.78(m,3H),1.62-1.68(m,1H),1.44-1.56(m,4H),1.33-1.43(m,4H),1.19-1.30(m,2H),1.12(s,3H),1.08(s,3H),1.05(s,3H),0.99-1.10(m,5H),0.94(d,J=6.5Hz,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物23(158mg,0.25mmol)溶于无水THF(10mL)中,在-10~-5℃和氮气保护下,向反应体系中缓慢滴入CH3MgCl溶液(1.0M,1mL),滴加完毕后自然升至室温反应2h。TLC检测完全反应后,在0℃左右向反应体系中慢慢滴入饱和NH4Cl溶液直至无气泡产生为止,过滤出固体,滤液用乙酸乙酯(3×30mL)萃取,合并有机相用饱和NaCl溶液(3×20mL)洗涤,无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=10:1)纯化,得到白色固体化合物24(97mg,60%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.1Hz,1H),4.00(dd,J=3.0,7.6Hz,1H),3.70-3.81(m,1H),3.21(dd,J=4.2,11.5Hz,1H),1.94-2.00(m,1H),1.78-1.90(m,1H),1.70-1.78(m,2H),1.63-1.69(m,1H),1.47-1.55(m,3H),1.28-1.47(m,10H),1.19(d,J=6.2Hz,3H),1.12(s,3H),1.08(s,3H),1.05(s,3H),1.03-1.10(m,3H),0.92(d,J=6.8Hz,3H),0.89(s,9H),0.88(s,9H),0.68(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物47的合成类似于化合物24的合成方法,化合物46(100mg,0.155mmol)与CH3MgCl反应和后处理得到白色固体化合物47(77mg,75%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.0Hz,1H),4.00(dd,J=3.2,7.7Hz,1H),3.84–3.74(m,1H),3.21(dd,J=4.1,11.5Hz,1H),1.93-2.02(m,1H),1.78-1.88(m,1H),1.69-1.78(m,2H),1.62-1.69(m,1H),1.51-1.55(m,1H),1.31-1.50(m,8H),1.24-1.31(m,3H),1.19(d,J=5.6Hz,3H),1.12(s,3H),1.08(s,3H),1.05(s,3H),1.02-1.08(m,6H),0.88-0.92(m,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物25的合成类似于化合物24的合成方法,以CH3CH2MgCl溶液(2.0M)替代CH3MgCl溶液(1.0M)进行反应和后处理,得到白色固体化合物25(124mg,75%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.1Hz,1H),4.00(dd,J=3.0,7.5Hz,1H),3.42-3.52(m,1H),3.21(dd,J=4.0,11.4Hz,1H),1.94-2.02(m,1H),1.78-1.90(m,1H),1.70-1.78(m,2H),1.63-1.69(m,1H),1.49-1.58(m,5H),1.34-1.49(m,7H),1.28-1.34(m,3H),1.12(s,3H),1.08(s,3H),1.05(s,3H),0.99-1.06(m,3H),0.91-0.96(m,6H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物48的合成类似于化合物24的合成方法,以CH3CH2MgCl溶液(2.0M)替代CH3MgCl溶液(1.0M)进行反应和后处理,化合物46(97mg,0.15mmol)经乙基格氏反应和后处理得到白色固体化合物48(79mg,78%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.1Hz,1H),3.99(dd,J=3.1,7.5Hz,1H),3.46-3.58(m,1H),3.21(dd,J=4.1,11.5Hz,1H),1.94-2.02(m,1H),1.78-1.87(m,1H),1.69-1.77(m,2H),1.62-1.68(m,1H),1.22-1.58(m,19H),1.12(s,3H),1.07(s,3H),1.05(s,3H),0.87-1.02(m,7H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物26的合成类似于化合物24的合成方法,以CH2=CHCH2MgCl溶液(1.0M)替代CH3MgCl溶液(1.0M),化合物23(158mg,0.25mmol)经过反应和后处理得到白色固体化合物26(140mg,83.2%)。1H NMR(400MHz,CDCl3)δ5.70-5.92(m,1H),5.49(d,J=3.6Hz,1H),5.04-5.25(m,2H),4.00(dd,J=3.5,9.2Hz,1H),3.49-3.67(m,1H),3.21(dd,J=4.8,14.2Hz,1H),2.25-2.35(m,1H),2.10-2.19(m,1H),1.93-2.00(m,1H),1.28-1.89(m,15H),1.12(s,3H),1.08(s,3H),1.05(s,3H),1.00-1.10(m,5H),0.83-0.94(m,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物49的合成类似于化合物24的合成方法,以CH2=CHCH2MgCl溶液(1.0M)替代CH3MgCl溶液(1.0M),化合物46(103mg,0.16mmol)经烯丙基格氏反应和后处理得到白色固体化合物49(87mg,79%)。1H NMR(500MHz,CDCl3)δ5.77-5.89(m,1H),5.49(d,J=3.0Hz,1H),5.08-5.20(m,2H),4.00(dd,J=2.9,7.5Hz,1H),3.59-3.77(m,1H),3.21(dd,J=4.0,11.5Hz,1H),2.24-2.35(m,1H),2.09-2.19(m,1H),1.93-2.02(m,1H),1.78-1.87(m,1H),1.69-1.78(m,2H),1.62-1.69(m,1H),1.50-1.55(m,2H),1.31-1.49(m,9H),1.23-1.30(m,2H),1.12(s,3H),1.05(s,3H),1.02(s,3H),0.97-1.08(m,5H),0.92(d,J=6.4Hz,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.03(s,3H).
化合物27的合成类似于化合物19的合成方法,化合物24(87mg,0.134mmol)经反应和后处理得到白色固体化合物27(42mg,75%)。1H NMR(500MHz,CDCl3)δ5.52(d,J=2.7Hz,1H),3.91(dd,J=2.4,7.0Hz,1H),3.70-3.80(m,1H),3.26(dd,J=4.7,10.6Hz,1H),1.98-2.04(m,1H),1.85-1.96(m,1H),1.69-1.85(m,5H),1.30-1.52(m,14H),1.20(d,J=2.7Hz,3H),1.18(s,3H),1.14(s,3H),1.10(s,3H),0.94(d,J=6.5Hz,3H),0.69(s,3H).13C NMR(125MHz,DMSO-d6)δ150.86,125.05,75.19,72.04,66.38,56.25,54.92,49.56,42.07,40.98,36.24,35.99,35.48,35.10,31.68,31.52,28.04,27.27,27.10,25.80,23.78,23.66,23.52,20.85,20.32,18.69,11.65.ESI-HRMS(m/z)[M+Na]+:calcd for C27H46NaO3441.3339;found 441.3336.
化合物50的合成类似于化合物19的合成方法,化合物47(99mg,0.15mmol)经反应和后处理得到白色固体化合物50(45mg,70%)。1H NMR(500MHz,CDCl3)δ5.52(d,J=2.9Hz,1H),3.90(dd,J=7.6,2.5Hz,1H),3.75-3.83(m,1H),3.26(dd,J=10.8,4.5Hz,1H),1.98-2.05(m,1H),1.84-1.94(m,1H),1.70-1.84(m,4H),1.24-1.52(m,17H),1.17-1.21(m,6H),1.14(s,3H),1.10(s,3H),0.93(d,J=6.5Hz,3H),0.69(s,3H).13C NMR(125MHz,CDCl3)δ153.33,123.63,77.10,74.02,68.14,56.20,55.30,49.82,42.67,41.45,40.30,39.83,39.73,39.44,36.86,36.24,35.87,35.62,28.50,27.25,27.06,26.12,23.47,23.31,21.32,20.65,18.67,11.75.ESI-HRMS(m/z)[M+Na]+:calcd for C28H48NaO3 455.3496;found 455.3516.
化合物28的合成类似于化合物19的合成方法,化合物25(130mg,0.2mmol)经反应和后处理得到白色固体化合物28(69mg,79.8%)。1H NMR(500MHz,CDCl3):δ5.51(d,J=3.0Hz,1H),3.90(m,1H),3.46-3.49(m,1H),3.25(dd,J=4.5,11.10Hz,1H),1.99-2.02(m,1H),1.86-1.96(m,1H),1.72-1.81(m,4H),1.30-1.54(m,17H),1.18(s,3H),1.14(s,3H),1.10(s,3H),0.91-0.96(m,6H),0.69(s,3H).13C NMR(125MHz,CDCl3)δ153.30,123.66,77.07,73.99,73.88,56.21,55.22,49.82,42.66,41.44,40.28,39.44,36.86,36.25,35.75,33.34,31.80,30.22,28.51,27.25,27.06,26.11,23.32,21.30,20.66,18.77,11.76,9.76.ESI-HRMS(m/z)[M+Na]+:calcd for C28H48NaO3 455.3496;found 455.3489.
