CN101298466B - 齐墩果酸衍生物及其制备方法和应用 - Google Patents
齐墩果酸衍生物及其制备方法和应用 Download PDFInfo
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- CN101298466B CN101298466B CN200810124176.2A CN200810124176A CN101298466B CN 101298466 B CN101298466 B CN 101298466B CN 200810124176 A CN200810124176 A CN 200810124176A CN 101298466 B CN101298466 B CN 101298466B
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- oleanolic acid
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- BGXZIBSLBRKDTP-UHFFFAOYSA-N methyl 9-(4-chloroanilino)-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate Chemical compound C12=C3SC(C(=N)OC)=NC3=CC=C2N=CN=C1NC1=CC=C(Cl)C=C1 BGXZIBSLBRKDTP-UHFFFAOYSA-N 0.000 description 1
- KQNYTTDHCMFOME-UHFFFAOYSA-N methyl n-[[3-[(4-tert-butylpiperazin-1-yl)methyl]-8-fluoro-2-phenylquinoline-4-carbonyl]amino]-n-phenylcarbamate Chemical compound C=1C=CC=CC=1N(C(=O)OC)NC(=O)C(C1=CC=CC(F)=C1N=C1C=2C=CC=CC=2)=C1CN1CCN(C(C)(C)C)CC1 KQNYTTDHCMFOME-UHFFFAOYSA-N 0.000 description 1
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- RCSBCWXPGSPJNF-UHFFFAOYSA-N n-[4-[5-[3-chloro-4-(trifluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl]butyl]-4-(1,8-naphthyridin-2-yl)butanamide Chemical compound C1=C(Cl)C(OC(F)(F)F)=CC=C1C(O1)=NN=C1CCCCNC(=O)CCCC1=CC=C(C=CC=N2)C2=N1 RCSBCWXPGSPJNF-UHFFFAOYSA-N 0.000 description 1
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- HBEDNENASUYMPO-LJQANCHMSA-N n-hydroxy-4-[[(2r)-3-oxo-2-(thiophen-2-ylmethyl)-2,4-dihydroquinoxalin-1-yl]methyl]benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1CN1C2=CC=CC=C2NC(=O)[C@H]1CC1=CC=CS1 HBEDNENASUYMPO-LJQANCHMSA-N 0.000 description 1
- VQVCFYIDCWPSNE-UHFFFAOYSA-N n-methyl-3-[(2-naphthalen-2-ylacetyl)amino]benzamide Chemical compound CNC(=O)C1=CC=CC(NC(=O)CC=2C=C3C=CC=CC3=CC=2)=C1 VQVCFYIDCWPSNE-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000000955 oleanolic acid group Chemical group 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000001582 osteoblastic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002966 pentacyclic triterpenoids Chemical class 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
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- 210000003625 skull Anatomy 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
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- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 description 1
- FRACPXUHUTXLCX-BELIEFIBSA-N tert-butyl N-{1-[(1S)-1-{[(1R,2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopropylethyl]-2-oxopyridin-3-yl}carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN(C1=O)[C@@H](CC2CC2)C(=O)N[C@@H](C[C@@H]3CCNC3=O)[C@H](C(=O)NCC4=CC=CC=C4)O FRACPXUHUTXLCX-BELIEFIBSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明在齐墩果酸母核的A环引入羰基、吲哚杂环、吡嗪杂环、喹啉杂环、苯腙环等功能基团,所得齐墩果酸衍生物均能用于抗骨质疏松药物及健康食品,且绝大多数对由活性维生素D引起的骨细胞分化有强烈的抑制作用,本发明齐墩果酸衍生物的制备方法清楚、易行,容易控制生成各种结构的衍生物,可用于抗骨质疏松药物及健康食品,制成口服液、片剂、胶囊剂等剂型。
Description
技术领域
本发明涉及从齐墩果酸出发合成的一系列的衍生物,具体为齐墩果酸衍生物及其制备方法和应用。
背景技术
骨质疏松症被成为无声无息的流行病,是一种以骨组织量的减少和微观结构的退化为特征,致使骨脆性增加并易于发生骨折的疾病,这种疾病特别易于发生停经后的女性。据推测到2010年,我国骨质疏松症患者将达到1.15亿人。如何治疗骨质疏松症的药物现在已经成为国内外研究的热点之一。
在中国传统医药中,有不少已被证实确有治疗骨质疏松症的效果。申请者根据中医理论在对30多种中药提取物对破骨细胞功能抑制作用的筛选中发现牛膝的甲醇提取物具有最强的活性,进一步化学分离、结构鉴定及活性检测工作表明其活性成分为齐墩果酸苷类,并且发现齐墩果酸也具有一定的活性。这些牛膝提取物和化合物的作用已申请专利并公开(李建新等,专利:牛膝的三萜类提取物及在抗骨质疏松药物的用途,申请号:03133105.4,2003年)。
齐墩果酸(Oleanolic acid,简称OA),是一种五环三萜类化合物。早在1908年,英国的F.B.Powers就从木樨科植物油橄榄(Oleaeuropeae L.)的叶中提取得到了齐墩果酸。人们发现齐墩果酸及其衍生物具有多种生物活性,如抗炎、抗肿瘤、抗病毒、调节免疫功能、抑止血小板凝聚、降血脂、降血糖、保肝、护肾、抗艾滋病毒等。但是,对于齐墩果酸衍生物在抗骨质疏松活性方面未见其他人研究论文。申请者对齐墩果酸衍生物、制备及抗骨质疏松用途进行了研究,并申请专利并公开(李建新,专利:齐墩果酸及其衍生物、制法及用途,专利号:200510038096.1)。
发明内容
本发明要解决的技术问题是:从齐墩果酸母核得到新的齐墩果酸衍生物,并对其在抗骨质疏松活性方面的应用进行研究。
本发明的技术方案是:齐墩果酸衍生物,为A-G齐墩果酸母核的A环衍生物,A-G齐墩果酸母核结构式如下:
所述衍生物包括:
(1)在A-G齐墩果酸母核的A环2,3位引入单羰或双羰基的齐墩果酸衍生物:
引入单羰的衍生物R1为羰基,R2为氢,引入双羰基的衍生物R1和R2都为羰基;
(2)在A-G齐墩果酸母核的A环2,3位引入吲哚环的齐墩果酸衍生物,其结构式如下:
其中R3,R4,R5,R6各自独立为氢、羟基、卤素、直链或支链C1-C8的低级烷基、羧基、三氟甲基、乙酰基、直链或支链低级烷氧基、卤代烷基、芳基、芳氧基或氨基,其中直链或者支链C1-C8烷烃为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、异构戊基、异构己基、异构庚基和异构辛基;
(3)在A-G齐墩果酸母核的A环2,3位引入喹啉环的齐墩果酸衍生物,其结构式如下:
其中R3,R4,R5,R6各自独立为氢、羟基、卤素、直链或支链C1-C8的低级烷基、羧基、三氟甲基、乙酰基、直链或支链低级烷氧基、卤代烷基、芳基、芳氧基或氨基;
(4)在A-G齐墩果酸母核的A环2,3位引入吡嗪环的齐墩果酸衍生物,其结构式如下:
R7, 其中R9,R10,R11,R12各自独立为H,C1-14的烷基或者不饱和烃基,卤素F、Cl、Br、I,OH,NH2,OMe,OC2H5,NO2,CN,CF3,COOMe,COPh,COOH,Ph为苯基;或者R7和R8各自独立为H,C1-14的烷基或者不饱和烃基,卤素F、Cl、Br、I,OH,NH2,OMe,OC2H5,NO2,CN,CF3,COOMe,COPh,COOH,Ph,Ph为苯基;
(5)在A-G齐墩果酸母核的A环3位引入苯腙的齐墩果酸衍生物,其结构式如下:
R12’,R13,R14,R15,R16各自为氢、羟基、卤素、直链或支链C1-C8的低级烷基、羧基、三氟甲基、乙酰基、直链或支链低级烷氧基、卤代烷基、芳基、芳氧基或氨基。
本发明中的A-G齐墩果酸母核已在专利CN200510038096.1中公开。
A环2,3位是单羰或双羰基的齐墩果酸衍生物的制备方法为:A-G齐墩果酸母核的3位经Jones氧化成单羰,再经SeO2进一步氧化成双羰基化合物的齐墩果酸衍生物。A环3位是羰基的A-G齐墩果酸衍生物的制备:合成A-G齐墩果酸母核,然后将其和氯铬酸吡啶盐在氮气保护下,在二氯甲烷中,室温搅拌,加入乙醚,滤除沉淀,滤液浓缩,硅胶柱分离,得3位是单羰的齐墩果酸衍生物;A环2,3位是双羰基的齐墩果酸衍生物的制备方法为:3-羰基的A-G齐墩果酸母核和二氧化硒在乙酸中加热回流数小时,反应结束后,反应液冷却,过滤,滤液减压浓缩,残留物溶于乙醚,用饱和食盐水洗涤,无水硫酸镁干燥,除去乙醚,得到2,3位双羰基的齐墩果酸衍生物。
A环连接有吲哚环的齐墩果酸衍生物的制备方法为:首先合成3位是羰基的A-G齐 墩果酸母核,然后同带有R3,R4,R5,R6取代基的苯肼或其盐酸盐衍生物,在酸性溶液中,回流,生成吲哚环的齐墩果酸衍生物;带有R3,R4,R5,R6取代基的苯肼或盐酸盐衍生物的特征结构式如下:
对于所述酸性溶液,当选用冰醋酸时,则加热回流,反应结束,加入蒸馏水,乙醚萃取,浓缩,分离;当选用盐酸时,则在乙醇溶液中,加入3N盐酸回流反应,反应结束后,减压蒸除溶剂,加入蒸馏水,用二氯甲烷提取,浓缩,分离。
A环连接有喹啉环的齐墩果酸衍生物的制备方法为:在氮气保护下,将带有R3,R4,R5,R6取代基的邻氨基苯甲醛衍生物和3-羰基的A-G齐墩果酸母核的无水乙醇溶液中加入氢氧化钾乙醇液,回流,反应液冷却,用二氯甲烷提取,无水硫酸镁干燥,减压浓缩,硅胶柱分离,得到A环连接有喹啉环的齐墩果酸衍生物;其中邻氨基苯甲醛衍生物的特征结构式如下:
