CN1927861B - Garcinia acid derivatives, preparation method and application thereof in pharmacy - Google Patents
Garcinia acid derivatives, preparation method and application thereof in pharmacy Download PDFInfo
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- CN1927861B CN1927861B CN2006100882515A CN200610088251A CN1927861B CN 1927861 B CN1927861 B CN 1927861B CN 2006100882515 A CN2006100882515 A CN 2006100882515A CN 200610088251 A CN200610088251 A CN 200610088251A CN 1927861 B CN1927861 B CN 1927861B
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Abstract
The present invention discloses one kind of gambogic acid derivative and its preparation process and pharmaceutical application. The gambogic acid derivative has its general expression shown. It has antitumor effect and may be used in preparing antitumor medicines.
Description
Technical field
The present invention relates to a kind of novel Gamboges acid derivative and preparation method thereof and the application of this Gamboges acid derivative in the preparation antitumor drug.
Background technology
The natural compounds morellic acid separates from the Gamboge of Garcinia platymiscium first finds that morellic acid (Gambogic acid) is the antineoplastic important effective constituent of gamboge.Morellic acid can be optionally effective kill tumor cell, and to normal hemopoietic system and not influence of immunologic function, studies have shown that morellic acid and derivative thereof are the agonist and the apoptotic inductors of caspase, can be used as a kind of cell death inducer that effectively is at kinds of tumors.The natural product morellic acid can be optionally effective kill tumor cell, and to normal hemopoietic system and not influence of immunologic function.
Because morellic acid and and derivative compound have significant cytotoxicity, in order to search out the more excellent compound of biological activity, scholars have showed keen interest to the chemically modified synthetic and the dependency structure position of Gamboges acid derivative, San Diego, USA Marxim institute of materia medica CAISUI XIONG research group (US2003078292, WO0044216), studying aspect the structure of modification modification of natural product morellic acid, related morellic acid structure of modification modification work mainly concentrates on C-30, C-8, C-6, C-12, C-9,10.
The internal metabolism process of latest find morellic acid mainly is an oxidative metabolism in morellic acid meta-bolites research, and in general the oxidative metabolism product mainly contains the existence of the N-dealkylation, N-oxidation products etc. of hydroxylation, epoxide and amido.Effectively metabolite very likely becomes newfound guide's thing, becomes new drug and finds and the important channel of designing.The present invention gets around aforementioned thinking, the Gamboges acid derivative of seeking high-efficiency low-toxicity on this basis is as new type antineoplastic medicine, the chemical structure design of carrying out Gamboges acid derivative from the meta-bolites of medicine, water-soluble angle is synthetic, and it is carried out anti-tumor biological research, wish to obtain more optimized structure, more remarkable treatment effect, special antineoplastic compound.
Summary of the invention
The objective of the invention is at above-mentioned technical problem a kind of meta-bolites based on medicine is provided, improve water-soluble, improve anti-tumor biological, the ultimate principle of drug application design and a series of novel Gamboges acid derivative that designs with good resistance tumor promotion.
Another object of the present invention provides the preparation method of above-mentioned Gamboges acid derivative.
A further object of the invention provides the application of above-mentioned Gamboges acid derivative in the preparation antitumor drug.
The objective of the invention is to realize by following technical measures:
A kind of Gamboges acid derivative is the described compound of general formula (I):
R wherein
1, R
2, R
3, R
4Identical or different, independent separately H, halogen, hydroxyl, mercaptan, cyano group, amino, nitro, itrate group, guanidine radicals, amide group,-oxyl, hydrocarbon sulfoamido, alkylacyloxy, hydrocarbon sulfonate ester group, carboxyl, aldehyde radical, ester group, heterocyclic radical, sulfenyl and corresponding sulfone or the sulfoxide represented; R
5And R
6Identical or different, independent separately H, the alkyl represented; (32,33) position, the empty line in (37,38) position part are identical or different, independently separately represent ethylene linkage, epoxy group(ing), o-dihydroxy, and R
1, R
2, R
3, R
4When being H simultaneously, at least one is o-dihydroxy for (32,33) position, the empty line part in (37,38) position.
Described Gamboges acid derivative is worked as R
1, R
2, R
3, R
4When representing-oxyl, hydrocarbon sulfoamido, alkylacyloxy, hydrocarbon sulfonate ester group, sulfenyl and corresponding sulfone or sulfoxide, alkyl wherein is C
2-8Optical activity is arranged or do not have the active unsaturated alkyl of optics, C
1-8Optical activity is arranged or do not have the active saturated alkane of optics, C
4-8Heterocyclic arene base or C
6-8Aryl, the C of replacement
4-8The heterocyclic arene base or the C of replacement
6-8Aryl; R
1, R
2, R
3, R
4The heterocyclic radical of representative is the heterocycle of the saturated or fractional saturation of 5-7 unit; R
5And R
6The alkyl of representative is C
1-4Saturated alkane or C
2-4Unsaturated alkyl.
Described Gamboges acid derivative is worked as R
1, R
2, R
3, R
4When representing-oxyl, hydrocarbon sulfoamido, alkylacyloxy, hydrocarbon sulfonate ester group, sulfenyl and corresponding sulfone or sulfoxide, alkyl wherein is C
2-5Optical activity is arranged or do not have the active unsaturated alkyl of optics, C
1-5Optical activity is arranged or do not have the active saturated alkane of optics, C
4-8Heterocyclic arene base or C
6-8Aryl, the C of replacement
4-8The heterocyclic arene base or the C of replacement
6-8Aryl.
Described Gamboges acid derivative, wherein R
1, R
2, R
3, R
4The halogen of representative is F, Cl, Br, I.
Described Gamboges acid derivative, wherein amino is NH
2, NHR
8, NR
9R
10, and R
8, R
9Or R
10Be C
2-8Optical activity is arranged or do not have the active unsaturated alkyl of optics, C
1-8Optical activity is arranged or do not have the active saturated alkane of optics, C
4-8Heterocyclic arene base or C
6-8Aryl, the C of replacement
4-8The heterocyclic arene base or the C of replacement
6-8Aryl.
Described Gamboges acid derivative, wherein amide group is CONH
2, CONHR
11, CONR
12R
13, and R
11, R
12Or R
13Be C
2-8Optical activity is arranged or do not have the active unsaturated alkyl of optics, C
1-8Optical activity is arranged or do not have the active saturated alkane of optics, C
4-8Heterocyclic arene base or C
6-8Aryl, the C of replacement
4-8The heterocyclic arene base or the C of replacement
6-8Aryl.
Described Gamboges acid derivative, wherein ester group is COOR
14, and R
14Be C
2-8Optical activity is arranged or do not have the active unsaturated alkyl of optics, C
1-8Optical activity is arranged or do not have the active saturated alkane of optics, C
4-8Heterocyclic arene base or C
6-8Aryl, the C of replacement
4-8The heterocyclic arene base or the C of replacement
6-8Aryl.
The aryl of the replacement described in the above-mentioned Gamboges acid derivative or heterocyclic arene base are by C
1-5Alkyl, C
1-5Aromatic ring yl or aromatic heterocyclic that alkoxyl group or hydroxyl replace.
Heterocycle described in the above-mentioned Gamboges acid derivative is the heterocycle that contains 1～2 N, O or S.
Described Gamboges acid derivative, described saturated hydrocarbyl is a methyl, ethyl has optical activity or does not have the active propyl group of optics, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl or octyl group; Described unsaturated alkyl is allyl group, propenyl, 1-butylene, 2-butylene, isopentene, 2-amylene, 2-methyl-2-amylene, 2-methyl-2-hexene, 2-methyl-2,4-hexadiene, 2-methyl-2,4-heptadiene, 2-methyl-2,5-heptadiene; Described aryl is that wherein halogen is F, Cl, Br or I to (adjacent) dihydroxy-benzene, 2,3 or 4 halogen-substituted phenol; Described heterocyclic radical is furans, pyrazine, pyridine, piperidines, piperazine, methylpiperazine, morpholine, the imidazoles of optically active hydroxybutyrolactone, 2-methylthiazol, furans, pyrazine, pyridine piperidines, piperazine, methylpiperazine, morpholine, imidazoles and halogen, hydroxyl, cyano group,-oxyl, amino or carboxyl substituted.
Described Gamboges acid derivative, wherein R
1, R
2, R
3, R
4Identical or different, independent separately H, halogen, hydroxyl, carboxyl, aldehyde radical, cyano group, nitro, mercaptan, the C of representing
2-5Alkanoyloxy, amide group, hydrocarbon sulfonate ester group, amino, methylamino-, ethylamino, dimethylamino, diethylin, piperazine, methylpiperazine, pyrazine, morpholine; (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, epoxy group(ing), the o-dihydroxy represented; R
5And R
6Identical or different, independent separately H, methyl, ethyl, propyl group, butyl, allyl group, propenyl, 1-butylene, 2-butylene, the isopentene represented.
Described Gamboges acid derivative, wherein R
1, R
2, R
3, R
4Identical or different, independent separately H, hydroxyl, carboxyl, aldehyde radical, fluorine, chlorine, cyano group, nitro, amino, the alkylacyloxy represented; (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented; R
5And R
6Identical or different, independent separately H, methyl, ethyl, propyl group, allyl group, the propenyl represented.
Described Gamboges acid derivative, wherein R
1, R
2, R
3, R
4Identical or different, independent separately H, hydroxyl, the C of representing
1-8Alkylacyloxy, aldehyde radical; (32,33) position, the independent separately ethylene linkage of representing of the empty line part in (37,38) position; R
5And R
6Identical or different, from independent H, methyl, ethyl, allyl group, the propenyl represented.
Described Gamboges acid derivative, wherein R
1, R
3The independent separately H that represents; R
2, R
4Identical or different, independent separately H, hydroxyl, acetoxyl group, the aldehyde radical represented; (32,33) position, the independent separately ethylene linkage of representing of the empty line part in (37,38) position; R
5And R
6Identical or different, independent separately H, methyl, ethyl, propyl group, allyl group, the propenyl represented.
Described Gamboges acid derivative, wherein R
1, R
2, R
3, R
4The independent separately H that represents; (32,33) position, (37,38) position void are rule partly different, independent separately ethylene linkage, the epoxy group(ing) represented; Perhaps (32,33) position, the empty line in (37,38) position part are identical, the independent separately epoxy group(ing) of representing; R
5And R
6Identical or different, independent separately H, methyl, ethyl, propyl group, allyl group, the propenyl represented.
Described Gamboges acid derivative, wherein R
1, R
2, R
3, R
4Identical or different, independent separately H, halogen, hydroxyl, ester group,-oxyl, cyano group, nitro, mercaptan, the C of representing
2-5Alkanoyloxy, amide group, methylamino-, ethylamino, dimethylamino, diethylin, piperazine, methylpiperazine, pyrazine, morpholine; (32,33) position, the empty line in (37,38) position part are identical or different, independently separately represent ethylene linkage, o-dihydroxy, and can not be ethylene linkage simultaneously; R
5And R
6Identical or different, independent separately represent methylidene, ethyl, propyl group, sec.-propyl, butyl, isobutyl-.
Described Gamboges acid derivative, wherein R
1, R
2, R
3, R
4Identical or different, independent separately H, hydroxyl, the-oxyl represented; (32,33) position, the empty line in (37,38) position part are identical or different, independently separately represent ethylene linkage, o-dihydroxy, and can not be ethylene linkage simultaneously; R
5And R
6Identical or different, independent separately represent methylidene, ethyl, propyl group, butyl.
Described Gamboges acid derivative, wherein R
1, R
2, R
3, R
4The identical independent separately H that represents; (32,33) position, the empty line in (37,38) position part are identical or different, independently separately represent ethylene linkage, o-dihydroxy, and can not be ethylene linkage simultaneously; R
5And R
6Identical or different, independent separately represent methylidene, ethyl, propyl group, butyl.
The preparation method of described Gamboges acid derivative, this method is: general formula (A) is the Gamboges acid derivative or the morellic acid of 6,30 replacements, with (A) is starting raw material, adopt oxidising agent to carry out oxidizing reaction and get final product, perhaps the product that oxidizing reaction is obtained carries out halo, amination, amination, hydrocarbonylation, cyano groupization, carboxylation, nitrated, mercaptanization, hydrocarbon sulfonate esterification, hydrocarbon acidylate, epoxidation or hydroxylation reaction again;
In the general formula (A), R
5And R
6Identical or different, independent separately H, the alkyl represented.
Alkyl among the preparation method of described Gamboges acid derivative is C
1-4Saturated alkane or C
2-4Unsaturated alkyl; C wherein
1-4Saturated alkane be methyl, ethyl, propyl group, butyl; C
2-4Unsaturated alkyl be allyl group, propenyl, 1-butylene, 2-butylene, isopentene.
