CN102250189A - Glycyrrhetic acid derivative with 1, 12-diene-3-ketone skeleton, its preparation method and medicinal uses - Google Patents
Glycyrrhetic acid derivative with 1, 12-diene-3-ketone skeleton, its preparation method and medicinal uses Download PDFInfo
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Abstract
Relating to the medicine field, the invention specifically relates to a glycyrrhetic acid derivative with a 1, 12-diene-3-ketone skeleton or a pharmaceutically acceptable salt thereof, their preparation method and medicinal uses, in particular their application in preparing antitumor drugs. Pharmacological experiment results show that these compounds have good antitumor activity and can be used for preparing antitumor drugs clinically.
Description
Technical field
The present invention relates to pharmaceutical field, be specifically related to a kind ofly have 1, Enoxolone derivative or its pharmacy acceptable salt of 12-diene-3-ketone skeleton, their preparation method, contain the medicinal compositions of these derivatives and their medicinal use, particularly the application in the preparation antitumor drug.
Background technology
Radix Glycyrrhizae is one of China's herbal variety commonly used, and Shennong's Herbal is classified it on medicine as and taken advantage of.Theory of traditional Chinese medical science thinks, the flat flavor of Radix Glycyrrhizae property is sweet, has with middle emergency, moistening lung, detoxifies, eliminates the phlegm, effects such as cough-relieving, qualcomm meridian, sharp qi and blood, coordinating the actions of various ingredients in a prescription.Potenlini (glycyrrhizic acid) and aglycon glycyrrhetinic acid (glycyrrhetic acid) thereof are the main active ingredient of Radix Glycyrrhizae.Studies show that Potenlini and glycyrrhetinic acid have anti-inflammatory, antiulcer agent, antiviral, reducing blood-fat, removing free radical, protect the liver and multiple biological activity (Asl MN, Hosseinzadeh H.PhytotherRes, 2008,22 (6): 709-724) such as anti-curing oncoma.
Yet long-term or heavy dose of such medicine of use can cause pseudohyperaldosteronism, and its feature shows as sodium retention, potassium is drained and increased, thereby causes oedema, hypertension, tetraplegia and hypokalemia etc.Its reason may be that therefore energy and cortin A ring " 3-ketone-4-alkene " is competitive combines with the avtive spot of 5 β-reductase enzyme, from then on suppresses the activity of this enzyme owing to have " 11-ketone-12-alkene " structure in such Compound C ring.5 β-reductase enzyme is the important enzyme system of control agent inner cortex hormone metabolism, suppress the clearance rate that its activity will reduce cortin, improve the transformation period of cortin simultaneously, thereby cause pseudohyperaldosteronism (Atherden LM.Biochem J, 1958,69 (1): 75-78; Shibata S, Takahashi K, Yano S, Harada M, et al.Chem Pharm Bull, 1987,35 (5): 1910-1918).Studies show that 11-deoxidation glycyrrhetinic acid and derivative thereof can overcome or reduce false aldosterone side effect (Kagawa CM.Endocrinology, 1960,67:125-132; Farina C, Pinza M, Pifferi G.Il Farmaco, 1998,53 (1): 22-32).
Aspect anti-curing oncoma, (Nishino H, Yoshioka K can prophylaxis of tumours take place in glycyrrhetinic acid, Iwashima A, et al.JpnJ Cancer Res, 1986,77 (1): 33-38), suppress tumor cell proliferation, inducing tumor cell differentiation (Ukil A, Biswas A, Das T, et al.J Immunol, 2005,175 (2): 1161-1169) with apoptosis (Hibasami H, Iwase H, Yoshioka K, et al.Int JMol Med, 2006,17 (2): 215-219).Yet, the anti-tumor activity of glycyrrhetinic acid relatively low (Huang Wei, Huang Jiqun, Zhang Dongfang, etc. combination of Chinese tradiational and Western medicine hepatopathy magazine, 2003,13 (3): 148-150; Huang Wei, Huang Jiqun, Zhang Dongfang, etc. Chinese lung cancer magazine, 2003,6 (4): 254-257), people have carried out glycyrrhetinic acid structural modification and transformation for this reason.