A环连接有吡嗪环的齐墩果酸衍生物的制备方法为:(1)3-羰基的A-G齐墩果酸衍生物与带有R7和R8取代基的二胺类衍生物及硫,在吗啉或者二甲苯溶剂中,回流,生成吡嗪杂环衍生物;(2)2,3-双羰基的A-G齐墩果酸母核与带有R7和R8取代基的二胺类衍生物在冰醋酸下生成吡嗪杂环衍生物;其中二胺类衍生物的结构式特征如下:
A环3位连有苯腙的齐墩果酸衍生物的制备方法为:带有R12’,R13,R14,R15,R16取代基的苯肼衍生物与3-羰基的A-G齐墩果酸衍生物在冰醋酸下,加热回流,进行缩合,得到苯腙类齐墩果酸衍生物,其苯肼衍生物的结构式特征如下:
本发明还可对齐墩果酸衍生物的28位及其它位的结构修饰:引入R基团,所述R基团可以为氨基酸、脂肪醇、脂肪酸、杂环化合物或者糖链的修饰,糖在下列种类中选择:半乳糖,氨基半乳糖,木糖,夫糖,果糖,葡萄糖,葡萄糖胺,葡萄糖醛酸,甘露糖,唾液酸及其他天然存在的糖,以1-2个糖的糖链为中心:
对齐墩果酸衍生物的28位及其它位的结构进行修饰的制备方法为:将齐墩果酸衍生物羧基酰化,得到酰氯化合物,同时从氨基酸用SOCl2,和MeOH制备氨基酸羧基得到保护的氨基酸甲酯盐酸盐;将酰氯化合物和氨基酸甲酯盐酸盐在Et3N和CH2Cl2的条件下反应,得到氨基酸甲酯衍生物,以4M NaOH,MeOH,四氢呋喃THF的条件脱保护,得氨基酸去甲酯衍生物;其中所用的氨基酸为天然存在的所有氨基酸和人工合成的D型氨基酸。
本发明的齐墩果酸衍生物可用于抗骨质疏松药物及健康食品,制成口服液、片剂、胶囊剂等剂型。
本发明在齐墩果酸母核A环引入羰基、吲哚杂环、吡嗪杂环、喹啉杂环、苯腙环等功能基团,所得齐墩果酸衍生物均能用于抗骨质疏松药物及健康食品,且绝大多数对由活性维生素D引起的骨细胞分化有强烈的抑制作用,本发明齐墩果酸衍生物的制备方法清楚、易行,容易控制生成各种结构的衍生物。
附图说明
图1是本发明齐墩果酸衍生物2-9的制备流程图,其中条件:(a)氯铬酸吡啶盐氧化;(b)与苯肼衍生物在AcOH中回流1小时;(c)吗啉溶液,加入乙二胺、硫一起回流;(d)吗啉溶液,加入1,2-苯肼衍生物、硫一起回流;(e)与邻氨基苯甲醛的无水乙醇溶液,加入氢氧化钾乙醇液回流24小时。
图2是本发明齐墩果酸衍生物10-12的制备流程图,其中条件:(a)二氧杂环乙烷溶液,加入SeO2,H2O,AcOH回流;(b)1,2-联苯-1,2-乙二胺,在AcOH回流2小时;(c)4-硝基邻苯二胺,在AcOH中回流2小时。
图3是本发明齐墩果酸衍生物13的制备流程图,条件(a)在AcOH(醋酸)中回流1小时。
图4是本发明齐墩果酸衍尘物28位具有氨基酸的制备流程图,条件:(a)ClCOCOCl,CH2Cl2,r.t;(b)SOCl2,MeOH;(c)Et3N,CH2Cl2;(d)4M NaOH,MeOH,四氢呋喃THF,图中英文缩写表示的氨基酸为甘氨酸(Gly),丙氨酸(Ala),缬氨酸(Val),亮氨酸(Leu),异亮氨酸(Ile),苯丙氨酸(Phe)。
图5是本发明齐墩果酸衍生物28位具有糖苷的制备流程图,条件:
(a)K2CO3/Bu4NBr/DCM,回流4小时:(b)NaOMe/MeOH,图中英文缩写表示的糖苷为半乳糖(Gal),葡萄糖(Glu),木糖(Xyl),阿拉伯糖(Arab)。
具体实施方式
下面结合具体实施例说明本发明。
实施例1:
如图1,3-羰基齐墩果酸衍生物2的制备:在氮气保护下,在二氯甲烷(200mL)中,加入A-G齐墩果酸母核1(4.56g,10mmol)和氯铬酸吡啶盐(5.75g,5.3mol eq,PCC),室温搅拌4小时。反应完后加入适量乙醚,滤除沉淀,滤液浓缩后,硅胶柱分离,淋洗液:乙酸乙酯/石油醚,得到化合物2(4.17g,产率92%)。
3-羰基齐墩果酸衍生物2:mp 187℃;H NMR(300MHz,CDCl3)δ:5.32(1H,s),2.85(1H,dd,J=3Hz,15Hz);13C NMR(CDCl3,75MHz)δ:217.7,184.2,143.6,122.3;ESI-MS(negative)m/z:454[M-H]-。
实施例2:
如图1,齐墩果酸衍生物3-6的制备:在氮气保护下,3-羰基齐墩果酸衍生物2(0.191mmol)、苯肼衍生物(1.05eq)和冰醋酸(10mL)的混合物,加热回流1小时。反应液慢慢加入50毫升蒸馏水中,然后用乙醚(4×20mL)萃取。萃取液浓缩后,硅胶柱分离,淋洗液:乙酸乙酯/石油醚,得到齐墩果酸衍生物3-6,数据如下:
齐墩果酸衍生物3:产率69%;mp 229-230℃;H NMR(300MHz,CDCl3)δ:7.70(1H,s),7.42(1H,d,J=6Hz),7.31-7.26(2H,m),7.13-7.03(2H,m),5.40(1H,s);13C NMR(CDCl3,75MHz)δ:184.5,143.3,140.8,136.0,128.2,122.8,120.9,118.8,117.9,110.3, 106.8;ESI-MS(negative)m/z:526[M-H]-。
齐墩果酸衍生物4:产率60%;mp 173℃;H NMR(300MHz,CDCl3)δ:7.73(1H,s),7.37(1H,d,J=3Hz),7.19(1H,d,J=6Hz),7.07-7.04(1H,m),5.40(1H,s);13C NMR(CDCl3,75MHz)δ:184.3,143.3,142.5,134.4,129.4,124.6,122.8,121.0,117.6,111.2,106.8;ESI-MS(negative)m/z:561[M-H]-。
齐墩果酸衍生物5:产率60%;mp 251℃;H NMR(300MHz,CDCl3)δ:8.27(1H,s),7.95(1H,s),7.85(H,d,J=9Hz),7.29-7.26(1H,m),5.41(1H,s),2.95(1H,d,J=12Hz); 13C NMR(CDCl3,75MHz)δ:184.6,173.3,143.0,142.3,139.3,127.9,122.8,121.8,119.6,109.8,108.4;ESI-MS(negative)m/z:570[M-H]-。
齐墩果酸衍生物6:产率61%;mp 200℃;H NMR(300MHz,CDCl3)δ:8.39(1H,d,J=3Hz),8.18(1H,s),8.06-8.02(1H,m),7.31-7.26(1H,m),5.41(1H,t,J=3Hz),2.90(1H,dd,J=3Hz,15Hz);13C NMR(CDCl3,75MHz)δ:183.8,144.2,143.3,141.2,139.3,127.8,122.7,116.9,115.3,110.0,109.5;ESI-MS(negative)m/z:572[M-H]-。
实施例3:
如图1,齐墩果酸衍生物7、8的制备:将硫(1.5g,47mmol)和不同的二胺类化合物(1.5mL,25mmol)加入3-羰基齐墩果酸衍生物2(2.27g,5mmol)的吗啉(20mL)溶液中,混合物加热回流2-4小时。反应物用硅胶柱分离,淋洗液:乙酸乙酯/石油醚,分别得到齐墩果酸衍生物7、8,数据如下:
齐墩果酸衍生物7:产率70%;mp 267℃;H NMR(300MHz,CDCl3)δ:8.44(1H,s),8.28(1H,s),5.37(1H,s),3.0(1H,d,J=15Hz),2.91-2.85(1H,m);13C NMR(CDCl3,75MHz)δ:183.7,159.8,150.4,143.5,142.4,141.2,122.4;ESI-MS m/z:490[M+H]+。
齐墩果酸衍生物8:产率67%;mp 152℃;H NMR(300MHz,CDCl3)δ:8.03-7.96(2H,m),7.68-7.64(2H,m),5.39(1H,t,J=3Hz),3.26(1H,d,J=15Hz);13C NMR(CDCl3,75MHz)δ:184.0,161.2,152.0,143.6,142.3,140.7,129.0,128.9,128.7,128.0,122.7;ESI-MS(negative)m/z:539[M-H]-。
实施例4:
如图1:2,3喹啉齐墩果酸衍生物9的制备:在氮气保护下,在邻氨基苯甲醛(0.25g,1.45mmol)和3-羰基齐墩果酸衍生物2(658mg,1.45mmol)的无水乙醇(15mL)溶液中慢慢加入氢氧化钾乙醇液(0.5mL),回流24小时。反应液冷却后,用二氯甲烷(3×30mL)提取。提取液用硫酸镁干燥后,除去二氯甲烷,产物用硅胶柱分离,淋洗液:乙酸乙酯 /石油醚,得到3喹啉齐墩果酸衍生物9(产率72%)。
3喹啉齐墩果酸衍生物9:mp 294℃;H NMR(300MHz,CDCl3)δ:8.00(1H,d,J=3Hz),7.71-7.67(2H,m),7.61-7.56(1H,m),7.44-7.39(1H,m),5.38(1H,t,J=3Hz),2.96-2.85(2H.m),2.54(1H,d,J=15Hz);13C NMR(CDCl3,75MHz)δ:184.1,166.0,147.3,143.7,135.3,128.8,128.6,128.0,126.9,126.5,125.4,122.5;ESI-MS(negative)m/z:538[M-H]-。
实施例5:
如图2,吡嗪齐墩果酸衍生物11和喹喔啉齐墩果酸12的制备:3-羰基齐墩果酸衍生物2(4.54g,10mmol)和二氧化硒(1.34g,1.2mmol)的乙酸(10mL)溶液加热回流24小时,反应液冷却后,过滤,滤液减压浓缩除去液体。残留物溶于乙醚中,乙醚液用食盐水洗涤,用无水硫酸镁干燥后,除去乙醚,得到化合物2,3-二羰基齐墩果酸衍生物10。
2,3-二羰基齐墩果酸衍生物10(468mg,1mmol),二胺类化合物(1.2mmol)和冰醋酸(10mL)在氮气保护下回流2小时。反应液减压浓缩后,用硅胶柱分离,淋洗液:乙酸乙酯/石油醚,分别得到齐墩果酸衍生物11和12。
吡嗪齐墩果酸衍生物11:产率53%;mp 238℃;H NMR(300MHz,CDCl3)δ:7.43-7.26(10H,m),5.39(1H,s),3.02-2.83(2H,m);13C NMR(CDCl3,75MHz)δ:184.3,164.9,161.8,149.7,148.7,143.2,139.8,139.6,130.0,129.9,128.0,127.9,123.2;ESI-MS(negative)m/z:641[M-H]-。
喹喔啉齐墩果酸衍生物12:产率44%;mp 176℃;H NMR(300MHz,CDCl3)δ:8.96(1H,s),8.47-8.41(2H,m),5.40(1H,s);13C NMR(CDCl3,75MHz)δ:184.2,164.0,155.8,147.0,143.6,143.3,140.8,129.6,125.4,122.4;ESI-MS(negative)m/z:584[M-H]-。
实施例6:
如图3,齐墩果酸腙衍生物13的制备:在氮气保护下,将3-羰基齐墩果酸衍生物2(0.191mmol)、2,4二硝基苯肼(1.05eq)和冰醋酸(10mL)的混合物加热回流1小时。反应结束后滴入蒸馏水(50mL),然后用乙醚萃取(4×20mL)。萃取物用硅胶柱分离,淋洗液:乙酸乙酯/石油醚,得到齐墩果酸腙衍生物13。
齐墩果酸腙衍生物13:产率65%;mp 272℃;H NMR(300MHz,CDCl3)δ:11.19(1H,s),9.15(1H,s),8.32(1H,d,J=9Hz),7.87(1H,d,J=9Hz),5.33(1H,s),2.86(1H,d,J=12Hz);13C NMR(CDCl3,75MHz)δ:166.9,145.5,143.6,143.6,137.4,129.9,128.9,123.6,122.6,122.3,116.4;ESI-MS(negative)m/z:633[M-H]-.