Used oxidising agent is hydrogen peroxide, alkyl hydrogen peroxide, organic peroxide acid, metachloroperbenzoic acid, tin anhydride, peroxy tert-butyl alcohol, ceric ammonium nitrate, sodium dichromate 99, crosses tert-butyl acrylate, potassium osmate, the Tripotassium iron hexacyanide, clorox, perosmic anhydride and methylmorpholine-N oxide compound among the preparation method of described Gamboges acid derivative.
The preparation method of described Gamboges acid derivative, this method may further comprise the steps:
A. general formula (A) and tin anhydride, peroxy tert-butyl alcohol are reacted in methylene dichloride or trichloromethane, temperature of reaction prepares R between subzero 10 ℃ to 70 ℃
1, R
2, R
3, R
4Identical or different, independent separately H, hydroxyl, the aldehyde radical represented, (32,33) position, the empty line part in (37,38) position are removed R
1, R
2, R
3, R
4Be outer independent separately general formula (I) compound of representing ethylene linkage of H; Perhaps
b.
I. with the independent separately ethylene linkage, R represented of the empty part of ruling in (32,33) position, (37,38) position of step a preparation
1, R
2, R
3, R
4In have at least general formula (I) compound and the metachloroperbenzoic acid of a hydroxyl in methylene dichloride or trichloromethane, to react, temperature of reaction is between subzero 10 ℃ to 40 ℃, preparation (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage or the epoxy group(ing) represented, and (32,33) position, (37,38) position can not be ethylene linkage, R
1, R
2, R
3, R
4In have at least a hydroxyl general formula (I) compound; Perhaps
Ii. with the independent separately ethylene linkage, R represented of the empty part of ruling in (32,33) position, (37,38) position of step a preparation
1, R
2, R
3, R
4In have at least general formula (I) compound of a hydroxyl and Yi Xian Yi Suan Vanadium, peroxy tert-butyl alcohol in dry-out benzene or toluene, to react, temperature of reaction is between subzero 10 ℃ to 40 ℃, Stereoselective preparation (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage or the epoxy group(ing) represented, and (32,33) position, (37,38) position can not be ethylene linkage, R
1, R
2, R
3, R
4In have the single optical isomer of general formula (I) compound of a hydroxyl at least; Perhaps
Iii. with the independent separately ethylene linkage, R represented of the empty part of ruling in (32,33) position, (37,38) position of step a preparation
1, R
2, R
3, R
4In have general formula (I) compound of a hydroxyl and four different oxygen propyl group titaniums, CaH at least
2, silica gel H, 4
Molecular sieve, (+)-diethyl tartrate or (-)-diethyl tartrate, anhydrous peroxy tert-butyl alcohol react in dry toluene and methylene dichloride mixing solutions, temperature of reaction is between subzero 75 ℃ to 25 ℃, Stereoselective preparation (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented, and (32,33) position, (37,38) position can not be ethylene linkage, R
1, R
2, R
3, R
4In have the single optical isomer of general formula (I) compound of a hydroxyl at least; Perhaps
c.
I. general formula (I) compound and tolysulfonyl halogen, the dimethyl aminopyridine with step b preparation reacts in methylene dichloride, and temperature of reaction prepares R between subzero 10 ℃ to 45 ℃
1, R
2, R
3, R
4In have general formula (I) compound of representing halogen atom at least; Perhaps
Ii. the i of step c is prepared R
1, R
2, R
3, R
4In have at least general formula (I) compound of representing halogen atom and amine or heterogeneous ring compound, alkali reagent in methylene dichloride, to react, temperature of reaction prepares R between subzero 10 ℃ to 45 ℃
1, R
2, R
3, R
4Identical or different, have general formula (I) compound of representing heterocyclic radical at least; Perhaps
Iii. with the R of step b preparation
1, R
2, R
3, R
4In have at least general formula (I) compound and alkali, the halogenated alkane of a representation hydroxy in acetone, to react, temperature of reaction prepares R between 0 ℃ to 85 ℃
1, R
2, R
3, R
4Identical or different, wherein have at least one to be general formula (I) compound of-oxyl; Perhaps
Iv. with the R of step b preparation
1, R
2, R
3, R
4In have general formula (I) compound of a representation hydroxy and pyridine, dimethyl aminopyridine, C at least
1-5The acid anhydrides of carboxylic acid is in methylene dichloride, and temperature of reaction prepares R between 0 ℃ to 45 ℃
1, R
2, R
3, R
4Identical or different, wherein have at least one to be general formula (I) compound of alkylacyloxy; Perhaps
V. the i of step c is prepared R
1, R
2, R
3, R
4In have at least one to represent general formula (I) compound and trimethylammonium silicon chlorides, sodium iodide, the sodium cyanide of halogen atom in acetonitrile, to react, temperature of reaction prepares R between 0 ℃ to 80 ℃
1, R
2, R
3, R
4Identical or different, wherein have at least one to be general formula (I) compound of cyano group; Perhaps
Vi. with the R of step b preparation
1, R
2, R
3, R
4In have at least general formula (I) compound and clorox, TEMPO, sodium bicarbonate, Potassium Bromide, the tetrabutylammonium chloride of a representation hydroxy in methylene dichloride, to react, temperature of reaction prepares R between 0 ℃ to 40 ℃
1, R
2, R
3, R
4In have general formula (I) compound of a representation carboxy at least; Perhaps
Vii. with the R of step b preparation
1, R
2, R
3, R
4In have at least general formula (I) compound, the acetyl thiourea of a representation hydroxy in ethanol, to react, temperature of reaction prepares R between 0 ℃ to 100 ℃
1, R
2, R
3, R
4In have general formula (I) compound of representing thiol group at least; Perhaps
Viii. with the R of step b preparation
1, R
2, R
3, R
4In have at least the sodium salt of general formula (I) compound of a representation hydroxy and mercaptan or thiophenol or sylvite and hydrocarbonylation reagent in benzene, to react, prepare R
1, R
2, R
3, R
4In have general formula (I) compound of representing sulfenyl at least; Perhaps
Ix. the i of step c is prepared R
1, R
2, R
3, R
4In have general formula (I) compound of representing halogen atom and Sodium Nitrite at least in acetonitrile or dimethyl sulfoxide (DMSO), solvent dimethylformamide reaction, temperature of reaction prepares R between 0 ℃ to 60 ℃
1, R
2, R
3, R
4In have general formula (I) compound of representing nitro at least; Perhaps
X. with the R of step b preparation
1, R
2, R
3, R
4In have at least general formula (I) compound and hydrocarbon sulfonic acid halide, the pyridine of a representation hydroxy in ether, to react, temperature of reaction prepares R between 0 ℃ to 35 ℃
1, R
2, R
3, R
4In have general formula (I) compound of representing the hydrocarbon sulfonate ester at least; Perhaps
D. general formula (A) and metachloroperbenzoic acid are reacted in methylene dichloride or trichloromethane, temperature of reaction prepares R between subzero 10 ℃ to 40 ℃
1, R
2, R
3, R
4Be H, (32,33) position, the empty line in (37,38) position part are identical or different, independently separately represents ethylene linkage, epoxy group(ing), and (32,33) position, (37,38) can not be general formula (I) compound of ethylene linkage; Perhaps
E. the Gamboges acid derivative of 6,30 replacements of general formula (A) and AD-mix-α or AD-mix-β, methylsulfonyl ammonia are reacted in the mixed solvent of the trimethyl carbinol, Virahol or acetonitrile and water, temperature of reaction prepares R between 0 ℃ to 35 ℃
1, R
2, R
3, R
4Be H, (32,33) position, the empty line in (37,38) position part are identical or different, independently separately represents ethylene linkage, o-dihydroxy, and (32,33) position, (37,38) can not be general formula (I) compound of ethylene linkage, comprise all single diastereomers.
The application of described Gamboges acid derivative in the medicine of preparation treatment tumour.
Can there be one or more unsymmetrical carbons in compound of the present invention in its molecule, form optical isomer.Although all these all use a molecular formula to represent here, the present invention includes single, isolating isomer and miscellany, comprise the mixture of racemic modification.The utilization Stereoselective synthesizing process promptly obtains single isomer.
The english abbreviation implication that relates among the present invention is as follows:
SeO
2(tin anhydride), t-BuOOH (peroxy tert-butyl alcohol), m-CPBA (metachloroperbenzoic acid),
VO (acac)
2(etheric acid vanadium), Ti (O-iPr)
4(four different oxygen propyl group titaniums), DET (diethyl tartrate),
DMAP (4-N, N-dimethyl aminopyridine), DCC (dicyclohexylcarbodiimide),
TEMPO (tetramethyl piperidine-oxide compound),
AD-mix-α (by the mixture of the 2 analog derivative of salt of wormwood, the Tripotassium iron hexacyanide, potassium osmate, hydroquinine preparation),
AD-mix-β (by the mixture of the 2 analog derivative of salt of wormwood, the Tripotassium iron hexacyanide, potassium osmate, dihydro-quinidine preparation),
Halogenation (halogenating reaction), Alkylation (alkylation reaction), Acylation (acylation reaction), Amination (nitrogenizing reaction).
The preparation of formula of of the present invention (I) type Gamboges acid derivative can be represented with following chemical equation 1:
A. with the compound of general formula (A) and tin anhydride, peroxy tert-butyl alcohol prepared in reaction corresponding compounds (B) in methylene dichloride;
?b.
I. the compound that step a is obtained (B) (R
1, R
2, R
3, R
4In a hydroxyl is arranged) and cross chloro-benzoic acid prepared in reaction in methylene dichloride corresponding general formula (I) compound or intermediate;
The compound that ii obtains step a (B) (R
1, R
2, R
3, R
4In have a hydroxyl at least) in dry-out benzene or toluene, react with Yi Xian Yi Suan Vanadium, peroxy tert-butyl alcohol, the gained compound is the single optical isomer of general formula (I) compound;
Iii. the compound that step a is obtained (B) (R
1, R
2, R
3, R
4In a hydroxyl is arranged) with four different oxygen propyl group titaniums, CaH
2, silica gel H, 4
Molecular sieve, (+)-diethyl tartrate or (-)-diethyl tartrate, anhydrous peroxy tert-butyl alcohol react in dry toluene and methylene dichloride mixing solutions, and Stereoselective prepares the single optical isomer of general formula (I) compound;
C. step b is prepared compound (R
1, R
2, R
3, R
4In have a representation hydroxy at least) prepare general formula (I) compound by following steps:
I. step b is prepared compound and tolysulfonyl halogen, dimethyl aminopyridine react in methylene dichloride;
Ii. the i of step c is prepared compound and heterogeneous ring compound, triethylamine, alkali react in methylene dichloride;
Iii. step b is prepared compound and alkali, halogenated alkane react in acetone;
Iv. step b is prepared compound and pyridine, dimethyl aminopyridine, C
1-5The acid anhydrides of carboxylic acid reacts in methylene dichloride;
V. the i of step c is prepared compound and trimethylammonium silicon chlorides, sodium iodide, sodium cyanide react in acetonitrile;
Vi. compound (the R that step b is obtained
1, R
2, R
3, R
4In have one at least and represent aldehyde radical) react in methylene dichloride with clorox, TEMPO, sodium bicarbonate, Potassium Bromide, tetrabutylammonium chloride;
The sodium of vii. that the i of step c is prepared compound and mercaptan, thiophenol and sylvite, hydrocarbonylation reagent react in benzene;
Viii. the i of step c is prepared compound and Sodium Nitrite are in acetonitrile or dimethyl sulfoxide (DMSO), solvent dimethylformamide reaction;
Ix. step b is prepared compound and hydrocarbon sulfonic acid halide, pyridine react in ether.
Chemical equation 1:
In the above-mentioned chemical equation 1, compound (B) is R
1, R
2, R
3, R
4Identical or different, independent separately H, hydroxyl, the aldehyde radical represented; (32,33) position, (37,38) position void are rule, and on behalf of ethylene linkage, part is independent separately (remove R
1, R
2, R
3, R
4Be H) general formula (I) compound.X represents halogen (F, Cl, Br, I).
I in the step b)), ii), iii) prepared compound is R
1, R
2, R
3, R
4Identical or different, independently represent H, hydroxyl, aldehyde radical separately, but R
1, R
2, R
3, R
4In have a representation hydroxy at least; (32,33) position, (37,38) position void are rule, and part is identical or different independently represents ethylene linkage, epoxy group(ing) separately, but can not be general formula (I) compound of ethylene linkage simultaneously.Method i) product of gained is a racemoid, ii), iii) the product of two kinds of synthetic method gained is single optical isomer.