化合物51的合成类似于化合物19的合成方法,化合物48(95mg,0.14mmol)经反应和后处理得到白色固体化合物51(46mg,73%)。1H NMR(500MHz,CDCl3)δ5.52(d,J=2.5Hz,1H),3.90(dd,J=2.5,7.4Hz,1H),3.57–3.47(m,1H),3.26(dd,J=4.1,10.6Hz,1H),1.98-2.03(m,1H),1.84-1.93(m,1H),1.69-1.84(m,4H),1.26-1.54(m,19H),1.18(s,3H),1.14(s,3H),1.10(s,3H),0.91-0.97(m,6H),0.69(s,3H).13C NMR(125MHz,CDCl3)δ153.33,123.65,77.12,74.04,73.32,56.22,55.34,49.83,42.68,41.46,40.32,39.45,37.48,37.34,36.88,36.26,36.05,35.94,35.63,28.51,27.28,27.07,26.14,23.31,21.33,20.67,18.69,11.76,9.90.ESI-HRMS(m/z)[M+Na]+:calcd for C29H50NaO3 469.3652;found469.3663.
化合物29的合成类似于化合物19的合成方法,化合物26(125mg,0.186mmol)经反应和后处理得到白色固体化合物29(73mg,88%)。1H NMR(500MHz,CDCl3)δ5.78-5.89(m,1H),5.52(d,J=3.0Hz,1H),5.14(d,J=15.3Hz,2H),3.91(dd,J=2.5,7.9Hz,1H),3.57-3.65(m,1H),3.26(dd,J=4.7,10.6Hz,1H),2.27-2.36(m,1H),2.09-2.19(m,1H),1.98-2.05(m,1H),1.86-1.95(m,1H),1.71-1.84(m,4H),1.52-1.58(m,2H),1.39-1.52(m,8H),1.18(s,3H),1.14(s,3H),1.10(s,3H),1.06-1.15(m,5H),0.94(d,J=6.5Hz,3H),0.69(s,3H).13C NMR(125MHz,CDCl3)δ153.33,134.90,123.65,118.09,77.10,74.01,71.26,56.21,55.21,49.82,42.67,42.03,41.71,41.45,40.30,39.44,36.87,36.25,35.72,29.66,28.47,27.26,27.07,26.12,23.32,21.32,20.66,18.76,11.76.ESI-HRMS(m/z)[M+Na]+:calcd for C29H48NaO3 467.3496;found 467.3438.
化合物52的合成类似于化合物19的合成方法,化合物49(110mg,0.16mmol)经反应和后处理得到白色固体化合物52(59mg,80%)。1H NMR(500MHz,CDCl3)δ5.78-5.90(m,1H),5.52(d,J=2.4Hz 1H),5.14(d,J=13.3Hz,2H),3.90(dd,J=1.2,4.2Hz,1H),3.60-3.69(m,1H),3.26(dd,J=3.1,9.2Hz,1H),2.26-2.36(m,1H),2.08-2.20(m,1H),1.96-2.06(m,1H),1.84-1.94(m,1H),1.65-1.84(m,5H),1.24-1.54(m,16H),1.18(s,3H),1.14(s,3H),1.10(s,3H),0.93(d,J=6.0Hz,3H),0.69(s,3H).13C NMR(125MHz,CDCl3)δ153.33,134.90,123.65,118.07,76.12,74.04,70.66,56.22,55.32,49.83,42.68,42.02,41.46,40.32,39.45,37.33,36.88,36.25,35.66,28.51,27.28,27.07,26.14,23.32,22.13,22.05,21.33,20.67,18.69,11.76.ESI-HRMS(m/z)[M+Na]+:calcd for C30H50NaO3 481.3652;found 481.3719.
实施例5 化合物56、59、60和77的合成
将化合物PPh=CHCO2C2H5(696mg,2.0mmol)溶于无水甲苯(10mL)中,氮气保护下,迅速向反应体系中加入化合物23(631mg,1.0mmol),加料完毕后升温回流6h。TLC检测完全反应后,浓缩反应液,硅胶柱层析(PE:EA=25:1)纯化,得到白色固体化合物53(666mg,95%)。1H NMR(500MHz,CDCl3)δ6.90-7.01(m,1H),5.80(d,J=15.6Hz,1H),5.49(d,J=3.1Hz,1H),4.18(q,J=7.1Hz,2H),4.00(dd,J=3.2,7.6Hz,1H),3.21(dd,J=4.1,11.4Hz,1H),2.20-2.30(m,1H),2.03-2.14(m,1H),1.93-2.01(m,1H),1.70-1.87(m,3H),1.62-1.69(m,1H),1.32-1.49(m,7H),1.24-1.32(m,10H),1.12(s,3H),1.08(s,3H),1.05(s,3H),0.93(d,J=6.5Hz,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物74的合成类似于化合物53的合成方法,化合物46(470mg,0.73mmol)经Wittig反应和后处理得到白色固体化合物74(496mg,95%)。1H NMR(500MHz,CDCl3)δ6.90-7.01(m,1H),5.81(d,J=15.7Hz,1H),5.49(d,J=3.1Hz,1H),4.18(q,J=7.1Hz,2H),3.99(dd,J=3.3,7.5Hz,1H),3.21(dd,J=4.3,11.5Hz,1H),2.08-2.23(m,2H),1.94-2.00(m,1H),1.78-1.85(m,1H),1.69-1.78(m,2H),1.63-1.69(m,1H),1.46-1.54(m,3H),1.32-1.46(m,6H),1.29(t,J=7.1Hz,3H),1.23-1.31(m,3H),1.12(s,3H),1.08(s,3H),1.05(s,3H),1.00-1.08(m,4H),0.91(d,J=6.7Hz,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
将化合物53(457mg,0.652mmol)溶于无水CH3OH(20mL)中,氮气保护下向反应体系中加入10%Pd/C(91.4mg),加料完毕后置换成氢气体系,室温反应过夜。TLC检测完全反应后,反应液用硅藻土过滤,滤饼用CH3OH淋洗,滤液浓缩得到白色的固体化合物54(449mg,98%)。未经纯化直接用于下一步反应。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.1Hz,1H),4.13(q,J=7.1Hz,2H),3.99(dd,J=3.1,7.4Hz,1H),3.21(dd,J=4.0,11.5Hz,1H),2.29(t,J=7.6Hz,2H),1.93-2.00(m,1H),1.78-1.86(m,1H),1.70-1.78(m,2H),1.59-1.69(m,2H),1.49-1.55(m,2H),1.30-1.43(m,6H),1.26(t,J=7.1Hz,3H),1.21-1.29(m,3H),1.12(s,3H),1.08(s,3H),1.05(s,3H),0.99-1.08(m,6H),0.89(s,9H),0.88(s,9H),0.86-0.91(m,3H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物75的合成类似于化合物54的合成方法,化合物74(520mg,0.727mmol)经反应和后处理得到白色固体化合物75(516mg,99%)。未经纯化直接用于下一步反应。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.1Hz,1H),4.12(q,J=7.1Hz,2H),4.00(dd,J=3.1,7.5Hz,1H),3.21(dd,J=4.1,11.5Hz,1H),2.28(t,J=7.5Hz,2H),1.94-2.01(m,1H),1.78-1.86(m,1H),1.69-1.78(m,2H),1.59-1.69(m,3H),1.43-1.56(m,3H),1.31-1.40(m,6H),1.26(t,J=7.1Hz,3H),1.21-1.30(m,4H),1.12(s,3H),1.08(s,3H),1.05(s,3H),1.01-1.09(m,5H),0.87-0.91(m,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物54(170mg,0.242mmol)溶于无水甲醇(10mL)和THF(10mL)的混合溶剂中,完全溶解后向反应体系中加入无水K2CO3(44mg,0.3146mmol),加料完毕后在室温下搅拌24h。TLC检测完全反应后,浓缩反应液,向残留物中加入H2O(10mL)和DCM(50mL)的混合溶剂,用1N盐酸调溶液的pH值为3左右,分出DCM层,水相用DCM(3×50mL)萃取,合并有机相用饱和NaCl溶液(3×30mL)洗涤,无水Na2SO4干燥,浓缩,硅胶柱层析(PE:EA=5:1)纯化,得到白色固体化合物55(139mg,85%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.1Hz,1H),4.00(dd,J=3.0,7.5Hz,1H),3.21(dd,J=4.0,11.5Hz,1H),2.35(td,J=2.4,7.8Hz,2H),1.94-2.01(m,1H),1.78-1.87(m,1H),1.69-1.78(m,2H),1.60-1.69(m,2H),1.50-1.60(m,3H),1.31-1.49(m,7H),1.18-1.31(m,3H),1.12(s,3H),1.08(s,3H),1.05(s,3H),1.01-1.09(m,4H),0.87-0.91(m,3H),0.90(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物56的合成类似于化合物19的合成方法,化合物55(128mg,0.19mmol)经反应和后处理得到白色固体化合物56(67mg,79%)。1H NMR(500MHz,DMSO-d6)δ11.95(brs,1H),5.36(d,J=2.8Hz,1H),4.48-4.55(m,1H),4.10-4.20(m,1H),3.56-3.64(m,1H),2.95-3.06(m,1H),2.19(t,J=7.3Hz,2H),1.90-1.96(m,1H),1.71-1.81(m,2H),1.57-1.68(m,2H),1.38-1.57(m,5H),1.28-1.38(m,6H),1.09-1.25(m,3H),1.06(s,6H),0.96-1.03(m,4H),0.98(s,3H),0.88(d,J=6.4Hz,3H),0.63(s,3H).13C NMR(125MHz,DMSO-d6)δ174.48,150.90,125.06,75.23,72.07,56.30,55.03,49.60,42.14,41.01,39.34,39.17,36.27,36.04,35.22,35.12,33.73,28.12,27.29,27.13,25.84,25.03,24.98,23.69,20.87,20.39,18.60,11.66.ESI-HRMS(m/z)[M+Na]+:calcd for C28H46NaO4 469.3288;found469.3291.