实施例7:
本发明齐墩果酸衍生物的氨基酸类衍生物(2a-m,3a-m,4a-m,7a-m,8a-m,13a-m)的一般制备方法,以3-羰基齐墩果酸衍生物2为例,如图4:
将3-羰基齐墩果酸衍生物2溶解在10mL二氯甲烷中,加入干燥草酰氯(1.5mL),室温反应24小时。反应物减压浓缩后再加己烷(3×5mL)后,减压浓缩得3-羰基齐墩果酸酰氯。在5mL的相关氨基酸甲酯溶液中加入上述3-羰基齐墩果酸酰氯,室温搅拌2小时。反应物浓缩,硅胶柱分离,淋洗液:乙酸乙酯/石油醚,分别得到相应的化合物2a-f。相关氨基酸可为甘氨酸(Gly),丙氨酸(Ala),缬氨酸(Val),亮氨酸(Leu),异亮氨酸(Ile),苯丙氨酸(Phe)。
化合物2a-f在4N氢氧化钠(1.2mL)的甲醇-四氢呋喃(1∶1.5,5mL)中搅拌室温过夜,反应液用2N盐酸中和,除去有机溶剂后用二氯甲烷提取分别得到化合物2g-m。
化合物3a-m,4a-m,7a-m,8a-m,13a-m分别从齐墩果酸衍生物3,4,7,8,13开始,按照化合物2a-m方法合成。
化合物2a:产率89%;mp 101℃;1H NMR(300MHz,CDCl3)δ:6.52(1H,t,J=6Hz),5.47(1H,s),4.16-4.09(1H,m),3.86-3.80(1H,m),3.76(3H,s);13C NMR(CDCl3,75MHz)δ:217.6,178.2,170.5,144.3,123.0;ESI-MS m/z:526[M+H]+,548[M+Na]+.
化合物2b:产率90%;mp 103℃;1H NMR(300MHz,CDCl3)δ:6.53(1H,d,J=6Hz),5.36(1H,s),4.39-4.35(1H,m),3.64(3H,s);13C NMR(CDCl3,75MHz)δ:217.3,177.2,173.4,143.6,122.8;ESI-MS m/z:540[M+H]+,562[M+Na]+.
化合物2c:产率86%;mp 215℃;1H NMR(300MHz,CDCl3)δ:6.42(1H,d,J=6Hz),5.46(1H,s),4.46(1H,s),3.72(3H,s);13C NMR(CDCl3,75MHz)δ:218.0,178.0,172.8,144.1,123.4;ESI-MS m/z:568[M+H]+,590[M+Na]+.
化合物2d:产率85%;mp 146℃;1H NMR(300MHz,CDCl3)δ:6.33(1H,d,J=6Hz),5.44(1H,t,J=3Hz),4.55-4.53(1H,m),3.71(3H,s);13C NMR(CDCl3,75MHz)δ:217.6,177.5,173.5,143.9,122.9;ESI-MS m/z:582[M+H]+,604[M+Na]+.
化合物2e:产率89%;mp 98℃;1H NMR(300MHz,CDCl3)δ:6.46(1H,d,J=6Hz),5.45(1H,s),4.52(1H,t,J=3Hz),3.71(3H,s);13C NMR(CDCl3,75MHz)δ:217.7,177.4,172.3,143.8,123.0;ESI-MS m/z:582[M+H]+,604[M+Na]+.
化合物2f:产率90%;mp 82℃;1H NMR(300MHz,CDCl3)δ:7.28-7.23(3H,m),7.11-7.08(2H,m),6.38(1H,d,J=6Hz),5.30(1H,s),4.77-4.75(1H,m),3.70(3H,s);13C NMR(CDCl3,75MHz)δ:217.6,177.5,172.0,143.7,136.1,129.3,128.4,127.0,123.0;ESI-MS m/z:616[M+H]+.
化合物2g:产率90%;mp 140℃;1H NMR(300MHz,CDCl3)δ:6.7(1H,s),5.48(1H,s),4.14-3.86(2H,m);13C NMR(CDCl3,75MHz)δ:218.1,179.8,172.0,144.2,123.5;ESI-MS m/z:511[M+H]+.
化合物2h:产率89%;mp 134℃;1H NMR(300MHz,CDCl3)δ:6.68(1H,d,J=6Hz),5.46(1H,s),4.47-4.43(1H,m);13C NMR(CDCl3,75MHz)δ:218.1,179.4,175.3,144.0,123.5;ESI-MS m/z:526[M+H]+.
化合物2i:产率91%;mp 232℃;1H NMR(300MHz,CDCl3)δ:6.53(1H,d,J=9Hz),5.46(1H,t,J=3Hz),4.47(1H,t,J=3Hz);13C NMR(CDCl3,75MHz)δ:217.9,179.1,175.4,143.9,123.4;ESI-MS m/z:554[M+H]+.
化合物2j:产率86%;mp 142℃;1H NMR(300MHz,CDCl3)δ:6.33(1H,d,J=9Hz),5.44(1H,t,J=3Hz),4.55-4.53(1H,m);13C NMR(CDCl3,75MHz)δ:218.4,179.3,175.4,143.8,123.4;ESI-MS m/z:568[M+H]+.
化合物2k:产率88%;mp 142℃;1H NMR(300MHz,CDCl3)δ:6.55(1H,d,J=9Hz),5.45(1H,s),4.53-4.50(1H,m);13C NMR(CDCl3,75MHz)δ:218.1,178.3,175.4,143.9,123.4;ESI-MS m/z:568[M+H]+.
化合物2m:产率90%;mp 128℃;1H NMR(300MHz,CDCl3)δ:7.31-7.17(5H,m),6.44(1H,d,J=6Hz),5.23(1H,s),4.71-4.69(1H,m),3.30-3.06(2H,m);13C NMR(CDCl3,75MHz)δ:218.2,179.8,173.7,143.6,135.8,129.5,128.8,127.4,123.5;ESI-MS m/z:602[M+H]+.
化合物3a:产率84%;mp 140℃;1H NMR(300MHz,CDCl3)δ:7.81(1H,s),7.46-7.43(1H,m),7.34-7.28(1H,m),7.16-7.08(2H,m),6.61(1H,s),5.60(1H,s),4.18(1H,dd,J=6Hz,18Hz),3.90-3.78(4H,m);13C NMR(CDCl3,75MHz)δ:178.4,170.5,144.0,140.8,136.1,128.1,123.6,120.9,118.8,117.9,110.4,106.7;ESI-MS m/z:621[M+Na]+.
化合物3b:产率87%;mp 129℃;1H NMR(300MHz,CDCl3)δ:7.84(1H,s),7.42(1H,d,J=9Hz),7.30-7.25(1H,m),7.11-7.05(2H,m),6.64(1H,d,J=9Hz),5.55(1H,s),4.50-4.46(1H,m),3.74(3H,s);13C NMR(CDCl3,75MHz)δ:177.6,173.6,143.6,140.9,136.1,128.1,123.6,120.9,118.8,117.9,110.4,106.7;ESI-MS m/z:635[M+Na]+.
化合物3c:产率89%;mp 122℃;1H NMR(300MHz,CDCl3)δ:7.86(1H,s),7.45(1H,d,J=9Hz),7.33-7.25(1H,m),7.16-7.08(2H,m),6.50(1H,d,J=6Hz),5.58(1H,s),4.50(1H,t,J=6Hz),3.73(3H,s);13C NMR(CDCl3,75MHz)δ:178.2,172.7,143.9,141.2,136.5,128.6,123.9,121.3,119.2,118.3,110.7,107.1;ESI-MS m/z:663[M+Na]+.
化合物3d:产率82%;mp 145℃;1H NMR(300MHz,CDCl3)δ:7.82(1H,s),7.42(1H,d,J=9Hz),7.30-7.25(1H,m),7.11-7.05(2H,m),6.40(1H,d,J=6Hz),5.54(1H,s),4.56(1H,d,J=6Hz),3.70(3H,s);13C NMR(CDCl3,75MHz)δ:177.6,173.4,143.6,140.8,136.1,128.2,123.5,120.9,118.8,117.9,110.3,106.7;ESI-MS m/z:677[M+Na]+.
