CN102079772A - Pentacyclic triterpene-13,28-lactone compounds as well as preparation method and application thereof - Google Patents

Pentacyclic triterpene-13,28-lactone compounds as well as preparation method and application thereof Download PDF

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CN102079772A
CN102079772A CN 201010580457 CN201010580457A CN102079772A CN 102079772 A CN102079772 A CN 102079772A CN 201010580457 CN201010580457 CN 201010580457 CN 201010580457 A CN201010580457 A CN 201010580457A CN 102079772 A CN102079772 A CN 102079772A
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ring
group
lactone
compound
hydrogen
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丁晔
张士薄
张奕华
彭司勋
赖宜生
黄张建
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中国药科大学
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Abstract

The invention discloses pentacyclic triterpene-13,28-lactones with antineoplastic activity, shown as a general formula I, or pharmaceutically acceptable salts thereof as well as a preparation method and medical application thereof, belonging to the field of biological medicines. The preparation method of the compounds, provided by the invention, has the advantages of mild reaction conditions, simplicity in operation, higher yield as well as strong practicability and structural universality. Shown by a pharmacologic test result, the compounds provided by the invention have favorable antineoplastic activity and can be applied as an antineoplastic drug in clinic.

Description

一类五环三萜-13,28-内酯化合物、其制备方法和用途 A class of pentacyclic triterpene -13,28- lactone compounds, their preparation and use

技术领域 FIELD

[0001] 本发明涉及药物领域,具体涉及一类五环三萜-13J8-内酯化合物及其制备方法,本发明还进一步涉及它们在制备抗肿瘤药物中的应用。 [0001] The present invention relates to the pharmaceutical field, particularly relates to a class of pentacyclic triterpene -13J8- lactone compound and its preparation method, the present invention further relates to their use in the manufacture of anti-tumor drugs.

背景技术 Background technique

[0002] 齐墩果烷型(oleanane)和乌苏烷型(ursane)等五环三萜类化合物在植物界中分布极为广泛,是许多常用中草药的主要有效成分,具有广泛的生物活性(Neoplasma,2004, 51,327-333)。 [0002] oleanane type (oleanane) and ursane type (ursane) and other pentacyclic triterpenoids extremely widely distributed in the plant kingdom, it is the main active ingredient of many commonly used herbs, have broad biological activity (Neoplasma 2004, 51,327-333). 基于这些天然化合物结构的优化和衍生是天然药物化学研究的热点之一。 And optimization based on these natural compounds derived from one of the hot structure of natural medicine chemistry.

[0003] [0003]

Figure CN102079772AD00071

[0004] 新近研究发现,天然五环三萜类化合物的重要成员-齐墩果烷-13,内酯具有显著的抗肿瘤活性。 [0004] Recent studies have found that an important member of a natural pentacyclic triterpene compound - oleanane -13, lactones have significant anti-tumor activity. 例如,Zhang等从platycodon grandiflorum根中分离的内酯(1,2) 对人食道癌细胞ECA-109显示强效的细胞毒作用(IC5tl分别为0. 93,0. 59 μ Μ) (Molecules, 2007,12,832-841)。 Eg, Zhang et platycodon grandiflorum isolated from root lactone (1,2) on human esophageal cancer cell ECA-109 show potent cytotoxicity (IC5tl respectively 0. 93,0. 59 μ Μ) (Molecules, 2007,12,832-841). Yamaguchi 等从betula ermanii 树皮中提取的内酯(3,4)可作为化学预防剂,具有抑制鼠皮肤癌的发生和发展的作用(Chemistry & Biodiversity,2009,6, 1093-1100)。 Yamaguchi et al extracted from the bark of betula ermanii lactone (3,4) as a chemopreventive agent, inhibiting the occurrence and development of cancer effect Mouse Skin (Chemistry & Biodiversity, 2009,6, 1093-1100). 上述发现引起人们对五环三萜内酯的高度关注和重视。 These findings aroused great concern and attention pentacyclic triterpenoid lactone.

[0005] [0005]

Figure CN102079772AD00072

[0006] [0006]

[0007] [0007]

[0008] 但是,目前研究五环三萜内酯依然存在诸多问题。 [0008] However, the current study pentacyclic triterpenoid lactones are still many problems. 首先,由于此类化合物在天然植物中含量低,很难提供适量及结构多样性的化合物供药效筛选,更难于提供用于临床研究的大量样品;其次,通过化学合成方法来获得这类结构复杂的内酯难度大,且鲜有文献报道。 First, because a low content of such compounds in the native plant, is difficult to provide the appropriate amount of the compound structural diversity and screening for efficacy, more difficult to provide a large number of samples used in clinical studies; secondly, such structures obtained by chemical synthesis methods complex lactone difficult and rarely reported in the literature. 虽有几例应用过氧化物法制备齐墩果烷内酯,但条件非常苛刻。 Although a few embodiments Peroxidase SYSTEM Gather-bearing alkoxy-lactone, but very harsh. 例如,Ali等采用臭氧法合成12位羟基取代的齐墩果烷内酯时需要在_70°C下反应(PhytOChemiStry,2002,60, 295-299.)。 When needed e.g., Ali et synthesis of 12-substituted hydroxy-lactone oleanane method using ozone reaction at _70 ° C (PhytOChemiStry, 2002,60, 295-299.). 再者,采用过氧化物法制备齐墩果烷内酯容易破坏底物结构上的一些敏感基团,如双键、羟基、氨基等。 Further, a peroxide-bearing SYSTEM Gather lactone easily broken sensitive alkoxy groups on the substrate structure, such as a double bond, a hydroxyl group, an amino group and the like. 因此,过氧化物法制备五环三萜内酯的应用范围较窄。 Thus, the application peroxide prepared pentacyclic triterpenoid lactone narrower.

7发明内容 SUMMARY 7

[0009] 本发明首次公开了一类新型五环三萜-13J8-内酯化合物及其制备方法和医药用途。 [0009] The present invention discloses for the first time a novel class of pentacyclic triterpene -13J8- lactone compound and its preparation method and medical use. 与文献报道的过氧化物法相比,本发明化合物的制备方法不仅反应条件温和,不会破坏结构上对过氧化剂敏感的基团和具有活泼氢的基团,而且操作简单、收率较高、副反应很少,易于后处理,同时还具有实用性和普适性。 Compared with the peroxide method reported in the literature, the preparation of compounds of the present invention is not only mild reaction conditions, the oxidizing agent will not damage the structure of the labile groups having an active hydrogen group, and simple, high yield, little reaction, easy post-treatment, but also has practical and universal. 药理实验结果表明,本发明化合物具有优良的抗肿瘤活性,因此,该类化合物在临床上可作为抗肿瘤药物应用。 Pharmacological Experimental results show that the compounds of the present invention have excellent antitumor activity, and therefore, such compounds in clinical applications as anticancer drugs.

[0010] 本发明的目的之一在于提供通式I所示的五环三萜-13,28-内酯化合物或其药学上可接受的盐: [0010] One object of the present invention is to provide a pharmaceutically formula I as pentacyclic triterpene -13,28- lactone compound or a pharmaceutically acceptable salt thereof:

[0011] [0011]

Figure CN102079772AD00081

[0012]其中: [0012] wherein:

[0013] Cl与C2之间为碳碳单键或碳碳双键; [0013] The carbon-carbon single bond or a carbon-carbon double bond between Cl and C2;

[0014] C9与Cll之间为碳碳单键或碳碳双键; Is a carbon-carbon single bond or a carbon-carbon double bond between the [0014] C9 to Cll;

[0015] R1选自氢、羰基氧、羟基、氨基、含1〜8个碳原子的烷氧基、含1〜8个碳原子的酰氧基、3-羧基-1-丙酰氧基、含1〜8个碳原子的酰胺基、肟基、或者与R2形成异噁唑[4, 5-b]环; [0015] R1 is selected from hydrogen, a carbonyl oxygen, a hydroxy group, an amino group containing 1~8 carbon atoms, an alkoxy group having 1~8 carbon atoms, an acyloxy group, a 3-carboxy-1-propionyloxy, an amide group, an oxime group having 1~8 carbon atoms, or form isoxazole [4, 5-b] ring with R2;

[0016] R2选自氢、羰基氧、羟基、氨基、腈基、羟肟基、含1〜8个碳原子的烷氧基、含1〜 8个碳原子的酰氧基、或者与R1形成异噁唑W,5-b]环; [0016] R2 is selected from hydrogen, a carbonyl oxygen, a hydroxy group, an amino group, a nitrile group, a hydroxamic group, an alkoxy group having 1~8 carbon atoms, an acyloxy group having 1 ~ 8 carbon atoms, or forms with R1 isoxazol-W, 5-b] ring;

[0017] [0017]

Figure CN102079772AD00082

[0018] A环为六元碳环,或者A环的C2与C3位断开后扩环形成内酰胺类七元环,或者A 环的C2与C3位开环形成3,4-开环产物; [0018] Ring A is a six membered carbocyclic ring, or ring A is C2 and C3 position after disconnection expandase formed membered ring lactam, C2 or C3 position of the A ring and the ring opening of 3,4-ring-opened product ;

[0019] [0019]

Figure CN102079772AD00083

[0020] B环为六元碳环;[0021] R3选自氢或甲基; [0020] B ring is a six-membered carbocyclic ring; [0021] R3 is selected from hydrogen or methyl;

[0022] R4选自氢或甲基。 [0022] R4 is selected from hydrogen or methyl.

[0023] 具体地说,通式I化合物或其药学上可接受的盐,其特征在于所述通式I化合物 [0023] Specifically, the compound I or a pharmaceutically acceptable salt of the general formula, wherein the compound of formula I

为: for:

[0024] [0024]

Figure CN102079772AD00091

[0025]其中: [0025] wherein:

[0026] R1选自氢、羰基氧、羟基、氨基、含1〜8个碳原子的烷氧基、含1〜8个碳原子的酰氧基、3-羧基-1-丙酰氧基、含1〜8个碳原子的酰胺基、肟基、或者与R2形成异噁唑[4, 5-b]环; [0026] R1 is selected from hydrogen, a carbonyl oxygen, a hydroxy group, an amino group containing 1~8 carbon atoms, an alkoxy group having 1~8 carbon atoms, an acyloxy group, a 3-carboxy-1-propionyloxy, an amide group, an oxime group having 1~8 carbon atoms, or form isoxazole [4, 5-b] ring with R2;

[0027] R2选自氢、羰基氧、羟基、氨基、腈基、羟肟基、含1〜8个碳原子的烷氧基、含1〜 8个碳原子的酰氧基、与R1形成异噁唑W,5-b]环; [0027] R2 is selected from hydrogen, a carbonyl oxygen, a hydroxy group, an amino group, a nitrile group, a hydroxamic group, an alkoxy group having 1~8 carbon atoms, an acyloxy group having 1 ~ 8 carbon atoms, and R1 form a different oxazole-W, 5-b] ring;

[0028] [0028]

Figure CN102079772AD00092

[0029] A环为六元碳环,或者A环的C2与C3位断开后扩环形成内酰胺类七元环,或者A 环的C2与C3位开环形成3,4-开环产物; [0029] Ring A is a six membered carbocyclic ring, or ring A is C2 and C3 position after disconnection expandase formed membered ring lactam, C2 or C3 position of the A ring and the ring opening of 3,4-ring-opened product ;

[0030] [0030]

Figure CN102079772AD00093

[0031] B环为六元碳环; [0031] B ring is a six-membered carbocyclic ring;

[0032] R3选自氢或甲基; [0032] R3 is selected from hydrogen or methyl;

[0033] R4选自氢或甲基。 [0033] R4 is selected from hydrogen or methyl.

[0034] 进一步地,通式I (包括la、lb、Ic)所示的化合物或其药学上可接受的盐,其特征在于: [0034] Further, a compound of Formula I (including la, lb, Ic), or a pharmaceutically acceptable salt thereof shown, wherein:

[0035] R1选自羟基、羰基氧、3-羧基-1-丙酰氧基、乙酰氧基、或者与R2形成异噁唑[4, 5-b]环; [0035] R1 is selected from hydroxy, carbonyloxy, carboxy-1-propionyloxy group, an acetyl group, or with R2 form isoxazole [4, 5-b] ring;

[0036] R2选自氢、腈基、或者与R1形成异噁唑W,5-b]环; [0036] R2 is selected from hydrogen, nitrile group, or with R1 form isoxazol-W, 5-b] ring;

[0037] [0037]

异噁唑【4,5-b】环 Isoxazole [4,5-b] ring

A环扩环形成内酰胺类七元环 A ring formed expandase seven-membered ring lactams

A环开环形成3, 4-开环产物 A ring opening to form a 3-, 4-ring-opened product

Figure CN102079772AD00101

[0038] A环为六元碳环,或者A环的C2与C3位断开后扩环形成内酰胺类七元环,或者A 环的C2与C3位开环形成3,4-开环产物; [0038] Ring A is a six membered carbocyclic ring, or ring A is C2 and C3 position after disconnection expandase formed membered ring lactam, C2 or C3 position of the A ring and the ring opening of 3,4-ring-opened product ;

[0039] [0039]

Figure CN102079772AD00102

[0040] B环为六元碳环; [0040] B ring is a six-membered carbocyclic ring;

[0041] R3选自氢或甲基; [0041] R3 is selected from hydrogen or methyl;

[0042] R4选自氢或甲基。 [0042] R4 is selected from hydrogen or methyl.