化合物57的合成类似于化合物3的合成方法,化合物54(150mg,0.2133mmol)经LiAlH4还原和后处理得到白色固体化合物57(141mg,100%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=2.9Hz,1H),4.00(dd,J=2.8,7.3Hz,1H),3.64(t,J=6.6Hz,2H),3.21(dd,J=3.9,11.3Hz,1H),1.94-2.01(m,1H),1.78-1.88(m,1H),1.69-1.78(m,2H),1.63-1.69(m,1H),1.43-1.55(m,3H),1.31-1.43(m,8H),1.27-1.31(m,2H),1.16-1.23(m,2H),1.12(s,3H),1.08(s,3H),1.05(s,3H),1.01-1.09(m,5H),0.88-0.91(m,3H),0.90(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物76的合成类似于化合物3的合成方法,化合物75(105mg,0.1464mmol)经LiAlH4还原反应和后处理得到白色固体化合物76(92mg,93%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.2Hz,1H),4.00(dd,J=3.1,7.4Hz,1H),3.60-3.68(m,2H),3.21(dd,J=4.2,11.5Hz,1H),1.95-2.00(m,1H),1.78-1.86(m,1H),1.70-1.78(m,2H),1.63-1.69(m,1H),1.43-1.53(m,2H),1.14-1.42(m,15H),1.12(s,3H),1.08(s,3H),1.05(s,3H),1.00-1.09(m,5H),0.87-0.91(m,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物58的合成类似于化合物18的合成方法,化合物57(100mg,0.151mmol)经甲醚化和后处理得到白色固体化合物58(94mg,92%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.0Hz,1H),4.00(dd,J=3.0,7.4Hz,1H),3.36(t,J=6.7Hz,2H),3.33(s,3H),3.21(dd,J=4.0,11.5Hz,1H),1.96-1.98(m,1H),1.83-1.93(m,1H),1.70-1.82(m,2H),1.64-1.67(m,1H),1.45-1.60(m,8H),1.24-1.37(m,12H),1.12(s,3H),1.08(s,3H),1.05(s,3H),0.89(s,9H),0.88(s,9H),0.88-0.91(m,3H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物59的合成类似于化合物19的合成路线,化合物58(85mg,0.126mmol)经脱保护和后处理得到白色固体化合物59(51mg,91%)。1H NMR(500MHz,CDCl3)δ5.52(d,J=2.9Hz,1H),3.91(dd,J=2.9,7.1Hz,1H),3.37(t,J=6.7Hz,2H),3.33(s,3H),3.26(dd,J=4.2,10.7Hz,1H),1.98-2.05(m,1H),1.83-1.93(m,1H),1.70-1.82(m,4H),1.61-1.69(m,3H),1.53-1.60(m,2H),1.24-1.52(m,14H),1.18(s,3H),1.14(s,3H),1.10(s,3H),0.91(d,J=6.4Hz,3H),0.68(s,3H).13C NMR(125MHz,CDCl3)δ153.26,123.62,77.05,73.99,72.94,58.49,56.18,55.35,49.79,42.63,41.42,40.25,39.41,36.83,36.22,35.84,35.60,29.67,28.48,27.23,27.04,26.54,26.11,25.92,23.31,21.29,20.63,18.67,11.73.ESI-HRMS(m/z)[M+Na]+:calcd for C29H50NaO3469.3652;found 469.3646.
化合物60的合成类似于化合物19的合成方法,化合物57(103mg,0.156mmol)经脱保护和后处理得到白色固体化合物60(51mg,75%)。1H NMR(500MHz,DMSO-d6)δ5.36(d,J=2.2Hz,1H),4.47-4.55(m,1H),4.31(t,J=5.1Hz,1H),4.12-4.19(m,1H),3.58-3.66(m,1H),3.35-3.39(m,2H),2.96-3.04(m,1H),1.90-1.97(m,1H),1.71-1.81(m,2H),1.57-1.69(m,2H),1.49-1.57(m,1H),1.12-1.48(m,17H),1.06(s,6H),1.00-1.03(m,2H),0.98(s,3H),0.89(d,J=6.2Hz,3H),0.63(s,3H).13C NMR(125MHz,DMSO-d6)δ150.84,125.00,75.18,72.02,60.69,56.25,55.06,49.57,42.09,40.95,40.00,39.12,36.22,36.00,35.52,35.15,32.56,28.08,27.24,27.08,25.94,25.78,25.40,23.62,20.82,20.33,18.60,11.61.ESI-HRMS(m/z)[M+Na]+:calcd for C28H48NaO3 455.3496;found 455.3500.
化合物77的合成类似于化合物19的合成方法,化合物76(85mg,0.13mmol)经脱保护反应和后处理得到白色固体化合物77(45mg,78%)。1H NMR(500MHz,DMSO-d6)δ5.37(d,J=2.5Hz,1H),4.37-4.43(m,1H),4.18-4.23(m,1H),3.99-4.08(m,1H),3.59-3.67(m,1H),3.33-3.43(m,2H),2.97-3.06(m,1H),1.90-1.97(m,1H),1.72-1.82(m,2H),1.58-1.69(m,2H),1.51-1.58(m,1H),1.13-1.47(m,17H),1.07(s,6H),0.97-1.05(m,4H),0.99(s,3H),0.89(d,J=6.3Hz,3H),0.64(s,3H).13C NMR(125MHz,DMSO-d6)δ150.77,124.93,75.11,71.94,60.61,56.17,54.97,49.50,42.01,40.87,39.13,39.06,36.15,35.92,35.36,35.08,32.42,29.33,27.97,27.16,27.00,25.68,25.43,25.41,23.52,20.74,20.24,18.52,11.53.ESI-HRMS(m/z)[M+Na]+:calcd for C29H50NaO3 469.3652;found 469.3643.