化合物3e:产率88%;mp 148℃;1H NMR(300MHz,CDCl3)δ:7.80(1H,s),7.42(1H,d,J=9Hz),7.30-7.25(1H,m),7.13-7.03(2H,m),6.52(1H,d,J=9Hz),5.55(1H,t,J=3Hz),4.53(1H,t,J=6Hz),3.70(3H,s);13C NMR(CDCl3,75MHz)δ:177.7,172.3,143.5,140.9,136.1,128.1,123.6,120.9,118.8,117.9,110.4,106.7;ESI-MS m/z:655[M+H]+,677[M+Na]+.
化合物3f:产率89%;mp 158℃;1H NMR(300MHz,CDCl3)δ:7.79(1H,s),7.41(1H,d,J=9Hz),7.30-7.02(8H,m),6.44(1H,d,J=6Hz),5.40(1H,s),4.78-4.75(1H,m),3.70(3H,s);13C NMR(CDCl3,75MHz)δ:177.7,171.9,143.4,140.8,136.1,129.4,128.5,127.1,123.6,120.9,118.8,117.9,110.4,106.7;ESI-MS m/z:689[M+H]+
化合物3g:产率86%;mp 226℃;1H NMR(300MHz,CDCl3)δ:7.76(1H,s),7.42(1H,d,J=6Hz),7.31-7.26(1H,m),7.14-7.05(1H,m),6.76(1H,s),5.57(1H,t,J=3Hz),4.11(1H,dd,J=3Hz,15Hz),3.92(1H,dd,J=3Hz,15Hz));13C NMR(CDCl3,75MHz)δ:180.0,172.1,144.0,140.9,136.2,128.3,124.0,121.1,119.0,118.0,110.5,106.8;ESI-MSm/z:585[M+H]+.
化合物3h:产率89%;mp 220℃;1H NMR(300MHz,CDCl3)δ:7.84(1H,s),7.42(1H,d,J=6Hz),7.31-7.26(1H,m),7.13-7.06(2H,m),6.70(1H,d,J=6Hz),5.56(1H,t,J=3Hz),4.47-4.43(1H,m);13C NMR(CDCl3,75MHz)δ:180.0,175.0,143.8,140.9,136.3,128.3,124.1,121.1,119.0,118.0,110.5,106.8;ESI-MS m/z:599[M+H]+,621[M+Na]+.
化合物3i:产率90%;mp 223℃;1H NMR(300MHz,CDCl3)δ:7.83(1H,s),7.43(1H,d,J=9Hz),7.31-7.29(1H,m),7.12-7.03(2H,m),6.54(1H,d,J=9Hz),5.56(1H,s),4.46-4.42(1H,m);13C NMR(CDCl3,75MHz)δ:179.6,174.9,143.7,140.9,136.3,128.3,124.0,121.1,119.0,118.0,110.5,106.8;ESI-MS m/z:627[M+H]+.
化合物3j:产率88%;mp 208℃;1H NMR(300MHz,CDCl3)δ:7.80(1H,s),7.42(1H,d,J=6Hz),7.31-7.26(1H,m),7.14-7.03(2H,m),6.49(1H,d,J=6Hz),5.54(1H,t,J=3Hz),4.49-4.42(1H,m);13C NMR(CDCl3,75MHz)δ:180.3,174.7,144.0,140.9,136.3,128.3,124.1,121.1,119.0,118.0,110.5,106.8;ESI-MS m/z:641[M+H]+,663[M+Na]+.
化合物3k:产率90%;mp 206℃;1H NMR(300MHz,CDCl3)δ:7.85(1H,s),7.43(1H,d,J=6Hz),7.31-7.26(1H,m),7.11-7.05(2H,m),6.58(1H,d,J=6Hz),5.56(1H,s),4.53(1H,t,J=3Hz);13C NMR(CDCl3,75MHz)δ:178.9,175.6,143.6,140.8,136.3,128.3,123.9,121.1,119.0,121.1,119.0,118.0,110.5,106.8;ESI-MS m/z:641[M+H]+,663[M+Na]+.
化合物3m:产率91%;mp 205℃;1H NMR(300MHz,CDCl3)δ:7.77(1H,s),7.41-7.06(9H,m),6.40(1H,d,J=3Hz),5.29(1H,t,J=3Hz),4.70-4.64(1H,m);13CNMR(CDCl3,75MHz)δ:181.0,172.8,143.6,140.9,136.3,135.8,129.5,129.0,128.3,127.5,124.1,121.1,119.0,118.0,110.5,106.8;ESI-MS m/z:675[M+H]+,697[M+Na]+.
化合物4a:产率85%;mp 162℃;1H NMR(300MHz,CDCl3)δ:7.91(1H,s),7.37(1H,d,J=3Hz),7.20(1H,d,J=9Hz),7.07-7.04(1H,m),6.59(1H,s),5.58(1H,s),4.17(1H,dd,J=6Hz,18Hz),3.84(1H,dd,J=3Hz,18Hz),3.76(3H,s);13C NMR(CDCl3,75MHz)δ:178.5,170.6,144.2,142.6,134.5,129.4,124.6,123.6,121.1,117.6,111.4,106.8;ESI-MS m/z:633[M+H]+.
化合物4b:产率83%;mp 118℃;1H NMR(300MHz,CDCl3)δ:7.83(1H,s),7.37(1H,s),7.21(1H,d,J=9Hz),7.06-7.04(1H,m),6.64(1H,d,J=6Hz),5.57(1H,s),4.51-4.47(1H,m),3.74(3H,s);13C NMR(CDCl3,75MHz)δ:177.7,173.7,143.7,142.6,134.6,129.5,124.7,123.6,121.1,117.6,111.4,106.9;ESI-MS m/z:647[M+H]+,669[M+Na]+.
化合物4c:产率87%;mp 161℃;1H NMR(300MHz,CDCl3)δ:7.84(1H,s),7.37(1H,d,J=3Hz),7.20(1H,d,J=9Hz),7.07-7.03(1H,m),6.47(1H,d,J=6Hz),5.56(1H,s),4.47(1H,t,J=3Hz),3.71(3H,s);13C NMR(CDCl3,75MHz)δ:177.9,172.4,143.6,142.6,134.6,129.5,124.7,123.6,121.1,117.6,111.4,106.9;ESI-MS m/z:675[M+H]+.
化合物4d:产率89%;mp 119℃;1H NMR(300MHz,CDCl3)δ:7.79(1H,s),7.37(1H,d,J=3Hz),7.20(1H,d,J=9Hz),7.07-7.04(1H,m),6.39(1H,d,J=6Hz),5.54(1H,t,J=3Hz),4.59-4.53(1H,m),3.71(3H,s);13C NMR(CDCl3,75MHz)δ:177.8,173.6, 143.8,142.6,134.6,129.5,124.7,123.5,121.2,117.6,111.4,106.9;ESI-MS m/z:689[M+H]+.
化合物4e:产率88%;mp 160℃;1H NMR(300MHz,CDCl3)δ:7.95(1H,s),7.37(1H,d,J=3Hz),7.20(1H,d,J=9Hz),7.07-7.04(1H,m),6.54(1H,d,J=6Hz),5.56(1H,t,J=3Hz),4.55-4.51(1H,m),3.70(3H,s);13C NMR(CDCl3,75MHz)δ:177.7,172.3,143.6,142.6,134.5,129.4,124.6,123.6,121.1,117.6,111.4,106.8;ESI-MS m/z:711[M+Na]+.
化合物4f:产率85%;mp 165℃;1H NMR(300MHz,CDCl3)δ:7.78(1H,s),7.39-7.06(8H,m),6.46(1H,d,J=6Hz),5.42(1H,s),4.83-4.77(1H,m),3.72(3H,s),3.25-3.05(2H,m);13C NMR(CDCl3,75MHz)δ:177.7,171.9,143.4,142.5,136.1,134.6,129.3,128.5,127.1,124.5,123.5,121.0,117.5,111.3,106.7;ESI-MS m/z:745[M+Na]+.
化合物4g:产率88%;mp 250℃;1H NMR(300MHz,CDCl3)δ:7.89(1H,s),7.35(1H,d,J=3Hz),7.18(1H,d,J=9Hz),7.05-7.02(1H,m),6.57(1H,t,J=3Hz),5.55(1H,t,J=3Hz),4.15(1H,dd,J=6Hz,18Hz),3.83(1H,dd,J=3Hz,18Hz);13C NMR(CDCl3,75MHz)δ:179.7,171.9,144.2,142.6,134.5,129.4,124.6,123.6,121.1,117.6,111.4,106.8;ESI-MS m/z:641[M+Na]+.
化合物4h:产率88%;mp 234℃;1H NMR(300MHz,CDCl3)δ:7.85(1H,s),7.38(1H,d,J=3Hz),7.20(1H,d,J=6Hz),7.07-7.03(1H,m),6.65(1H,d,J=6Hz),5.56(1H,t,J=6Hz),4.55-4.41(1H,m);13C NMR(CDCl3,75MHz)δ:180.5,174.6,144.0,142.5,134.5,129.4,124.6,124.0,121.2,117.6,111.4,106.7;ESI-MS m/z:633[M+H]+,655[M+Na]+.
化合物4i:产率89%;mp 204℃;1H NMR(300MHz,CDCl3)δ:7.83(1H,s),7.36(1H,d,J=3Hz),7.19(1H,d,J=9Hz),7.06-7.03(1H,m),6.46(1H,d,J=6Hz),5.55(1H,t,J=3Hz),4.49-4.45(1H,m);13C NMR(CDCl3,75MHz)δ:180.0,173.5,143.6,142.6,134.6,129.5,124.7,123.6,121.1,117.6,111.4,106.9;ESI-MS m/z:661[M+H]+.
化合物4j:产率90%;mp 197℃;1H NMR(300MHz,CDCl3)δ:7.86(1H,s),7.37(1H,d,J=3Hz),7.22-7.19(1H,m),7.07-7.03(1H,m),6.49(1H,d,J=6Hz),5.54(1H,t,J=3Hz),4.48-4.42(1H,m);13C NMR(CDCl3,75MHz)δ:180.6,174.5,144.0,142.5,134.5,129.4,124.6,123.5,121.1,117.6,111.4,106.7;ESI-MS m/z:697[M+Na]+.
化合物4k:产率90%;mp 224℃;1H NMR(300MHz,CDCl3)δ:7.94(1H,s),7.38 (1H,d,J=3Hz),7.20(1H,d,J=9Hz),7.07-7.03(1H,m),6.57(1H,d,J=6Hz),5.57(1H,s),4.52(1H,t,J=6Hz);13C NMR(CDCl3,75MHz)δ:179.0,175.7,143.6,142.5,134.6,129.4,124.6,123.8,121.1,117.6,111.4,106.7;ESI-MS m/z:697[M+Na]+.