[0043] 具体地讲,通式I (包括la、lb、Ic)所示的五环三萜_13,内酯优选自下列化合物: [0043] Specifically, the formula I (including la, lb, Ic) shown pentacyclic triterpenoid _13, lactone compounds preferably selected from the following:

[0044] (1) 3 β -乙酰氧基-12-氧代齐墩果烷-13,28-内酯(化合物编号:Ia_l,下同) [0044] (1) 3 β - acetoxy-12-oxo-oleanane -13,28- lactone (Compound No.: Ia_l, the same below)

[0045] [0045]

Figure CN102079772AD00103

[0046] (2)3 β-羟基-12-氧代齐墩果烷-9(11)-烯-13J8-内酯(Ib-I) [0046] (2) 3 β- hydroxy-12-oxo-oleanane-9 (11) - ene -13J8- lactone (Ib-I)

[0047] [0047]

Figure CN102079772AD00104

[0048] (3) 3,12-二氧代齐墩果烷-9 (11)-烯-13,观-内酯(Ib_2) [0048] (3) 3,12-dioxo-oleanane-9 (11) - ene -13 Concept - lactone (Ib_2)

[0049] [0049]

Figure CN102079772AD00111

[0050] (4) 3 β-(3-羧基-1-丙酰氧基)-12-氧代齐墩果烷-9 (11)-烯-13,内酯(Ib-3) [0050] (4) 3 β- (3- carboxy-1-propionyloxy) -12-oxo-oleanane-9 (11) - ene -13-lactone (Ib-3)

[0051] [0051]

Figure CN102079772AD00112

[0052] (5)3 β-羟基-12-氧代乌苏烷-9(11)-烯-13J8-内酯(Ib_4) [0052] (5) 3 β- ursane-hydroxy-12-oxo-9 (11) - ene -13J8- lactone (Ib_4)

[0053] [0053]

Figure CN102079772AD00113

[0054] (6) 12-氧代异噁唑[4,5-b]齐墩果烷_9 (11)-烯-13,沘-内酯(Ib_5) [0054] (6) isoxazolyl-oxo-12- [4,5-b] _9 Oleanane (11) - ene-13, Bi - lactone (Ib_5)

[0055] [0055]

Figure CN102079772AD00114

[0056] (7) A-扩环-3a_氮杂-12-氧-齐墩果烷-9 (11)-烯-13,观-内酯(Ib_6) [0056] (7) A- expandase -3a_ aza -12- oxo - Oleanane 9 (11) - ene -13 Concept - lactone (Ib_6)

[0057] [0057]

Figure CN102079772AD00121

[0058] (8) 2-腈基-3-失碳-3,4-开环-12-氧-齐墩果烷-9 (11)-烯-13,28-内酯(Ib-7) [0058] (8) 2-3-carbonitrile lost carbon ring opening -12- oxo-3,4 - Oleanane 9 (11) - ene -13,28- lactone (Ib-7)

[0059] [0059]

Figure CN102079772AD00122

[0060] (9) 2-氰基-3,12-二氧代齐墩果烷-1,9(11)-二烯-13,沘-内酯(Ic-I) [0060] (9) 2-cyano-3,12-dioxo-oleanane-1,9 (11) - diene-13, Bi - lactone (Ic-I)

[0061] [0061]

Figure CN102079772AD00123

[0062] 所述的通式I (包括la、lb、Ic)的化合物,进一步优选自2_氰基_3,12-二氧代齐墩果烷-1,9(11)-二烯-13,观-内酯(Ic-I)。 Compound [0062] The Formula I (including la, lb, Ic), and further preferably from cyano _3,12- 2_ Oleanane dioxo-1,9 (11) - diene - 13, concept - lactone (Ic-I).

[0063] 本发明的另一目的在于提供本发明通式I (包括la、lb、Ic)所述化合物的制备方法,其特征为在于,式II所示的五环三萜类化合物在脱氢剂的作用下,脱除C13位的氢和C28位羧基上的氢,生成通式I (包括la、lb、Ic)所示的五环三萜_13,28-内酯化合物: [0063] Another object of the present invention is to provide general formula I according to the present invention (including la, lb, Ic) the preparation of compounds, which is characterized in that, pentacyclic triterpenes in the dehydrogenation of Formula II under the action of the agent, the C13 removal of hydrogen and hydrogen on carboxyl C28 position of general formula I (including la, lb, Ic) _13,28- pentacyclic triterpene lactone compound represented by:

[0064] [0064]

Figure CN102079772AD00124

[0065] 其中,R1、R2、R3和R4的定义如前所述 [0065] wherein, R1, R2, R3 and R4 are as previously defined

[0066] 采用的脱氢剂选自2,3_ 二氯-5,6-二氰苯醌、四氯苯醌、二氧化硒、1,1-二苯基-2-三硝基苯胼、2,2,6,6-四甲基哌啶氮氧自由基或二氧化硒中的一种或多种;采用的反应溶剂为苯、甲苯、二甲苯、二氧六环、乙腈、四氢呋喃、二氯甲烷、氯仿、二氯乙烷、甲醇、 丙酮、乙酸乙酯或N,N-二甲基甲酰胺中的一种或多种;反应温度为50-120°C。 [0066] The dehydrogenating agent used is selected from 2,3_-dichloro-5,6-dicyano-benzoquinone, chloranil, selenium dioxide, 1,1-diphenyl-2-trinitrobenzene corpus, 2,2,6,6-tetramethyl-piperidinyloxy radical or selenium dioxide in one or more of nitrogen; the reaction solvent used is benzene, toluene, xylene, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, dichloroethane, methanol, acetone, ethyl acetate or N, one or more N- dimethyl formamide; reaction temperature is 50-120 ° C.

[0067] 式II所示的五环三萜类化合物(II1〜II9)的合成方法如下: Pentacyclic triterpenoids (II1~II9) synthesis method shown in [0067] Formula II as follows:

[0068] (1) 3 β -乙酰氧基-12-氧代齐墩果烷-28-羧酸(II1) [0068] (1) 3 β - acetoxy-12-oxo-oleanane -28- carboxylic acid (II1)

[0069] 以齐墩果酸(OA)为原料,分别经以8位羧基的苄酯化、C3位羟基的乙酰化、C12位的氧化及U8位脱苄基反应制得式(II1)化合物: [0069] The oleanolic acid (OA) as the raw material, respectively, by 8 bits benzyl esterified carboxy, C3-hydroxyl compound acetylation, C12 and U8 oxidation bit position prepared by debenzylation of formula (II1) :

[0070] [0070]

Figure CN102079772AD00131

[0071] Reagents and conditions : (a) PhCH2Cl ; (b)Ac20 ; (C)H2O2 ; (d)H2, Pd-C. [0071] Reagents and conditions: (a) PhCH2Cl; (b) Ac20; (C) H2O2; (d) H2, Pd-C.

[0072] 0)3 β-羟基-12-氧代齐墩果烷-9(11)-烯-28-羧酸(II2) [0072] 0) 3 β- hydroxy-12-oxo-oleanane-9 (11) - en-28-carboxylic acid (II2)

[0073] 以上述中间体7为原料,分别经C9 (11)位构建双键、C3位脱乙酰基、以8位脱苄基反应制得式(II2)化合物: [0073] In the above-described intermediate 7 as a raw material, respectively, through C9 (11) Construction of the double bond position, C3 deacetylation bit to 8 prepared by debenzylation of formula (II2) compound:

[0074] [0074]

Figure CN102079772AD00132

[0075] Reagents and conditions : (a) Br2, HBr ; (b) KOH ; (c)H2, Pd-C. [0075] Reagents and conditions: (a) Br2, HBr; (b) KOH; (c) H2, Pd-C.

[0076] (3) 3,12-二氧代齐墩果烷-9 (11)-烯-28-羧酸(II3) [0076] (3) 3,12-dioxo-oleanane-9 (11) - en-28-carboxylic acid (II3)

[0077] 以上述中间体9为原料,分别经C3位氧化、以8位脱苄基反应制得式(II3)化合物: [0077] In the above-described intermediate 9 as a raw material, respectively, through the C3 position oxidized to 8 debenzylation of formula to obtain a compound (II3):

[0078][0079] Reagents and conditions : (a) Jones reagent ; (b)H2, Pd-C. [0078] [0079] Reagents and conditions: (a) Jones reagent; (b) H2, Pd-C.

[0080] G) 12-氧代异噁唑W,5_b]齐墩果烷-9 (11)-烯-28-羧酸(II4) [0080] G) 12- oxo-isoxazolyl W, 5_b] Oleanane 9 (11) - en-28-carboxylic acid (II4)

[0081] 以上述中间体10为原料,分别经C2位亲核加成、成环、C28位脱苄基反应制得式(II4)化合物: [0081] In the above-described Intermediate 10 as starting material, were treated with C2 position nucleophilic addition to form a ring compound, C28 position prepared by debenzylation of formula (II4):

[0082] [0082]

Figure CN102079772AD00141

[0083] Reagents and conditions : (a) HCOOC2H5 ; (b) NH2OH · HCl ; (C)H2,Pd-C. [0083] Reagents and conditions: (a) HCOOC2H5; (b) NH2OH · HCl; (C) H2, Pd-C.

[0084] (5) 2-氰基-3,12-二氧代齐墩果烷-1,9(11)-二烯-28-羧基(II5) [0084] (5) 2-cyano-3,12-dioxo-oleanane-1,9 (11) - diene carboxyl -28- (II5)

[0085] 以上述中间体II4为原料,分别经Kemp反应、DDQ脱氢制得式(II5)化合物: [0085] In the above-described intermediate II4 as raw material, respectively, by reaction Kemp, DDQ dehydrogenation of the compound of formula (II5):

[0086] [0086]

Figure CN102079772AD00142

[0087] Reagents and conditions : (a) NaOMe ; (b)DDQ. [0087] Reagents and conditions: (a) NaOMe; (b) DDQ.

[0088] (6) 3 β - (3-羧基-1-丙酰氧基)-12-氧代齐墩果烷_9 (11)-烯_28_羧基(I I6) 化合物: [0088] (6) 3 β - (3- carboxy-1-propionyloxy) -12-oxo Oleanane _9 (11) - ene _28_ carboxyl (I I6) Compound:

[0089] 以上述中间体II2为原料,与丁二酸酐反应制得式(II6)化合物: [0089] In the above-described intermediate II2 as starting material, prepared by reaction of a compound of formula (II6) with succinic anhydride:

[0090] [0090]

Figure CN102079772AD00143

[0091] Reagents and conditions : (a) (CH3CH2CO)2O. [0091] Reagents and conditions: (a) (CH3CH2CO) 2O.

[0092] (7) A-扩环-3a_氮杂-12-氧-齐墩果烷-9 (11)-烯-28-羧基(II7) [0092] (7) A- expandase -3a_ aza -12- oxo - Oleanane 9 (11) - en-28-carboxyl group (the II7)

[0093] 以上述中间体10为原料,分别进行C3位羟肟化,A环扩环,以8位脱苄基反应制得式(II7)化合物: [0093] In the above-described Intermediate 10 as starting material, respectively, the C3 position of hydroxamic, A ring expansion ring, 8 to debenzylation to produce a formula (the II7) compound:

[0094][0095] Reagents and conditions : (a) NH2OH · HCl ; (b)TsCl ; (c)H2, Pd-C. [0094] [0095] Reagents and conditions: (a) NH2OH · HCl; (b) TsCl; (c) H2, Pd-C.

[0096] (8) 2-腈基-3-失碳-3,4-开环_12_氧-齐墩果烷_9 (11)-烯_28_羧基(II8) [0096] (8) 2-3-carbonitrile carbon loss oxo-3,4-ring opening _12_ - Oleanane _9 (11) - ene _28_ carboxy (II8)

[0097] 以上述中间体14为原料,分别进行A环开环,以8位脱苄基反应制得式(II8)化合物: [0097] In the above-described Intermediate 14 as starting material, respectively A ring opening to 8 prepared by debenzylation of formula (II8) compound:

[0098] [0098]

Figure CN102079772AD00151

[0099] [0099]

Figure CN102079772AD00152

[0100] (9)3 β-羟基-12-氧代乌苏烷-9(11)-烯-28-羧基(II9) [0100] (9) 3 β- ursane-hydroxy-12-oxo-9 (11) - en-28-carboxy (II9)

[0101] 以乌苏酸(UA)为原料,分别经以8位羧基的苄酯化、C3位羟基的乙酰化、C12位的氧化、Cll (9)位烯化、C3位脱乙酰基及以8位脱苄基反应制得式(II9)化合物: Acetylation [0101] In ursolic acid (UA) as the raw material, respectively, by 8 bits benzyl esterified carboxy, C3-hydroxyl group, C12 position oxide, Cll (9) bits alkylene, C3-bit deacetylation and to 8 prepared by debenzylation of formula (II9) compound:

[0102] [0102]

Figure CN102079772AD00153

[0103] Reagents and conditions : (a) PhCH2Cl ; (b)Ac20 ; (c) H2O2 ; (d) Br2, HBr ; (e)K0H ; (f)H2, Pd-C. [0103] Reagents and conditions: (a) PhCH2Cl; (b) Ac20; (c) H2O2; (d) Br2, HBr; (e) K0H; (f) H2, Pd-C.

[0104] 本发明的进一步目的在于提供一种含有效剂量的本发明通式I (包括la、lb、Ic)10/19 页 [0104] A further object of the present invention is to provide general formula I containing an effective dose of the present invention (including la, lb, Ic) 10/19 page

化合物和药学上可接受的载体或辅料的药物组合物。 A compound and a pharmaceutically acceptable carrier or excipient in a pharmaceutical composition.

[0105] 本发明化合物可以单独或与一种或一种以上的药学上可接受的载体组合制成制剂以供给药。 [0105] Compounds of the invention may be used alone or pharmaceutically acceptable one or more carriers in combination with a formulation prepared for administration. 例如,溶剂、稀释剂等,可以用口服剂型给药,如片剂、胶囊、可分散粉末、颗粒剂等。 For example, solvents, diluents and the like, may be used for oral dosage forms such as tablets, capsules, dispersible powders, granules and the like. 本发明药物组合物的各种剂型可以按照药学领域中熟知的方法进行制备。 Various dosage forms of the pharmaceutical compositions of the present invention may be prepared according to methods well known in the pharmaceutical art. 这些药用制剂中可以含有与载体组合的例如0. 05%〜90%重量的活性成分,更常见约15%〜60% 之间重量的活性成分。 These pharmaceutical preparations may contain the active ingredient in combination with a carrier, for example, 0.05% by weight of ~ 90%, by weight of the active ingredient more usually between about 15% ~ 60%. 本发明化合物剂量可以是0. 005〜5000mg/kg/天,也可根据疾病严重程度或剂型的不同使用剂量超出此剂量范围。 The present invention may be a compound doses 0. 005~5000mg / kg / day, the dose can be outside of this range depending on the severity of the disease dosage or dosage form.