实施例6化合物64-66和81-83的合成
化合物61的合成类似于化合物20的合成方法,化合物54(181mg,0.26mmol)与CH3MgCl反应和后处理得到白色固体化合物61(133mg,74.7%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.1Hz,1H),4.00(dd,J=2.9,7.5Hz,1H),3.21(dd,J=4.1,11.5Hz,1H),1.93-2.01(m,1H),1.78-1.87(m,1H),1.70-1.78(m,2H),1.63-1.69(m,1H),1.43-1.53(m,4H),1.31-1.42(m,8H),1.27-1.30(m,2H),1.21(s,6H),1.12(s,3H),1.08(s,3H),1.05(s,3H),0.99-1.09(m,6H),0.87-0.90(m,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物78的合成类似于化合物20的合成方法,化合物75(100mg,0.14mmol)与CH3MgCl反应和后处理得到白色固体化合物78(89mg,90%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.2Hz,1H),4.00(dd,J=3.2,7.5Hz,1H),3.21(dd,J=4.2,11.5Hz,1H),1.95-2.01(m,1H),1.78-1.87(m,1H),1.69-1.78(m,2H),1.63-1.69(m,1H),1.49-1.58(m,2H),1.43-1.49(m,3H),1.30-1.41(m,8H),1.23-1.30(m,4H),1.21(s,6H),1.12(s,3H),1.08(s,3H),1.05(s,3H),1.02-1.10(m,5H),0.91-0.92(m,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物62的合成类似于化合物21的合成方法,化合物54(181mg,0.257mmol)与CH3CH2MgCl反应和后处理得到白色固体化合物62(162mg,88%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.0Hz,1H),4.00(dd,J=2.9,7.4Hz,1H),3.21(dd,J=4.0,11.5Hz,1H),1.95-2.01(m,1H),1.78-1.87(m,1H),1.70-1.78(m,2H),1.63-1.68(m,1H),1.49-1.59(m,2H),1.42-1.49(m,6H),1.31-1.42(m,8H),1.15-1.22(m,2H),1.12(s,3H),1.08(s,3H),1.08(s,3H),1.00-1.09(m,6H),0.85-0.90(m,9H),0.90(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物79的合成类似于化合物21的合成方法,化合物75(122mg,0.17mmol)与新制的CH3CH2MgCl反应和后处理得到白色固体化合物79(97mg,78%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=2.7Hz,1H),4.00(dd,J=2.5,7.0Hz,1H),3.21(dd,J=3.9,11.4Hz,1H),1.95-2.01(m,1H),1.78-1.87(m,1H),1.69-1.77(m,2H),1.63-1.69(m,1H),1.51-1.60(m,4H),1.43-1.48(m,5H),1.34-1.41(m,9H),1.23-1.31(m,8H),1.12(s,3H),1.08(s,3H),1.05(s,3H),0.84-0.91(m,9H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物63的合成类似于化合物22的合成方法,化合物54(181mg,0.257mmol)与CH2=CHCH2MgCl反应和后处理得到白色固体化合物63(154mg,81%)。1H NMR(500MHz,CDCl3)δ5.79-5.91(m,2H),5.49(d,J=3.1Hz,1H),5.08-5.18(m,4H),4.00(dd,J=3.0,7.4Hz,1H),3.21(dd,J=4.0,11.5Hz,1H),2.22(d,J=7.0Hz,4H),1.94-2.02(m,1H),1.78-1.87(m,1H),1.69-1.77(m,2H),1.63-1.68(m,1H),1.51-1.55(m,2H),1.25-1.47(m,13H),1.12(s,3H),1.08(s,3H),1.05(s,3H),0.99-1.08(m,5H),0.89(s,9H),0.88(s,9H),0.88-0.91(m,3H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物80的合成类似于化合物22的合成方法,化合物75(108mg,0.15mmol)与CH2=CHCH2MgCl反应和后处理得到白色固体化合物80(91mg,80%)。1H NMR(500MHz,CDCl3)δ5.80-5.92(m,2H),5.49(d,J=2.1Hz,1H),5.08-5.18(m,4H),4.00(dd,J=2.3,7.0Hz,1H),3.21(dd,J=3.5,11.3Hz,1H),2.23(d,J=6.7Hz,4H),1.94-2.01(m,1H),1.78-1.87(m,1H),1.69-1.78(m,2H),1.62-1.69(m,1H),1.49-1.56(m,3H),1.40-1.48(m,4H),1.31-1.40(m,8H),1.15-1.30(m,7H),1.12(s,3H),1.07(s,3H),1.05(s,3H),0.88-0.89(m,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物64的合成类似于化合物19的合成方法,化合物61(112mg,0.162mmol)经反应和后处理得到白色固体化合物64(60mg,80%)。1H NMR(500MHz,CDCl3)δ5.52(d,J=3.0Hz,1H),3.91(dd,J=2.9,7.9Hz,1H),3.26(dd,J=4.7,10.8Hz,1H),1.98-2.04(m,1H),1.85-1.94(m,1H),1.69-1.84(m,4H),1.25-1.52(m,15H),1.21(s,6H),1.18(s,3H),1.14(s,3H),1.10(s,3H),1.04-1.11(m,4H),0.92(d,J=6.6Hz,3H),0.69(s,3H).13C NMR(125MHz,CDCl3+CD3OD-d4)δ152.55,123.56,76.23,72.95,70.16,56.06,55.09,49.68,43.36,42.16,40.91,39.14,39.12,36.30,35.97,35.53,35.31,28.01(2C),27.94,26.39,26.34,26.24,25.41,24.36,22.76,20.46,20.27,18.10,11.12.ESI-HRMS(m/z)[M+Na]+:calcd for C30H52NaO3 483.3809;found483.3807.
化合物81的合成类似于化合物19的合成方法,化合物78(84mg,0.12mmol)经脱保护反应和后处理得到白色固体化合物81(44mg,78%)。1H NMR(500MHz,CDCl3)δ5.52(d,J=3.0Hz,1H),3.91(dd,J=2.0,6.9Hz,1H),3.26(dd,J=4.2,10.4Hz,1H),1.98-2.04(m,1H),1.84-1.94(m,1H),1.66-1.84(m,4H),1.31-1.52(m,16H),1.22-1.31(m,5H),1.21(s,6H),1.18(s,3H),1.14(s,3H),1.10(s,3H),0.92(d,J=6.5Hz,3H),0.69(s,3H).13C NMR(125MHz,DMSO-d6)δ150.82,125.01,75.17,72.02,68.68,56.25,55.04,49.56,43.69,42.08,40.95,39.12,36.21 36.00,35.50,35.20,30.32,29.22(3C),28.09,27.24,27.09,25.79,25.56,23.90,23.63,20.82,20.34,18.61,11.61.ESI-HRMS(m/z)[M+Na]+:calcdfor C31H54NaO3 497.3965;found 497.3987.
化合物65的合成类似于化合物19的合成方法,化合物62(143mg,0.2mmol)经反应和后处理得到白色固体化合物65(80mg,82%)。1H NMR(500MHz,CDCl3)δ5.52(d,J=2.7Hz,1H),3.90(dd,J=2.4,7.8Hz,1H),3.26(dd,J=4.8,11.1Hz,1H),1.98-2.04(m,1H),1.84-1.94(m,1H),1.69-1.84(m,4H),1.28-1.52(m,19H),1.18(s,3H),1.14(s,3H),1.05-1.12(m,7H),0.92(d,J=6.5Hz,3H),0.86(t,J=7.5Hz,6H),0.69(s,3H).13C NMR(125MHz,CDCl3)δ153.30,123.65,77.08,74.62,74.02,56.22,55.40,49.83,42.66,41.45,40.29,39.46,38.25,36.86,36.25,35.96,35.67,31.01,30.96,28.51,27.26,27.06,26.74,26.13,23.83,23.31,21.31,20.66,18.70,11.75,7.76(2C).ESI-HRMS(m/z)[M+Na]+:calcdfor C32H56NaO3 511.4122;found 511.4127.
化合物82的合成类似于化合物19的合成方法,化合物79(95mg,0.13mmol)经脱保护反应和后处理得到白色固体化合物82(52mg,80%)。1H NMR(500MHz,CDCl3)δ5.52(d,J=3.1Hz,1H),3.90(dd,J=2.8,7.8Hz,1H),3.26(dd,J=4.6,10.8Hz,1H),1.98-2.04(m,1H),1.85-1.93(m,1H),1.56-1.83(m,7H),1.31-1.52(m,17H),1.23-1.31(m,5H),1.18(s,3H),1.14(s,3H),1.10(s,3H),0.91(d,J=6.5Hz,3H),0.86(t,J=7.5Hz,6H),0.69(s,3H).13CNMR(125MHz,CDCl3)δ153.28,123.65,77.06,74.60,74.00,56.21,55.39,49.82,42.64,41.43,40.28,39.44,38.16,36.85,36.25,35.89,35.64,30.98(2C),30.72,28.50,27.25,27.06,26.12,26.02,23.39,23.31,21.30,20.65,18.71,11.73,7.74(2C).ESI-HRMS(m/z)[M+Na]+:calcd for C33H58NaO3 525.4278;found 525.4332.
化合物66的合成类似于化合物19的合成方法,化合物63(111mg,0.15mmol)经反应和后处理得到白色固体化合物66(65mg,85%)。1H NMR(500MHz,CDCl3)δ5.80-5.91(m,2H),5.52(d,J=2.9Hz,1H),5.07-5.19(m,4H),3.91(dd,J=1.7,7.3Hz,1H),3.26(dd,J=4.6,10.7Hz,1H),2.23(d,J=6.7Hz,4H),1.97-2.05(m,1H),1.84-1.93(m,1H),1.69-1.83(m,5H),1.24-1.52(m,18H),1.18(s,3H),1.14(s,3H),1.10(s,3H),0.91(d,J=6.4Hz,3H),0.69(s,3H).13C NMR(125MHz,CDCl3)δ153.31,133.80(2C),123.64,118.56(2C),77.10,74.03,73.45,56.21,55.38,49.82,43.69,43.64,42.66,41.45,40.31,39.45,39.23,36.87,36.25,35.89,35.63,28.50,27.27,27.06,26.58,26.13,23.79,23.31,21.32,20.66,18.68,11.76.ESI-HRMS(m/z)[M+Na]+:calcd for C34H56NaO3 535.4122;found535.4121.