化合物4m:产率88%;mp 223℃;1H NMR(300MHz,CDCl3)δ:7.85(1H,s),7.38-7.04(8H,m),6.41(1H,d,J=6Hz),5.28(1H,s),4.69-4.63(1H,m);13C NMR(CDCl3,75MHz)δ:179.5,171.4,143.5,142.5,135.8,134.6,129.5,128.9,127.5,124.7,124.0,121.2,117.6,111.4,106.7;ESI-MS m/z:731[M+Na]+.
化合物7a:产率87%;mp 116℃;1H NMR(300MHz,CDCl3)δ:8.42(1H,d,J=3Hz),8.27(1H,d,J=3Hz),6.54(1H,d,J=3Hz),5.54(1H,t,J=3Hz),4.14(1H,dd,J=3Hz,18Hz),3.84(1H,dd,J=3Hz,18Hz),3.76(3H,s);13C NMR(CDCl3,75MHz)δ:178.4,170.7,159.9,150.5,144.3,142.5,141.4,123.3;ESI-MS m/z:562[M+H]+,584[M+Na]+.
化合物7b:产率89%;mp 107℃;1H NMR(300MHz,CDCl3)δ:8.43(1H,d,J=3Hz),8.27(1H,d,J=3Hz),6.61(1H,d,J=6Hz),5.52(1H,t,J=3Hz),4.51-4.43(1H,m),3.73(3H,s);13C NMR(CDCl3,75MHz)δ:177.5,173.8,160.0,150.5,143.8,142.5,141.2,123.2;ESI-MS m/z:598[M+Na]+.
化合物7c:产率86%;mp 103℃;1H NMR(300MHz,CDCl3)δ:8.42(1H,s),8.27(1H,s),6.43(1H,d,J=6Hz),5.52(1H,s),4.46(1H,t,J=6Hz),3.70(3H,s);13C NMR(CDCl3,75MHz)δ:177.9,172.5,159.8,150.6,143.7,142.5,141.5,123.3;ESI-MS m/z:604[M+H]+.
化合物7d:产率83%;mp 132℃;1H NMR(300MHz,CDCl3)δ:8.42(1H,d,J=3Hz),8.27(1H,d,J=3Hz),6.36(1H,d,J=6Hz),5.51(1H,t,J=3Hz),4.58-4.51(1H,m),3.70(3H,s);13C NMR(CDCl3,75MHz)δ:177.7,173.6,159.9,150.5,143.9,142.5,141.4,123.2;ESI-MS m/z:618[M+H]+.
化合物7e:产率87%;mp 110℃;1H NMR(300MHz,CDCl3)δ:8.41(1H,d,J=3Hz),8.27(1H,d,J=3Hz),6.48(1H,d,J=9Hz),5.52(1H,s),4.54-4.50(1H,m),3.69(3H,s);13C NMR(CDCl3,75MHz)δ:177.6,172.4,159.8,150.6,143.7,142.5,141.5,123.3;ESI-MS m/z:640[M+Na]+.
化合物7f:产率83%;mp 127℃;1H NMR(300MHz,CDCl3)δ:8.42(1H,d,J=3Hz),8.27(1H,d,J=3Hz),7.28-7.09(5H,m),6.41(1H,d,J=6Hz),5.37(1H,t,J=3 Hz),4.80-4.74(1H,m),3.69(3H,s);13C NMR(CDCl3,75MHz)δ:177.7,172.1,159.8,150.6,143.6,142.5,141.4,136.1,129.4,128.6,127.2,123.3;ESI-MS m/z:652[M+H]+.
化合物7g:产率86%;mp 172℃;1H NMR(300MHz,CDCl3)δ:8.54(1H,s),8.13(1H,s),7.02(1H,s),5.69(1H,s),4.10-3.94(2H,m),3.79(1H,d,J=18Hz);13C NMR(CDCl3,75MHz)δ:178.7,172.0,161.7,150.3,144.0,143.3,138.7,124.1;ESI-MS m/z:548[M+H]+.
化合物7h:产率88%;mp 152℃;1H NMR(300MHz,CDCl3)δ:8.52(1H,d,J=3Hz),8.14(1H,d,J=3Hz),7.12(1H,d,J=6Hz),5.67(1H,t,J=3Hz),4.45-4.41(1H,m),3.64(1H,d,J=18Hz m);13C NMR(CDCl3,75MHz)δ:178.1,175.0,161.6,150.2,143.6,143.3,124.0;ESI-MS m/z:561[M+H]+.
化合物7i:产率83%;mp 172℃;1H NMR(300MHz,CDCl3)δ:8.50(1H,s),8.27(1H,s),6.77(1H,d,J=6Hz),5.62(1H,s),4.49(1H,s);13C NMR(CDCl3,75MHz)δ:178.0,173.5,161.1,149.8,143.5,143.2,139.7,123.6;ESI-MS m/z:590[M+H]+.
化合物7j:产率83%;mp 140℃;1H NMR(300MHz,CDCl3)δ:8.51(1H,s),8.23(1H,s),6.83(1H,d,J=6Hz),5.63(1H,t,J=3Hz),4.59-4.53(1H,m),3.36(1H,d,J=15Hz m);13C NMR(CDCl3,75MHz)δ:177.9,174.6,161.2,149.9,143.6,143.3,139.5,123.7;ESI-MS m/z:604[M+H]+,626[M+Na]+.
化合物7k:产率86%;mp 136℃;1H NMR(300MHz,CDCl3)δ:8.50(1H,d,J=3Hz),8.26(1H,d,J=3Hz),6.84(1H,d,J=6Hz),5.62(1H,t,J=3Hz),4.54(1H,t,J=3Hz),3.26(1H,d,J=18Hz m);13C NMR(CDCl3,75MHz)δ:177.7,173.4,161.1,149.8,143.6,143.3,139.6,123.6;ESI-MS m/z:604[M+H]+,626[M+Na]+.
化合物7m:产率89%;mp 151℃;1H NMR(300MHz,CDCl3)δ:8.53(1H,s),8.19(1H,s),7.26-7.20(5H,m),6.71(1H,d,J=6Hz),5.26(1H,s),4.80(1H,s),3.49-3.40(1H,m),3.30-3.21(2H,m);13C NMR(CDCl3,75MHz)δ:178.7,172.5,161.5,150.2,143.2,143.0,139.2,136.6,129.9,128.3,127.0,124.2;ESI-MS m/z:638[M+H]+,660[M+Na]+.
化合物8a:产率85%;mp 134℃;1H NMR(300MHz,CDCl3)δ:8.02-7.94(2H,m),7.67-7.63(2H,m),6.56(1H,s),5.56(1H,s),4.15(1H,dd,J=6Hz,18Hz),3.88-3.81(1H,m),3.75(3H,s),3.23(1H,d,J=15Hz);13C NMR(CDCl3,75MHz)δ:178.4,170.6,161.1,151.9,144.2,142.2,129.0,128.9,128.7,128.1,123.3;ESI-MS m/z:612[M+H]+.
化合物8b:产率83%;mp 97℃;1H NMR(300MHz,CDCl3)δ:8.03-7.98(2H,m), 7.67-7.64(2H,m),6.61(1H,d,J=6Hz),5.54(1H,s),4.52-4.45(1H,m),3.73(3H,s),3.25(1H,d,J=18Hz);13C NMR(CDCl3,75MHz)δ:177.6,173.8,161.2,151.9,143.8,142.3,129.1,128.9,128.7,128.0,123.3;ESI-MS m/z:648[M+Na]+.
化合物8c:产率86%;mp 108℃;H NMR(300MHz,CDCl3)δ:8.01-7.94(2H,m),7.65-7.63(2H,m),6.43(1H,d,J=6Hz),5.54(1H,s),4.46(1H,t,J=6Hz),3.68(3H,s),3.23(1H,d,J=15Hz);13C NMR(CDCl3,75MHz)δ:177.8,172.5,161.1,152.0,143.6,142.2,140.8,128.9,128.9,128.6,128.1,123.3;ESI-MS m/z:654[M+H]+,676[M+Na]+.
化合物8d:产率88%;mp 134℃;1H NMR(300MHz,CDCl3)δ:8.03-7.96(2H,m),7.67-7.64(2H,m),6.36(1H,d,J=9Hz),5.53(1H,s),4.59-4.52(1H,m),3.70(3H,s),3.25(1H,d,J=18Hz);13C NMR(CDCl3,75MHz)δ:177.7,173.6,163.0,161.2,151.9,143.8,142.3,129.0,128.9,128.7,128.0,123.3;ESI-MS m/z:690[M+Na]+.
化合物8e:产率83%;mp 98℃;1H NMR(300MHz,CDCl3)δ:8.02-7.94(2H,m),7.67-7.63(2H,m),6.49(1H,d,J=9Hz),5.54(1H,s),4.53(1H,t,J=6Hz),3.69(3H,s),3.24(1H,d,J=18Hz);13C NMR(CDCl3,75MHz)δ:177.6,172.4,161.1,152.0,143.7,142.2,129.0,128.9,128.7,128.1,123.3,122.9;ESI-MS m/z:690[M+Na]+.
化合物8f:产率83%;mp 101℃;H NMR(300MHz,CDCl3)δ:8.03-7.95(2H,m),7.67-7.65(2H,m),7.29-7.09(5H,m),6.42(1H,d,J=6Hz),5.39(1H,s),4.81-4.75(1H,m),3.69(3H,s);13C NMR(CDCl3,75MHz)δ:177.7,172.1,161.2,151.9,143.6,142.3,136.2,139.4,129.1,128.9,128.7,128.6,127.2,123.4;ESI-MS m/z:724[M+Na]+.
化合物8g:产率87%;mp 159℃;1H NMR(300MHz,CDCl3)δ:8.02-7.96(2H,m),7.70-7.65(2H,m),7.15(1H,s),5.75(1H,s),4.26-4.07(2H,m);13C NMR(CDCl3,75MHz)δ:178.8,171.8,162.2,152.4,143.8,142.5,138.7,129.7,129.1,129.1,125.8,124.5;ESI-MSm/z:598[M+H]+,620[M+Na]+.