[0106] 本发明的再一目的是提供本发明代表化合物在制备治疗慢性炎症和肿瘤药物中的应用。 [0106] A further object of the present invention is to provide the representative compound of the invention in the manufacture of chronic inflammation and therapeutic applications in cancer medicine.

[0107] 本发明化合物可以与其他抗肿瘤药物例如烷化剂(如环磷酰胺或顺钼)、抗代谢药(如5-氟尿嘧啶或羟基脲)、拓扑异构酶抑制剂(如喜树碱)、有丝分裂抑制剂(如紫杉醇或长春碱)、DNA插入剂(如阿霉素)联合应用,另外还可以与放射治疗联合应用。 [0107] The compounds of this invention may be other antitumor agents such as alkylating agents (e.g. cyclophosphamide or molybdenum cis), antimetabolites (e.g., 5-fluorouracil or hydroxyurea), topoisomerase inhibitors (e.g., camptothecin ), mitotic inhibitors (e.g. vinblastine or paclitaxel), DNA intercalators combination (e.g., doxorubicin), also may be combined with radiation therapy. 这些其他抗肿瘤药物或放射治疗可以与本发明化合物同时或在不同时间给予。 These other anticancer drugs or radiation therapy may be administered simultaneously or with a compound of the present invention at different times. 这些联合治疗可以产生协同作用从而有助于改善治疗效果。 The combination therapy may work synergistically in order to help improve the therapeutic effect.

[0108] 下面是本发明的代表化合物的部分药理试验及结果: [0108] The following compounds are representative of the portion of the pharmacological test results and the present invention:

[0109] 四甲基氮唑蓝比色法体外抗肿瘤试验 [0109] Methyl thiazolyl tetrazolium blue assay in vitro Antitumor test

[0110] 按常规采用四甲基氮唑蓝比色法(MTT)评价本发明化合物对7种人癌细胞株的抗增殖活性。 [0110] using a conventional colorimetric Methyl thiazolyl tetrazolium blue (MTT) Evaluation of antiproliferative activity of the compounds of the present invention, seven human cancer cell lines. MTT法已广泛用于大规模的抗肿瘤药物筛选、细胞毒性试验以及肿瘤放射敏感测定等。 MTT assay has been widely used in large-scale screening of anticancer drugs, as well as tumor cytotoxicity assay measuring radiation sensitive like. 选择目前处于II期临床试验治疗胰腺癌和慢性肾病的CDDO-Me (RTA-402, bardoxolone methyl)作为阳性对照药。 Select currently in clinical trials for pancreatic cancer and chronic kidney disease II CDDO-Me (RTA-402, bardoxolone methyl) as a positive control drug. 值得指出的是,⑶DO-Me是目前临床研究最为深入、 生物活性最强的一个五环三萜化合物,权威杂志曾专门对其进行过综述(Nature Reviews Cancer,2007,7,357-69)。 It is worth noting, ⑶DO-Me is the most in-depth clinical studies, the strongest biological activity of a pentacyclic triterpenoids, authoritative magazine has been dedicated to be reviewed (Nature Reviews Cancer, 2007,7,357-69).

[0111] 人癌细胞株:肝癌细胞H印G2、SMMC-7721、BEL-7402、宫颈癌细胞Hela、乳腺癌细胞MCF-7、肺癌细胞H460和黑色素瘤细胞A-375。 [0111] human cancer cell lines: HCC cell H printed G2, SMMC-7721, BEL-7402, cervical cancer cell Hela, breast cancer cell line MCF-7, lung cancer cells H460 and melanoma cells A-375.

[0112] 人正常细胞:肝细胞L02。 [0112] normal human cells: liver cell L02.

[0113] 实验方法如下:取处于指数生长期状态良好的细胞一瓶,加入0. 25 %胰蛋白酶消化,使贴壁细胞脱落,制成每毫升含5X IO4〜7 X IO4个细胞的悬液。 [0113] Experiment method is as follows: taking the exponential growth phase in a good state of the cell bottle, was added 0.25% trypsin the adherent cells off to prepare a suspension containing per ml 5X IO4~7 X IO4 cells of . 取细胞悬液接种于96孔板上,每孔100 μ L,置恒温CO2培养箱中培养M小时。 Cell suspension were seeded in 96-well plates, 100 μ L per well, set the thermostat M h CO2 incubator. 换液,加入受试化合物(化合物用DMSO溶解后用培养液稀释,受试化合物浓度分别为5Χ 10_5,1. 25Χ 10_5,3. 125Χ 10_6, 7. 812Χ 1(Γ7,1. 953Χ l(T7mol/L),每孔200 μ L,培养48 小时。将MTT (浓度为5mg/mL)加入96孔板中,每孔20 μ L,培养箱中反应4小时。吸去上清液,加入DMS0,每孔150 μ L,平板摇床上振摇5分钟。用酶联免疫检测仪在波长为570nm处测定每孔的吸收度,计算细胞抑制率。实验结果如表1所示。 Was changed, was added the test compound (the compound dissolved in DMSO was diluted with the culture solution, the concentration of the test compound were 5Χ 10_5,1. 25Χ 10_5,3. 125Χ 10_6, 7. 812Χ 1 (Γ7,1. 953Χ l (T7mol / L), each well 200 μ L, for 48 hours. the MTT (at a concentration of 5mg / mL) was added a 96 well plate, each well 20 μ L, incubator for 4 hours. the supernatant was aspirated and added DMS0 , each well 150 μ L, shaker plate shaken for 5 minutes with the ELISA to 570nm at a wavelength of absorption of each well is measured to calculate the inhibition rate. the results shown in table 1.

[0114] 细胞抑制率=(阴性对照组OD值-受试物组OD值)/阴性对照组OD值X 100 %。 [0114] Cell inhibition ratio = (OD value of negative control - OD value of the test substance group) / OD value of the negative control group X 100%.

[0115] 表1本发明代表化合物对部分肿瘤细胞增殖的抑制活性(IC5tl,μ mol/L) [0115] TABLE 1 Representative compounds of the invention on the inhibition of tumor cell proliferation activity (IC5tl, μ mol / L)

[0116]Compound HepG2 SMMC-7721 Bel-7402 Hela MCF-7 H460 A-375 L02CDDO-Me 1.57 4.14 1.31 1.73 3.05 2.79 1.41 3.24^Ia-I 45.85 48.91 >50 >50 >50 >50 >50 >50Ibl >50 >50 44.55 >50 >50 41.23 >50 45.61Ib-2 38.58 >50 47.78 >50 48.91 >50 45.68 39.45Ib-3 49.46 >50 >50 43.33 >50 31.23 >50 40.23Ib-4 39.91 >50 35.66 39.42 42.39 47.99 >50 >50Ib-5 >50 32.29 >50 47.76 42.33 >50 36.88 >50Ib-6 >50 >50 39.96 >50 35.68 >50 >50 >50Ib-7 >50 48.8 >50 >50 44.5 >50 >50 >50Ic-I 2.58 9.04 2.13 5.37 3.70 10.58 2.30 7.59 [0116] Compound HepG2 SMMC-7721 Bel-7402 Hela MCF-7 H460 A-375 L02CDDO-Me 1.57 4.14 1.31 1.73 3.05 2.79 1.41 3.24 ^ Ia-I 45.85 48.91> 50> 50> 50> 50> 50> 50Ibl> 50 > 50 44.55> 50> 50 41.23> 50 45.61Ib-2 38.58> 50 47.78> 50 48.91> 50 45.68 39.45Ib-3 49.46> 50> 50 43.33> 50 31.23> 50 40.23Ib-4 39.91> 50 35.66 39.42 42.39 47.99 > 50> 50Ib-5> 50 32.29> 50 47.76 42.33> 50 36.88> 50Ib-6> 50> 50 39.96> 50 35.68> 50> 50> 50Ib-7> 50 48.8> 50> 50 44.5> 50> 50> 50Ic -I 2.58 9.04 2.13 5.37 3.70 10.58 2.30 7.59

[0117] 一系列肿瘤细胞测试结果表明,化合物Ic-I具有广谱的抗肿瘤作用,其IC5tl值均处于微摩尔级别。 [0117] The test results show a series of tumor cells, Compound Ic-I have a broad spectrum of anti-tumor effect, which values ​​are in IC5tl micromolar level. 其中,Ic-I对H印G2、Bel-7402、MCF-7、A-375等细胞的作用尤其突出,与阳性对照药⑶DO-Me活性相当。 Wherein, Ic-I H India particularly prominent role G2, Bel-7402, MCF-7, A-375 cells and the like, and the positive control drug ⑶DO-Me considerable activity. 与此同时,Ic-I对正常细胞L02的毒性则低于⑶D0_Me。 Meanwhile, Ic-I toxicity to normal cells L02 below ⑶D0_Me.

具体实施方式 Detailed ways

[0118] 为了进一步阐明本发明,下面给出一系列实施例,这些实施例完全是例证性的,它们仅用来对本发明具体描述,不应当理解为对本发明的限制。 [0118] To further clarify the present invention, the following series of examples are given, these embodiments are purely illustrative, they are only used detailed description of the present invention should not be construed as limiting the present invention.

[0119] 实施例1 [0119] Example 1

[0120] 3 β -羟基齐墩果烷-12-烯-28-羧酸苄酯(5)的制备 Hydroxyl Oleanane -28- 12-ene-carboxylic acid benzyl ester (5) - 3 β [0120]

[0121]将齐墩果酸(100g,220mmol)和碳酸钾(61g,440mmol)置于 DMF(800mL)中,于50〜55 °C下20分钟内滴加氯化苄(33mL,290mmO 1),滴加完毕后维持该温度继续反应3〜4小时,将反应液冷至室温,过滤,滤饼以DMF(50mLX3)洗涤,得到的母液倾入冰水中(3000mL)中,有大量白色固体析出,静置待固体颗粒变大后,抽滤,用水充分洗涤,干燥得白色固体5(114g,95. 5% )。 [0121] The oleanolic acid (100g, 220mmol) and potassium carbonate (61g, 440mmol) was placed DMF (800mL), the at 50~55 ° C was added dropwise over 20 minutes benzyl chloride (33mL, 290mmO 1) after dropwise addition maintaining the temperature and reaction was continued for 3 to 4 hours, the reaction was cooled to room temperature, filtered, the filter cake in DMF (50mLX3) washing the resulting mother liquor was poured into ice water (3000 mL of), a large amount of white solid precipitated and allowed to stand until the solid particles were larger, filtered off with suction, washed well with water, and dried to give a white solid 5 (114g, 95. 5%). 化合物5是已知化合物,其CAS号为303114-51-4。 Compound 5 is a known compound CAS Number 303114-51-4.

[0122] 实施例2 [0122] Example 2

[0123] 3 β -乙酰氧基齐墩果烷-12-烯-28-羧酸苄酯(6)的制备 Preparation acetoxy Oleanane -28- 12-ene-carboxylic acid benzyl ester (6) - 3 β [0123]

[0124] 将化合物5(5.46g,10mmol)溶于吡啶(20mL)中,0°C缓慢滴加乙酸酐(10. 2g, 1 OOmmol),滴加完毕后加入DMAP (0. 12g,Immo 1),有固体析出,室温下继续反应1〜2小时, 加入适量二氯甲烷(50mL)溶解,溶液用5%稀盐酸溶液,饱和碳酸氢钠溶液,饱和食盐水溶液各洗涤3次,无水硫酸钠干燥,减压去除溶剂后得白色固体6(5. 4g,91. 3%)0化合物6 是已知化合物,CAS号为357953-27-6。 [0124] Compound 5 (5.46g, 10mmol) was dissolved in pyridine (20mL) in a, 0 ° C was slowly added dropwise acetic anhydride (10. 2g, 1 OOmmol), was added DMAP (0. 12g After the addition was complete, Immo 1 ), solid was precipitated, the reaction was continued at room temperature for 1 to 2 hours, add appropriate amount of dichloromethane (50mL) was dissolved, and the solution washed with 5% dilute hydrochloric acid solution, saturated sodium bicarbonate solution, washed with a saturated saline solution three times each, dried over anhydrous sulfate sodium sulfate, and the solvent removed under reduced pressure to give a white solid 6 (5. 4g, 91. 3%) 0 compound 6 is a known compound, CAS number is 357953-27-6.

[0125] 实施例3 [0125] Example 3

[0126] 3 β -乙酰氧基-12-氧代齐墩果烷-28-羧酸苄酯(7)的制备 Preparation of 12-oxo-acetoxy Oleanane -28- carboxylic acid benzyl ester (7) - 3 β [0126]

[0127] 将化合物6 (5. 88g,IOmmol)溶于适量二氯甲烷(50mL),加入甲酸(IOmL), H2O2 (1. 36g,40mmol),室温反应M小时,TLC监测反应进程,待原料点消失后,用饱和碳酸氢钠溶液将反应液洗至近中性,饱和食盐水溶液洗涤3次,无水硫酸钠干燥,减压去除溶剂后得浅黄色固体,AcOH-H2O重结晶得白色固体7(4. 7g,78% )。 [0127] Compound 6 (5. 88g, IOmmol) was dissolved in an appropriate amount of dichloromethane (50 mL), was added formic acid (IOmL), H2O2 (1. 36g, 40mmol), rt M h, TLC monitored the reaction progress until the starting material after point disappears, the reaction with saturated sodium bicarbonate solution, washed to near neutral solution, three times with saturated brine solution, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure to give a pale yellow solid, AcOH-H2O to give a white solid was recrystallized from 7 (4. 7g, 78%). 化合物7是已知化合物,CAS 号为;357953-28-7。 Compound 7 is a known compound, CAS number of; 357953-28-7.