化合物83的合成类似于化合物19的合成方法,化合物80(83mg,0.11mmol)经脱保护反应和后处理得到白色固体化合物83(48mg,83%)。1H NMR(500MHz,CDCl3)δ5.81-5.89(m,2H),5.52(d,J=2.9Hz,1H),5.10-5.15(m,4H),3.91(dd,J=2.5,7.7Hz,1H),3.26(dd,J=4.5,10.7Hz,1H),2.23(d,J=6.4Hz,4H),1.98-2.04(m,1H),1.84-1.93(m,1H),1.70-1.83(m,4H),1.31-1.49(m,16H),1.27-1.31(m,5H),1.18(s,3H),1.14(s,3H),1.10(s,3H),0.91(d,J=6.4Hz,3H),0.69(s,3H).13C NMR(125MHz,CDCl3)δ153.26,133.73(2C),123.57,118.49(2C),77.06,73.98,73.40,56.15,55.34,49.76,43.60(2C),42.60,41.39,40.25,39.39,39.10,36.80,36.18,35.81,35.59,30.52,28.45,27.20,26.99,26.10,25.93,23.32,23.24,21.26,20.60,18.64,11.68.ESI-HRMS(m/z)[M+Na]+:calcd for C35H58NaO3549.4278;found 549.4299.
实施例7 化合物71-73和88-90的制备
化合物67的合成类似于化合物23的合成方法,化合物57(185mg,0.28mmol)经IBX氧化和后处理得到白色固体化合物67(161mg,87%)。1H NMR(500MHz,CDCl3)δ9.76(s,1H),5.49(d,J=3.1Hz,1H),3.99(dd,J=3.1,7.4Hz,1H),3.21(dd,J=4.0,11.5Hz,1H),2.42(t,J=7.3Hz,2H),1.94-2.01(m,1H),1.69-1.87(m,4H),1.61-1.68(m,2H),1.43-1.58(m,6H),1.31-1.42(m,8H),1.16-1.24(m,2H),1.12(s,3H),1.07(s,3H),1.05(s,3H),0.87-0.90(m,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物84的合成类似于化合物23的合成方法,化合物76(761mg,1.13mmol)经IBX氧化反应和后处理得到白色固体化合物84(669mg,88%)。1H NMR(400MHz,CDCl3)δ9.76(s,1H),5.49(d,J=3.2Hz,1H),4.00(dd,J=3.2,7.5Hz,1H),3.21(dd,J=4.1,11.4Hz,1H),2.39-2.44(m,2H),1.94-2.01(m,1H),1.69-1.86(m,4H),1.59-1.69(m,4H),1.31-1.47(m,9H),1.23-1.29(m,4H),1.12(s,3H),1.08(s,3H),1.05(s,3H),0.86-0.92(m,6H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物68的合成类似于化合物20的合成方法,化合物67(160mg,0.243mmol)与1MCH3MgCl反应和后处理得到白色固体化合物68(131mg,79.8%)。1H NMR(500MHz,CDCl3)δ5.49(s,1H),4.00(dd,J=2.3,7.1Hz,1H),3.75-3.84(m,1H),3.21(dd,J=3.4,11.4Hz,1H),1.95-2.01(m,1H),1.72-1.85(m,4H),1.63-1.67(m,1H),1.41-1.60(m,10H),1.28-1.34(m,4H),1.18(d,J=6.1Hz,3H),1.12(s,3H),1.08(s,3H),1.05(s,3H),1.03-1.09(m,5H),0.88-0.90(m,3H),0.90(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物85的合成类似于化合物20的合成方法,化合物84(101mg,0.15mmol)与CH3MgCl(3.0mL,3.0mmol)反应和后处理得白色固体化合物85(79mg,76%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.2Hz,1H),4.00(dd,J=3.2,7.5Hz,1H),3.76–3.84(m,1H),3.22(dd,J=4.1,11.5Hz,1H),1.95–2.01(m,1H),1.78–1.87(m,1H),1.70–1.78(m,2H),1.63–1.69(m,1H),1.51–1.57(m,2H),1.25–1.49(m,15H),1.19(d,J=6.2Hz,3H),1.13(s,3H),1.08(s,3H),1.05(s,3H),1.01–1.09(m,5H),0.90-0.91(m,3H),0.90(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.03(s,3H).
化合物69的合成类似于化合物21的合成方法,化合物67(160mg,0.243mmol)与CH3CH2MgCl反应和后处理得到白色固体化合物69(134mg,80%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=3.1Hz,1H),4.00(dd,J=3.1,7.5Hz,1H),3.46-3.56(m,1H),3.21(dd,J=4.1,11.5Hz,1H),1.94-2.00(m,1H),1.69-1.86(m,3H),1.59-1.68(m,1H),1.31-1.58(m,17H),1.12(s,3H),1.08(s,3H),1.05(s,3H),0.99-1.10(m,5H),0.93(t,J=7.5Hz,3H),0.87-0.90(m,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物86的合成类似于化合物21的合成方法,化合物84(101mg,0.15mmol)与CH3CH2MgCl反应和后处理得白色固体化合物86(83mg,79%)。1H NMR(500MHz,CDCl3)δ5.49(d,J=2.1Hz,1H),4.00(dd,J=2.8,7.4Hz,1H),3.46-3.57(m,1H),3.21(dd,J=3.7,11.4Hz,1H),1.94-2.02(m,1H),1.78-1.87(m,1H),1.69-1.78(m,2H),1.64-1.67(m,1H),1.24-1.55(m,22H),1.12(s,3H),1.08(s,3H),1.05(s,3H),0.99-1.08(m,5H),0.94(t,J=2.1Hz,3H),0.89(s,9H),0.88(s,9H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物70的合成类似于化合物22的合成方法,化合物67(108mg,0.154mmol)与CH2=CHCH2MgCl反应和后处理得到白色固体化合物70(86mg,80%)。1H NMR(400MHz,CDCl3)δ5.78-5.89(m,1H),5.49(d,J=3.2Hz,1H),5.12-5.16(m,2H),4.00(dd,J=3.2,7.5Hz,1H),3.60-3.67(m,1H),3.21(dd,J=4.1,11.4Hz,1H),2.26-2.34(m,1H),2.09-2.18(m,1H),1.96-1.99(m,1H),1.62-1.88(m,5H),1.54-1.57(m,2H),1.44-1.52(m,4H),1.32-1.41(m,7H),1.26-1.29(m,1H),1.12(s,3H),1.08(s,3H),1.05(s,3H),1.03-1.05(m,2H),0.86-0.92(m,24H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.03(s,3H).
化合物87的合成类似于化合物22的合成方法,化合物84(101mg,0.15mmol)与CH2=CHCH2MgCl反应和后处理得到白色固体化合物87(86mg,80%)。1H NMR(400MHz,CDCl3)δ5.77-5.88(m,1H),5.49(d,J=3.2Hz,1H),5.10-5.17(m,2H),4.00(dd,J=7.5,3.2Hz,1H),3.60-3.68(m,1H),3.21(dd,J=4.1,11.4Hz,1H),2.26-2.34(m,1H),2.09-2.19(m,1H),1.94-2.01(m,1H),1.63-1.87(m,5H),1.49-1.55(m,2H),1.40-1.43(m,4H),1.24-1.35(m,10H),1.12(s,3H),1.08(s,3H),1.04(s,3H),1.02-1.04(m,2H),0.84-0.94(m,24H),0.67(s,3H),0.08(s,3H),0.07(s,3H),0.04(s,3H),0.02(s,3H).
化合物71的合成类似于化合物19的合成方法,化合物68(139mg,0.21mmol)经脱保护和后处理得到白色固体化合物71(69mg,73%)。1H NMR(500MHz,CDCl3)δ5.52(d,J=2.9Hz,1H),3.90(dd,J=2.9,7.8Hz,1H),3.75-3.82(m,1H),3.26(dd,J=4.8,11.0Hz,1H),1.98-2.03(m,1H),1.84-1.93(m,1H),1.63-1.84(m,5H),1.29-1.52(m,18H),1.19(d,J=6.3Hz,3H),1.18(s,3H),1.14(s,3H),1.10(s,3H),0.92(d,J=6.4Hz,3H),0.69(s,3H).13CNMR(125MHz,DMSO-d6)δ150.83,125.02,75.16,72.01,65.74,56.24,55.03,49.55,42.08,40.95,39.16(2C),36.22,35.98,35.54,35.15,28.11,28.08,27.24,27.08,25.83,25.78,25.65,23.62(2C),20.82,20.32,18.60,11.61.ESI-HRMS(m/z)[M+Na]+:calcd forC29H50NaO3 469.3652;found 469.3674.