化合物8h:产率85%;mp 172℃;H NMR(300MHz,CDCl3)δ:8.01-7.99(2H,m),7.69-7.67(2H,m),7.17(1H,s),5.71(1H,s),4.52(1H,s),4.04(1H,d,J=15Hz);13C NMR(CDCl3,75MHz)δ:178.4,175.0,162.1,152.4,143.5,142.5,138.9,129.7,129.1,126.1,124.3;ESI-MS m/z:611[M+H]+.
化合物8i:产率87%;mp 160℃;H NMR(300MHz,CDCl3)δ:8.01-7.98(2H,m),7.68-7.65(2H,m),6.88(1H,d,J=6Hz),5.63(1H,s),4.57(1H,t,J=6Hz),3.82(1H,d,J=18Hz);13C NMR(CDCl3,75MHz)δ:178.3,173.6,161.9,152.3,143.1,142.4,139.3, 129.5,129.0,126.4,124.1;ESI-MS m/z:662[M+Na]+.
化合物8j:产率83%;mp 161℃;H NMR(300MHz,CDCl3)δ:8.02-7.98(2H,m),7.69-7.66(2H,m),6.93(1H,d,J=6Hz),5.66(1H,s),4.63-4.57(1H,m),3.89(1H,d,J=18Hz);13C NMR(CDCl3,75MHz)δ:178.3,174.6,162.0,152.3,143.4,142.5,139.2,129.6,129.1,126.3,124.2;ESI-MS m/z:676[M+Na]+.
化合物8k:产率88%;mp 150℃;H NMR(300MHz,CDCl3)δ:8.01-7.97(2H,m),7.68-7.65(2H,m),6.94(1H,d,J=6Hz),5.63(1H,s),4.60(1H,t,J=3Hz),3.82(1H,d,J=18Hz);13C NMR(CDCl3,75MHz)δ:178.0,173.6,161.9,152.3,143.2,142.5,139.3,129.5,129.0,126.4,124.1;ESI-MS m/z:676[M+Na]+.
化合物8m:产率89%;mp 197℃;H NMR(300MHz,CDCl3)δ:8.02-7.93(2H,m),7.69-7.66(2H,m),7.26-7.23(5H,m),6.87(1H,d,J=6Hz),5.23(1H,s),4.95(1H,s),3.91(1H,d,J=18Hz),3.34-3.19(2H,m);13C NMR(CDCl3,75MHz)δ:178.4,172.3,162.3,152.4,142.5,136.9,130.0,129.7,129.1,128.0,127.0,126.1,124.8,53.8,53.1;ESI-MS m/z:688[M+H]+.
化合物13a:产率84%;mp 127℃;1H NMR(300MHz,CDCl3)δ:11.17(1H,s),9.12(1H,s),8.31-8.27(1H,m),7.95(1H,d,J=9Hz),6.51(1H,s),5.48(1H,s),4.14(1H,dd,J=6Hz,18Hz),3.84(1H,dd,J=3Hz,18Hz),3.77(3H,s);13C NMR(CDCl3,75MHz)δ:178.1,170.5,166.9,145.5,144.4,137.5,129.9,128.9,123.6,122.9,116.4;ESI-MS(negative)m/z:704[M-H]-.
化合物13b:产率83%;mp 186℃;1H NMR(300MHz,CDCl3)δ:11.17(1H,s),9.12(1H,s),8.31-8.27(1H,m),7.95(1H,d,J=9Hz),6.57(1H,d,J=6Hz),5.46(1H,s),4.49-4.45(1H,m),3.74(3H,s);13C NMR(CDCl3,75MHz)δ:177.3,173.7,166.9,145.5,143.9,137.5,129.9,128.9,123.6,122.9,116.4;ESI-MS(negative)m/z:718[M-H]-.
化合物13c:产率86%;mp 140℃;1H NMR(300MHz,CDCl3)δ:11.18(1H,s),9.12(1H,s),8.31-8.27(1H,m),7.95(1H,d,J=9Hz),6.41(1H,d,J=9Hz),5.46(1H,t,J=3Hz),4.46(1H,t,J=6Hz),3.71(3H,s);13C NMR(CDCl3,75MHz)δ:177.8,172.6,167.0,145.6,143.9,137.5,129.0,128.6,123.7,123.0,116.4;ESI-MS(negative)m/z:746[M-H]-.
化合物13d:产率85%;mp 122℃;1H NMR(300MHz,CDCl3)δ:11.17(1H,s),9.12(1H,s),8.31-8.27(1H,m),7.95(1H,d,J=9Hz),6.33(1H,d,J=6Hz),5.45(1H,t,J=3Hz),4.55-4.53(1H,m),3.72(3H,s);13C NMR(CDCl3,75MHz)δ:177.5,173.5,166.9, 145.5,144.0,137.5,129.9,128.9,123.5,122.8,116.4;ESI-MS(negative)m/z:760[M-H]-.
化合物13e:产率82%;mp 235℃;1H NMR(300MHz,CDCl3)δ:11.16(1H,s),9.11(1H,s),8.30-8.27(1H,m),7.95(1H,d,J=9Hz),6.46(1H,d,J=6Hz),5.45(1H,s),4.52(1H,t,J=6Hz),3.72(3H,s);13C NMR(CDCl3,75MHz)δ:177.4,172.3,166.9,145.5,143.8,137.4,129.9,128.9,123.5,123.0,122.9,116.4;ESI-MS(negative)m/z:760[M-H]-.
化合物13f:产率84%;mp 224℃;1H NMR(300MHz,CDCl3)δ:11.16(1H,s),9.11(1H,s),8.30-8.26(1H,m),7.95(1H,d,J=9Hz),7.28-7.09(5H,m),6.37(1H,d,J=6Hz),5.31(1H,s),4.77-4.75(1H,m),3.70(3H,s);13C NMR(CDCl3,75MHz)δ:177.4,172.0,166.9,145.5,143.7,137.4,136.0,129.9,129.3,128.9,128.4,127.0,123.5,123.0,116.6;ESI-MS(negative)m/z:704[M-H]-.
化合物13g:产率86%;mp 151℃;1H NMR(300MHz,CDCl3)δ:11.18(1H,s),9.12(1H,s),8.32-8.28(1H,m),7.95(1H,d,J=12Hz),6.71(1H,d,J=3Hz),5.48(1H,s),4.13-3.88(2H,m);13C NMR(CDCl3,75MHz)δ:179.8,172.2,166.8,145.6,144.2,137.5,130.1,129.2,123.7,123.5,116.4;ESI-MS(negative)m/z:690[M-H]-.
化合物13h:产率87%;mp 141℃;1H NMR(300MHz,CDCl3)δ:11.17(1H,s),9.12(1H,s),8.30-8.28(1H,m),7.96(1H,d,J=9Hz),6.61(1H,d,J=6Hz),5.47(1H,t,J=3Hz),4.46-4.42(1H,m);13C NMR(CDCl3,75MHz)δ:180.1,174.9,166.8,145.7,144.2,137.6,131.0,130.1,129.1,123.7,116.6;ESI-MS(negative)m/z:704[M-H]-.
化合物13i:产率83%;mp 209℃;1H NMR(300MHz,CDCl3)δ:11.18(1H,s),9.13(1H,s),8.32-8.28(1H,m),7.96(1H,d,J=9Hz),6.54(1H,d,J=9Hz),5.47(1H,s),4.46-4.42(1H,m);13C NMR(CDCl3,75MHz)δ:179.4,175.2,166.8,145.7,143.9,137.6,130.1,129.1,123.7,123.4,116.6;ESI-MS(negative)m/z:732[M-H]-.
化合物13j:产率88%;mp 171℃;1H NMR(300MHz,CDCl3)δ:11.17(1H,s),9.13(1H,s),8.31-8.27(1H,m),7.96(1H,d,J=9Hz),6.44(1H,d,J=6Hz),5.45(1H,s),4.47(1H,m);13C NMR(CDCl3,75MHz)δ:180.0,175.0,166.8,145.7,144.2,137.6,130.1,129.1,123.7,116.6;ESI-MS(negative)m/z:746[M-H]-.
化合物13k:产率89%;mp 151℃;1H NMR(300MHz,CDCl3)δ:11.18(1H,s),9.13(1H,s),8.29-8.28(1H,d,J=3Hz),7.96(1H,d,J=9Hz),6.54(1H,d,J=6Hz),5.47(1H,s),4.45(1H,t,J=6Hz);13C NMR(CDCl3,75MHz)δ:179.0,177.0,166.7,145.7,144.0,137.6,130.1,129.1,123.7,123.4,116.6;ESI-MS(negative)m/z:746[M-H]-.
化合物13m:产率86%;mp 148℃;1H NMR(300MHz,CDCl3)δ:11.18(1H,s),9.12(1H,s),8.30-8.28(1H,m),7.96(1H,d,J=9Hz),7.34-7.19(5H,m),6.61(1H,d,J=6Hz),5.22(1H,s),4.62-5.51(1H,m);13C NMR(CDCl3,75MHz)δ:180.6,173.7,166.8,145.7,143.8,137.6,135.7,130.1,129.5,129.1,128.9,127.5,123.7,123.5,116.6;ESI-MS(negative)m/z:780[M-H]-.
实施例8:
图5为齐墩果酸类衍生物的糖苷类衍生物2n-q,3n-q,7n-q,8n-q,13n-q的一般制备方法,糖苷为半乳糖(Gal),葡萄糖(Glu),木糖(Xyl),阿拉伯糖(Arab),以3-羰基齐墩果酸衍生物2为例:
将3-羰基齐墩果酸衍生物2(0.43mmol)、乙酰基保护的葡萄糖溴(Br-glucoside,1.3eq)、碳酸钾(151mg,2.5eq)和四丁基溴化胺(Bu4NBr,56mg,0.4eq)在二氯甲烷-水(二氯甲烷-水=10∶1)溶剂中回流4-5小时。用薄层层析TLC跟踪反应,反应完毕后,加入二氯甲烷适量,用水洗涤后,有机层脱水,减压浓缩,得到反应物;将该反应物与甲醇钠(0.05eq)在甲醇(15mL)中室温搅拌24小时后,用1M的盐酸中和,产物用硅胶柱分离,淋洗液:乙酸乙酯/石油醚,分别得到相应的化合物2n-q。
化合物3n-q,7n-q,8n-q,13n-q分别从齐墩果酸衍生物3,7,8,13开始,按照化合物2n-q方法合成。
化合物2n:产率69%;mp 210℃;1H NMR(300MHz,CDCl3)δ:5.41(1H,d,J=6Hz),5.30(1H,t,J=3Hz),4.12-3.24(6H,m);13C NMR(CDCl3,75MHz)δ:218.2,176.5,143.6,122.3,94.5,74.1,70.4,68.3;ESI-MS m/z:639[M+Na]+.