[0128] 实施例4 [0128] Example 4

[0129] 3β-乙酰氧基-12-氧代齐墩果烷-28-羧酸(II1)的制备 Preparation of [0129] 3β- acetoxy-12-oxo-oleanane -28- carboxylic acid (II1) of

[0130] 化合物7(0. 6g,lmmol)溶于适量四氢呋喃(15mL),加入催化量的钯碳(0. 06g),常温常压下与氢气反应制得白色固体II1O). 50g,98% )。 [0130] Compound 7 (0. 6g, lmmol) was dissolved in an appropriate amount in tetrahydrofuran (15mL), a catalytic amount of palladium on carbon (0. 06g), as a white solid II1O reaction with hydrogen at ambient temperature and pressure). 50g, 98% ). 化合物II1是已知化合物,CAS号为357953-29-8。 Compound II1 is a known compound, CAS number is 357953-29-8.

[0131] 实施例5 [0131] Example 5

[0132] 3β-乙酰氧基-12-氧代齐墩果烷-9(11)-烯-28-羧酸苄酯(8)的制备 Preparation en-28-carboxylic acid benzyl ester (8) - acetoxy-12-oxo-oleanane -9 (11) [0132] 3β-

[0133] 将化合物7(6. 04g, 1 Ommol)溶于乙酸(300mL)中,滴加催化量的氢溴酸(40%,乙酸)溶液,加热至40〜45°C,缓慢滴加液溴(1.6g,10mmOl)的乙酸溶液,滴加完毕后,搅拌片刻,另加液溴(3.2g,20mmol)的乙酸溶液,室温下反应M小时。 [0133] Compound 7 (6. 04g, 1 Ommol) dissolved in acetic acid (300 mL) was added dropwise a catalytic amount of hydrobromic acid (40% acetic acid) was heated to 40~45 ° C, was slowly added dropwise bromine (1.6g, 10mmOl) in acetic acid, after completion of the dropwise addition, stirred for a while, plus liquid bromine (3.2g, 20mmol) in acetic acid, the reaction M hour at room temperature. 反应结束后,将溶液倾入冰水中,收集析出固体,分别用饱和亚硫酸钠溶液,水洗涤,烘干,得淡黄色粗品,甲醇重结晶,得白色固体8(4. 39g,79.8% )。 After completion of the reaction, the solution was poured into ice water, the precipitated solid was collected, were washed with a saturated sodium sulfite solution, washed with water and dried to give a pale yellow crude product was recrystallized from methanol to give a white solid 8 (4. 39g, 79.8%).

[0134] mp 216-218°C ; [0134] mp 216-218 ° C;

[0135] ESI-MS :603[M+H]+ ; [0135] ESI-MS: 603 [M + H] +;

[0136] 1HNMR(300M Hz, CDCl3, 25°C,TMS) : δ 7. 34-7. 26 (m, 5Η), 5. 7 (s, 1Η), 5. 16 (d, J = 12. 6Hz,1Η),5· 11 (d, J = 12. 6Hz, 1Η) ,4. 46 (m, 1Η), 3. 03 (m, 1Η), 2. 93 (d, J = 4. 5Ηζ,1Η), 2. 05(s,3H),2· 01,1. 57,1. 16,1. 00,0. 95,0. 92,0. 89 (s, each 3Η) ppm. [0136] 1HNMR (300M Hz, CDCl3, 25 ° C, TMS):. Δ 7. 34-7 26 (m, 5Η), 5. 7 (s, 1Η), 5. 16 (d, J = 12. 6Hz, 1Η), 5 · 11 (d, J = 12. 6Hz, 1Η), 4. 46 (m, 1Η), 3. 03 (m, 1Η), 2. 93 (d, J = 4. 5Ηζ, 1Η), 2. 05 (s, 3H), 2 · 01,1. 57,1. 16,1. 00,0. 95,0. 92,0. 89 (s, each 3Η) ppm.

[0137] 实施例6 [0137] Example 6

[0138] 3β_羟基-12-氧代齐墩果烷-9(11)-烯-28-羧酸苄酯(9)的制备 Preparation en-28-carboxylic acid benzyl ester (9) - [0138] 3β_-hydroxy-12-oxo-oleanane-9 (11)

[0139]将化合物 8(6. 02g,IOmmol),氢氧化钾(33. 6g,600mmol)溶于甲醇(300mL),加入回流30〜45分钟,减压去除溶剂,剩余固体用6mol/L的稀盐酸溶液洗至近中性,水层用二氯甲烷(lOOmLX;?)提取,有机层用饱和碳酸氢钠溶液,饱和食盐水溶液各洗涤3次,无水硫酸钠干燥,减压去除溶剂后得白色固体9(5. 32g,95%)0 [0139] Compound 8 (6. 02g, IOmmol), potassium hydroxide (33. 6g, 600mmol) was dissolved in methanol (300 mL), was added at reflux for 30~45 minutes, the solvent was removed under reduced pressure, the residual solid was 6mol / L of solution was washed with dilute hydrochloric acid to nearly neutral aqueous layer was extracted with dichloromethane (lOOmLX ;?), the organic layer was washed with saturated sodium bicarbonate solution, saturated saline solution was washed 3 times each, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure to give as a white solid 9 (5. 32g, 95%) 0

[0140] mp 197-198°C ; [0140] mp 197-198 ° C;

[0141] ESI-MS m/z :561[M+H]+; [0141] ESI-MS m / z: 561 [M + H] +;

[0142] 1HNMR(300M Hz, CDCl3, 25°C,TMS) : δ 7. 34-7. 26 (m, 5H), 5. 7 (s, 1H), 5. 16 (d, J = 12. 6Hz, 1Η),5. 11 (d, J = 12. 6Hz, 1Η),3. 22-3. 17 (m, 1Η),3. 03 (m, 1Η),2. 25 (d, J = 4. 5Ηζ, 1Η),1· 14,1. 02,1. 00,0. 96,0. 92,0. 89,0. 81 (s, each 3Η)ppm. [0142] 1HNMR (300M Hz, CDCl3, 25 ° C, TMS):. Δ 7. 34-7 26 (m, 5H), 5. 7 (s, 1H), 5. 16 (d, J = 12. 6Hz, 1Η), 5. 11 (d, J = 12. 6Hz, 1Η), 3. 22-3. 17 (m, 1Η), 3. 03 (m, 1Η), 2. 25 (d, J = 4. 5Ηζ, 1Η), 1 · 14,1. 02,1. 00,0. 96,0. 92,0. 89,0. 81 (s, each 3Η) ppm.

[0143] 实施例7 [0143] Example 7

[0144] 3β_羟基-12-氧代齐墩果烷-9(11)-烯-28-羧酸(II2)的制备 Preparation en-28-carboxylic acid (II2) is - [0144] 3β_-hydroxy-12-oxo-oleanane-9 (11)

[0145] 参照II1的制备方法,由化合物9与钯碳、氢气反应制得白色固体II2,收率98%。 [0145] Referring to the production method II1, II2 white solid from Compound 9 and palladium on carbon, hydrogen reaction, yield 98%.

[0146] mp 294-296 °C ; [0146] mp 294-296 ° C;

[0147] ESI-MS m/z :469 [Μ—ΗΓ ; [0147] ESI-MS m / z: 469 [Μ-ΗΓ;

[0148] 1HNMR (300M Hz, CDCl3, 25 °C,TMS) : δ 5. 8 (s,1H),3. 24 (m,1H),3. 19 (m,1H), 2. 93 (d, J = 4. 5Hz, 1H),1. 25,1. 17,1. 03,1. 00,1. 00,0. 89,0. 83 (s, each 3H) ppm. [0148] 1HNMR (300M Hz, CDCl3, 25 ° C, TMS): δ 5. 8 (s, 1H), 3 24 (m, 1H), 3 19 (m, 1H), 2. 93 (d.. , J = 4. 5Hz, 1H), 1. 25,1. 17,1. 03,1. 00,1. 00,0. 89,0. 83 (s, each 3H) ppm.

[0149] 实施例8 [0149] Example 8

[0150] 3,12-二氧代齐墩果烷-9(11)-烯-28-羧酸苄酯(10)的制备[0151] 将化合物9 (5. 6g,IOmmo 1)溶于丙酮QOOmL)中,0°C下缓慢滴加琼斯试剂(3. 8mL),滴加完毕后室温反应10〜20分钟,TLC监测反应进程,待原料点消失后,减压去除溶剂,加水至残留物中,用二氯甲烷(100mLX3)提取,有机层用饱和碳酸氢钠溶液,饱和食盐水溶液各洗涤3次,无水硫酸钠干燥,减压去除溶剂后得淡棕色固体,快速硅胶柱层析制得白色固体10 (4. 9g,88% )。 [0150] 3,12-dioxo-oleanane-9 (11) - en-28-carboxylic acid benzyl ester was prepared (10) [0151] Compound 9 (5. 6g, IOmmo 1) was dissolved in acetone QOOmL), the 0 ° C under Jiaqiong Si reagent was slowly added dropwise (3. 8mL), after the addition was complete the reaction at room temperature 10-20 min, TLC monitoring progress of the reaction, until the disappearance of starting material point, the solvent was removed under reduced pressure, water was added to the residue extracted with dichloromethane (100 ml x 3), the organic layer was washed with saturated sodium bicarbonate solution, saturated saline solution was washed 3 times each, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure to give a pale brown solid, manufactured by column chromatography on flash silica gel to give a white solid 10 (4. 9g, 88%).

[0152] mp 146-147°C ; [0152] mp 146-147 ° C;

[0153] ESI-MS m/z :559[M+H]+ ; [0153] ESI-MS m / z: 559 [M + H] +;

[0154] 1HNMR(300M Hz, CDCl3, 25°C,TMS) : δ 7. 38-7. 28 (m, 5H), 5. 8 (s, 1H), 5. 16 (d, J = 12. 6Ηζ,1Η),5· 11 (d, J = 12. 6Ηζ,1Η,),3· 06 (m,1Η),2· 78 (d, J = 4. 5Ηζ,1Η),2· 66,2. 49, 2. 17 (m, each 1Η),1. 26,1. 11,1. 07,1. 00,0. 97,0. 95,0. 89 (s, each 3H) ppm. [0154] 1HNMR (300M Hz, CDCl3, 25 ° C, TMS):. Δ 7. 38-7 28 (m, 5H), 5. 8 (s, 1H), 5. 16 (d, J = 12. 6Ηζ, 1Η), 5 · 11 (d, J = 12. 6Ηζ, 1Η,), 3 · 06 (m, 1Η), 2 · 78 (d, J = 4. 5Ηζ, 1Η), 2 · 66,2 . 49, 2. 17 (m, each 1Η), 1. 26,1. 11,1. 07,1. 00,0. 97,0. 95,0. 89 (s, each 3H) ppm.

[0155] 实施例9 [0155] Example 9

[0156] 3,12-二氧代齐墩果烷-9(11)-烯-28-羧酸(II3)的制备 Preparation en-28-carboxylic acid (II3) - A oleanane dioxo-9 (11) [0156] 3,12

[0157] 参照II1的制备方法,由化合物10与钯碳、氢气反应制得白色固体113,收率98%。 [0157] Referring to Preparation II1 is prepared from compound 10 with palladium on carbon, the reaction of hydrogen 113 as a white solid, yield 98%.

[0158] mp 264-268 °C ; [0158] mp 264-268 ° C;

[0159] ESI-MS m/z :469 [M+H]+ ; [0159] ESI-MS m / z: 469 [M + H] +;

[0160] 1HNMR(300M Hz,CDCl3, 25°C,TMS) : δ 5. 8(s, 1H),3· 02 (m, 1H),2· 93 (d, J = 4. 8Hz, 1H),2. 66,2. 49,2. 22 (m, each 1H),1. 30,1. 29,1. 25,1. 23,1. 19,1. 13,1. 09 (s, each 3H) ppm. [0160] 1HNMR (300M Hz, CDCl3, 25 ° C, TMS): δ 5. 8 (s, 1H), 3 · 02 (m, 1H), 2 · 93 (d, J = 4. 8Hz, 1H) , 2. 66,2. 49,2. 22 (m, each 1H), 1. 30,1. 29,1. 25,1. 23,1. 19,1. 13,1. 09 (s, each 3H) ppm.

[0161] 实施例10 [0161] Example 10

[0162] 2-羟次甲基-3,12-二氧代齐墩果烷-9(11)-烯-28-羧酸苄酯(11)的制备 Preparation en-28-carboxylic acid benzyl ester (11) - [0162] 2-hydroxy-3,12-dioxo-methine Oleanane 9 (11)

[0163] 将化合物10(5. 58g,10mmol)溶于干燥的二氯甲烷中,0°C加入新制甲醇钠(3. Mg,60mmol),形成混悬液,搅拌片刻后,缓慢滴加甲酸乙酯(3. 33g,45mmol),室温反应12小时,反应结束后,0°C下调节反应液pH值至中性,二氯甲烷稀释,有机层用饱和碳酸氢钠溶液,饱和食盐水溶液各洗涤3次,无水硫酸钠干燥,减压去除溶剂后得淡黄色固体,经快速硅胶柱层析制得白色固体11(5. 3g,90. 2% )。 After [0163] Compound 10 (5. 58g, 10mmol) was dissolved in dry dichloromethane, 0 ° C was added freshly prepared sodium methoxide (3. Mg, 60mmol), to form a suspension, stirring the mixture was slowly added dropwise formic acid ethyl ester (3. 33g, 45mmol), at room temperature for 12 hours. after completion of the reaction, the reaction solution pH was adjusted to 0 ° C under neutral, diluted with dichloromethane, the organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution each washed 3 times, dried over anhydrous sodium sulfate, and under reduced pressure to give a light yellow solid after removal of the solvent, by flash silica gel chromatography as a white solid 11 (5. 3g, 90. 2%).