In resulting general formula (I) compound, R
1, R
2, R
3, R
4Identical or different, independent separately H, halogen, hydroxyl, mercaptan, cyano group, amino, nitro, itrate group, guanidine radicals, amide group,-oxyl, hydrocarbon sulfoamido, alkylacyloxy, hydrocarbon sulfonate ester group, carboxyl, aldehyde radical, ester group, heterocyclic radical, sulfenyl and corresponding sulfone or the sulfoxide represented.(32,33) position, the empty line in (37,38) position part are identical or different, the independent separately ethylene linkage (R that represents
1, R
2, R
3, R
4Be H and (32,33) position, the empty line part in (37,38) position is represented except the ethylene linkage simultaneously), epoxy group(ing); R
5And R
6Identical or different, independent separately H, the alkyl represented; X represents halogen (F, Cl, Br, I); R
15Be C
1-5Alkane or C
2-4Unsaturated alkyl; R
7, R
18Be alkyl, particularly C
2-8Optical activity is arranged or do not have the active unsaturated alkyl of optics, C
1-8Optical activity is arranged or do not have the active saturated alkane of optics, C
4-8Heterocyclic arene base or C
6-8Aryl, the C of replacement
4-8The heterocyclic arene base or the C of replacement
6-8Aryl.
The preparation of general formula of the present invention (I) type Gamboges acid derivative can also be represented by chemical equation 2:
A) with the compound of general formula (A) and tin anhydride, prepared in reaction corresponding compounds (B) in methylene dichloride;
B) compound (B) (R that step a) is prepared
1, R
2, R
3, R
4In have general formula (I) compound of a representation hydroxy at least), prepare general formula compound (I) by following steps:
I) compound (B) and tolysulfonyl halogen, dimethyl aminopyridine are reacted in methylene dichloride;
Ii) with step I) prepared compound and heterogeneous ring compound, triethylamine, alkali reacts in methylene dichloride;
Iii) compound (B) and alkali, halogenated alkane are reacted in acetone;
Iv) with compound (B) and pyridine, dimethyl aminopyridine, C
1-5The acid anhydrides of carboxylic acid reacts in methylene dichloride;
V) compound (B) and trimethylammonium silicon chlorides, sodium iodide, sodium cyanide are reacted in acetonitrile;
Vi) with compound (B) (R
1, R
2, R
3, R
4In have one at least and represent aldehyde radical) react in methylene dichloride with clorox, TEMPO, sodium bicarbonate, Potassium Bromide, tetrabutylammonium chloride;
Vii) with step I) prepared compound, acetyl thiourea react in ethanol;
Viii) with step I) prepared compound and Sodium Nitrite be in acetonitrile or dimethyl sulfoxide (DMSO), solvent dimethylformamide reaction;
Ix) will in ether, react by compound (B) and hydrocarbon sulfonic acid halide, pyridine.
Chemical equation 2:
In the above-mentioned chemical equation 2, compound (B) is with aforementioned.In general formula (I) compound, R
1, R
2, R
3, R
4Identical or different (except that R
1, R
2, R
3, R
4Be H), independent separately H, halogen, hydroxyl, cyano group,-oxyl, thiol group, amino, alkylacyloxy, hydrocarbon sulfonate ester group, carboxyl, aldehyde radical, the heterocyclic radical represented.(32,33) position, the independent separately ethylene linkage of representing of the empty line part in (37,38) position; R
5And R
6Identical or different, independent separately H, the alkyl represented.X, R
15, R
7, R
18Described in chemical equation 1.
With general formula (A) is raw material, according to step a), the b of correspondence) after, become ester method, carboxyl to become the method for acid amides to prepare R according to the carboxyl of organic synthesis field routine
1, R
2, R
3, R
4Identical or different (except that R
1, R
2, R
3, R
4Be H), independently represent H, halogen, hydroxyl, cyano group,-oxyl, thiol group, amino, alkylacyloxy, hydrocarbon sulfonate ester group, carboxyl, aldehyde radical, heterocyclic radical separately, and have at least one to be general formula (I) compound of ester group or amide group.
The preparation of general formula of the present invention (I) type Gamboges acid derivative can also be represented by chemical equation 3:
With compound (A) and the corresponding general formula of metachloroperbenzoic acid prepared in reaction in methylene dichloride (I) compound.
Chemical equation 3:
In the above-mentioned chemical equation 3, with general formula (A) general formula (I) compound that to be raw material prepare through the metachloroperbenzoic acid epoxidation reaction as above, R wherein
5And R
6Identical or different, independent separately H, the alkyl represented.
The preparation of general formula of the present invention (I) type Gamboges acid derivative also can be represented by chemical equation 4:
General formula (A) compound and AD-mix-α or AD-mix-β, methylsulfonyl ammonia are reacted in the trimethyl carbinol and water mixed solvent.
Chemical equation 4:
In the above-mentioned chemical equation 4, be raw material with general formula (A), AD-mix-α or AD-mix-β, methylsulfonyl ammonia react in the trimethyl carbinol and water mixed solvent, the general formula for preparing (I) compound, wherein R
5And R
6Identical or different, independent separately H, the alkyl represented.
Beneficial effect of the present invention:
At present, the screening active ingredients of antineoplastic compound is that the cytotoxic activity with compound embodies routinely, experimental data shows that The compounds of this invention has significant cytotoxicity (seeing the embodiment experimental data for details) to vitro human lung carcinoma cell (A549), colon cancer cell (HT-29), gastric carcinoma cells (BGC823), human liver cancer cell (Bel7402) and Proliferation of Human Ovarian Cell (SKOV3).
The invention will be further elaborated by the following examples, but do not limit the present invention in any way.
Embodiment
The silicagel column that the 100-200 order silica gel that related column chromatography step adopts Haiyang Chemical Plant, Qingdao to produce among the embodiment is loaded carries out column chromatography.Remove starting raw material A and be morellic acid through conventional esterification, alkylation reaction gained, agents useful for same is commercially available among the embodiment.
Embodiment 1:(37,38)-and epoxy-6-methoxyl group-morellic acid methyl esters (1a) and (32,33), (37,38)-bis-epoxy-6-methoxyl group-morellic acid methyl esters (1b) synthetic
Under 0 ℃, the 6-methoxyl group-morellic acid methyl esters with 328mg (0.5mmol) in the flask of 50ml is dissolved in the CH of 20ml
2Cl
2In, after the stirring and dissolving, adding metachloroperbenzoic acid 104mg (0.6mmol), room temperature reaction is after 6 hours, and stopped reaction concentrates column chromatography, petrol ether/ethyl acetate (4: 1) wash-out.Separate obtaining two compounds (1a), compound (1b), be yellow solid.
Compound (1a) 120mg wherein, mp:72-75 ℃, yield is 36%.
IR(film)：v＝2969，1731，1708，1621，1586，1460，1?379，878?cm
-1。
1H?NMR(300M，CDCl
3)：δ7.45(1H，d，J＝6.84Hz，H-10)，6.67(1H，d，J＝10.2Hz，H-4)，5.96(1H，m，H-27)，5.54(1H，d，J＝10.2Hz，H-3)，5.07(1H，m，H-32)，3.84(3H，s，6-OCH
3)，3.45(3H，s，COOCH
3)，3.43(1H，m，H-11)，3.30(1H，d，H-31a)，3.15(1H，m，H-31b)，2.98(2H，d，J＝6.99?Hz，H-26)，2.68(1H，t，H-37)，2.51(1H，d，J＝7.4Hz，?H-22)，2.31(1H，m，H-21a)，1.85(2H，m，H-36)，1.76(3H，s，H-25)，1.72(2H，m，H-20)，1.69(3H，s，H-29)，1.66(3H，s，H-34)，1.63(3H，s，H-35)，1.60(3H，s，H-39)，1.58(3H，s，H-40)，1.44(1H，m，H-21b)，1.47(3H，m，H-24)，1.28(3H，s，H-19)。
ESI-MS；673[M+H]
+，695[M+Na]
+.
Compound (1b) 80mg, yield is 24%, Mp:70-73 ℃.
IR(film)：v＝2928，1713，1708，1621，1587，1461，1381，1144，880cm
-1.
1HNMR(300M，CDCl
3)：δ7.46(1H，d，J＝6.9Hz，H-10)，6.69(1H，d，J＝10.1Hz，H-4)，6.02(1H，m，H-27)，5.58(1H，d，J＝10.1Hz，H-3)，3.83(3H，s，6-OCH
3)，3.45(3H，s，COOCH
3)，3.43(1H，m，H-11)，2.98(2H，m，H-26)，3.15(2H，m，H-31)，2.70(1H，m，H-32)，2.89(1H，m，H-37)，2.53(1H，m，H-22)，2.31(1H，m，H-21a)，1.40(1H，m，H-21b)，1.98(2H，m，H-36)，1.77(3H，s，H-25)，1.72(2H，m，H-20)，1.67(3H，s，H-29)，1.48(3H，s，H-34)，1.43(3H，s，H-40)，1.47(6H，brs，H-39，H-24)，1.94(3H，s，H-35)，1.28(3H，s，H-19).
ESI-MS：689[M+H]
+，711[M+Na]
+.
HRMS(M+Na)m/z711.3130(calcd?for?C
40H
48O
10?Na?711.3145).
Embodiment 2:(32,33), (37,38)-bis-epoxy-morellic acid (2)
Under 0 ℃, in the flask of 50ml, add the CH of 20ml
2Cl
2, add the morellic acid of 500mg (0.80mmol) and the metachloroperbenzoic acid of 165mg (0.96mmol) then, heat up naturally, stirred 27 hours under the room temperature, concentrate column chromatography, petrol ether/ethyl acetate (4: 1) wash-out, get yellow thickness compound (2), 40mg, yield are 35%.
IR(film)：v＝3452，2969，2927，1731，1713，1708，1681，1586，1460，1379cm
-1。
1H?NMR(500MHz，CDCl
3)：δ7.45(1H，d，J＝6.84Hz，H-10)，6.67(1H，d，J＝10.2Hz，H-4)，5.96(1H，m，H-27)，5.54(1H，d，J＝10.2Hz，H-3)，3.84(3H，s，6-OCH
3)，3.45(3H，s，COOCH
3)，3.43(1H，m，H-11)，3.30(1H，d，H-31a)，3.15(1H，m，H-31b)，2.98(2H，d，J＝6.99Hz，H-26)，2.70(2H，m，H-37，H-32)，2.51(1H，d，J＝7.4Hz，H-22)，2.31(1H，m，H-21a)，1.85(2H，m，H-36)，1.76(3H，s，H-25)，1.72(2H，m，H-20)，1.69(3H，s，H-29)，1.66(3H，s，H-34)，1.63(3H，s，H-35)，1.60(3H，s，H-39)，1.58(3H，s，H-40)，1.44(1H，m，H-21b)，1.47(3H，m，H-24)，1.28(3H，s，H-19).
ESI-MS：661[M+H]
+，683[M+Na]
+，659[M-H]
-.
HRMS(M+Na)m/z683.2821(calcd?for?C
38H
44O
10Na?683.2883)。
Embodiment 3:40-hydroxyl-6-methoxyl group-morellic acid methyl esters (3)
With SeO
27.6mg (0.068mmol) be mixed in the 10ml methylene dichloride with 75%t-BuOOH 185mg (2.06 mmol), behind the stirring at room 30min, dropping contains the dichloromethane solution 2ml of 6-methoxyl group-morellic acid methyl esters 450mg (0.69mmol), and reaction is 19 hours under the room temperature.Stopped reaction steams and removes methylene dichloride, ether dilution residual reactant, and organic phase is successively with 5% sodium hydroxide solution, water, saturated common salt washing, anhydrous MgSO
4Drying steams solvent, and petrol ether/ethyl acetate (2: 1) wash-out gets faint yellow chip solid (3) 280mg, mp:98-100 ℃. productive rate 61%.
IR(KBr)：v＝3467，3416，2966，2925，1734，1709，1655，1607，1586，1463，1427，1384，1225，1143，1046cm
-1.
1HNMR(300M，CDCl
3)：δ7.53(1H，d，J＝6.70Hz，H-10)，6.68(1H，d，J＝2.3Hz，H-4)，5.95(1H，m，H-27)，5.53(1H，d，J＝6.1Hz，H-3)，5.12(1H，m，H-37)，5.09(1H，m，H-32)，4.11(2H，s，H-40)，3.81(3H，s，6-OCH
3)，3.43(3H，s，COOCH
3)，3.41(1H，m，H-11)，3.37(1H，m，H-31a)，3.26(1H，m，H-31b)，2.96(2H，m，H-26)，2.51(1H，d，J＝9.31Hz，H-22)，2.30(1H，m，H-21a)，2.04(2H，m，H-36)，1.75(3H，s，H-25)，1.72(2H，m，H-20)，1.69(3H，s，H-34)，1.65(3H，s，H-35)，1.68(3H，s，H-39)，1.38(1H，m，H-21b)，1.44(3H，s，H-24)，1.28(3H，s，H-19)。
HRMS(M+H)m/z673.3369(calcd?for?C
40H
49O
9?673.3377).