化合物88的合成类似于化合物19的合成方法,化合物85(90mg,0.13mmol)经脱保护反应和后处理得到白色固体化合物88(42mg,70%)。1H NMR(400MHz,CDCl3)δ5.51(d,J=3.1Hz,1H),3.90(dd,J=2.8,8.1Hz,1H),3.75-3.81(m,1H),3.25(dd,J=4.9,10.3Hz,1H),1.98-2.03(m,1H),1.70-1.92(m,6H),1.33-1.50(m,14H),1.28-1.33(m,6H),1.19(d,J=6.1Hz,3H),1.17(s,3H),1.14(s,3H),1.10(s,3H),0.91(d,J=6.4Hz,3H),0.68(s,3H).13CNMR(100MHz,CD3OD-d4)δ154.05,125.63,77.92,74.49,68.60,58.08,57.05,51.69,43.85,42.55,41.00,40.71,40.27,37.99,37.75,37.13,31.84,31.33,30.81,29.64,28.05,27.83,27.23,26.97,24.18,23.52,21.94,21.66,19.35,12.34.ESI-HRMS(m/z)[M+Na]+:calcd for C30H52NaO3 483.3809;found 483.3803.
化合物72的合成类似于化合物19的合成方法,化合物69(123mg,0.18mmol)经脱保护和后处理得到白色固体化合物72(62mg,75%)。1H NMR(500MHz,CDCl3)δ5.52(d,J=2.8Hz,1H),3.90(dd,J=2.4,7.5Hz,1H),3.46-3.55(m,1H),3.26(dd,J=4.5,10.5Hz,1H),1.98-2.03(m,1H),1.84-1.92(m,1H),1.66-1.84(m,5H),1.21-1.62(m,15H),1.18(s,3H),1.14(s,3H),1.10(s,3H),1.06-1.15(m,5H),0.90-0.95(m,6H),0.69(s,3H).13C NMR(125MHz,CDCl3)δ153.33,123.67,77.14,74.06,73.36,56.24,55.42,49.85,42.69,41.47,40.34,39.47,37.03,36.89,36.27,35.94,35.66,30.16,28.53,27.29,27.08,26.19,26.15,26.09,23.32,21.34,20.68,18.73,11.77,9.87.ESI-HRMS(m/z)[M+Na]+:calcd forC30H52NaO3 483.3809;found 483.3809.
化合物89的合成类似于化合物19的合成方法,化合物86(99mg,0.14mmol)经脱保护反应和后处理得到白色固体化合物89(48mg,72%)。1H NMR(400MHz,CDCl3)δ5.51(d,J=2.9Hz,1H),3.90(dd,J=3.4,7.5Hz,1H),3.48-3.55(m,1H),3.25(dd,J=5.1,10.6Hz,1H),1.97-2.05(m,1H),1.85-1.92(m,1H),1.69-1.85(m,5H),1.25-1.51(m,22H),1.17(s,3H),1.14(s,3H),1.10(s,3H),0.88-0.95(m,6H),0.68(s,3H).13C NMR(100MHz,CD3OD-d4)δ152.64,124.21,76.52,73.08,72.51,56.67,55.65,50.29,42.44,41.14,39.59,39.31,36.58,36.34,35.70,30.42,29.94,29.62,29.40,28.21,26.64,26.42,25.82,25.67,25.45,22.75,20.53,20.25,17.94,10.93,8.94.ESI-HRMS(m/z)[M+Na]+:calcd forC31H54NaO3 497.3965;found 497.3990.
化合物73的合成类似于化合物19的合成方法,化合物70(125mg,0.178mmol)经脱保护和后处理得到白色固体化合物73(72mg,85%)。1H NMR(400MHz,CDCl3)δ5.77-5.90(m,1H),5.52(d,J=2.8Hz,1H),5.10-5.17(m,2H),3.90(dd,J=2.3,7.6Hz,1H),3.61-3.68(m,1H),3.26(dd,J=4.9,10.4Hz,1H),2.25-2.35(m,1H),2.09-2.19(m,1H),1.96-2.05(m,1H),1.85-1.94(m,1H),1.66-1.85(m,4H),1.24-1.51(m,15H),1.18(s,3H),1.14(d,J=5.1Hz,3H),1.10(s,3H),0.97-1.09(m,4H),0.92(d,J=6.4Hz,3H),0.69(s,3H).13C NMR(100MHz,CDCl3)δ152.44,134.01,122.79,117.10,76.23,75.78,73.15,69.80,55.36,54.54,48.98,41.80,41.05,40.58,39.45,38.59,36.00,35.98,35.39,35.03,34.75,27.62,26.41,26.19,25.25,25.22,22.42,20.45,19.79,17.83,10.88.ESI-HRMS(m/z)[M+Na]+:calcd for C31H52NaO3 495.3809;found 495.3802.
化合物90的合成类似于化合物19的合成方法,化合物87(86mg,0.12mmol)经脱保护反应和后处理得到白色固体化合物90(47mg,81%)。1H NMR(400MHz,CDCl3)δ5.77-5.89(m,1H),5.52(d,J=2.8Hz,1H),5.10-5.17(m,2H),3.90(dd,J=2.3,7.5Hz,1H),3.61-3.68(m,1H),3.26(dd,J=4.8,10.5Hz,1H),2.25-2.35(m,1H),2.09-2.19(m,1H),1.96-2.06(m,1H),1.85-1.94(m,1H),1.70-1.85(m,4H),1.24-1.52(m,19H),1.18(s,3H),1.14(s,3H),1.10(s,3H),1.05-1.09(m,2H),0.91(d,J=6.4Hz,3H),0.69(s,3H).13C NMR(100MHz,CDCl3+CD3OD(minor)-d4)δ153.70,135.34,124.05,117.72,77.74,74.06,71.17,56.71,55.85,50.36,43.01,42.05,41.77,40.29,39.86,37.17,36.99,36.70,36.26,36.05,30.48,28.83,27.29,27.26,26.39,26.32,25.99,23.65,21.49,21.06,19.02,12.05.ESI-HRMS(m/z)[M+Na]+:calcd for C32H54NaO3 509.3965;found 509.3976.
实施例8:胆酸衍生物抑制细胞胆固醇合成的活性测试
材料和仪器:胎牛血清(货号:S1580)购自Biowest公司;Dulbecco’s modifiedEagle’s medium(DMEM)(货号:12100-046),Ham’s F-12培养基(货号:21700-075),AmplexRed胆固醇测定试剂盒(货号:A12216)购自Thermo Fisher Scientific公司;脂蛋白缺陷血清(密度大于1.215g/ml)是本实验室用胎牛血清通过超速离心制备而成;10cm培养皿(货号:430167)和96孔黑色酶标板(货号:3916)购自Corning公司;Synergy Neo多功能酶标仪购自BioTek公司;羟丙基-β-环糊精(货号:THPB-P)购自Cyclodextrin TechnologiesDevelopment公司;PBS缓冲液(137mM氯化钠,2.7mM氯化钾,10mM磷酸氢二钠,2mM磷酸二氢钾);RIPA裂解液RIPA buffer(50mM三羟甲基氨基甲烷pH 8.0,150mM氯化钠,0.1%(wt/vol)十二烷基硫酸钠,1.5%(wt/vol)NP40,0.5%脱氧胆酸钠,2mM氯化镁);BCA蛋白定量试剂盒购自碧云天公司;二甲基亚砜(DMSO)购自Sigma公司;所有化合物均溶于DMSO中。