[0164] mp 110-114°C ; [0164] mp 110-114 ° C;

[0165] ESI-MS :587 [M+H]+ ; [0165] ESI-MS: 587 [M + H] +;

[0166] 1HWRGOOm Hz, CDCl3, 25 "C, TMS) : δ 14. 85 (d, J = 2. 4Hz, 1H) ,8. 75 (s, 1H), 7. 34-7. 26(m,5H) ,5. 7(s, 1H), 5. 16 (d, J = 12. 6Ηζ,1Η),5· 11 (d, J = 12. 6Ηζ,1Η),3· 03 (m, 1H),2. 83 (d, J = 4. 5Hz, 1H),2. 61 (d, J = 14. 4Hz, 1H),2. 25 (d, J = 14. 4Hz, 1H),1. 24, 1. 15,1. 14,1. 01,0. 98,0. 94,0. 85 (s, each 3H) ppm. [0166] 1HWRGOOm Hz, CDCl3, 25 "C, TMS): δ 14. 85 (d, J = 2. 4Hz, 1H), 8 75 (s, 1H), 7. 34-7 26 (m,.. 5H), 5. 7 (s, 1H), 5. 16 (d, J = 12. 6Ηζ, 1Η), 5 · 11 (d, J = 12. 6Ηζ, 1Η), 3 · 03 (m, 1H) , 2. 83 (d, J = 4. 5Hz, 1H), 2. 61 (d, J = 14. 4Hz, 1H), 2. 25 (d, J = 14. 4Hz, 1H), 1. 24, 1. 15,1. 14,1. 01,0. 98,0. 94,0. 85 (s, each 3H) ppm.

[0167] 实施例11 [0167] Example 11

[0168] 12-氧代异噁唑W,5_b]齐墩果烷-9 (11)-烯-28-羧酸苄酯(12)的制备 [0168] isoxazole-oxo-12- W, oleanane -9 (11) 5_b] - Preparation en-28-carboxylic acid benzyl ester (12)

[0169]将化合物 11(5. 8g,IOmmol),盐酸羟胺(6. 95g, IOOmmol)溶于乙醇(100mL,95%), 加热回流1小时,反应完毕,浓缩,残留物乙酸乙酯(50mL)溶解,有机层用饱和碳酸氢钠溶液,饱和食盐水溶液各洗涤3次,无水硫酸钠干燥,减压去除溶剂后得白色固体12(4. Sg, 82. 7% )。 [0169] Compound 11 (5. 8g, IOmmol), hydroxylamine hydrochloride (6. 95g, IOOmmol) was dissolved in ethanol (100mL, 95%), refluxed for 1 hour, completion of the reaction, concentrated and the residue was ethyl acetate (50 mL ) was dissolved, and the organic layer was washed with saturated sodium bicarbonate solution, saturated saline solution was washed 3 times each, dried over anhydrous sodium sulfate, and under reduced pressure to give a white solid 12 (4. Sg, 82. 7% after removal of the solvent).

[0170] mp 120-122V ; [0170] mp 120-122V;

[0171] ESI-MS :584 [M+H]+; [0171] ESI-MS: 584 [M + H] +;

19[0172] 1HNMR(300M Hz, CDCl3, 25°C,TMS) : δ 8. 05 (s, 1H), 7. 34-7. 26 (m, 5H), 5. 8 (s, 1H), 5. 16 (d, J = 12. 6Hz, 1H),5. 11 (d, J = 12. 6Hz, 1H),3. 10 (m, 1H),2. 80 (d, J = 4. 5Hz, 1H), 2. 75 (d, J = 15Hz, 1H),3. 38 (d, J = 15Hz, 1H),1. 37,1. 26,1. 12,1. 01,0. 99,0. 95,0. 90 (s, each 3H) ppm. 19 [0172] 1HNMR (300M Hz, CDCl3, 25 ° C, TMS):. Δ 8. 05 (s, 1H), 7. 34-7 26 (m, 5H), 5. 8 (s, 1H), 5. 16 (d, J = 12. 6Hz, 1H), 5. 11 (d, J = 12. 6Hz, 1H), 3. 10 (m, 1H), 2. 80 (d, J = 4. 5Hz , 1H), 2. 75 (d, J = 15Hz, 1H), 3. 38 (d, J = 15Hz, 1H), 1. 37,1. 26,1. 12,1. 01,0. 99, 0. 95,0. 90 (s, each 3H) ppm.

[0173] 实施例12 [0173] Example 12

[0174] 12-氧代异噁唑W,5_b]齐墩果烷-9 (11)-烯-28-羧酸(H4)的制备 [0174] isoxazole-oxo-12- W, 5_b] Oleanane 9 (11) - en-28-carboxylic acid was prepared (H4) of

[0175] 参照II1的制备方法,由化合物12与钯碳、氢气反应制得白色固体114,收率98%。 [0175] Referring to Preparation II1 is prepared from compound 12 with palladium on carbon, the reaction of hydrogen 114 as a white solid, yield 98%.

[0176] mp 224-226 °C ; [0176] mp 224-226 ° C;

[0177] ESI-MS :492 [Μ-ΗΓ ; [0177] ESI-MS: 492 [Μ-ΗΓ;

[0178] 1HNMR (300M Hz, CDCl3, 25 °C,TMS) : δ 8. 05 (s,1H),5. 8 (s,1H),3. 03 (m,1H), 2. 93 (d, J = 4. 5Hz, 1H),2. 78 (d, J = 15. 3Hz, 1H),2. 40 (d, J = 15. 3Hz, 1H),1. 35,1. 31, [0178] 1HNMR (300M Hz, CDCl3, 25 ° C, TMS):.. Δ 8. 05 (s, 1H), 5 8 (s, 1H), 3 03 (m, 1H), 2. 93 (d , J = 4. 5Hz, 1H), 2. 78 (d, J = 15. 3Hz, 1H), 2. 40 (d, J = 15. 3Hz, 1H), 1. 35,1. 31,

1. 26,1. 16,1. 01,0. 97,0. 85 (s, each 3H) ppm. 1. 26,1. 16,1. 01,0. 97,0. 85 (s, each 3H) ppm.

[0179] 实施例13 [0179] Example 13

[0180] 2-氰基-3-羟基-12-氧代齐墩果烷-2,9(11)-二烯-28-羧酸(1¾的制备 Preparation of carboxylic acid-diene -28- (1¾ of - [0180] 2-cyano-3-hydroxy-12-oxo-oleanane-2,9 (11)

[0181] 将化合物II4(0.49g,lmmOl),溶于甲醇(6mL)、乙醚(12mL)的混合溶液,0°C下加入甲醇钠(1. 62g,30mmol),稍候室温反应45分钟,二氯甲烷稀释,用5%稀盐酸酸化,有机层用饱和碳酸氢钠洗3次,饱和食盐水洗3次,无水硫酸钠干燥,减压去除溶剂后得淡黄色固体13(0. 44g,89% )。 [0181] Compound II4 (0.49g, lmmOl), was dissolved in methanol (6 mL), diethyl ether (12 mL) mixed solution, 0 ° C for sodium methoxide (1. 62g, 30mmol) was added, wait 45 minutes at room temperature, diluted with dichloromethane, acidified with 5% hydrochloric acid, the organic layer was washed with saturated sodium bicarbonate 3 times, washed three times with brine, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure to give a pale yellow solid 13 (0. 44g, 89%). 产品无需进一步纯化,纯度满足下一步反应的要求。 Product was used without further purification, meet the requirements of purity for the next reaction.

[0182] mp 198-200 °C ; [0182] mp 198-200 ° C;

[0183] ESI-MS :492 [Μ-ΗΓ ; [0183] ESI-MS: 492 [Μ-ΗΓ;

[0184] 1HNMR (300M Hz, CDCl3, 25 °C,TMS) : δ 8. 01 (s,1H),5. 9 (s,1H),3. 03 (m,1H), [0184] 1HNMR (300M Hz, CDCl3, 25 ° C, TMS):. Δ 8. 01 (s, 1H), 5 9 (s, 1H), 3 03 (m, 1H),.

2. 93(d, J = 4. 5Hz, 1H),2. 41(d,J = 9. OHz, 1H),2. 26(d, J = 9. OHz, 1H),1. 26,1. 21,1. 24, 1.20,1. 16,1.00,0. 91 (s, each 3H)ppm. 2. 93 (d, J = 4. 5Hz, 1H), 2. 41 (d, J = 9. OHz, 1H), 2. 26 (d, J = 9. OHz, 1H), 1. 26,1 . 21,1. 24, 1.20,1. 16,1.00,0. 91 (s, each 3H) ppm.

[0185] 实施例14 [0185] Example 14

[0186] 2-氰基-3,12-二氧代齐墩果烷-1,9(11)-二烯-28-羧酸(II5)的制备 -28- Preparation diene carboxylic acid (II5) is - [0186] 2-Cyano-3,12-dioxo-oleanane-1,9 (11)

[0187]将化合物 13(0. 25g,0. 51mmol)和二氰二氯苯醌(DDQ) (0. 25g,0. 51mmol)溶于无水苯(20mL)中,加热回流20分钟,反应结束后,过滤,滤液浓缩,快速柱层析得白色固体II5(0. 23g,91. 1% ) ο 化合物II5 是已知化合物,CAS 号为218600-44-3。 [0187] Compound 13 (0. 25g, 0. 51mmol) and dicyandiamide chloranil (DDQ) (0. 25g, 0. 51mmol) was dissolved in anhydrous benzene (20mL) was heated at reflux for 20 minutes, the reaction after filtration, the filtrate was concentrated, flash chromatography to give a white solid II5 (0. 23g, 91. 1%) ο II5 compound is a known compound, CAS number is 218600-44-3.

[0188] mp 180-182°C ; [0188] mp 180-182 ° C;

[0189] ESI-MS m/z :490 [M_H]〜492 [M+H]+ ; [0189] ESI-MS m / z: 490 [M_H] ~492 [M + H] +;

[0190] 1HNMR (300M Hz,CDCl3, 25°C,TMS) : δ 8. 05 (1Η, s), 5. 99 (1H, s), 3. 03-2. 98 (2H,m), 1. 55,1. 38,1. 34,1. 22,1. 00,0. 91,0. 85 (each 3H, s, CH3) ppm. [0190] 1HNMR (300M Hz, CDCl3, 25 ° C, TMS):. Δ 8. 05 (1Η, s), 5. 99 (1H, s), 3. 03-2 98 (2H, m), 1 . 55,1. 38,1. 34,1. 22,1. 00,0. 91,0. 85 (each 3H, s, CH3) ppm.

[0191] 实施例15 [0191] Example 15

[0192] 3 β-(3-羧基-1-丙酰氧基)-12-氧代齐墩果烷-9 (11)-烯-28-羧基(II6)的制备 Preparation en-28-carboxy (II6) is - [0192] 3 β- (3- carboxy-1-propionyloxy) -12-oxo-oleanane-9 (11)

[0193]化合物 II2 (2. Og, 4. 26mmol)、丁二酸酐(1. 7g, 17. Ommo 1) ,DMAP (0. 51g,4. 26mmol) 溶于二氯甲烷(50mL),加热回流12小时,反应液用水、饱和食盐水各洗涤三次,无水硫酸钠干燥,过滤、浓缩,快速柱层析得化合物II6(1.99g,82. 1%)0 [0193] Compound II2 (2. Og, 4. 26mmol), succinic anhydride (1. 7g, 17. Ommo 1), DMAP (0. 51g, 4. 26mmol) was dissolved in dichloromethane (50mL), heated under reflux 12 hours, the reaction solution was washed with water, washed three times with water and saturated brine each, dried over anhydrous sodium sulfate, filtered, and concentrated to flash column chromatography to give compound II6 (1.99g, 82. 1%) 0

[0194] mp 186-190°C ;[0195] ESI-MS :571[M+H]+ ; [0194] mp 186-190 ° C; [0195] ESI-MS: 571 [M + H] +;

[0196] 1HNMR (300M Hz,DMS0_d6,25 °C,TMS) : δ 5· 8 (s,1H),4· 51 (m,1H),2· 98 (m,1H), 2. 93 (d, J = 4. 5Hz, 1H),2· 69-2. 64(m,4H),1. 57,1. 26,1. 61,1. 09,1. 06,1. 00,0. 94(s, each 3H) ppm. [0196] 1HNMR (300M Hz, DMS0_d6,25 ° C, TMS): δ 5 · 8 (s, 1H), 4 · 51 (m, 1H), 2 · 98 (m, 1H), 2. 93 (d , J = 4. 5Hz, 1H), 2 · 69-2. 64 (m, 4H), 1. 57,1. 26,1. 61,1. 09,1. 06,1. 00,0. 94 (s, each 3H) ppm.

[0197] 实施例16 [0197] Example 16

[0198] 3-羟基亚胺基-12-氧代齐墩果烷-9 (11)-烯-28-羧酸苄酯(14)的制备 Preparation en-28-carboxylic acid benzyl ester (14) - 12-oxo-hydroxyimino oleanane-9 (11) [0198] 3-

[0199]将化合物 10(5. 6g,IOmmol),盐酸羟胺(1. 0g,15mmol)和碳酸氢钠(1. ^g, 15mmol)溶于乙醇(IOOmL)中,60°C下反应12小时,浓缩,二氯甲烷稀释,有机层用水,饱和食盐水各洗涤3次,无水硫酸钠干燥,浓缩,快速硅胶柱层析制得白色固体14(5. Og, 88% )。 [0199] Compound 10 (5. 6g, IOmmol), hydroxylamine hydrochloride (1. 0g, 15mmol) and sodium bicarbonate (1. ^ g, 15mmol) was dissolved in ethanol (IOOmL), the reaction at 60 ° C 12 hours , concentrated, diluted with dichloromethane, the organic layer was washed with water, washed with water and saturated brine each three times, dried over anhydrous sodium sulfate, concentrated and flash silica gel chromatography as a white solid 14 (5. Og, 88%).