Synthesizing of embodiment 4:40-acetoxyl group-6-methoxyl group-morellic acid methyl esters (4)
40-hydroxyl-6-methoxyl group-morellic acid methyl esters 85mg (0.13mmol) is dissolved among the methylene dichloride 5ml, pyridine 0.25ml (3.16mmol), catalytic amount DMAP2.0mg (0.013mmol), diacetyl oxide 0.29ml (3.16mmol) add stirring successively, room temperature reaction 20 hours, reaction solution dilutes with methylene dichloride, then with 1% dilute hydrochloric acid wash, the washing of washing, saturated common salt, anhydrous MgSO
4Drying steams solvent, and petrol ether/ethyl acetate (4: 1) wash-out gets yellow viscous material (4) 30mg, productive rate 33%.
IR(KBr)：v＝3467，3416，2963，2925，1746，1732，1709，1655，1607，1586，1460，1428，1384，1225，1143，1046cm
-1。
1HNMR(300M，CDCl
3)：δ7.53(1H，d，J＝6.70Hz，H-10)，6.68(1H，d，J＝2.3Hz，H-4)，5.95(1H，m，H-27)，5.53(1H，d，J＝6.1Hz，H-3)，5.12(1H，m，H-37)，5.09(1H，m，H-32)，4.20(2H，s，H-40)，3.81(3H，s，6-OCH
3)，3.43(3H，s，COOCH
3)，3.41(1H，m，H-11)，3.37(1H，m，H-31a)，3.26(1H，m，H-31b)，2.96(2H，m，H-26)，2.51(1H，d，J＝9.31Hz，H-22)，2.30(1H，m，H-21a)，2.19(3H，s，40-COCH3)，2.04(2H，m，H-36)，1.75(3H，s，H-25)，1.72(2H，m，H-20)，1.69(3H，s，H-34)，1.65(3H，s，H-35)，1.68(3H，s，H-39)，1.38(1H，m，H-21b)，1.44(3H，s，H-24)，1.28(3H，s，H-19)。
ESI-MS?715[M+H]
+，737[M+Na]
+，753[M+K]
+
Embodiment 5:(34,40)-dihydroxyl-6-methoxyl group-morellic acid methyl esters (5) synthetic
SeO2 24mg (0.25mmol) and 75%t-BuOOH 0.25ml (2.3mmol) are mixed in the 10ml methylene dichloride, and behind the stirring at room 30min, dripping concentration is 6-methoxyl group-morellic acid methyl esters dichloromethane solution 5ml of 0.152M, and reaction is 7 hours under the room temperature.Stopped reaction steams and removes methylene dichloride, ether dilution residual reactant, and organic phase is water, saturated common salt washing successively, anhydrous Na
2SO
4Drying steams solvent, and petrol ether/ethyl acetate (1: 1) wash-out gets yellow dope 70mg, yield 13%.
1HNMR(300M，CDCl
3)：δ7.44(1H，d，J＝6.96Hz，H-10)，6.69(1H，d，J＝10.3Hz，H-4)，5.72(1H，t，H-27)，5.57(1H，d，J＝10.2Hz，H-3)，5.50(1H，m，H-37?or?H-32)，5.35(1H，m，H-37?or?H-32)，3.98(4H，m，H-35，H-39)，3.82(3H，s，6-OCH
3)，3.47(1H，m，H-11)，3.36(3H，s，COOCH
3)，3.40(1H，m，H-31a)，3.16(1H，m，H-31b)，2.90(2H，m，H-26)，2.52(1H，m，H-22)，2.32(1H，m，H-21a)，2.09(2H，m，H-36)，1.83(3H，s，H-29)，1.72(2H，m，H-20)，1.67(3H，m，H-34)，1.69(3H，s，H-25)，1.59(3H，s，H-40)，1.47(1H，m，H-24)，1.39(1H，m，H-21b).1.23(3H，s，H-19).
ESI-MS：689[M+H]
+，711[M+Na]
+.
HRMS(M+H)m/z689.3309(calcd?for?C
40H
49O
10?689.3326)。
Synthesizing of embodiment 6:34-hydroxyl-morellic acid (6)
With SeO
26mg (0.05mmol) and 75%t-BuOOH 270mg (3.0mmol) are mixed in the 10ml methylene dichloride, and behind the stirring at room 30min, dripping concentration is the morellic acid dichloromethane solution 2ml of 0.5M, and reaction is 12 hours under the room temperature.Stopped reaction steams and removes methylene dichloride, and ether dilution residual reactant machine is water, saturated common salt washing successively mutually, anhydrous Na
2SO
4Drying steams solvent, and petrol ether/ethyl acetate (1: 1) wash-out gets yellow solid 130mg, and mp:103-105 ℃, productive rate 21%.
IR(KBr)：v＝3457，3420，2970，2923，1736，1689，1623，1592，1454，1436，1400，1381，1330，1176，1138，1047cm
-1。
1HNMR(300M，CDCl
3)：δ?7.54(1H，d，J＝6.5Hz，H-10)，6.59(1H，d，J＝10Hz，H-4)，5.75(1H，m，H-27)，5.43(1H，d，J＝10.0Hz，H-3)，5.38(1H，m，H-37)，5.05(1H，m，H-32)，3.9(2H，d，J＝5.5Hz，H-34)，3.49(1H，m，H-11)，3.31(1H，m，H-31a)，3.13(1H，dd，J＝8.6Hz，8.6Hz，H-31b)，2.93(2H，dd，J＝4.4Hz，4.3Hz?H-26)，2.50(1H，d，J＝9.3Hz，H-22)，2.31(1H，dd，J＝4.5Hz，4.4Hz，H-21?a)，2.03(2H，m，H-36)，1.78(3H，m，H-25)，1.72(3H，s，H-29)，1.70(2H，m，H-20)，1.65(3H，s，H-35)，1.66(3H，s，H-39)，1.55(3H，s，H-40)，1.41(1H，m，H-24)，1.37(1H，m，H-21b).1.25(3H，s，H-19)。
ESI-MS?667[M+Na]
+，683[M+K]
+。
HRMS(M+Na)m/z667.2888(calcd?for?C
38H
44O
9Na?667.2883)。
Embodiment 7:34-hydroxyl-40-aldehyde radical-morellic acid (7)
SeO2 6mg (0.05mmol) and 75%t-BuOOH 270mg (1mmol) are mixed in the 10ml methylene dichloride, and behind the stirring at room 30min, dripping concentration is the dichloromethane solution 2ml of 40-aldehyde radical-morellic acid of 0.5M, and reaction is 12 hours under the room temperature.Stopped reaction steams and removes methylene dichloride, ether dilution residual reactant, and organic phase is water, saturated common salt washing successively, anhydrous Na
2SO
4Drying steams solvent, and petrol ether/ethyl acetate (2: 1) wash-out gets yellow solid 40mg, yield 6.1%.Mp：105-107℃.
IR(KBr)：v＝3470，3418，2972，2924，2854，1736，1687，1634，1592，1454，1436，1400，1380，1331，1240，1176，1138，1046，1018cm
-1。
1HNMR(300M，CDCl
3)：δ12.80(1H，s，6-OH)，9.32(1H，s，CHO)，7.57(1H，d，J＝6.9Hz，H-10)，7.32(1H，m，H-32)，6.68(1H，d，J＝10.1Hz，H-4)，6.50(1H，d，J＝10.1Hz，H-3)，6.3(1H，m，H-27)，5.4(1H，m，H-3)，3.95(2H，brd，J＝12.7Hz，H-34)，3.50(1H，m，H-11)，3.30(2H，brdd，H-31)，2.98(2H，m，H-26)，2.07(2H，m，H-36)，2.72(1H，d，J＝9.3?Hz，H-22)，2.37(1H，dd，H-21a)，2.31(1H，m，H-21a)，2.15(2H，m，H-36)，1.72(2H，m，H-20)，1.70(3H，s，H-29)，1.45(3H，s，H-24)，1.55(3H，s，H-40)，1.68(3H，s，H-35)，1.40(1H，m，H-21b)，1.28(3H，s，H-19)。
ESI-MS：657[M-H]
+。
HRMS(M+Na)m/z681.2643(calcd?for?C
38H
42O
10Na?681.2676)。
Embodiment 8:(34,40)-dihydroxyl-morellic acid (8)
With SeO
260mg (0.5mmol) and 75%t-BuOOH 270mg (3mmol) are mixed in the 10ml methylene dichloride, and behind the stirring at room 30min, dripping concentration is morellic acid (I) the dichloromethane solution 2ml of 0.5M, and reaction is 12 hours under the room temperature.Stopped reaction steams and removes methylene dichloride, ether dilution residual reactant, and organic phase is water, saturated common salt washing successively, anhydrous Na
2SO
4Drying steams solvent, and petrol ether/ethyl acetate (1: 1) wash-out gets yellow solid 100mg, and mp:85-87 ℃, yield 15%.
IR(KBr)：v＝3474，3416，2963，2923，1734，1714，1635，1592，1435，1401，1330，1176，1260，1095，1022，802cm
-1。
1HNMR(300M，CDCl
3)：δ?137.61(1H，d，J＝6.9Hz，H-10)，6.65(1H，d，J＝9.9?Hz，H-4)，5.9(1H，m，H-27)，5.58(1H，d，J＝10.0Hz，H-3)，5.39(1H，m，H-32)，3.9(4H，brd，J＝9.6Hz?H-34，H-40)，3.52(1H，m，H-11)，3.33(2H，m，H-31a)，3.10(1H，dd，?J＝14.7Hz，7.6Hz，H-31b)，2.93(2H，d，J＝7.23Hz，H-26)，2.68(1H，t，H-37)，2.51(1H，d，J＝9.0Hz，H-22)，2.31(1H，dd，J＝4.5Hz，4.8Hz，H-21a)，2.13(2H，m，H-36)，1.46(1H，m，H-24)，1.45(1H，m，H-21b)，1.80(3H，m，H-25)，1.78(3H，s，H-29)，1.72(2H，m，H-20)，1.68(3H，s，H-35)，1.69(3H，s，H-39)，1.56(3H，s，H-19)。
ESI-MS?661[M+H]
+，683[M+Na]
+。
HRMS(M+Na)m/z683.2820(calcd?for?C
38H
44O
10Na?683.2832)。
Embodiment 9:40-hydroxyl-(37R, 38S)-epoxy-6-methoxyl group-morellic acid methyl esters (9)
In the flask of 50ml, with four different oxygen propyl group titanium 0.28ml (0.95mmol), CaH
26.9mg, silica gel H 6.9mg, 4
Molecular sieve 13.7mg is dissolved among the anhydrous methylene chloride 20ml; argon shield;-20 ℃ drip (+)-diethyl tartrate 0.3mg (11.4mmol) down; behind the 10min, add compound 40-hydroxyl-6-methoxyl group-morellic acid methyl esters 638mg (0.95mmol), behind the stirring 15min; under-40 ℃; dropping contains the toluene solution 1ml of anhydrous peroxy tert-butyl alcohol 0.3ml (1.9mmol), reacts stirring 3 hours down at subzero 30～subzero 40 ℃, and it is complete to put into the refrigerator question response.Add 10% aqueous tartaric acid solution 15ml in system, stirring at room to reaction mixture is transparent clarification, then solution is poured in the frozen water, uses extracted with diethyl ether, merges organic layer, uses the 10%KOH aqueous solution successively, water, saturated common salt water washing, MgSO
4Drying is steamed and is removed ether solution, and rapid column chromatography obtains colourless liquid 192mg, productive rate 30%.
IR(KBr)：v＝3467，3416，2960，2925，1736，1709，1655，1608，1586，1465，1427，1384，1220，1143，1080，1048cm
-1.
1HNMR(300M，CDCl
3)：δ7.53(1H，d，J＝6.70Hz，H-10)，6.68(1H，d，J＝2.3Hz，H-4)，5.95(1H，m，H-27)，5.53(1H，d，J＝6.1Hz，H-3)，5.12(1H，m，H-37)，5.09(1H，m，H-32)，4.11(2H，s，H-40)，3.81(3H，s，6-OCH
3)，3.43(3H，s，COOCH
3)，3.41(1H，m，H-11)，3.37(1H，m，H-31a)，3.26(1H，m，H-31b)，2.96(2H，m，H-26)，2.51(1H，d，J＝9.31Hz，H-22)，2.30(1H，m，H-21a)，2.04(2H，m，H-36)，1.75(3H，s，H-25)，1.72(2H，m，H-20)，1.69(3H，s，H-34)，1.65(3H，s，H-35)，1.68(3H，s，H-39)，1.38(1H，m，H-21b)，1.44(3H，s，H-24)，1.28(3H，s，H-19)。
ESI-MS?689[M+H]
+，711[M+Na]
+，727[M+K]
+
Ultimate analysis: C
40H
48O
10Found C 69.55%H 6.98%O 23.03%; Calcd C 69.75%H 7.02%O 23.23%.