原理:细胞中的胆固醇主要来源于两方面:吸收外源的脂蛋白复合物中的胆固醇和内源的重新合成。在脂蛋白缺陷血清的培养条件下,细胞的胆固醇主要来自于自身的重新合成,因此常在这种条件下分析细胞的胆固醇合成能力。Amplex Red胆固醇测定试剂盒提供了一个简单而灵敏的荧光定量方法实现胆固醇的定量检测,利用胆固醇氧化酶催化胆固醇产生H2O2,在辣根过氧化酶存在的条件下,H2O2与Amplex Red反应生成高度发荧光的Resorufin。Resorufin的荧光强度可以通过多功能酶标仪在激发光为560nm波长,发射光为590nm波长的条件下检测,从而实现胆固醇的定量。
方法:CHO-7中国仓鼠卵巢细胞是CHO-K1细胞在脂蛋白缺陷血清条件得到的一个亚克隆细胞系,正常饲养在5%(vol/vol)胎牛血清的DMEM:F-12(1:1)培养基中。第一天,CHO-7细胞以2x 106个细胞每10cm培养皿的密度铺好。第二天,用含有1%(wt/vol)羟丙基-β-环糊精,5%(vol/vol)脂蛋白缺陷血清的DMEM/F-12(1:1)培养基处理,羟丙基-β-环糊精可以结合胆固醇从而去除细胞膜上的大部分胆固醇,极大的激活细胞合成胆固醇。此外在脂蛋白缺陷血清的培养下,由于去除了血清中的胆固醇也可以激活细胞合成胆固醇。一小时后,PBS缓冲液清洗细胞两次,以去除羟丙基-β-环糊精。随后加入含有10μM浓度化合物的5%脂蛋白缺陷血清DMEM:F-12(1:1)培养基,处理一天后,收集细胞,用PBS洗一次得到细胞沉淀。加入300μl RIPA裂解液裂解细胞,取5μl裂解液用于BCA蛋白定量,剩余裂解液加入1.2ml氯仿:甲醇(2:1)在37度充分混匀一小时。13200rpm离心10分钟,吸取600μl下层有机相,在氮气下吹干,用100μl反应缓冲液(0.1M磷酸钾pH 7.4,0.05M氯化钠,5mM胆酸,0.1%Triton X-100)溶解脂类。取30ul溶解好的脂类以及梯度稀释好的胆固醇标准品,加入320μl在反应缓冲液配置的工作液(300μM Amplex Red,2U/ml辣根过氧化酶,2U/ml胆固醇氧化酶),37度避光反应半小时,混匀后100μl每孔加入,96孔黑色酶标板。利用Synergy Neo多功能酶标仪,在激发光波长为560nm,发射光波长为590nm的条件下,检测产生的Resorufin的荧光强度。根据胆固醇标准品换算出样品中的胆固醇含量,再用除以蛋白的含量,即得到细胞中胆固醇水平的相对定量,反映出化合物抑制细胞胆固醇合成的活性。
部分胆酸衍生物抑制细胞内胆固醇合成的活性测试结果如图1所示;
结果与评价:本发明制备的胆酸衍生物具有较好的抑制胆固醇合成和降低胆固醇的活性。以DMSO对照组细胞中的胆固醇含量为100%,尤其化合物45处理后细胞中胆固醇含量仅为对照组的20%,接近细胞的基底水平,显著地抑制细胞胆固醇的合成。化合物64、81、44和65处理组细胞中胆固醇含量依次为对照组的25.5%、27.1%、27.6%和29.7%;化合物82、43、73、51、72、88、52、71和89处理组细胞中胆固醇含量依次为对照组的31.2%、32.1%、34.5%、35.2%、36.3%、37.5%、38.6%、39.1%和40%;化合物42、21、59、66、77、90和50处理组细胞中胆固醇含量依次为对照组的41.1%、41.5%、42.6%、45.2%、47.5%、49.4%、50%;化合物29、60、19、27、28、22、36、13、83、38和15处理组细胞中胆固醇含量依次为对照组的55.2%、60.3%、65.1%、65.4%、66.2%、67.5%、70.7%、72.5%、73.2%、74.3%和76.1%。综上结果,本发明一系列胆酸衍生物具有较好的抑制胆固醇合成和降低胆固醇的活性,且不同结构的衍生物活性不同,具有较好的构效关系。因此,本发明胆酸衍生物适用于制备预防和治疗高胆固醇血症和动脉粥样硬化的药物。
实施例9:胆酸衍生物在胆固醇依赖的细胞生长实验中的应用
材料和仪器:24孔板购自Corning公司;结晶紫(货号:229288)、多聚甲醛(货号:P6148)和胆固醇(货号:C8667)购自Sigma公司;CanoScan 4400F扫描仪购自Canon公司。
原理:如实施例8中所示,细胞中的胆固醇主要来源于外源的吸收和内源的重新合成。胆固醇对于细胞的正常生长是必需的,在没有外源胆固醇供给的时候,细胞只能通过自身的内源性合成来维持细胞的生长。CHO-7细胞在脂蛋白缺陷血清的培养条件下,能通过自身合成胆固醇实现正常生长。若化合物抑制细胞胆固醇的合成,将导致细胞的死亡,而添加外源胆固醇则可以挽救细胞的死亡。因此这种胆固醇依赖的生长实验可以直观的反映化合物抑制胆固醇合成的特异性。结晶紫是一种碱性染料,可以和细胞中的核酸结合把细胞核染成蓝色,是一种常用的反映细胞数量的染色方法。
方法:第一天,将CHO-7细胞以5000个细胞每孔的密度接种于24孔板中。第二天,PBS清洗两次去除血清中残留的脂蛋白,换成5%脂蛋白缺陷DMEM:F-12(1:1)培养基,如图2所示加入10μM化合物以及有或无10μg/ml的胆固醇。每隔两天换液一次,十天后吸掉培养基,PBS洗一次。加入4%多聚甲醛固定30分钟,PBS洗三次。加入0.5%结晶紫水溶液,染色30分钟。PBS清洗5次,水洗一次,晾干后用CanoScan 440F扫描仪扫描图像。部分胆酸衍生物对胆固醇依赖的细胞生长实验测试结果如图2所示;
结果与评价:本发明制备的该类胆酸衍生物能够有效抑制细胞胆固醇的合成,从而降低体内胆固醇的含量。如图2所示,DMSO对照组细胞在有或无添加外源胆固醇的条件下,均能正常增殖生长。本发明化合物45、64、81、44、65、82、43、73、51、72、88、52、71、29、36和83在无添加胆固醇的长时间培养条件下,细胞由于缺少胆固醇不能增殖而死亡。而添加外源胆固醇能挽救这些化合物导致的细胞死亡,说明上述化合物显著而特异地抑制胆固醇合成。因此,本发明该类胆酸衍生物适用于制备预防和治疗高胆固醇血症和动脉粥样硬化的药物。
实施例10:胆酸衍生物与洛伐他汀单独和联合用药时降低血液和肝脏中胆固醇和甘油三酯水平的活性
材料和仪器:C57BL/6J小鼠购自上海灵畅生物科技公司;基础饲料(Chow diet)和中等脂肪中等胆固醇饲料MFMC(含10%猪油脂肪、0.2%胆固醇和0.5%胆酸钠的基础饲料)购自上海斯莱克实验动物公司;甲基纤维素(货号:M7027)和Tween 80(货号:P8074)购自Sigma公司;Precellys 24匀浆仪购自Bertin公司;总胆固醇试剂盒(液体单试剂,氧化酶法)和甘油三酯测定试剂盒(液体单试剂,甘油磷酸氧化酶法)购自上海科华生物公司;Eon酶标仪购自BioTek公司。
原理:胆固醇的重新合成是人体胆固醇的主要来源,肝脏是胆固醇合成的主要器官。血液中胆固醇长期过高会引起动脉粥样硬化,因此降低血液和肝脏中的胆固醇水平是重要的降脂靶点。洛伐他汀(Lovastatin)等多种他汀类药物均可强烈抑制胆固醇的合成,从而实现降胆固醇的疗效,同时也有一定程度的降甘油三酯的疗效。
方法:8周大的C57BL/6J小鼠,随机分成5组,每组5只小鼠。第1组小鼠喂养正常基础饲料(Chow),第2至5组喂养中等脂肪中等胆固醇饲料(MFMC)。每组小鼠每天灌胃给药一次,灌胃液成分为含有0.5%甲基纤维素和0.5%Tween 80的0.9%氯化钠。第1和2组小鼠,喂空白灌胃液;第3组喂60毫克每千克体重的洛伐他汀(Lova);第4组喂60毫克每千克体重的化合物45;第5组喂60毫克每千克体重的洛伐他汀和化合物45。连续喂药6周后,禁食4小时,处死小鼠,取血液和肝脏用于后续分析总胆固醇和甘油三酯含量。血液收集后室温静置半小时,1500g离心10分钟,上清即为血清。吸取9μl血清,分别加入350μl总胆固醇和甘油三酯测定试剂,混匀后37度孵育30分钟,100μl每孔加入96孔板,Eon酶标仪测定505nm波长处,吸光度值,根据胆固醇和甘油三酯标准品换算出血清中总胆固醇和甘油三酯的含量。
肝脏中总胆固醇和甘油三酯含量的分析:小鼠取血后,用PBS心脏灌流,摘取肝脏,取约30mg肝脏,准确称重记录。加入1.2ml氯仿:甲醇(2:1),Precellys 24匀浆仪6500rpm匀浆三次,每次10秒。37度混匀1小时,加入200μl超纯水,震荡混匀,室温静置10分钟,13200rpm离心10分钟,吸取600μl下层有机相至新管,氮气吹干,100μl酒精重新溶解。取6μl溶解好的脂类,分别加入350μl总胆固醇和甘油三酯测定试剂,以下方法同血清中测定总胆固醇和甘油三酯方法。统计学分析,*表示中等脂肪中等胆固醇喂养小鼠,不同给药组与空白对照组之间的统计学差异,*P<0.05,**P<0.01,***P<0.001,ns,无显著性差异;#表示洛伐他汀和化合物45联合用药组与二者单独给药组之间的统计学差异,#P<0.05,统计学方法:Dunnett多重比较检测后的单因素方差分析。