[0200] mp 94-96 °C ; [0200] mp 94-96 ° C;

[0201] ESI-MS m/z :574 [Μ+ΗΓ ; [0201] ESI-MS m / z: 574 [Μ + ΗΓ;

[0202] 1HNMR(300M Hz,CDCl3, 25°C,TMS) : δ 7. 37—7. 26 (m,5H),5. 72 (s,1H),5. 14 (d,J = 12Hz, 1H),5. 13 (d, J = 12Hz, 1H),3. 20 (m, 1H),3. 08 (m, 1H),2. 76 (d, J = 4. 5Hz, 1H),1. 14, 1. 02,1. 00,0. 96,0. 92,0. 89,0. 81 (s, each 3H)ppm. [0202] 1HNMR (300M Hz, CDCl3, 25 ° C, TMS):. Δ 7. 37-7 26 (m, 5H), 5 72 (s, 1H), 5 14 (d, J = 12Hz,.. 1H), 5. 13 (d, J = 12Hz, 1H), 3. 20 (m, 1H), 3. 08 (m, 1H), 2. 76 (d, J = 4. 5Hz, 1H), 1 . 14, 1. 02,1. 00,0. 96,0. 92,0. 89,0. 81 (s, each 3H) ppm.

[0203] 实施例17 [0203] Example 17

[0204] A-扩环-3a_氮杂-12-氧-齐墩果烷-9 (11)-烯-28-羧酸苄酯(15)的制备 -12- aza oxygen [0204] A- expandase -3a_ - Preparation en-28-carboxylic acid benzyl ester (15) - oleanane 9 (11)

[0205] 将化合物14(2. Og, 3. 5mmol),对甲苯苯磺酰氯(0. 66g,3. 5mmol)溶于吡啶(50mL) 中,常温反应12小时,浓缩,乙酸乙酯溶解,有机层用5 %稀盐酸,饱和碳酸氢钠,饱和食盐水各洗涤3次,无水硫酸钠干燥,浓缩,快速硅胶柱层析制得白色固体15(1. 7g,83% )。 [0205] Compound 14 (2. Og, 3. 5mmol), p-toluenesulfonyl chloride (0. 66g, 3. 5mmol) was dissolved in pyridine (50mL), a room temperature for 12 hours, concentrated, dissolved in ethyl acetate, The organic layer was washed with 5% hydrochloric acid, saturated sodium bicarbonate, washed with saturated brine each three times with water, dried over anhydrous sodium sulfate, concentrated and flash silica gel chromatography as a white solid 15 (1. 7g, 83%).

[0206] mp 156-158°C ; [0206] mp 156-158 ° C;

[0207] ESI-MS m/z :574 [Μ+ΗΓ ; [0207] ESI-MS m / z: 574 [Μ + ΗΓ;

[0208] 1HNMR(300Μ Ηζ,CDCl3, 25°C,TMS) : δ 7. 37-7. 26 (m, 5H), 5. 83 (s, 1H), 5. 77 (s, 1H), 5. 14 (d, J = 12Hz, 1H),5· 13 (d, J = 12Hz, 1Η),3. 06 (m, 1Η),2. 79 (d, J = 4. 5Hz, 1Η),1. 14, [0208] 1HNMR (300Μ Ηζ, CDCl3, 25 ° C, TMS):. Δ 7. 37-7 26 (m, 5H), 5. 83 (s, 1H), 5. 77 (s, 1H), 5 . 14 (d, J = 12Hz, 1H), 5 · 13 (d, J = 12Hz, 1Η), 3. 06 (m, 1Η), 2. 79 (d, J = 4. 5Hz, 1Η), 1 . 14,

1. 02,1. 00,0. 96,0. 92,0. 89,0. 81 (s, each 3Η)ppm. 1. 02,1. 00,0. 96,0. 92,0. 89,0. 81 (s, each 3Η) ppm.

[0209] 实施例18 [0209] Example 18

[0210] A-扩环-3a_氮杂-12-氧-齐墩果烷-9 (11)-烯-28-羧酸(II7)的制备 -12- aza oxygen [0210] A- expandase -3a_ - Preparation en-28-carboxylic acid (the II7) - A oleanane 9 (11)

[0211] 参照II1的制备方法,由化合物15与钯碳、氢气反应制得白色固体II7,收率98%。 [0211] Referring to Preparation II1 is prepared from compound 15 with palladium on carbon, hydrogen reacting the II7 white solid, yield 98%.

[0212] mp 135-137°C ; [0212] mp 135-137 ° C;

[0213] ESI-MS :483 [M+H]+; [0213] ESI-MS: 483 [M + H] +;

[0214] 1HNMR (300M Hz,DMS0_d6,25 °C,TMS) : δ 7· 12 (s,1H),5· 83 (s,1H),3· 06 (m,1H), [0214] 1HNMR (300M Hz, DMS0_d6,25 ° C, TMS): δ 7 · 12 (s, 1H), 5 · 83 (s, 1H), 3 · 06 (m, 1H),

2. 79 (d, J = 4·5Ηζ,1Η),1· 14,1. 02,1. 00,0. 96,0. 92,0. 89,0. 81 (s,each 3H) ppm. 2. 79 (d, J = 4 · 5Ηζ, 1Η), 1 · 14,1. 02,1. 00,0. 96,0. 92,0. 89,0. 81 (s, each 3H) ppm.

[0215] 实施例19 [0215] Example 19

[0216] 2-腈基-3-失碳-3,4-开环_12_氧-齐墩果烷_9 (11)-烯_28_羧酸苄酯(16) 的制备 -3,4-oxygen ring opening _12_ [0216] 2--3-carbonitrile carbon loss - _28_ -ene-carboxylate (16) - oleanane _9 (11)

[0217]将化合物 14 (2. Og, 3. 5mmol),二氯亚砜(4. 2g,35mmol)溶于二氧六环(50mL)中, 常温反应15分钟,浓缩,乙酸乙酯稀释,有机层用饱和碳酸氢钠,饱和食盐水各洗涤3次,无水硫酸钠干燥,浓缩,快速硅胶柱层析制得白色固体16(1. 5g,75% )。 [0217] Compound 14 (2. Og, 3. 5mmol), thionyl chloride (4. 2g, 35mmol) was dissolved in dioxane (50mL), the reaction for 15 minutes at room temperature, concentrated, diluted with ethyl acetate, The organic layer was washed with saturated sodium bicarbonate, washed with saturated brine each three times, dried over anhydrous sodium sulfate, concentrated and flash silica gel chromatography as a white solid 16 (1. 5g, 75%).

[0218] mp 145-148°C ; [0218] mp 145-148 ° C;

[0219] ESI-MS m/z :556 [Μ+ΗΓ ;[0220] 1HNMR(300M Hz, CDCl3, 25 "C, TMS) : δ 7. 37-7. 26 (m, 5H), 5. 71 (s, 1H), 5. 14 (d, J =12Hz, 1H),5· 13 (d, J = 12Hz, 1H),4· 99 (s, 1H),4· 74 (s,1Η),3· 06 (m, 1H),2· 79 (d, J = [0219] ESI-MS m / z: 556 [Μ + ΗΓ; [0220] 1HNMR (300M Hz, CDCl3, 25 "C, TMS): δ 7. 37-7 26 (m, 5H), 5. 71. (s, 1H), 5. 14 (d, J = 12Hz, 1H), 5 · 13 (d, J = 12Hz, 1H), 4 · 99 (s, 1H), 4 · 74 (s, 1Η), 3 · 06 (m, 1H), 2 · 79 (d, J =

4. 5Hz, 1H),1. 14,1. 02,1. 00,0· 96,0· 92,0· 89,0· 81 (s,each 3H) ppm. 4. 5Hz, 1H), 1. 14,1. 02,1. 00,0 · 96,0 · 92,0 · 89,0 · 81 (s, each 3H) ppm.

[0221] 实施例20 [0221] Example 20

[0222] 2-腈基-3-失碳-3,4_开环-12-氧-齐墩果烷-9(11)-烯-28-羧酸(II8)的制备 -3,4_ oxygen ring opening -12- [0222] 2- carbonitrile carbon loss-3 - en-28-carboxylic acid prepared in (II8) - A oleanane 9 (11)

[0223] 参照II1的制备方法,由化合物16与钯碳、氢气反应制得白色固体118,收率98%。 [0223] Referring to Preparation II1 is prepared from compound 16 with palladium on carbon, the reaction of hydrogen 118 as a white solid, yield 98%.

[0224] mp 136-138°C ; [0224] mp 136-138 ° C;

[0225] ESI-MS m/z :466 [Μ+ΗΓ ; [0225] ESI-MS m / z: 466 [Μ + ΗΓ;

[0226] 1HNMR(300Μ Hz, CDCl3, 25 °C,TMS) : δ 5. 78 (s,1H),4. 76 (s,1H),4. 33 (s,1H), 3. 06 (m, 1H),2· 79 (d, J = 4. 5Hz, 1Η),1. 14,1. 02,1. 00,0· 96,0· 92,0· 89,0· 81 (s, each 3Η) ppm. [0226] 1HNMR (300Μ Hz, CDCl3, 25 ° C, TMS):.. Δ 5. 78 (s, 1H), 4 76 (s, 1H), 4 33 (s, 1H), 3. 06 (m , 1H), 2 · 79 (d, J = 4. 5Hz, 1Η), 1. 14,1. 02,1. 00,0 · 96,0 · 92,0 · 89,0 · 81 (s, each 3Η) ppm.

[0227] 实施例21 [0227] Example 21

[0228] 3 β -羟基乌苏烷-12-烯-28-羧酸苄酯(17)的制备 Hydroxyl-12-en-28 Usu-carboxylate (17) - 3 β [0228]

[0229] 参照化合物5的制备方法,由乌苏酸与氯化苄反应制得白色固体17,收率97%。 [0229] Referring to the preparation of Compound 5 by reaction of benzyl chloride with ursolic acid as a white solid 17 in 97% yield. 化合物17是已知化合物,CAS号为192211-41-9。 Compound 17 is a known compound, CAS number is 192211-41-9.

[0230] 实施例22 [0230] Example 22

[0231] 3β-乙酰氧基乌苏烷-12-烯-28-羧酸苄酯(18)的制备 Preparation of [0231] 3β- Ji Wusu acetoxymethyl-12-en-28-carboxylate (18)

[0232] 参照化合物6的制备方法,由化合物17与醋酸酐反应制得白色固体18,收率92%。 [0232] Referring to the preparation of Compound 6 as a white solid from compound 18 with acetic anhydride 17 prepared in 92% yield.

[0233] mp 172-174°C ; [0233] mp 172-174 ° C;

[0234] ESI-MS :627 [M+K]+; [0234] ESI-MS: 627 [M + K] +;

[0235] IHNMR(300M Hz, CDCl3, 25°C, TMS) : δ 7. 32-7. 25 (m,5H),5. 23 (m,1H),5. 12 (d,J = 12. 5Hz, 1H),4· 99 (d, J = 12. 5Hz, 1Η),4· 49 (t, J = 8Hz, 1Η),1. 35,1. 31,1. 26,1. 16,1. 01, [0235] IHNMR (300M Hz, CDCl3, 25 ° C, TMS):.. Δ 7. 32-7 25 (m, 5H), 5 23 (m, 1H), 5 12 (d, J = 12.. 5Hz, 1H), 4 · 99 (d, J = 12. 5Hz, 1Η), 4 · 49 (t, J = 8Hz, 1Η), 1. 35,1. 31,1. 26,1. 16,1 . 01,

0. 97,0. 85(s, each 3Η)ppm ; . 0. 97,0 85 (s, each 3Η) ppm;

[0236] 实施例23 [0236] Example 23

[0237] 3 β -乙酰氧基-12-氧代乌苏烷-28-羧酸苄酯(19)的制备 Preparation of 12-oxo-acetoxy -28- ursane acid benzyl ester (19) - 3 β [0237]

[0238] 参照化合物7的制备方法,由化合物18与双氧水反应制得白色固体19,收率81%。 [0238] Referring to the preparation of Compound 7 from Compound 18 and the reaction of hydrogen peroxide 19 as a white solid, yield 81%.

[0239] mp 179-180°C ; [0239] mp 179-180 ° C;

[0240] ESI-MS :605 [M+H]+; [0240] ESI-MS: 605 [M + H] +;

[0241] 1HNMR(300M Hz, CDCl3, 25°C,TMS) : δ 7. 61-7. 35 (m,5Η),5. 21 (d,J = 12. 5Ηζ,1Η), [0241] 1HNMR (300M Hz, CDCl3, 25 ° C, TMS):.. Δ 7. 61-7 35 (m, 5Η), 5 21 (d, J = 12. 5Ηζ, 1Η),

5. 10 (d, J = 12. 5Hz, 1H),4. 49 (m, 1H),2. 84 (m, 1H),2. 62 (m, 1H),2. 39 (m, 1H),1. 35,1. 31, 5. 10 (d, J = 12. 5Hz, 1H), 4. 49 (m, 1H), 2. 84 (m, 1H), 2. 62 (m, 1H), 2. 39 (m, 1H) , 1. 35, 1. 31,

1. 26,1. 16,1. 01,0. 97,0. 85 (s, each 3H) ppm ; .... 1. 26,1 16,1 01,0 97,0 85 ppm (s, each 3H);

[0242] 实施例M [0242] Example M

[0243] 3β-乙酰氧基-12-氧代乌苏烷-9(11)-烯-28-羧酸苄酯Q0)的制备 (11) [0243] 3β- acetoxy-12-oxo-ursane -9-- en-28-carboxylate Q0) Preparation of

[0244] 参照化合物8的制备方法,由化合物19与液溴反应制得白色固体20,收率80%。 [0244] Reference compound 8 is prepared, the compound 19 was reacted with bromine to obtain a white solid 20 in 80% yield.