Embodiment 10:40-hydroxyl-(37,38)-epoxy-6-methoxyl group-morellic acid methyl esters (10)
In the 25ml round-bottomed flask, add 5ml dry-out benzene and 40-hydroxyl-6-methoxyl group-morellic acid methyl esters 638 (0.95mmol) 136mg (0.73mmol), under 0 ℃ of the argon shield, add VO (acac)
210mg (0.04 mmol) adds peroxy tert-butyl alcohol 0.5ml (1.46mmol) after 10 minutes, reaction mixture at room temperature stirred 12 hours, added the less water cancellation, the mixed solution extracted with diethyl ether.Organic phase is used saturated sodium thiosulfate successively, saturated sodium bicarbonate solution, saturated common salt washing, anhydrous magnesium sulfate drying.Steam and remove ether solution, rapid column chromatography obtains yellow sticky solid 62mg, productive rate 45%.
Spectral data is isomers with (9) with (9).
Embodiment 11:40-chloro-6-methoxyl group-morellic acid methyl esters (11)
In the 25ml flask, compound 40-hydroxyl-6-methoxyl group-morellic acid methyl esters 564 mg (0.84mmol) are dissolved among the methylene dichloride 15ml, add Tosyl chloride 193mg (1.01mmol) and dimethyl aminopyridine 206mg (1.68mmol) under 0 ℃ successively, 0 ℃ was reacted 8 hours down, reaction solution dilutes with methylene dichloride, then with 2% dilute hydrochloric acid wash, the washing of washing, saturated common salt, anhydrous MgSO
4Drying steams solvent, column chromatography, and petrol ether/ethyl acetate (4: 1) wash-out gets yellow viscous material 230mg, productive rate about 51%.
IR(KBr)：v＝2925，2853，1731，1686，1640，1586，1462，1426，1378，1260，1236，1172，1145，1115，1020，600cm
-1.
1HNMR(300M，CDCl
3)：δ7.53(1H，d，J＝6.70Hz，H-10)，6.68(1H，d，J＝2.3Hz，H-4)，5.95(1H，m，H-27)，5.56(1H，d，J＝6.1Hz，H-3)，5.20(1H，m，H-37)，5.08(1H，m，H-32)，4.05(2H，s，H-40)，3.81(3H，s，6-OCH
3)，3.43(3H，s，COOCH
3)，3.41(1H，m，H-11)，3.37(1H，m，H-31a)，3.26(1H，m，H-31b)，2.96(2H，m，H-26)，2.53(1H，d，J＝9.31Hz，H-22)，2.30(1H，m，H-21a)，2.04(2H，m，H-36)，1.75(3H，s，H-25)，1.72(2H，m，H-20)，1.69(3H，s，H-34)，1.65(3H，s，H-35)，1.68(3H，s，H-39)，1.44(3H，s，H-24)，1.38(1H，m，H-21b)，1.28(3H，s，H-19)。
ESI-MS?691[M+H]
+，713[M+Na]
+
Ultimate analysis: C
40H
47ClO
8Found C 69.40% H 6.78% Cl 5.03% O 18.42%; CalcdC 69.50% H 6.85% Cl 5.13% O 18.52%.
Embodiment 12:34,40-two chloro-6-methoxyl groups-morellic acid methyl esters (12)
In the 25ml flask, with compound 34,40-dihydroxyl-6-methoxyl group-morellic acid methyl esters 578mg (0.84mmol) is dissolved among the methylene dichloride 15ml, add Tosyl chloride 483 mg (2.5mmol) and dimethyl aminopyridine 368mg (3.0mmol) under 0 ℃ successively, 0 ℃ was reacted 12 hours down, reaction solution dilutes with methylene dichloride, then with 2% dilute hydrochloric acid wash, the washing of washing, saturated common salt, anhydrous MgSO
4Drying steams solvent, column chromatography, and petrol ether/ethyl acetate (16: 1) wash-out gets yellow viscous material 274mg, productive rate about 45%.
IR(KBr)：v＝2925，2853，1731，1686，1640，1586，1462，1426，1378，1260，1236，1172，1145，1115，1020?cm
-1.
1HNMR(300M，CDCl
3)：δ7.53(1H，d，J＝6.70Hz，H-10)，6.68(1H，d，J＝2.3Hz，H-4)，5.95(1H，m，H-27)，5.58(1H，d，J＝6.1Hz，H-3)，5.08(1H，m，H-37)，5.04(1H，m，H-32)，4.05(2H，s，H-40)，4.0(2H，s，H-34)，3.83(3H，s，6-OCH
3)，3.42(3H，s，COOCH
3)，3.41(1H，m，H-11)，3.37(1H，m，H-31a)，3.26(1H，m，H-31b)，2.96(2H，m，H-26)，2.53(1H，d，J＝9.31Hz，H-22)，2.30(1H，m，H-21a)，2.04(2H，m，H-36)，1.75(3H，s，H-25)，1.72(2H，m，H-20)，1.67(3H，s，H-35)，1.68(3H，s，H-39)，1.42(3H，s，H-24)，1.38(1H，m，H-21b)，1.26(3H，s，H-19)。
ESI-MS?725[M+H]
+，747[M+Na]
+
Ultimate analysis: C
40H
46Cl
2O
8Found C 66.13%, H 6.19%, and Cl 9.59%, and O 17.75%;
Calcd?C?66.20％，H?6.39％，Cl?9.77％，O?17.64％。
Embodiment 13:40-piperazine-6-methoxyl group-morellic acid methyl esters (13)
40-chloro-6-methoxyl group-morellic acid methyl esters 97mg (0.14mmol) is dissolved among the methylene dichloride 5ml, drip piperazine 1.38ml (1.38mmol) under 0 ℃ successively, reaction solution is a water white transparency, stir, room temperature reaction 10 hours, reaction solution dilutes with methylene dichloride, wash with water then, saturated common salt washing, anhydrous MgSO
4Drying steams solvent, the residue column chromatography, and petrol ether/ethyl acetate (1: 1) wash-out gets faint yellow solid 60mg, and mp 118-120 ℃, productive rate about 60%.
IR(KBr)：v＝3476，2965，2921，2852，1680，1633，1589，1412，1381，1261，1083，1040，803cm
-1.
1HNMR(300M，CDCl
3)：δ7.53(1H，d，J＝6.70Hz，H-10)，6.68(1H，d，J＝2.3Hz，H-4)，5.95(1H，m，H-27)，5.58(1H，d，J＝6.1Hz，H-3)，5.08(1H，m，H-37)，5.04(1H，m，H-32)，4.0(2H，s，H-34)，3.83(3H，s，6-OCH
3)，3.42(3H，s，COOCH
3)，3.41(1H，m，H-11)，3.37(1H，m，H-31a)，3.26(1H，m，H-31b)，3.15(2H，s，H-40)，2.96(2H，m，H-26)，2.71(8H，m，Piperazine-H)，2.53(1H，d，J＝9.31Hz，H-22)，2.30(1H，m，H-21a)，2.04(2H，m，H-36)，1.75(3H，s，H-25)，1.71(2H，m，H-20)，1.66(3H，s，H-35)，1.68(3H，s，H-39)，1.42(3H，s，H-24)，1.37(1H，m，H-21b)，1.26(3H，s，H-19)。
ESI-MS?741[M+H]
+，763[M+Na]
+.
Ultimate analysis: C
44H
56N
2O
8, Found C 70.93%, H 7.51%, and N 3.59%, and O 17.24%; Calcd C71.33%, H 7.62%, and N 3.78%, and O 17.27%.
Embodiment 14:34,40-dimethoxy-6-methoxyl group-morellic acid methyl esters (14)
(34,40)-dihydroxyl-morellic acid 2.0g (3.1mmol) is dissolved among the acetone 50ml, adds anhydrous K
2CO
36.0g (43.4mmol), N
2Protection is stirred down, drips methyl iodide 4ml (64.4mmol) behind about 30min, and stirring reaction is 48 hours under the room temperature.After reaction finishes, remove by filter K
2CO
3, concentrate column chromatography, petrol ether/ethyl acetate (4: 1) wash-out.Concentrate faint yellow tabular crystal 1.3g, mp 92-95 ℃, yield is 62%.
IR(KBr)：v＝2967，2923，1734，1714，1635，1592，1436，1401，1332，1176，1260，1095，1022?cm
-1.
1HNMR(300M，CDCl
3)：δ137.61(1H，d，J＝6.9Hz，H-10)，6.65(1H，d，J＝9.9?Hz，H-4)，5.9(1H，m，H-27)，5.58(1H，d，J＝10.0Hz，H-3)，5.39(2H，m，H-32，37)，3.84(4H，brd，J＝9.6Hz?H-34，H-40)，3.52(1H，m，H-11)，3.33(2H，m，H-31a)，3.24(6H，s，34-OCH
3，40-OCH
3)，3.10(1H，dd，J＝14.7Hz，7.6Hz，H-31b)，2.93(2H，d，J＝7.23Hz，H-26)，2.51(1H，d，J＝9.0Hz，H-22)，2.31(1H，dd，J＝4.5Hz，4.8Hz，H-21?a)，2.13(2H，m，H-36)1.80(3H，m，H-25)，1.78(3H，s，H-29)，1.72(2H，m，H-20)，1.68(3H，s，H-35)，1.69(3H，s，H-39)，1.46(1H，m，H-24)，1.45(1H，m，H-21b)，1.36(3H，s，H-19).
ESI-MS?717[M+H]
+，739[M+Na]
+.
Ultimate analysis: C
42H
52O
10.Found C 70.33%, and H 7.21%, and O 22.24%; Calcd C 70.37%, H 7.31%, and O 22.32%.
Embodiment 15:40-cyano group-6-methoxyl group-morellic acid methyl esters (15)
The sodium iodide of 40-hydroxyl-6-methoxyl group-morellic acid methyl esters 68mg (0.1mmol), sodium cyanide 9.8mg (0.2mmol) and catalytic amount is dissolved among anhydrous acetonitrile 5ml and the dimethyl formamide 5ml; nitrogen protection; drip trimethylchlorosilane 22mg (0.2mmol) under the room temperature; stir; be warming up to 60 ℃, react and stopped in 6 hours.Reaction solution to 20ml water, is used ether extraction three times then, and organic phase is washed with saturated common salt, anhydrous MgSO
4Drying steams solvent, and residue column chromatography petrol ether/ethyl acetate (2: 1) wash-out gets faint yellow solid 48mg, and mp 118-120 ℃, productive rate about 70%.
IR(KBr)：v＝2966，2925，2250，1733，1709，1655，1607，1586，1463，1428，1385，1225，1143，1042cm
-1.
1HNMR(300M，CDCl
3)：δ7.53(1H，d，J＝6.70Hz，H-10)，6.68(1H，d，J＝2.3Hz，H-4)，5.95(1H，m，H-27)，5.53(1H，d，J＝6.1Hz，H-3)，5.12(1H，m，H-37)，5.09(1H，m，H-32)，3.81(3H，s，6-OCH
3)，3.43(3H，s，COOCH
3)，3.41(1H，m，H-11)，3.37(1H，m，H-31a)，3.26(1H，m，H-31b)，3.18(2H，s，H-40)，2.96(2H，m，H-26)，2.51(1H，d，J＝9.31Hz，H-22)，2.30(1H，m，H-21a)，2.04(2H，m，H-36)，1.75(3H，s，H-25)，1.72(2H，m，H-20)，1.69(3H，s，H-34)，1.65(3H，s，H-35)，1.68(3H，s，H-39)，1.38(1H，m，H-21b)，1.44(3H，s，H-24).1.28(3H，s，H-19)。
ESI-MS?682[M+H]
+，704[M+Na]
+。
Ultimate analysis: C
41H
47NO
8, Found C 72.23%, H 6.95%, and N 2.05%, and O 18.77%;
Calcd?C?72.03％，H?6.78％，N?2.12％，O?18.84％。
Embodiment 16:40-nitro-6-methoxyl group-morellic acid methyl esters (16)
Sodium Nitrite 36mg (0.52mmol) is dissolved among the dimethyl sulfoxide (DMSO) 15ml, slowly adds 40-chloro-6-methoxyl group-morellic acid methyl esters 207mg (0.3mmol) then under the ice bath, room temperature reaction 7 hours.Reaction solution to water 50ml, is used ether extraction three times then, and organic phase is washed with saturated common salt, anhydrous MgSO
4Drying steams solvent, the residue column chromatography, and petrol ether/ethyl acetate (8: 1) wash-out gets faint yellow dope 63mg, productive rate about 30%.
IR(KBr)：v＝2966，2925，2240，1733，1709，1655，1660，1607，1586，1463，1410，1428，1385，1260，1225，1175，1042cm
-1.