部分胆酸衍生物与洛伐他汀药物单独和联用使用时降胆固醇和甘油三酯的活性测试结果如图3所示;
结果与评价:如图3A所示,中等脂肪中等胆固醇饲料喂养后,小鼠血清中的总胆固醇水平显著升高。化合物45和洛伐他汀单独给药后,显著降低血清中的总胆固醇水平,且二者效果相当。化合物45和洛伐他汀联用时,比二者单独使用时更进一步降低血清中的总胆固醇水平。如图3B所示,化合物45和洛伐他汀单独给药后,显著降低血清中的甘油三酯水平,二者效果相当。化合物45和洛伐他汀联用时,有降低血清中的甘油三酯的趋势。如图3C所示,化合物45和洛伐他汀单独给药后,显著降低肝脏中的总胆固醇含量,效果相当。二者联用时,进一步降低肝脏中总胆固醇的含量。如图3D所示,化合物45和洛伐他汀单独给药后,显著降低肝脏中的甘油三酯含量,效果相当。化合物45和洛伐他汀联用时,有降低肝脏中甘油三酯的趋势。
如图3所示,本发明制备的胆酸衍生物单独使用时具有和洛伐他汀相当的降胆固醇和甘油三酯效果,尤其联用时进一步降低胆固醇水平。因此,本发明胆酸衍生物适用于制备预防和治疗高胆固醇血症高甘油三酯血症,动脉粥样硬化的药物。
本发明提出的胆酸衍生物作为降低体内胆固醇和甘油三酯的化合物在预防和治疗高胆固醇血症高甘油三酯血症,动脉粥样硬化方面有着潜在的药物研究价值,为寻找新型的预防和治疗高胆固醇血症高甘油三酯血症,动脉粥样硬化药物提供了新思路。
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。
Claims (15)
1.一种胆酸衍生物,其特征在于,其结构如式(I)所示:
其中,n选自自然数,R选自酯基、羧酸、伯醇、取代仲醇、取代叔醇、取代醚。
2.如权利要求1所述的胆酸衍生物,其特征在于,所述自然数n选自2,3,4,5。
3.如权利要求1所述的胆酸衍生物,其特征在于,
所述酯基包括甲酯乙酯正丙酯异丙酯正丁酯异丁酯叔丁酯烯丙酯丙炔酯苯酯苄酯
所述羧酸为
所述伯醇为
所述取代仲醇包括甲基仲醇乙基仲醇正丙基仲醇异丙基仲醇正丁基仲醇异丁基仲醇叔丁基仲醇烯丙基仲醇丙炔基仲醇苯基仲醇苄基仲醇
所述取代叔醇包括二甲基叔醇二乙基叔醇二正丙基叔醇二异丙基叔醇二正丁基叔醇二异丁基叔醇二烯丙基叔醇二丙炔基叔醇二苯基叔醇二苄基叔醇
所述取代醚包括甲基醚乙基醚正丙基醚异丙基醚正丁基醚异丁基醚叔丁基醚烯丙基醚丙炔基醚苯基醚苄基醚
4.一种胆酸衍生物的制备方法,其特征在于,以石胆酸为起始原料,经过酯化、TBSCl保护、还原、碘代、氰基取代、脱TBS及氰基醇解反应得到化合物6;然后以化合物1或6为起始原料,经过氧化、溴代、脱溴、4,4-二甲基化、酯化、C-7位氧化、还原反应得到如式13或36所示的胆酸衍生物;所述制备方法如路线(1)所示:
5.一种胆酸衍生物的制备方法,其特征在于,以化合物13或36为起始原料,经过水解反应得到如式14或37所示的胆酸衍生物;或经过LiAlH4还原反应得到如式15或38所示的胆酸衍生物;或经过TBSCl保护、还原、甲醚化和脱TBS保护反应得到如式19或42所示的胆酸衍生物;所述制备方法如路线(2)所示:
6.一种胆酸衍生物的制备方法,其特征在于,以化合物13或36为起始原料,与CH3MgCl、C2H5MgCl或CH2=CHCH2MgCl分别发生格氏反应得到如式20-22或43-45所示的胆酸衍生物;所述制备方法如路线(3)所示:
7.一种胆酸衍生物的制备方法,其特征在于,以化合物17或40为起始原料,经过IBX氧化得到化合物23或46;再经过与CH3MgCl、C2H5MgCl或CH2=CHCH2MgCl分别发生格氏反应得到化合物24-26或47-49;然后再经过脱TBS保护反应得到如式27-29或50-52所示的胆酸衍生物;所述制备方法如路线(4)所示:
8.一种胆酸衍生物的制备方法,其特征在于,以化合物23或46为起始原料,经过Wittig反应、加氢还原反应得到化合物54或75;化合物54经水解和脱TBS保护反应得到如式56所示的胆酸衍生物;或以化合物54或75为起始原料,经过还原反应得到化合物57或76,然后经过脱保护反应得到如式60或77所示的胆酸衍生物;或化合物57经甲醚化和脱TBS保护反应得到化合物如式59所示的胆酸衍生物;所述制备方法如路线(5)所示:
9.一种胆酸衍生物的制备方法,其特征在于,以化合物54或75为起始原料,与CH3MgCl、C2H5MgCl或CH2=CHCH2MgCl分别发生格氏反应,然后进行脱TBS保护反应得到如式64-66或81-83所示的胆酸衍生物;所述制备方法如路线(6)所示:
10.一种胆酸衍生物的制备方法,其特征在于,以化合物57或76为起始原料,经过IBX氧化、与CH3MgCl、C2H5MgCl或CH2=CHCH2MgCl分别发生格氏反应,然后进行脱TBS保护反应得到如式71-73或88-90所示的胆酸衍生物;所述制备方法如路线(7)所示:
11.如权利要求1所述的胆酸衍生物在降低体内胆固醇和甘油三酯方面的应用。
12.如权利要求1所述的胆酸衍生物在制备预防和治疗高胆固醇血症,高甘油三酯血症和动脉粥样硬化药物中的应用。
13.如权利要求1所述的胆酸衍生物在抑制细胞胆固醇的合成的应用。
14.如权利要求1所述的胆酸衍生物在制备预防和治疗高胆固醇血症,高甘油三酯血症,动脉粥样硬化药物中与他汀类药物的联合应用。
15.如权利要求14所述的应用,其特征在于,所述他汀类药物包括洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、瑞舒伐他汀。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113563404A (zh) * | 2020-04-28 | 2021-10-29 | 华东师范大学 | 胆酸衍生物的制备方法 |
CN113563405A (zh) * | 2020-04-28 | 2021-10-29 | 华东师范大学 | 胆酸衍生物及其在降胆固醇中的应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997045440A1 (en) * | 1996-05-30 | 1997-12-04 | Medivir Ab | Cytostatic sterols |
CN101450963A (zh) * | 2007-11-30 | 2009-06-10 | 中国科学院上海药物研究所 | 葫芦烷型三萜皂苷化合物、其药物组合物及其制备方法和用途 |
WO2012024581A2 (en) * | 2010-08-20 | 2012-02-23 | Fate Therapeutics, Inc. | Oxysterol compounds |
-
2018
- 2018-05-31 CN CN201810549644.4A patent/CN110551166B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997045440A1 (en) * | 1996-05-30 | 1997-12-04 | Medivir Ab | Cytostatic sterols |
CN101450963A (zh) * | 2007-11-30 | 2009-06-10 | 中国科学院上海药物研究所 | 葫芦烷型三萜皂苷化合物、其药物组合物及其制备方法和用途 |
WO2012024581A2 (en) * | 2010-08-20 | 2012-02-23 | Fate Therapeutics, Inc. | Oxysterol compounds |
Non-Patent Citations (1)
Title |
---|
叶平: "《血脂异常诊断和治疗 第2版》", 31 December 2013, 人民军医出版社 * |
Cited By (4)
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CN113563404A (zh) * | 2020-04-28 | 2021-10-29 | 华东师范大学 | 胆酸衍生物的制备方法 |
CN113563405A (zh) * | 2020-04-28 | 2021-10-29 | 华东师范大学 | 胆酸衍生物及其在降胆固醇中的应用 |
CN113563405B (zh) * | 2020-04-28 | 2023-08-08 | 华东师范大学 | 胆酸衍生物及其在降胆固醇中的应用 |
CN113563404B (zh) * | 2020-04-28 | 2024-03-12 | 华东师范大学 | 胆酸衍生物的制备方法 |
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