[0245] mp 208-210 °C ; [0245] mp 208-210 ° C;

[0246] ESI-MS :603 [M+H]+; [0246] ESI-MS: 603 [M + H] +;

22[0247] 1HNMR(300M Hz, CDCl3, 25°C, TMS) : δ 7. 34-7. 26 (m, 5H), 5. 7 (s, 1H), 5. 16 (d, J = 12. 6Hz, 1H), 5. ll(d,J= 12. 6Hz, 1H), 4. 46 (m, 1H),3. 01 (m, 1H),2. 71-2. 67(d, J = 11. OHz, 1H) ,2. 51 (m, 1H) ,2. 01,1. 57,1. 16,1. 00,0· 95,0· 92,0· 89 (s, each 3H) ppm. 22 [0247] 1HNMR (300M Hz, CDCl3, 25 ° C, TMS):. Δ 7. 34-7 26 (m, 5H), 5. 7 (s, 1H), 5. 16 (d, J = 12 . 6Hz, 1H), 5. ll (d, J = 12. 6Hz, 1H), 4. 46 (m, 1H), 3. 01 (m, 1H), 2. 71-2. 67 (d, J = 11. OHz, 1H), 2. 51 (m, 1H), 2. 01,1. 57,1. 16,1. 00,0 · 95,0 · 92,0 · 89 (s, each 3H) ppm.

[0248] 实施例25 [0248] Example 25

[0249] 3β_羟基-12-氧代乌苏烷-9(11)-烯-28-羧酸苄酯Ql)的制备 (11) [0249] 3β_-hydroxy-12-oxo-ursane -9-- Ql, en-28-carboxylate) Preparation of

[0250] 参照化合物9的制备方法,由化合物20与氢氧化钾反应制得白色固体21,收率95%。 [0250] Referring preparation of compound 9 from compound 20 with potassium hydroxide as a white solid reactant 21, in 95% yield.

[0251] [0251]

[0252] [0252]

[0253] 12. 5Hz 1. 26,1 [0253] 12. 5Hz 1. 26,1

[0254] [0254]

[0255] [0255]

[0256] 98%。 [0256] 98%.

[0257] m. ρ· 242-244°C ; [0257] m ρ · 242-244 ° C.;

[0258] ESI-MS :470 [M+H] +,493 [M+Na] + ; [0258] ESI-MS: 470 [M + H] +, 493 [M + Na] +;

[0259] 1HNMR(300M Hz, DMS0_d6,25°C,TMS) : δ 5. 74 (s, 1H), 4. 41 (brs, 1H), 3. 01 (m, 1H), 2. 71-2. 67 (d, J = 11.0Hz,lH),2. 51(m,lH),l. 13,1· 09,1· 05,0· 95,0· 86,0· 73 (s,each 3H) ppm. [0259] 1HNMR (300M Hz, DMS0_d6,25 ° C, TMS): δ 5. 74 (s, 1H), 4. 41 (brs, 1H), 3. 01 (m, 1H), 2. 71-2 . 67 (d, J = 11.0Hz, lH), 2. 51 (m, lH), l. 13,1 · 09,1 · 05,0 · 95,0 · 86,0 · 73 (s, each 3H ) ppm.

[0260] 实施例27 [0260] Example 27

[0261] 3β-乙酰氧基-12-氧代齐墩果烷-13,内酯(Ia-I)的制备 -13, prepared [0261] 3β- acetoxy-12-oxo-oleanane-lactone (Ia-I) is

[0262]将化合物 II1 (0. 5g,0. 97mmol)和DDQ(0. 23g, 1. Ommo 1)溶于无水苯(20mL)中,加热回流48小时,反应结束后,过滤,滤液浓缩,快速柱层析得白色固体Ia-I (0. 21g,68% )。 [0262] Compound II1 (0. 5g, 0. 97mmol) and DDQ (0. 23g, 1. Ommo 1) was dissolved in anhydrous benzene (20mL) and heated to reflux for 48 hours. After completion of the reaction, filtered and the filtrate was concentrated , flash column chromatography to give a white solid Ia-I (0. 21g, 68%). 化合物Ia-I是已知化合物,CAS号为35959-11-6。 Compound Ia-I is a known compound, CAS number is 35959-11-6.

[0263] 实施例28 [0263] Example 28

[0264] 3β-羟基-12-氧代齐墩果烷一9(11)-烯-13,观-内酯(Ib-I)的制备 [0264] 3β- hydroxy-12-oxo-oleanane a 9 (11) - ene -13 Concept - lactone (Ib-I) is

[0265] 参照Ia-I的制备方法,由II2与DDQ反应制得白色固体让_1,收率82%。 [0265] Referring to the preparation of Ia-I, II2 by a reaction with DDQ _1 let a white solid, yield 82%.

[0266] m. ρ· 230-232 °C ; [0266] m ρ · 230-232 ° C.;

[0267] ESI-MS :469 [M+H]+; [0267] ESI-MS: 469 [M + H] +;

[0268] 1HNMR(300M Hz,CDCl3, 25°C,TMS) : δ 6. 0(s, IH,) ,3. 23 (m, 1H),2· 93 (m, 1H),1. 52, 1. 26,1. 12,1. 00,0. 96,0. 96,0. 85 (s, each 3H) ppm. [0268] 1HNMR (300M Hz, CDCl3, 25 ° C, TMS): δ 6. 0 (s, IH,), 3 23 (m, 1H), 2 · 93 (m, 1H), 1 52,.. 1. 26,1. 12,1. 00,0. 96,0. 96,0. 85 (s, each 3H) ppm.

[0269] 实施例四 [0269] Fourth Embodiment

[0270] 3,12-二氧代齐墩果烷-9 (11)-烯-13,观-内酯(Ib_2)的制备 [0270] 3,12-dioxo-oleanane-9 (11) - lactone (Ib_2) a - ene -13, View

[0271] 参照Ia-I的制备方法,由II3与DDQ反应制得白色固体让-2,收率84%。 [0271] Referring to the preparation of Ia-I, as a white solid by the reaction so II3 with DDQ -2, yield 84%.

[0272] mp 243-245 °C ; [0272] mp 243-245 ° C;

[0273] ESI-MS m/z :467 [M+H]+ ; [0273] ESI-MS m / z: 467 [M + H] +;

[0274] 1HNMR(300M Hz,CDCl3, 25°C,TMS) : δ 5. 8 (s,1H),2. 98 (m,1H),2. 66,2. 49,2. 22 (m, [0274] 1HNMR (300M Hz, CDCl3, 25 ° C, TMS): δ 5. 8 (s, 1H), 2 98 (m, 1H), 2 66,2 49,2 22 (m,....

mp 190-192 C ; ESI-MS :561[M+H]+ ; mp 190-192 C; ESI-MS: 561 [M + H] +;

1HNMR(300M Hz, CDCl3, 25°C,TMS) : δ 7. 28-7. 25 (m, 5H),6. 09 (s, 1H),5. 21 (d,J = ,1Η),5· 10 (d, J = 12. 5Hz, 1H), 3. 23 (m, 1H), 3. 01 (d, J = 7· 8HZ,1H),1· 35,1· 31, .16,1. 01,0. 97,0. 85 (s, each 3H) ppm ; 实施例沈 1HNMR (300M Hz, CDCl3, 25 ° C, TMS):. Δ 7. 28-7 25 (m, 5H), 6 09 (s, 1H), 5 21 (d, J =, 1Η), 5.. · 10 (d, J = 12. 5Hz, 1H), 3. 23 (m, 1H), 3. 01 (d, J = 7 · 8HZ, 1H), 1 · 35,1 · 31, .16,1 ... 01,0 97,0 85 ppm (s, each 3H); Shen Example

3β-羟基-12-氧代乌苏烷-9(11)-烯-28-羧酸(II9)的制备 Preparation en-28-carboxylic acid (II9) a - 3β- ursane-hydroxy-12-oxo-9 (11)

参照化合物II1的制备方法,由化合物21与钯碳、氢气反应得白色固体119,收率 Preparation II1 the reference compound, and the palladium on carbon 21, is reacted with hydrogen to give compound 119 as a white solid, yield

23each 1H),1. 57,1. 44,1. 38,1. 14,1. 11,1. 00,0. 92(s,each 3H)ppm. 23each 1H), 1. 57,1. 44,1. 38,1. 14,1. 11,1. 00,0. 92 (s, each 3H) ppm.

[0275] 实施例30 [0275] Example 30

[0276] 3β-(3_羧基-1-丙酰氧基)-12-氧代齐墩果烷-9(11)-烯-13J8-内酯(Ib_3) 的制备 [0276] 3β- (3_ carboxy-1-propionyloxy) -12-oxo-oleanane-9 (11) - Preparation of an ethylenically -13J8- lactone (Ib_3) of

[0277] 参照Ia-I的制备方法,由II6与DDQ反应制得白色固体rt_3,收率78%。 [0277] Referring to the preparation of Ia-I, to give a white solid rt_3 II6 reaction with DDQ, in 78% yield.

[0278] m. ρ· 255-257 °C ; [0278] m ρ · 255-257 ° C.;

[0279] ESI-MS :569 [M+H]+; [0279] ESI-MS: 569 [M + H] +;

[0280] 1HNMR (300M Hz, CDCl3, 25 "C , TMS) : δ 5. 9 (s, 1H), 4. 51 (m, 1H), 2. 97 (m, 1H), 2. 69-2. 64(m,4H),1. 46,1. 28,1. 20,0. 99,0. 97,0. 93,0. 93 (s, each 3H) ppm. [0280] 1HNMR (300M Hz, CDCl3, 25 "C, TMS): δ 5. 9 (s, 1H), 4. 51 (m, 1H), 2. 97 (m, 1H), 2. 69-2 . 64 (m, 4H), 1. 46,1. 28,1. 20,0. 99,0. 97,0. 93,0. 93 (s, each 3H) ppm.

[0281] 实施例31 [0281] Example 31

[0282] 3β-羟基-12-氧代乌苏烷-9(11)-烯-13,观-内酯(Ib_4)的制备 (11) [0282] 3β- hydroxy-12-oxo-ursane -9-- ene-13, Concept - lactone (Ib_4) of

[0283] 参照Ia-I的制备方法,由II9与DDQ反应制得白色固体Ib_4,收率85%。 [0283] Referring to the preparation of Ia-I, to give a white solid Ib_4 II9 reaction with DDQ, 85% yield.

[0284] mp 256-258 °C ; [0284] mp 256-258 ° C;

[0285] ESI-MS :469 [M+H]+,491 [M+Na]+ ; [0285] ESI-MS: 469 [M + H] +, 491 [M + Na] +;

[0286] 1HNMR (300M Hz, CDCl3,25 "C , TMS) : δ 6. 06 (s, 1H) , 3. 25-3. 20 (m, 1H), 2. 55-2. 51 (d, J=Il. 6Hz, 1H),1. 49,1. 26,1. 16,1. 05,0. 95,0. 93,0. 85 (s, each 3H)ppm. [0286] 1HNMR (300M Hz, CDCl3,25 "C, TMS):.. Δ 6. 06 (s, 1H), 3. 25-3 20 (m, 1H), 2. 55-2 51 (d, J = Il. 6Hz, 1H), 1. 49,1. 26,1. 16,1. 05,0. 95,0. 93,0. 85 (s, each 3H) ppm.

[0287] 实施例32 [0287] Example 32

[0288] 12-氧代异噁唑[4,5-b]齐墩果烷_9 (11)-烯-13,沘-内酯(Ib_5)的制备 [0288] isoxazole-oxo-12- [4,5-b] _9 Oleanane (11) - lactone (Ib_5) a - ene -13, Bi

[0289] 参照Ia-I的制备方法,由II4与DDQ反应制得白色固体让_5,收率89%。 [0289] Referring to the preparation of Ia-I, as a white solid from the reaction II4 so _5 with DDQ in 89% yield.

[0290] mp 278-280 °C ; [0290] mp 278-280 ° C;

[0291] ESI-MS m/z :492 [M+H]+ ; [0291] ESI-MS m / z: 492 [M + H] +;

[0292] 1HNMR(300M Hz, CDCl3, 25 "C , TMS) : δ 8. 08 (s, 1H), 6. 12 (s, 1H), 3. 03 (m, 1H), [0292] 1HNMR (300M Hz, CDCl3, 25 "C, TMS): δ 8. 08 (s, 1H), 6. 12 (s, 1H), 3. 03 (m, 1H),

2. 81 (d, J = 15. 0Hz, 1H) ,2. 40 (d, J = 15. OHz, 1H), 1. 57,1. 26,1. 61,1. 09,1. 06,1. 00, 0. 94 (s,each 3H) ppm. 2. 81 (d, J = 15. 0Hz, 1H), 2. 40 (d, J = 15. OHz, 1H), 1. 57,1. 26,1. 61,1. 09,1. 06, 1. 00, 0. 94 (s, each 3H) ppm.

[0293] 实施例33 [0293] Example 33

[0294] A-扩环-3a_氮杂-12-氧-齐墩果烷-9 (11)-烯-13,观-内酯(Ib_6)的制备 -12- aza oxygen [0294] A- expandase -3a_ - Oleanane 9 (11) -, alkenyl -13 Concept - lactone (Ib_6) of

[0295] 参照Ia-I的制备方法,由II7与DDQ反应制得白色固体让_6,收率71%。 [0295] Referring to the preparation of Ia-I, as a white solid by the reaction so II7 _6 with DDQ, 71% yield.

[0296] mp 167-169°C ; [0296] mp 167-169 ° C;

[0297] ESI-MS :482[M+H]+; [0297] ESI-MS: 482 [M + H] +;

[0298] 1HNMR(300M Hz,CDCl3, 25°C,TMS) : δ 6. 04 (s,1H),5· 53 (s, 1H),2· 98 (d, J = 12Hz, 1Η),1· 14,1.02,1.00,0. 96,0. 92,0. 89,0. 81 (s,each 3H) ppm. [0298] 1HNMR (300M Hz, CDCl3, 25 ° C, TMS): δ 6. 04 (s, 1H), 5 · 53 (s, 1H), 2 · 98 (d, J = 12Hz, 1Η), 1 · 14,1.02,1.00,0. 96,0. 92,0. 89,0. 81 (s, each 3H) ppm.

[0299] 实施例34 [0299] Example 34

[0300] 2-腈基-3-失碳-3,4_开环-12-氧-齐墩果烷-9(11)-烯-28-羧酸(Ib_7)的制备 Oxygen ring opening -12- [0300] 2- carbonitrile carbon loss -3,4_-3 - Oleanane 9 (11) - en-28-carboxylic acid was prepared (Ib_7) of

[0301] 参照Ia-I的制备方法,由II8与DDQ反应制得白色固体让_7,收率78%。 [0301] Referring to the preparation of Ia-I, as a white solid by the reaction so II8 _7 with DDQ, in 78% yield.