化合物2o:产率71%;mp 192℃;1H NMR(300MHz,C5D5N)δ:6.35(1H,d,J=9Hz),5.46(1H,s),4.48-4.04(6H,m);13C NMR(C5D5N,75MHz)δ:217.8,178.0,145.7,124.2,97.3,80.9;ESI-MS m/z:639[M+Na]+.
化合物2p:产率73%;mp 252℃;1H NMR(300MHz,C5D5N)δ:6.25(1H,d,J=3Hz),5.47(1H,s),4.42-3.82(5H,m),2.47(1H,dd,J=6,42Hz);13C NMR(C5D5N,75MHz)δ:217.7,178.2,145.7,122.3,97.8,79.9,75.26,72.4,69.3;ESI-MS m/z:609[M+Na]+.
化合物2q:产率70%;mp 240℃;1H NMR(300MHz,CDCl3)δ:5.41(1H,d,J=7.5Hz),5.32(1H,s),4.01-3.63(5H,m),2.86(1H,dd,J=5.1Hz,13.9Hz);13C NMR(CDCl3,75MHz)δ:218.4,176.3,143.2,122.3,94.3,73.1,70.4,67.8,66.0;ESI-MS m/z:587[M+H]+.
化合物3n:产率67%;mp 229℃;1H NMR(300MHz,CDCl3)δ:7.74(1H,s),7.43-7.03(4H,m,Ar),5.49(1H,d,J=6Hz),5.42(1H,s),4.17-3.40(6H,m);13C NMR(CDCl3,75MHz)δ:177.7,143.9,141.9,136.3,128.8,124.5,121.2,119.0,118.1,110.4,106.7,95.6;ESI-MS m/z:712[M+Na]+.
化合物3o:产率68%;mp 212℃;1H NMR(300MHz,CDCl3)δ:7.73(1H,s),7.42-7.02(4H,m,Ar),5.49(1H,d,J=6.6Hz),5.40(1H,s),4.15-3.46(6H,m);13C NMR(CDCl3,75MHz)δ:176.7,143.8,140.9,136.1,128.5,124.5,121.2,119.0,118.1,110.4,106.7,94.5,76.7,72.1,69.5,65.6;ESI-MS m/z:712[M+Na]+.
化合物3p:产率69%;mp 196℃;1H NMR(300MHz,CDCl3)δ:7.76(1H,s),7.43-7.05(4H,m,Ar),5.55(1H,d,J=6Hz),5.43(1H,s),4.02-3.39(5H,m);13C NMR(CDCl3,75MHz)δ:176.4,143.0,140.9,136.2,128.7,123.2,121.0,119.0,118.1,110.4,106.9,94.4,76.7,72.1,69.5,65.6;ESI-MS m/z:682[M+Na]+.
化合物3q:产率68%;mp 193℃;1H NMR(300MHz,CDCl3)δ:7.76(1H,s),7.42-7.03(4H,m,Ar),5.47-5.45(2H,m),4.04-3.66(5H,m);13C NMR(CDCl3,75MHz)δ:176.4,143.0,140.9,136.2,128.3,123.2,121.1,119.0,118.1,110.4,107.0,94.4,73.3;ESI-MS m/z:682[M+Na]+.
化合物7n:产率70%;mp 221℃;1H NMR(300MHz,C5D5N)δ:8.52(1H,d,J=2.1Hz),8.44(1H,d,J=2.4Hz),6.28(1H,d,J=6Hz),5.50(1H,t,J=3Hz),4.72-4.21(6H,m); 13C NMR(C5D5N,75MHz)δ:178.1,161.1,152.6,145.6,144.3,143.7,124.2,97.8,79.3,77.2,73.0,71.5,63.8;ESI-MS m/z:677[M+Na]+.
化合物7o:产率70%;mp 171℃;1H NMR(300MHz,CDCl3)δ:8.39(1H,d,J=2.1Hz),8.25(1H,d,J=2.4Hz),5.47(1H,d,J=8.1Hz),5.35(1H,s),3.79-3.21(6H,m),2.96(1H,d,J=16.8Hz),2.86(1H,d,J=14.4Hz),2.48(1H,d,J=17.4Hz);13C NMR(CDCl3,75MHz)δ:176.4,159.8,150.6,143.3,142.3,141.3,122.4,94.0,74.5,72.5,69.6,61.6,58.9;ESI-MS m/z:675[M+Na]+.
化合物7p:产率72%;mp 190℃;1H NMR(300MHz,CDCl3)δ:8.41(1H,s),8.25(1H,s),5.49(1H,s),5.33(1H,d,J=24Hz),3.96-3.38(5H,m),2.99-2.93(2H,m),2.49(1H,d,J=15Hz);13C NMR(CDCl3,75MHz)δ:176.5,159.9,150.6,143.1,142.5,141.4,122.8,97.6,76.0,72.2,69.6,65.9;ESI-MS m/z:645[M+Na]+.
化合物7q:产率72%;mp 200℃;1H NMR(300MHz,CDCl3)δ:8.41(1H,d,J=2.1 Hz),8.26(1H,d,J=2.4Hz),5.44(1H,s),5.40(1H,d,J=7.2Hz),4.01-3.63(5H,m),2.99-2.87(2H,m),2.49(1H,d,J=16.2Hz);13C NMR(CDCl3,75MHz)δ:176.4,159.9,150.7,143.0,142.4,141.3,122.7,94.3,73.1,70.8,67.8,66.0;ESI-MS m/z:645[M+Na]+.
化合物8n:产率70%;mp 223℃;1H NMR(300MHz,C5D5N)δ:8.24-8.21(2H,m),7.72-7.68(2H,m),6.30(1H,d,J=9Hz),5.51(1H,s),4.70-4.22(6H,m),2.79(1H,d,J=15Hz);13C NMR(C5D5N,75MHz)δ:178.1,162.9,154.3,145.6,143.9,143.2,130.7,124.7,97.8,79.3,77.2;ESI-MS m/z:725[M+Na]+.
化合物8o:产率71%;mp 216℃;1H NMR(300MHz,CDCl3)δ:8.01-7.92(2H,m),7.64-7.61(2H,m),5.49(1H,d,J=6Hz),5.38(1H,s),3.82-3.55(6H,m),3.22(1H,d,J=15Hz),2.87(1H,d,J=15Hz),2.62(1H,d,J=18Hz);13C NMR(CDCl3,75MHz)δ:176.6,161.2,151.9,143.2,142.2,140.5,129.1,128.9,128.7,128.6,122.7,94.0,76.4,69.6,61.6;ESI-MS m/z:725[M+Na]+.
化合物8p:产率68%;mp 213℃;1H NMR(300MHz,CDCl3)δ:8.01-7.92(2H,m),7.64-7.61(2H,m),5.50(1H,d,J=9Hz),5.39(1H,s),4.01-3.63(5H,m),3.99-3.49(5H,m),3.21(1H,d,J=18Hz),2.90(1H,d,J=12Hz),2.63(1H,d,J=18Hz);13C NMR(CDCl3,75MHz)δ:176.6,161.1,152.0,143.1,142.2,140.7,129.0,128.9,128.7,128.0,122.9,94.5,76.1;ESI-MS m/z:695[M+Na]+.
化合物8q:产率70%;mp 219℃;1H NMR(300MHz,CDCl3)δ:8.00-7.93(2H,m),7.65-7.63(2H,m),5.44-5.42(2H,m),4.01-3.63(5H,m),3.21(1H,d,J=18Hz),2.90(1H,d,J=13.8Hz),2.63(1H,d,J=18Hz);13C NMR(CDCl3,75MHz)δ:176.3,161.1,151.9,143.0,142.1,140.6,129.1,128.9,128.7,128.6,122.7,94.3,76.2,70.6,67.8,66.3;ESI-MSm/z:695[M+Na]+.
化合物13n:产率71%;mp 215℃;1H NMR(300MHz,C5D5N)δ:11.20(1H,s),9.14(1H,s),8.42(1H,d,J=9Hz),8.05-8.02(1H,m),6.29(1H,d,J=3Hz),5.47(1H,t,J=3Hz),4.70-4.22(5H,m);13C NMR(C5D5N,75MHz)δ:178.1,169.3,147.3,145.7,139.2,131.7,131.0,124.2,118.1,97.8,79.3,77.3,73.0,71.6;ESI-MS(negative)m/z:793[M-H]-.
化合物13o:产率70%;mp 210℃;1H NMR(300MHz,CDCl3)δ:11.16(1H,s),9.12(1H,s),8.28(1H,d,J=9Hz),7.96-7.91(1H,m),5.50(1H,s),5.32(1H,s),3.84-3.64(6H,m);13C NMR(CDCl3,75MHz)δ:176.7,167.1,145.6,143.8,137.6,130.2,129.0,123.7,122.4,116.6,93.9;ESI-MS(negative)m/z:793[M-H]-.
化合物13p:产率71%;mp 171℃;1H NMR(300MHz,C5D5N)δ:11.17(1H,s),9.13(1H,s),8.42(1H,d,J=9Hz),8.03-7.99(1H,m),6.22(1H,d,J=6Hz),5.45(1H,s),4.41-3.83(5H,m);13C NMR(C5D5N,75MHz)δ:178.2,169.2,147.3,145.7,139.2,131.7,124.3,118.1,97.3;ESI-MS(negative)m/z:763[M-H]-.