1HNMR(300M，CDCl
3)：δ7.54(1H，d，J＝6.70Hz，H-10)，6.68(1H，d，J＝2.3Hz，H-4)，5.95(1H，m，H-27)，5.53(1H，d，J＝6.1Hz，H-3)，5.50(1H，m，H-37)，5.10(1H，m，H-32)，4.95(2H，s，H-40)，3.81(3H，s，6-OCH
3)，3.43(3H，s，COOCH
3)，3.41(1H，m，H-11)，3.37(1H，m，H-31a)，3.26(1H，m，H-31b)，2.97(2H，m，H-26)，2.51(1H，d，J＝9.31Hz，H-22)，2.30(1H，m，H-21a)，2.06(2H，m，H-36)，1.75(3H，s，H-25)，1.72(2H，m，H-20)，1.69(3H，s，H-34)，1.65(3H，s，H-35)，1.68(3H，s，H-39)，1.39(1H，m，H-21b)，1.44(3H，s，H-24).1.28(3H，s，H-19)。
ESI-MS?702[M+H]
+，724[M+Na]
+.
Ultimate analysis: C
40H
47NO
10, Found C 68.23%, H 6.95%, and N 2.05%, and O 22.77%;
Calcd?C?68.46％，H?6.75％，N?2.00％，O?22.80％。
Embodiment 17:40-nitro-(32,33)-epoxy-6-methoxyl group-morellic acid methyl esters (17)
Under 0 ℃, in the flask of 50ml, add CH
2Cl
220ml, add then 40-nitro-6-methoxyl group-morellic acid methyl esters 70mg (0.1mmol) and between cross chloro-benzoic acid 25mg (0.12mmol), naturally heat up, stirred 15 hours under the room temperature, concentrate column chromatography, petrol ether/ethyl acetate (4: 1) wash-out, get yellow thickness compound 27mg, yield is 37%.
IR(film)：v＝2969，2927，1731，1713，1708，1681，1660，1586，1460，1379，1410，1126，1260，1050，400cm
-1。
1H?NMR(500MHz，CDCl
3)：δ7.45(1H，d，J＝6.84Hz，H-10)，6.67(1H，d，J＝10.2Hz，H-4)，5.96(1H，m，H-27)，5.54(1H，d，J＝10.2Hz，H-3)，5.48(1H，m，H-37)，3.83(3H，s，6-OCH
3)，3.45(3H，s，COOCH
3)，3.43(1H，m，H-11)，3.30(1H，d，H-31a)，3.15(1H，m，H-31b)，2.98(2H，d，J＝6.99Hz，H-26)，2.70(1H，m，H-32)，2.51(1H，d，J＝7.4Hz，?H-22)，2.31(1H，m，H-21a)，1.85(2H，m，H-36)，1.76(3H，s，H-25)，1.72(2H，m，H-20)，1.69(3H，s，H-29)，1.66(3H，s，H-34)，1.63(3H，s，H-35)，1.60(3H，s，H-39)，1.58(3H，s，H-40)，1.44(1H，m，H-21b)，1.47(3H，m，H-24)，1.28(3H，s，H-19).
ESI-MS：718[M+H]
+，740[M+Na]
+.
Ultimate analysis: C
40H
47NO
11, Found C 66.23%, H 6.75%, and N 2.05%, and O 24.77%;
Calcd?C?66.93％，H?6.60％，N?1.95％，O?24.52％。
Embodiment 18:6-methoxyl group-morellic acid methoxycarbonyl-40-p-toluenesulfonic esters (18)
In the flask of 50ml, add anhydrous diethyl ether 20ml, add Tosyl chloride 173mg (0.1mmol), 40-hydroxyl-6-methoxyl group-morellic acid methyl esters 68mg (0.1mmol) then, drip the anhydrous ether solution of anhydrous pyridine 9.0mg (0.11mmol), ether is little to boil, the adularescent solid is separated out, and stirs 13 hours under the room temperature.After reaction finishes, remove by filter white solid, filtrate water, 5% hydrochloric acid, 5% aqueous sodium hydroxide washes, the anhydrous MgSO of organic phase
4Dry.Concentrate column chromatography, petrol ether/ethyl acetate (4: 1) wash-out.Concentrate faint yellow tabular crystal 1.3g, mp 96-98 ℃, yield is 62%.
IR(KBr)：v＝3080，3030，2966，2925，1733，1709，1655，1607，1586，1575，1463，1428，1415，1385，1225，1200，1185，1143，1042，950cm
-1.
1HNMR(300M，CDCl
3)：δ7.54(1H，d，J＝6.70Hz，H-10)，6.94(4H，m，Ar-H)6.68(1H，d，J＝2.3Hz，H-4)，5.95(1H，m，H-27)，5.53(1H，d，J＝6.1Hz，H-3)，5.50(1H，m，H-37)，5.10(1H，m，H-32)，4.20(2H，s，H-40)，3.81(3H，s，6-OCH
3)，3.43(3H，s，COOCH
3)，3.41(1H，m，H-11)，3.37(1H，m，H-31a)，3.26(1H，m，H-31b)，2.97(2H，m，H-26)，2.51(1H，d，J＝9.31Hz，H-22)，2.34(3H，s，Ar-CH
3，2.30(1H，m，H-21a)，2.06(2H，m，H-36)，1.75(3H，s，H-25)，1.72(2H，m，H-20)，1.69(3H，s，H-34)，1.65(3H，s，H-35)，1.68(3H，s，H-39)，1.39(1H，m，H-21b)，1.44(3H，s，H-24).1.28(3H，s，H-19)。
ESI-MS?737[M+H]
+.
Ultimate analysis: C
48H
58O
11S, Found C 68.23%, H 6.85%, and S 3.45%, and O 20.76%;
Calcd?C?68.39％，H?6.93％，O?20.88％，S?3.80％。
Embodiment 19:40-carboxylic acid-6-methoxyl group-morellic acid methyl esters (19)
Under 0 ℃, in the flask of 50ml, add CH
2Cl
220ml, add clorox 67mg (0.9mmol), TEMPO 2.5mg (0.015mmol), sodium bicarbonate 25mg (0.3mmol), Potassium Bromide 36mg (0.3mmol), tetrabutylammonium chloride 80mg (0.3mmol) and 40-hydroxyl-6-methoxyl group-morellic acid methyl esters 205mg (0.3mmol) then successively, naturally heat up, stirred 24 hours under the room temperature, concentrate column chromatography, petrol ether/ethyl acetate (4: 1) wash-out, get yellow solid compound 70mg, mp 116-118 ℃, yield is 33%.
IR(KBr)：v＝3550，3316，2500，1736，1740，1709，1655，1607，1586，1463，1427，1384，1225，1143，1046cm
-1.
1HNMR(300M，CDCl
3)：δ7.53(1H，d，J＝6.70Hz，H-10)，6.68(1H，d，J＝2.3Hz，H-4)，5.95(1H，m，H-27)，5.53(1H，d，J＝6.1Hz，H-3)，6.12(1H，m，H-37)，5.10(1H，m，H-32)，3.81(3H，s，6-OCH
3)，3.43(3H，s，COOCH
3)，3.41(1H，m，H-11)，3.37(1H，m，H-31a)，3.26(1H，m，H-31b)，2.96(2H，m，H-26)，2.51(1H，d，J＝9.31Hz，H-22)，2.30(1H，m，H-21a)，2.04(2H，m，H-36)，1.89(3H，s，H-39)，1.75(3H，s，H-25)，1.72(2H，m，H-20)，1.69(3H，s，H-34)，1.65(3H，s，H-35)，1.38(1H，m，H-21b)，1.44(3H，s，H-24).1.28(3H，s，H-19)。
ESI-MS?687[M+H]
+.
Ultimate analysis: C
40H
46O
10, Found C 69.23%, H 6.58%, and O 22.76%;
Calcd?C?69.95％，H?6.75％，O?23.30％。
Embodiment 20:40-iodo-6-methoxyl group-morellic acid methyl esters (20)
The acetone that in the flask of 50ml, adds 20ml, add 40mg (0.24mmol) sodium iodide then, stir, drip the acetone soln 2ml that contains 138mg (0.2mmol) 40-chloro-6-methoxyl group-morellic acid methyl esters again, after dripping, stirred 24 hours under the room temperature, remove by filter precipitation, filtrate concentrates, column chromatography, petrol ether/ethyl acetate (4: 1) wash-out gets yellow dope 94mg, and yield is 63%.
IR(KBr)：v＝2925，2853，1732，1689，1640，1580，1462，1427，1378，1260，1236，1176，1145，1118，1026，587cm
-1.
1HNMR(300M，CDCl
3)：δ7.53(1H，d，J＝6.70Hz，H-10)，6.68(1H，d，J＝2.3Hz，H-4)，5.95(1H，m，H-27)，5.56(1H，d，J＝6.1Hz，H-3)，5.10(2H，m，H-37，H-32)，3.85(2H，s，H-40)，3.81(3H，s，6-OCH
3)，3.43(3H，s，COOCH
3)，3.41(1H，m，H-11)，3.37(1H，m，H-31a)，3.26(1H，m，H-31b)，2.96(2H，m，H-26)，2.53(1H，d，J＝9.3?1Hz，H-22)，2.30(1H，m，H-21a)，2.04(2H，m，H-36)，1.75(3H，s，H-25)，1.73(2H，m，H-20)，1.67(3H，s，H-34)，1.66(3H，s，H-35)，1.68(3H，s，H-39)，1.44(3H，s，H-24)，1.38(1H，m，H-21b)，1.28(3H，s，H-19)。
ESI-MS?783[M+H]
+，805[M+Na]
+
Ultimate analysis: C
40H
47IO
8Found C 61.40%, H 6.70%, and Cl 6.03%, and O 16.42%;
Calcd?C?61.38％，H?6.05％，I?16.21％，O?16.35％。
Embodiment 21:40-thiol group-6-methoxyl group-morellic acid methyl esters (21)
In the flask of 50ml, add in the anhydrous acetonitrile of 20ml, add 11.8mg (0.1mmol) acetyl thiourea then, after stirring, the 40-iodo-6-methoxyl group-morellic acid methyl esters that adds 108mg (0.13mmol) again, reflux after one hour, the solid of separating out is filtered in cooling, 90mg is arranged after the drying approximately, it is continued to join in the ethanol of 15ml, back flow reaction, aftertreatment gets yellow solid compound 43mg, mp 110-111 ℃, yield is 53%.
IR(KBr)：v＝2966，2925，2600，1736，1740，1709，1655，1607，1586，1463，1427，1384，1225，1143，1046，915cm
-1.
1HNMR(300M，CDCl
3)：δ7.55(1H，d，J＝6.70Hz，H-10)，6.67(1H，d，J＝2.3Hz，H-4)，5.95(1H，m，H-27)，5.53(1H，d，J＝6.1Hz，H-3)，6.12(1H，m，H-37)，5.06(1H，m，H-32)，3.82(3H，s，6-OCH
3)，3.43(3H，s，COOCH
3)，3.41(1H，m，H-11)，3.37(1H，m，H-31a)，3.30(2H，s，H-40)，3.25(1H，m，H-31b)，2.96(2H，m，H-26)，2.51(1H，d，J＝9.31Hz，H-22)，2.30(1H，m，H-21a)，2.04(2H，m，H-36)，1.86(3H，s，H-39)，1.75(3H，s，H-25)，1.73(2H，m，H-20)，1.69(3H，s，H-34)，1.65(3H，s，H-35)，1.38(1H，m，H-21b)，1.44(3H，s，H-24).1.27(3H，s，H-19)。
ESI-MS?689[M+H]
+.
Ultimate analysis: C
40H
48O
8S, Found C 69.70%, H 7.22%, and O 18.46%, and S 4.48%;
Calcd?C?69.74％，H?7.02％，O?18.58％，S?4.65％。
Embodiment 22:(37R, 38)-dihydroxyl-6-methoxyl group morellic acid methyl esters (22)
In the round-bottomed flask of 25ml, add trimethyl carbinol 5ml and water 5ml, and AD-mix-α 2.67g (1.91mmol), methylsulfonyl ammonia 182mg (1.91mmol), stirring at room 20min, after mixed solution change clarification stirs, under the ice-water bath, drip 6-methoxyl group morellic acid methyl esters (II) 1.0g (1.59mmol), after dropwising, keep 0 ℃ of reaction 48h, add S-WAT 2.0g (15.9mmol) cancellation then, behind the stirring at room 60min, stopped reaction, with ethyl acetate extraction three times (3 * 10ml), organic layer is with 5% potassium hydroxide aqueous solution and wash each three times, then with saturated common salt washing, MgSO
4After the drying, concentrate yellow dope, column chromatography, petrol ether/ethyl acetate (1: 1) wash-out obtains yellow solid 90mg, Mp:108-110 ℃. yield 11%.
IR(KBr)：v＝3315，3034，3012，2934，2927，1713，1641，1589，1435，1413，1316，1143，1086，1029?cm
-1.