[0302] mp 162-164°C ; [0302] mp 162-164 ° C;

[0303] ESI-MS :486[M+Na]+ ; [0303] ESI-MS: 486 [M + Na] +;

[0304] 1HNMR(300M Hz, CDCl3, 25 "C , TMS) : δ 6. 01 (s, 1H), 4. 78 (s, 1H), 4. 10 (s, 1H), [0304] 1HNMR (300M Hz, CDCl3, 25 "C, TMS): δ 6. 01 (s, 1H), 4. 78 (s, 1H), 4. 10 (s, 1H),

3. 01 (d, J = 15Ηζ,1Η),1· 14,1. 02,1. 00,0. 96,0. 92,0. 89,0. 81 (s,each 3H) ppm.[0305] 实施例35 3. 01 (d, J = 15Ηζ, 1Η), 1 · 14,1. 02,1. 00,0. 96,0. 92,0. 89,0. 81 ppm (s, each 3H). [0305 ] Example 35

[0306] 2-氰基-3,12-二氧代齐墩果烷-1,9(11)-二烯-13,内酯(Ic-I)的制备 [0306] 3,12 (11) 2-cyano-dioxo Oleanane 1,9 - diene -13 lactone (Ic-I) is

[0307] 参照Ia-I的制备方法,由II5与DDQ反应制得白色固体Ic_l,收率82%。 [0307] Referring to the preparation of Ia-I, to give a white solid Ic_l II5 reaction with DDQ, yield 82%.

[0308] mp 260-262 °C ; [0308] mp 260-262 ° C;

[0309] ESI-MS m/z :490 [M+H]+ ; [0309] ESI-MS m / z: 490 [M + H] +;

[0310] 1HNMR (300M Hz,CDCl3, 25°C,TMS) : δ 8. 01 (s,1H),5. 9 (s,1H),3. 03 (m,1H),1. 57, 1. 26,1. 61,1. 09,1. 06,1. 00,0. 94(s, each 3H)ppm. [0310] 1HNMR (300M Hz, CDCl3, 25 ° C, TMS):... Δ 8. 01 (s, 1H), 5 9 (s, 1H), 3 03 (m, 1H), 1 57, 1 . 26,1. 61,1. 09,1. 06,1. 00,0. 94 (s, each 3H) ppm.

Claims (10)

1.通式I所示的五环三萜-13,28-内酯化合物或其药学上可接受的盐: 1. Formula acceptable lactone compound or a pharmaceutically pentacyclic triterpene -13,28- I in salt thereof:
Figure CN102079772AC00021
其中:Cl与C2之间为碳碳单键或碳碳双键;C9与Cll之间为碳碳单键或碳碳双键;R1选自氢、羰基氧、羟基、氨基、含1〜8个碳原子的烷氧基、含1〜8个碳原子的酰氧基、3-羧基-1-丙酰氧基、含1〜8个碳原子的酰胺基、肟基、或者与R2形成异噁唑[4,5-b] 环;R2选自氢、羰基氧、羟基、氨基、腈基、羟肟基、含1〜8个碳原子的烷氧基、含1〜8个碳原子的酰氧基、或者与R1形成异噁唑[4,5-b]环; Wherein: between Cl and C2 is a single bond or a carbon-carbon double bond; C9 to Cll between a carbon-carbon single bond or a carbon-carbon double bond; Rl is selected from hydrogen, a carbonyl oxygen, a hydroxy group, an amino group-containing 1~8 carbon atoms, an alkoxy group containing 1~8 carbon atoms, an acyloxy group, a 3-carboxy-1-propionyloxy group, an amide group having 1~8 carbon atoms, an oxime group, or forms with R2 iso oxazole [4,5-b] ring; R2 is selected from hydrogen, a carbonyl oxygen, a hydroxy group, an amino group, a nitrile group, a hydroxamic group, an alkoxy group having 1~8 carbon atoms, having 1~8 carbon atoms an acyloxy group, or forms with R1 isoxazole [4,5-b] ring;
Figure CN102079772AC00022
异噁哩14,5-b]环A环为六元碳环,或者A环的C2与C3位断开后扩环形成内酰胺类七元环,或者A环的C2与C3位开环形成3,4-开环产物; Isoxazolyl miles 14,5-b] ring A is a six membered carbocyclic ring, or ring A is C2 and C3 position after disconnection expandase formed membered ring lactam, C2 or C3 position of the A ring and the ring opening 3,4-ring-opened product;
Figure CN102079772AC00023
内酰fe类七兀环 3,4-开环产物B环为六元碳环;R3选自氢或甲基;R4选自氢或甲基。 Wu fe seven - lactam ring opening product of 3,4-cyclic ring B is a six-membered carbocyclic ring; R3 is selected from hydrogen or methyl; R4 is selected from hydrogen or methyl.
2.如权利要求1所述的通式I化合物或其药学上可接受的盐,其特征在于所述通式I 化合物为: 2. A compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein said compound of formula I is:
Figure CN102079772AC00031
其中:R1选自氢、羰基氧、羟基、氨基、含1〜8个碳原子的烷氧基、含1〜8个碳原子的酰氧基、3-羧基-1-丙酰氧基、含1〜8个碳原子的酰胺基、肟基、或者与R2形成异噁唑[4,5-b] 环;R2选自氢、羰基氧、羟基、氨基、腈基、羟肟基、含1〜8个碳原子的烷氧基、含1〜8个碳原子的酰氧基、与R1形成异噁唑[4,5-b]环; Wherein: R1 is selected from hydrogen, a carbonyl oxygen, a hydroxy group, an amino group, an alkoxy group having 1~8 carbon atoms, an acyloxy group having 1~8 carbon atoms, a carboxy-1-propionyloxy-containing an amide group of 1~8 carbon atoms, an oxime group, or with R2 form isoxazole [4,5-b] ring; R2 is selected from hydrogen, a carbonyl oxygen, a hydroxy group, an amino group, a nitrile group, a hydroxamic group containing 1 alkoxy ~ 8 carbon atoms, having 1~8 carbon atoms, an acyloxy group, and R1 form isoxazole [4,5-b] ring;
Figure CN102079772AC00032
A环为六元碳环,或者A环的C2与C3位断开后扩环形成内酰胺类七元环,或者A环的C2与C3位开环形成3,4-开环产物; Ring A is a six-membered carbocyclic ring, or ring A is C2 and C3 position after disconnection expandase formed membered ring lactam, ring A or ring-opening C2 and C3 form a 3,4-ring-opened product;
Figure CN102079772AC00033
B环为六元碳环; R3选自氢或甲基; R4选自氢或甲基。 Ring B is a six-membered carbocyclic ring; R3 is selected from hydrogen or methyl; R4 is selected from hydrogen or methyl.
3.权利要求1和2所述的五环三萜-13,28-内酯化合物或其药学上可接受的盐,其特征在于所述化合物,其中:R1选自羟基、羰基氧、3-羧基-1-丙酰氧基、乙酰氧基、或者与R2形成异噁唑[4,5-b]环;R2选自氢、腈基、或者与R1形成异噁唑[4,5-b]环; Pharmaceutically pentacyclic triterpene -13,28- lactone compound or a pharmaceutically acceptable salt thereof according to claim 1 and 2, characterized in that said compound, wherein: R1 is selected from hydroxyl, carbonyl oxygen, 3- carboxy-1-propionyloxy group, an acetyl group, or form isoxazole [4,5-b] ring with R2; R2 is selected from hydrogen, nitrile group, or forms with R1 isoxazole [4,5-b ]ring;
Figure CN102079772AC00034
A环为六元碳环,或者A环的C2与C3位断开后扩环形成内酰胺类七元环,或者A环的C2与C3位开环形成3,4-开环产物; Ring A is a six-membered carbocyclic ring, or ring A is C2 and C3 position after disconnection expandase formed membered ring lactam, ring A or ring-opening C2 and C3 form a 3,4-ring-opened product;
Figure CN102079772AC00041
B环为六元碳环; R3选自氢或甲基; R4选自氢或甲基。 Ring B is a six-membered carbocyclic ring; R3 is selected from hydrogen or methyl; R4 is selected from hydrogen or methyl.
4.权利要求1至3所述的五环三萜-13,28-内酯,选自下列化合物:(1) 3 β -乙酰氧基-12-氧代齐墩果烷-13,28-内酯(化合物编号:Ia_l,下同) -13,28- pentacyclic triterpenoid lactone 1 to claim 3, selected from the following compounds: (1) 3 β - acetoxy-12-oxo-oleanane -13,28- lactone (compound No.: Ia_l, the same below)
Figure CN102079772AC00042
(2) 3 β -羟基-12-氧代齐墩果烷_9 (11)-烯-13,28-内酯(Ib-I) (2) 3 β - hydroxy-12-oxo-oleanane _9 (11) - ene -13,28- lactone (Ib-I)
Figure CN102079772AC00043
(3) 3,12- 二氧代齐墩果烷-9 (11)-烯-13,28-内酯(Ib_2) (3) 3,12-dioxo-oleanane-9 (11) - ene -13,28- lactone (Ib_2)
Figure CN102079772AC00044
(4) 3 β - (3-羧基-1-丙酰氧基)-12-氧代齐墩果烷_9 (11)-烯-13,28-内酯(Ib_3) (4) 3 β - (3- carboxy-1-propionyloxy) -12-oxo Oleanane _9 (11) - ene -13,28- lactone (Ib_3)
Figure CN102079772AC00045
(5) 3 β -羟基-12-氧代乌苏烷-9 (11)-烯-13,28-内酯(Ib_4) (5) 3 β - ursane-hydroxy-12-oxo-9 (11) - ene -13,28- lactone (Ib_4)
Figure CN102079772AC00051
(6) 12-氧代异噁唑[4,5-b]齐墩果烷_9 (11)-烯-13,28-内酯(Ib_5) (6) isoxazolyl-oxo-12- [4,5-b] _9 Oleanane (11) - ene -13,28- lactone (Ib_5)
Figure CN102079772AC00052
(7) A-扩环-3a-氮杂-12-氧-齐墩果烷_9 (11)-烯-13,28-内酯(Ib_6) (7) A- expandase -3a- aza -12- oxo - Oleanane _9 (11) - ene -13,28- lactone (Ib_6)
Figure CN102079772AC00053
(8) 2-腈基-3-失碳-3,4-开环-12-氧-齐墩果烷-9 (11)-烯-13,28-内酯(Ib_7) (8) 2-3-carbonitrile lost carbon ring opening -12- oxo-3,4 - Oleanane 9 (11) - ene -13,28- lactone (Ib_7)
Figure CN102079772AC00054
(9) 2-氰基-3,12- 二氧代齐墩果烷-1,9(11)-二烯-13,28-内酯(Ic-I) (9) 2-cyano-3,12-dioxo-oleanane-1,9 (11) - diene -13,28- lactone (Ic-I)
Figure CN102079772AC00055
5.权利要求1至4所述的五环三萜-13,28-内酯化合物优选为-.2-氰基_3,12- 二氧代齐墩果烷-1,9(11)-二烯-13,28-内酯(Ic-I)。 Pentacyclic triterpene -13,28- preferred lactone compounds according to claim 1 to 4 is cyano _3,12- -.2- dioxo oleanane-1,9 (11) - diene -13,28- lactone (Ic-I).
6.权利要求1至5所述的五环三萜-13,28-内酯化合物的制备方法,其特征在于,式II所示的化合物在脱氢剂的作用下,脱除C13位的氢和C28位羧基上的氢,分别生成式I (包括la、lb、Ic)所示的五环三萜-13,28-内酯化合物: Preparation pentacyclic triterpene -13,28- lactone compound of claim 1 to claim 5, characterized in that the compound of Formula II under the action of a dehydrogenation agent, the C13 removal of hydrogen hydrogen and a carboxyl group on C28 position, respectively of formula I (including la, lb, Ic) shown pentacyclic triterpene -13,28- lactone compound:
Figure CN102079772AC00061
其中,R1、R2、R3和R4的定义如前所述。 Wherein, R1, R2, R3 and R4 are as previously defined.
7.权利要求6的制备方法,其特征在于,采用的脱氢剂选自2,3-二氯-5,6-二氰苯醌、 四氯苯醌、二氧化硒、1,1-二苯基-2-三硝基苯胼、2,2,6,6-四甲基哌啶氮氧自由基或二氧化硒中的一种或多种。 The method of preparation according to claim 6, wherein the dehydrogenating agent used is selected from 2,3-dichloro-5,6-dicyano-benzoquinone, chloranil, selenium dioxide, 1,1-bis phenyl-2-trinitrobenzene corpus, 2,2,6,6-tetramethyl-piperidin-nitroxide selenium dioxide or one or more.
8.权利要求6的制备方法,其特征在于,采用的反应溶剂为苯、甲苯、二甲苯、二氧六环、乙腈、四氢呋喃、二氯甲烷、氯仿、二氯乙烷、甲醇、丙酮、乙酸乙酯或N,N-二甲基甲酰胺中的一种或多种;采用的反应温度为50-120°C。 The method of preparation of claim 6, wherein the reaction solvent used is benzene, toluene, xylene, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, dichloroethane, methanol, acetone, acetic acid carbonate or N, N- dimethylformamide one or more; the reaction temperature employed is 50-120 ° C.
9. 一种药物组合物,由治疗上有效剂量的权利要求1和2所述的式I (包括la、lb、Ic) 化合物和药学上可接受的载体或辅料组成。 9. A pharmaceutical composition as claimed by the therapeutically effective dose of the formula I according to claim 1 and 2 (including la, lb, Ic) a compound and a pharmaceutically acceptable carrier or adjuvant composition.
10.权利要求1至5所述的式I (包括la、lb、Ic)化合物在制备抗肿瘤药物中的用途。 10. Formula I (including la, lb, Ic) use of a compound in the preparation of antineoplastic 1-5 claim.
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