化合物13q:产率72%;mp 178℃;1H NMR(300MHz,CDCl3)δ:11.16(1H,s),9.12(1H,s),8.29(1H,d,J=9Hz),7.87-7.84(1H,m),5.43(1H,d,J=9Hz),5.37(1H,s),5.32(1H,s),4.02-3.65(5H,m);13C NMR(C5D5N,75MHz)δ:178.2,169.2,147.3,145.7,139.2,131.7,131.0,122.5,118.1,97.8;ESI-MS(negative)m/z:749[M-H]-
实施例9:齐墩果酸衍生物的抗破骨细胞分化作用:
参照文献Takahashi,N.;Akatsu,T.;Udagawa,N.;Sasaki,T.;Yamaguchi,A.;Moseley,J.M.;Martin,T.J.;Suda,T.Endocrinology 1988,123,2600.上的方法,利用小鼠骨髓细胞和成骨细胞的共同培养法。用出生两天的乳小鼠50匹,用70%的酒精消毒后,摘出头盖骨,用含有10%牛血清α-MEM培养基洗净后,用4毫升酶溶液(含有胶原酶Collagenase 0.1%和一种中性蛋白酶Dispase 0.2%的PBS溶液),摄氏37度振荡10分钟,丢弃细胞浮游液。添加4毫升新的酶溶液,摄氏37度振荡10分钟,该操作重复4次,收集每次的细胞浮游液,离心,收集细胞,并用10%牛血清α-MEM培养基稀释到5x106个细胞/培养皿,放入培养皿中,摄氏37度培养3天。培养完后,用Trypsin-EDTA溶液回收细胞,该细胞作为成骨细胞使用。
用6-9周的小鼠3匹,脱臼杀死,用70%的酒精消毒后,摘除胫骨,用剪刀剪去胫骨两端,用25G的针注射器以含有10%牛血清α-MEM培养基从远心端将培养基打入,收集培养液,离心,收集细胞,该细胞作为小鼠骨髓细胞使用。
将成骨细胞(细胞浓度2x104个细胞/毫升)0.5毫升、小鼠骨髓细胞(细胞浓度106个细胞/毫升)0.1毫升、活性维生素D(1α,25(OH)2VD3,10-8M)和本发明各齐墩果酸衍生物放入,共同培养6天,每两天交换培养液一次。
培养完成后,除去培养液,用10%甲醛的磷酸缓冲液2毫升固定细胞,除去固定液,用乙醇-丙酮混和液脱水,干燥。干燥后的培养皿,用AS-MX磷酸盐、酒石酸钠、二甲基甲酰胺、Fast Red Violet LB盐配成的染色液0.5m1室温放置12分钟,染色。2mL蒸馏水洗净后,显微镜观察有3各以上核的细胞。以活性维生素D组作为100%,其他组的数据与其相比教,得出百分数。数字越小活性越强。
结果清楚的表明实施例1-8中得到的各齐墩果酸衍生物,绝大部分化合物在20μM浓度时,对由活性维生素D引起的骨细胞分化显示了较强的抑制作用,其中化合物2a,8a,7k有极其强烈的抑制作用,表中带*的衍生物表示有意差;表2显示在0.2μM浓度时,本发明的齐墩果酸衍生物与目前临床使用的药物Alendronat sodiume相比作用稍强或几乎一样;表3显示了本发明齐墩果酸糖类衍生物也具有良好的活性。
表1.齐墩果酸及其衍生物对破骨细胞分化的作用(20μM)
Compd表示化合物,OCLs(%)为破骨细胞百分数;
Control:细胞与1α,25(OH)2VD3(10-8M)共同培养;
Alendronate sodiume:细胞与1α,25(OH)2VD3(10-8M)和Alendronate sodiume一起培养;
Normal:未加任何试剂;
A-G齐墩果酸母核1及实施例1-8得到的各齐墩果酸衍生物样品:细胞与1α,25(OH)2VD3(10-8M)和样品共同培养。
表中数据均表示为平均值±标准偏差(n=4)。Control作为100%,其他数据均表示为相对于Control的相对值。数据进行t-test分析,与对照组相比有显著差异,*p<0.05, **p<0.01。相对于Normal,#p<0.05。
表2.齐墩果酸及其衍生物对破骨细胞分化的作用
Compd表示化合物,OCLs(%)为破骨细胞百分数;
Control:细胞与1α,25(OH)2VD3(10-8M)共同培养;
Alendronate sodiume:细胞与1α,25(OH)2VD3(10-8M)和Alendronate sodiume一起培养;
Normal:未加任何试剂;
A-G齐墩果酸母核1及实施例1-8得到的各齐墩果酸衍生物样品:细胞与1α,25(OH)2VD3(10-8M)和样品共同培养。
表中数据均表示为平均值±标准偏差(n=4)。Control作为100%,其他数据均表示为相对于Control的相对值。数据进行t-test分析,与对照组相比有显著差异,*p<0.05, **p<0.01。相对于Normal,#p<0.05。
表3.齐墩果酸及其糖苷类衍生物对破骨细胞分化的作用
Compd表示化合物,OCLs(%)为破骨细胞百分数;
Control:细胞与1α,25(OH)2VD3(10-8M)共同培养;
Alendronate sodiume:细胞与1α,25(OH)2VD3(10-8M)和Alendronate sodiume一起培养;
Normal:未加任何试剂;
A-G齐墩果酸母核1及实施例1-8得到的齐墩果酸衍生物样品:细胞与1α,25(OH)2VD3(10-8M)和样品共同培养。
表中数据均表示为平均值±标准偏差(n=4)。Control作为100%,其他数据均表示为相对于Control的相对值。数据进行t-test分析,与对照组相比有显著差异,*p<0.05, **p<0.01。相对于Normal,#p<0.05。
Claims (9)
1.齐墩果酸衍生物,其特征是为A-G齐墩果酸母核的A环衍生物,A-G齐墩果酸母核结构式如下:
所述衍生物包括:
(1)在A-G齐墩果酸母核的A环2,3位引入喹啉环的齐墩果酸衍生物,其结构式如下:
其中R3,R4,R5,R6各自独立为氢、羟基、卤素、直链或支链C1-C8的烷基、羧基、三氟甲基、乙酰基、直链或支链低级烷氧基或氨基,其中直链或者支链C1-C8烷烃为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、异构戊基、异构己基、异构庚基和异构辛基;;
(2)在A-G齐墩果酸母核的A环2,3位引入吡嗪环的齐墩果酸衍生物,其结构式如下:
R7,其中R9,R10,R11,R12各自独立为H,C1-14的烷基,卤素中的F、Cl、Br、I,OH,NH2,OMe,OC2H5,NO2,CN,CF3,COOMe,COPh,COOH,Ph为苯基;或者R7和R8各自独立为H,C1-14的烷基,卤素中的F、Cl、Br、I,OH,NH2,OMe,OC2H5,NO2,CN,CF3,COOMe,COPh,COOH,Ph,Ph为苯基;
(3)在A-G齐墩果酸母核的A环3位引入苯腙的齐墩果酸衍生物,其结构式如下:
其中R12’,R13,R14,R15,R16各自为氢、羟基、卤素、直链或支链C1-C8的烷基、羧基、三氟甲基、乙酰基、直链或支链低级烷氧基或氨基,其中直链或者支链C1-C8烷烃为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、异构戊基、异构己基、异构庚基和异构辛基。
5.齐墩果酸衍生物,其特征是
所述衍生物包括:
(1)在A-G齐墩果酸母核的A环2,3位引入单羰或双羰基的齐墩果酸衍生物:
引入单羰的衍生物R1为羰基,R2为氢,引入双羰基的衍尘物R1和R2都为羰基;
(2)在A-G齐墩果酸母核的A环2,3位引入吲哚环的齐墩果酸衍生物,其结构式如下:
其中R3,R4,R5,R6各自独立为氢、羟基、卤素、直链或支链C1-C8的低级烷基、羧基、三氟甲基、乙酰基、直链或支链低级烷氧基或氨基,其中直链或者支链C1-C8烷烃为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、异构戊基、异构己基、异构庚基和异构辛基;
(3)在A-G齐墩果酸母核的A环2,3位引入喹啉环的齐墩果酸衍生物,其结构式如下:
其中R3,R4,R5,R6各自独立为氢、羟基、卤素、直链或支链C1-C8的低级烷基、羧基、三氟甲基、乙酰基、直链或支链低级烷氧基或氨基;
(4)在A-G齐墩果酸母核的A环2,3位引入吡嗪环的齐墩果酸衍生物,其结构式如下:
R7,其中R9,R10,R11,R12各自独立为H,C1-14的烷基,卤素中的F、Cl、Br、I,OH,NH2,OMe,OC2H5,NO2,CN,CF3,COOMe,COPh,COOH,Ph为苯基;或者R7和R8各自独立为H,C1-14的烷基,卤素中的F、Cl、Br、I,OH,NH2,OMe,OC2H5,NO2,CN,CF3,COOMe,COPh,COOH,Ph,Ph为苯基;
(5)在A-G齐墩果酸母核的A环3位引入苯腙的齐墩果酸衍尘物,其结构式如下:
其中R12’,R13,R14,R15,R16各自为氢、羟基、卤素、直链或支链C1-C8的低级烷基、羧基、三氟甲基、乙酰基、直链或支链低级烷氧基或氨基;
在上述五种衍生物的28位的结构修饰:引入R基团,所述R基团为氨基酸或者糖链,糖在下列种类中选择:半乳糖,氨基半乳糖,木糖,夫糖,果糖,葡萄糖,葡萄糖胺,葡萄糖醛酸,甘露糖,以及唾液酸,得到衍生物:
6.根据权利要求5所述的齐墩果酸衍生物的制备方法,其特征是其中A环3位是羰基的A-G齐墩果酸衍生物的制备:合成A-G齐墩果酸母核,然后将其和氯铬酸吡啶盐在氮气保护下,在二氯甲烷中,室温搅拌,加入乙醚,滤除沉淀,滤液浓缩,硅胶柱分离,得3位是单羰的齐墩果酸衍生物;A环2,3位是双羰基的齐墩果酸衍生物的制备方法为:3-羰基的A-G齐墩果酸母核和二氧化硒在乙酸中加热回流数小时,反应结束后,反应液冷却,过滤,滤液减压浓缩,残留物溶于乙醚,用饱和食盐水洗涤,无水硫酸镁干燥,除去乙醚,得到2,3位双羰基的齐墩果酸衍生物。
8.根据权利要求5所述的齐墩果酸衍生物的制备方法,其特征是:R基团为氨基酸的衍生物的制备方法为:将所述五种A-G齐墩果酸母核的A环衍生物羧基酰化,得到酰氯化合物,同时从氨基酸用SOCl2和MeOH制备氨基酸羧基得到保护的氨基酸甲酯盐酸盐;将酰氯化合物和氨基酸甲酯盐酸盐在Et3N和CH2Cl2的条件下反应,得到氨基酸甲酯衍生物,以4M NaOH,MeOH,THF的条件脱保护,得氨基酸去甲酯衍生物;其中所用的氨基酸为天然存在的所有氨基酸和人工合成的D型氨基酸。
9.权利要求1或5所述的齐墩果酸衍生物在制备抗骨质疏松药物及相关的健康食品中的应用。
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