1HNMR(300M，CDCl
3)：δ7.46(1H，d，J＝6.9Hz，H-10)，6.65(1H，d，J＝10.1Hz，H-4)，6.06(1H，t，H-27)，5.56(1H，d，J＝10.2Hz，H-3)，5.07(1H，brt，H-32)，4.74(2H，brs，37-OH，38-OH)，3.82(3H，s，6-OCH
3)，3.76(1H，d，J＝10.9?Hz，37-H)，3.43(1H，?m，H-11)，3.41(3H，s，COOCH
3)，3.34(2H，m，H-31a)，3.10(1H，dd，J＝14.7Hz，7.6Hz，H-31b)，2.92(2H，d，J＝7.23Hz，H-26)，2.51(1H，d，J＝9.0Hz，H-22)，2.31(1H，dd，J＝13.5Hz，4.8Hz，H-21a)，2.03(2H，m，H-36)，1.46(1H，m，H-24)，1.39(1H，m，H-21b)，1.76(5H，m，H-20，H-25)，1.65(3H，s，H-35)，1.69(6H，s，H-29，H-34)，1.67(3H，s，H-39)，1.55(3H，s，H-40)，1.28(3H，s，H-19).
ESI-MS：691[M+H]
+，713[M+Na]
+，729[M+K]
+.
HRMS(M+H)m/z?691.3483(calcd?for?C
40H
51O
10?691.3482)。
Embodiment 23:(37S, 38)-dihydroxyl-6-methoxyl group morellic acid methyl esters (23)
In the round-bottomed flask of 25ml, add trimethyl carbinol 3.5ml and water 3.5ml, and AD-mix-β 590mg (0.42mmol), methylsulfonyl ammonia 36mg (0.38mmol), stirring at room 20min, after mixed solution change clarification stirs, under the ice-water bath, drip 6-methoxyl group morellic acid methyl esters (II) 250mg (0.38mmol), after dropwising, keep 0 ℃ of reaction 48h, add the cancellation of 72mg (0.57mmol) S-WAT then, behind the stirring at room 60min, stopped reaction, with ethyl acetate extraction three times (3 * 10ml), organic layer is with 5% potassium hydroxide aqueous solution and wash each three times, then with saturated common salt washing, MgSO
4After the drying, concentrate yellow dope, column chromatography, petrol ether/ethyl acetate (1: 1) wash-out, purifying obtains yellow solid 62mg, Mp:110-113 ℃, yield 48%.
IR(KBr)：v＝3315，3034，3012，2934，2927，1713，1641，1589，1435，1413，1316，1143，1086，1029?cm
-1.
1HNMR(300M，CDCl
3)：δ7.45(1H，d，J＝6.9Hz，H-10)，6.65(1H，d，J＝10.1Hz，H-4)，6.06(1H，t，H-27)，5.56(1H，d，J＝10.2Hz，H-3)，5.07(1H，brt，H-32)，4.76(2H，brs，37-OH，38-OH)，3.82(3H，s，6-OCH
3)，3.75(1H，d，J＝10.9Hz，37-H)，3.43(1H，m，H-11)，3.41(3H，s，COOCH
3)，3.33(1H，m，H-31a)，3.10(1H，dd，J＝14.7Hz，7.6Hz，H.31b)，2.93(2H，d，J＝7.23Hz，H-26)，2.51(1H，d，J＝9.0Hz，H-22)，2.31(1H，dd，J＝13.5Hz，4.8Hz，H-21a)，2.03(2H，m，H-36)，1.76(5H，m，H-20，H-25)，1.65(3H，s，H-35)，1.69(6H，s，H-29，H-34)，1.67(3H，s，H-39)，1.55(3H，s，H-40)，1.46(1H，m，H-24)，1.39(1H，m，H-21b)，1.28(3H，s，H-19).
ESI-MS：691[M+H]
+，71?3[M+Na]
+，729[M+K]
+。
HRMS(M+H)m/z691.3483(calcd?for?C
40H
51O
10?691.3482)。
Embodiment 24:40-(methoxyphenol)-6-methoxyl group-morellic acid methyl esters (26)
Compound 40-chloro-6-methoxyl group-morellic acid methyl esters 138mg (0.2mmol) is dissolved among the acetonitrile 15ml, add Resorcinol 25mg (0.22mmol), Anhydrous potassium carbonate 43mg (0.31mmol), catalytic amount potassiumiodide 8mg under the room temperature successively, reaction solution is faint yellow muddiness, stirring at room, room temperature reaction stopped in 12 hours, and reaction solution is coffee-like muddy.Acetonitrile in the reaction solution steamed remove, dilute residue, wash with water, the saturated common salt washing, anhydrous MgSO with ethyl acetate
4Drying steams solvent, column chromatography, and petrol ether/ethyl acetate (2: 1) wash-out gets pale yellow powder 76mg, and Mp:109-112 ℃, productive rate about 50%.
IR(KBr)：v＝3467，3416，2966，2925，1736，1740，1709，1655，1607，1586，1463，1427，1384，1225，1143，1046cm
-1.
1HNMR(300M，CDCl
3)：δ7.55(1H，d，J＝6.70Hz，H-10)，6.91(1H，m，Ar-H)，6.67(1H，d，J＝2.3Hz，H-4)，6.37(1H，m，Ar-H)6.28(2H，m，Ar-H)5.95(1H，m，H-27)，5.53(1H，d，J＝6.1Hz，H-3)，5.12(1H，m，H-37)，5.06(1H，m，H-32)，4.30(2H，s，H-40)，3.82(3H，s，6-OCH
3)，3.43(3H，s，COOCH
3)，3.42(1H，m，H-11)，3.37(1H，m，H-31a)，3.25(1H，m，H-31b)，2.96(2H，m，H-26)，2.51(1H，d，J＝9.31Hz，H-22)，2.30(1H，m，H-21a)，2.04(2H，m，H-36)，1.86(3H，s，H-39)，1.75(3H，s，H-25)，1.73(2H，m，H-20)，1.69(3H，s，H-34)，1.65(3H，s，H-35)，1.38(1H，m，H-21b)，1.44(3H，s，H-24)，1.29(3H，s，H-19)。
ESI-MS?765[M+H]
+.
Ultimate analysis: C
46H
52O
10, Found C 72.70%, H 7.02%, and O 20.46%; Calcd C 72.23%, H6.85%, O 20.92%.
Embodiment 25: the cytotoxic activity data of target compound among the embodiment.
This mensuration adopts bromination tetrazole indigo plant (MTT) method routinely, promptly use the trysinization tumour cell, to contain the RPMI1640 nutrient solution preparation cell suspension of 10% calf serum, concentration is 10000 cells/ml, take the logarithm the vegetative period cell cultures in 96 well culture plates, every hole 100 μ l (containing 1000～1200 tumour cells).Next day, the administration group adds and contains the different concns compound, and every medicine is established 4～5 dosage groups, establishes 3 parallel holes at least for every group.Control group adds and the isopyknic solvent of compound.Put 5%CO
2In 37 ℃ of cultivations, discard nutrient solution after 4 days in the incubator, every hole adds 200 μ l 0.2%MTT solution (RPMI1640 preparation).37 ℃ are incubated 4 hours, supernatant discarded, and every hole adds DMSO 150 μ l dissolving first hairpin particle, behind the gentle agitation, uses microplate reader, measures optical density value (OD) under reference wavelength 450nm, detection wavelength 570nm condition.The tumour cell of handling with solvent control is a control group, calculates the inhibiting rate of medicine to tumour cell with following formula, and calculates IC
50
Reagent source:
MTT: bromination tetrazole indigo plant (Thiazolyl Blue Tetrazolum Bromide), the import of Sigma company;
RPMI 1640 substratum: GIBCO company product;
Pancreatin (Trypsin): GIBCO company product
DMSO: dimethyl sulfoxide (DMSO), the Beijing Chemical Plant produces;
Calf serum: military region animal doctor's centre of prevention and cure
Table one experimental data shows that The compounds of this invention has strong cytotoxicity to human lung carcinoma cell (A549), colon cancer cell (HT-29), gastric carcinoma cells (BGC823), human liver cancer cell (Bel7402) and Proliferation of Human Ovarian Cell (SKOV3).Wherein the cytotoxic activity of majority of compounds obviously is better than positive control drug morellic acid or suitable with its cytotoxic activity.Because the screening of antineoplastic compound is that cytotoxic activity with compound embodies routinely,, can mix the preparation antitumor drug so The compounds of this invention has anti-tumor activity with pharmaceutical carrier.
Table one, Gamboges acid derivative MTT The selection result of the present invention
| Compound number | IC 50(μM) | ? | ? | ? | |
| A549? | BGC823? | SKOV3? | HT-29? | Bel7402? | ? |
| 1a? | 0.95? | 0.47? | 0.4? | 1.41? | 0.9? |
| 1b? | 2.39? | 2.13? | 1.19? | 1.23? | 1.1? |
| 2? | 1.56? | 4.38? | 0.75? | 2.06? | 3.73? |
| 3? | 5.25? | 1.42? | 15.8? | 0.89? | 3.6? |
| 4? | 4.38? | 0.84? | 1.28? | 2.41? | 2.32? |
| 5? | 4.67? | 2.08? | 1.54? | 2.56? | 2.04? |
| 6? | 5.87? | 4.09? | 1.61? | 2.66? | 4.01? |
| 7? | 2.05? | 6.7? | 1.84? | 2.08? | 15? |
| 8? | 4.24? | 0.23? | 3.43? | 21.6? | 0.95? |
| 9? | 7.9? | 4.67? | 3.21? | 4.06? | 4.15? |
| 10? | 10.2? | 5.8? | 3.01? | 3.8? | 4.12? |
| 11? | 12.1? | 5.97? | 21? | 3.07? | 4.8? |
| 12? | 14? | 6.98? | 23? | 6.09? | 3.05? |
| 13? | 6.49? | 4.65? | 3.01? | 3.54? | 3.23? |
| 14? | 5.69? | 12.15? | 5.01? | 3.54? | 11.85? |
| 15? | 6.87? | 4.09? | 2.61? | 5.66? | 4.01? |
| 16? | 10.2? | 4.8? | 7.01? | 3.8? | 13.12? |
| 17? | 4.2? | 2.86? | 5.01? | 5.03? | 4.12? |
| 18? | 4.2? | 17.5? | 2.01? | 21.8? | 5.09? |
| 19? | 2.75? | 4.08? | 1.84? | 2.08? | 6.34? |
| 20? | 21.75? | 14.08? | 6.84? | 6.08? | 16.34? |
| 21? | 4.24? | 0.83? | 3.43? | 4.6? | 2.95? |
| 22? | 3.38? | 0.84? | 2.24? | 0.88? | 4.31? |
| 23? | 12? | 2.89? | 3.6? | 4.12? | 3.9? |
| 26? | 3.98? | 1.56? | 2.9? | 7.94? | 5.67? |
| Morellic acid | 5.81? | 4.51? | 3.06? | 5.61? | 3.31? |
Claims (16)
1. Gamboges acid derivative is the described compound of general formula (I):
R wherein
1, R
2, R
3, R
4Identical or different, independent separately H, halogen, hydroxyl, cyano group, nitro,-oxyl, alkylacyloxy, hydrocarbon sulfonate ester group, carboxyl, the aldehyde radical represented;
R
5And R
6Identical or different, independent separately H, the C of representing
1-4Saturated alkane or C
2-4Unsaturated alkyl;
(32,33) position, the empty line in (37,38) position part are identical or different, independently separately represent ethylene linkage, epoxy group(ing), o-dihydroxy, and R
1, R
2, R
3, R
4When being H simultaneously, at least one is o-dihydroxy for (32,33) position, the empty line part in (37,38) position;
Work as R
1, R
2, R
3, R
4When representing-oxyl, alkylacyloxy, hydrocarbon sulfonate ester group, alkyl wherein is C
2-8Unsaturated alkyl, C
1-8Saturated alkane, C
6-8Aryl or by C
1-5The C that alkyl replaces
6-8Aryl.
2. Gamboges acid derivative according to claim 1 is characterized in that R
1, R
2, R
3, R
4The halogen of representative is F, Cl, Br or I.
3. Gamboges acid derivative according to claim 1 is characterized in that described C
1-4Saturated alkane is methyl, ethyl, has optical activity or do not have the active propyl group of optics, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl; Described C
1-8Saturated alkane is methyl, ethyl, has optical activity or do not have the active propyl group of optics, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl or octyl group; Described C
2-4Unsaturated alkyl is allyl group, propenyl, 1-butylene, 2-butylene; C
2-8Unsaturated alkyl is allyl group, propenyl, 1-butylene, 2-butylene, isopentene, 2-amylene, 2-methyl-2-amylene, 2-methyl-2-hexene, 2-methyl-2,4-hexadiene, 2-methyl-2,4-heptadiene, 2-methyl-2,5-heptadiene.
4. Gamboges acid derivative according to claim 1 is characterized in that: R
1, R
2, R
3, R
4Identical or different, independent separately H, halogen, hydroxyl, carboxyl, aldehyde radical, cyano group, nitro, the C of representing
2-5Alkanoyloxy, toluenesulphonic acids ester group;
(32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, epoxy group(ing), the o-dihydroxy represented;
R
5And R
6Identical or different, independent separately H, methyl, ethyl, propyl group, butyl, allyl group, propenyl, 1-butylene, the 2-butylene represented.
5. Gamboges acid derivative according to claim 4 is characterized in that: R wherein
1, R
2, R
3, R
4Identical or different, independent separately H, hydroxyl, carboxyl, aldehyde radical, fluorine, chlorine, cyano group, the nitro represented;
(32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented;
R
5And R
6Identical or different, independent separately H, methyl, ethyl, propyl group, allyl group, the propenyl represented.
6. Gamboges acid derivative according to claim 1 is characterized in that: R wherein
1, R
2, R
3, R
4Identical or different, independent separately H, hydroxyl, the C of representing
1-8Alkylacyloxy, aldehyde radical;
(32,33) position, the independent separately ethylene linkage of representing of the empty line part in (37,38) position;
R
5And R
6Identical or different, from independent H, methyl, ethyl, allyl group, the propenyl represented.
7. Gamboges acid derivative according to claim 6 is characterized in that: R wherein
1, R
3The independent separately H that represents; R
2, R
4Identical or different, independent separately H, hydroxyl, acetoxyl group, the aldehyde radical represented;
(32,33) position, the independent separately ethylene linkage of representing of the empty line part in (37,38) position;
R
5And R
6Identical or different, independent separately H, methyl, ethyl, allyl group, the propenyl represented.
8. Gamboges acid derivative according to claim 1 is characterized in that: R
1, R
2, R
3, R
4Identical or different, independent separately H, halogen, hydroxyl, cyano group, nitro, the C of representing
2-5Alkanoyloxy;
(32,33) position, the empty line in (37,38) position part are identical or different, independently separately represent ethylene linkage, o-dihydroxy, and can not be ethylene linkage simultaneously;
R
5And R
6Identical or different, independent separately represent methylidene, ethyl, propyl group, sec.-propyl, butyl, isobutyl-.
9. Gamboges acid derivative according to claim 8 is characterized in that: R
1, R
2, R
3, R
4Identical or different, independent separately H, the hydroxyl represented;
(32,33) position, the empty line in (37,38) position part are identical or different, independently separately represent ethylene linkage, o-dihydroxy, and can not be ethylene linkage simultaneously;
R
5And R
6Identical or different, independent separately represent methylidene, ethyl, propyl group, butyl.
10. Gamboges acid derivative according to claim 9 is characterized in that: R
1, R
2, R
3, R
4The identical independent separately H that represents;
(32,33) position, the empty line in (37,38) position part are identical or different, independently separately represent ethylene linkage, o-dihydroxy, and can not be ethylene linkage simultaneously;
R
5And R
6Identical or different, independent separately represent methylidene, ethyl, propyl group, butyl.
11. the preparation method of the described Gamboges acid derivative of claim 1, it is characterized in that: general formula (A) is the Gamboges acid derivative or the morellic acid of 6,30 replacements, with (A) is starting raw material, adopt oxidising agent to carry out oxidizing reaction, perhaps the product that oxidizing reaction is obtained carries out halo, hydrocarbonylation, cyano groupization, carboxylation, nitrated, hydrocarbon sulfonate esterification, hydrocarbon acidylate, epoxidation or hydroxylation reaction again;
In the general formula (A), R
5And R
6Identical or different, independent separately H, the C of representing
1-4Saturated alkane or C
2-4Unsaturated alkyl.
12. the preparation method according to the described Gamboges acid derivative of claim 11 is characterized in that C
1-4Saturated alkane be methyl, ethyl, propyl group, butyl; C
2-4Unsaturated alkyl be allyl group, propenyl, 1-butylene, 2-butylene.
13. preparation method according to claim 11 is characterized in that used oxidising agent is hydrogen peroxide, alkyl hydrogen peroxide, metachloroperbenzoic acid, tin anhydride, peroxy tert-butyl alcohol, ceric ammonium nitrate, sodium dichromate 99, crosses tert-butyl acrylate, potassium osmate, the Tripotassium iron hexacyanide, clorox, perosmic anhydride and methylmorpholine-N oxide compound.
14. the preparation method of Gamboges acid derivative according to claim 11 is characterized in that may further comprise the steps:
A. general formula (A) and tin anhydride, peroxy tert-butyl alcohol are reacted in methylene dichloride or trichloromethane, temperature of reaction prepares R between subzero 10 ℃ to 70 ℃
1, R
2, R
3, R
4Identical or different, independent separately H, hydroxyl, the aldehyde radical represented, (32,33) position, the empty line part in (37,38) position are removed R
1, R
2, R
3, R
4Be outer independent separately general formula (I) compound of representing ethylene linkage of H; Perhaps
b.
I. with the independent separately ethylene linkage, R represented of the empty part of ruling in (32,33) position, (37,38) position of step a preparation
1, R
2, R
3, R
4In have at least general formula (I) compound and the metachloroperbenzoic acid of a hydroxyl in methylene dichloride or trichloromethane, to react, temperature of reaction is between subzero 10 ℃ to 40 ℃, preparation (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage or the epoxy group(ing) represented, and (32,33) position, (37,38) position can not be ethylene linkage, R
1, R
2, R
3, R
4In have at least a hydroxyl general formula (I) compound; Perhaps
Ii. with the independent separately ethylene linkage, R represented of the empty part of ruling in (32,33) position, (37,38) position of step a preparation
1, R
2, R
3, R
4In have at least general formula (I) compound of a hydroxyl and Yi Xian Yi Suan Vanadium, peroxy tert-butyl alcohol in dry-out benzene or toluene, to react, temperature of reaction is between subzero 10 ℃ to 40 ℃, Stereoselective preparation (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage or the epoxy group(ing) represented, and (32,33) position, (37,38) position can not be ethylene linkage, R
1, R
2, R
3, R
4In have the single optical isomer of general formula (I) compound of a hydroxyl at least; Perhaps
Iii. with the independent separately ethylene linkage, R represented of the empty part of ruling in (32,33) position, (37,38) position of step a preparation
1, R
2, R
3, R
4In have general formula (I) compound of a hydroxyl and four different oxygen propyl group titaniums, CaH at least
2, silica gel H,
Molecular sieve, (+)-diethyl tartrate or (-)-diethyl tartrate, anhydrous peroxy tert-butyl alcohol react in dry toluene and methylene dichloride mixing solutions, temperature of reaction is between subzero 75 ℃ to 25 ℃, Stereoselective preparation (32,33) position, the empty line in (37,38) position part are identical or different, independent separately ethylene linkage, the epoxy group(ing) represented, and (32,33) position, (37,38) position can not be ethylene linkage, R
1, R
2, R
3, R
4In have the single optical isomer of general formula (I) compound of a hydroxyl at least; Perhaps
c.
I. general formula (I) compound and tolysulfonyl halogen, the dimethyl aminopyridine with step b preparation reacts in methylene dichloride, and temperature of reaction prepares R between subzero 10 ℃ to 45 ℃
1, R
2, R
3, R
4In have general formula (I) compound of representing halogen atom at least; Perhaps
Iii. with the R of step b preparation
1, R
2, R
3, R
4In have at least general formula (I) compound and alkali, the halogenated alkane of a representation hydroxy in acetone, to react, temperature of reaction prepares R between 0 ℃ to 85 ℃
1, R
2, R
3, R
4Identical or different, wherein have at least one to be general formula (I) compound of-oxyl; Perhaps
Iv. with the R of step b preparation
1, R
2, R
3, R
4In have general formula (I) compound of a representation hydroxy and pyridine, dimethyl aminopyridine, C at least
1-5The acid anhydrides of carboxylic acid is in methylene dichloride, and temperature of reaction prepares R between 0 ℃ to 45 ℃
1, R
2, R
3, R
4Identical or different, wherein have at least one to be general formula (I) compound of alkylacyloxy; Perhaps
V. the i of step c is prepared R
1, R
2, R
3, R
4In have at least one to represent general formula (I) compound and trimethylammonium silicon chlorides, sodium iodide, the sodium cyanide of halogen atom in acetonitrile, to react, temperature of reaction prepares R between 0 ℃ to 80 ℃
1, R
2, R
3, R
4Identical or different, wherein have at least one to be general formula (I) compound of cyano group; Perhaps
Vi. with the R of step b preparation
1, R
2, R
3, R
4In have at least general formula (I) compound and clorox, TEMPO, sodium bicarbonate, Potassium Bromide, the tetrabutylammonium chloride of a representation hydroxy in methylene dichloride, to react, temperature of reaction prepares R between 0 ℃ to 40 ℃
1, R
2, R
3, R
4In have general formula (I) compound of a representation carboxy at least; Perhaps
Ix. the i of step c is prepared R
1, R
2, R
3, R
4In have general formula (I) compound of representing halogen atom and Sodium Nitrite at least in acetonitrile or dimethyl sulfoxide (DMSO), solvent dimethylformamide reaction, temperature of reaction prepares R between 0 ℃ to 60 ℃
1, R
2, R
3, R
4In have general formula (I) compound of representing nitro at least; Perhaps
X. with the R of step b preparation
1, R
2, R
3, R
4In have at least general formula (I) compound and hydrocarbon sulfonic acid halide, the pyridine of a representation hydroxy in ether, to react, temperature of reaction prepares R between 0 ℃ to 35 ℃
1, R
2, R
3, R
4In have general formula (I) compound of representing the hydrocarbon sulfonate ester at least; Perhaps
D. general formula (A) and metachloroperbenzoic acid are reacted in methylene dichloride or trichloromethane, temperature of reaction prepares R between subzero 10 ℃ to 40 ℃
1, R
2, R
3, R
4Be H, (32,33) position, the empty line in (37,38) position part are identical or different, independently separately represents ethylene linkage, epoxy group(ing), and (32,33) position, (37,38) can not be general formula (I) compound of ethylene linkage; Perhaps
E. the Gamboges acid derivative of 6,30 replacements of general formula (A) and AD-mix-α or AD-mix-β, methylsulfonyl ammonia are reacted in the mixed solvent of the trimethyl carbinol, Virahol or acetonitrile and water, temperature of reaction prepares R between 0 ℃ to 35 ℃
1, R
2, R
3, R
4Be H, (32,33) position, the empty line in (37,38) position part are identical or different, independently separately represents ethylene linkage, o-dihydroxy, and (32,33) position, (37,38) can not be general formula (I) compound of ethylene linkage, comprise all single diastereomers.
15. a Gamboges acid derivative is characterized in that this Gamboges acid derivative is 40-piperazine-6-methoxyl group-morellic acid methyl esters.
16. claim 1 or the 15 described Gamboges acid derivatives application in the medicine of preparation treatment tumour.
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| TWI432191B (en) * | 2010-06-11 | 2014-04-01 | Taiwan Sunpan Biotechnology Dev Co Ltd | Compounds isolated from gamboge resin , and pharmaceutical compositions comprising the same |
| CN102424683A (en) * | 2011-09-22 | 2012-04-25 | 中国药科大学 | Amino gambogate compounds, preparation method thereof and medicinal purpose thereof |
| CN102988341A (en) * | 2012-09-12 | 2013-03-27 | 广州医学院 | Tissue specificity proteasome inhibitor and application thereof |
| CN103159814B (en) * | 2013-03-28 | 2015-12-23 | 东华大学 | A kind of morellic acid ester derivative and its production and use |
| CN103242336A (en) * | 2013-06-04 | 2013-08-14 | 东华大学 | Gambogic acid-type derivative and preparation and application thereof |
| CN106478655B (en) * | 2015-08-31 | 2019-07-09 | 南开大学 | Gambogic acid compounds with anti-tumor activity and its preparation method and application |
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| CN1309125A (en) * | 2001-01-17 | 2001-08-22 | 中国药科大学 | Composition of gambogic acid compounds with anticancer activity and its preparing process |
| CN1535972A (en) * | 2003-04-08 | 2004-10-13 | 安徽省天科药物研究所 | New compound,its preparation method, medicine preparation using said compound as active component, its action and application |
| CN1563014A (en) * | 2004-04-16 | 2005-01-12 | 杭州民生药业集团有限公司 | New compound ramification of garcinia acid |
| CN1715283A (en) * | 2004-07-02 | 2006-01-04 | 中国科学院上海药物研究所 | Neogambogic acid derivative and its production and use |
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| CN1309125A (en) * | 2001-01-17 | 2001-08-22 | 中国药科大学 | Composition of gambogic acid compounds with anticancer activity and its preparing process |
| CN1535972A (en) * | 2003-04-08 | 2004-10-13 | 安徽省天科药物研究所 | New compound,its preparation method, medicine preparation using said compound as active component, its action and application |
| CN1563014A (en) * | 2004-04-16 | 2005-01-12 | 杭州民生药业集团有限公司 | New compound ramification of garcinia acid |
| CN1715283A (en) * | 2004-07-02 | 2006-01-04 | 中国科学院上海药物研究所 | Neogambogic acid derivative and its production and use |
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