People such as Safe disclose some Enoxolone derivatives in the international monopoly WO2008000070 that published on January 3rd, 2008, find 2-cyano group-3,11-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester (CDODA-Me) has good antineoplastic activity.People such as Salomatina disclose 2-cyano group-3 in Russ P (RU2393165), 11-oxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester (CDOTA-Me) has better inhibited activity to people's tumour KB-3-1, KB-8-5 and HeLa cell proliferation.2010, people such as Song have reported 2-cyano group-3,12-oxo-18 β-volatile oil-1,11-diene-30-carboxylate methyl ester (CDODO-Me-12) has good inhibition effect (Song D to human leukemia cell's propagation, Gao Y, Wang R, et al.Cancer Biol Ther, 2010,9 (2): 96-108).Yet these Enoxolone derivatives still keep " 11-ketone-12-alkene " or its similar " 11-alkene-12-ketone " skeleton.
In order to improve the anti-tumor activity of glycyrrhetinic acid, overcome simultaneously or reduce its pseudohyperaldosteronism, the invention discloses and a kind ofly have 1, the Enoxolone derivative of 12-diene-3-ketone skeleton.
Summary of the invention
The invention discloses and a kind ofly have 1, Enoxolone derivative, its preparation method and the medicinal use of 12-diene-3-ketone skeleton.Pharmacological evaluation shows that Enoxolone derivative of the present invention has good anti-tumor activity, and therefore, this compounds can be used for treating tumor disease.
Compound disclosed by the invention is the Enoxolone derivative shown in the general formula (I) or its pharmacy acceptable salt:
Wherein:
R
1Represent hydrogen atom, halogen atom, cyano group, hydroxyl, trifluoromethyl, sulfydryl, nitro, amino, C
1-C
6Alkyl, C
1-C
6Alkylamino, OR
3Or OC (O) R
3
R
2Represent CN, CH
2OC (Ph)
3, CO
2H, CO
2R
4, CH
2OH, CH
2OC (O) R
4Or C (O) NR
5R
6
R
3Represent C
1-C
6Alkyl;
R
4Represent C
1-C
6Alkyl or C
6-C
10Aromatic base, wherein said aromatic base can be randomly be selected from following group and replace with one or more: halogen atom, nitro, cyano group, amino or hydroxyl;
R
5And R
6Can be identical or different, represent hydrogen atom, C
1-C
6Alkyl or R
1And R
2Form 5-7 unit heterocyclic group with the nitrogen-atoms that connects with them, this heterocyclic group can randomly comprise other heteroatoms of one or more O of being selected from, S, N or NH, and this heterocyclic group can randomly be replaced to five replacements by following identical or different substituting group list, and described substituting group comprises: halogen atom, hydroxyl, nitro, cyano group, amino, C
1-C
6Alkyl or C
1-C
6Alkoxyl group;
Wherein, except following formula (a-c) compound:
Further, the Enoxolone derivative shown in the general formula (I) or its pharmacy acceptable salt is characterized in that:
R
1Represent H, OH, Cl, Br, I, CN, OR
3Or OC (O) R
3
R
2Represent CN, CH
2OC (Ph)
3, CO
2H, CO
2R
4, CH
2OH, CH
2OC (O) R
4Or C (O) NR
5R
6
R
3Represent CH
3
R
4Represent CH
3Or C
2H
5
NR
5R
6Represent NH
2, piperazinyl or imidazolyl.
Specifically, the Enoxolone derivative shown in the general formula (I) is preferably from following compounds:
2-iodo-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I
a);
2-cyano group-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I
b);
2-chloro-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I
D-1);
2-bromo-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I
D-2);
2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I
E-1);
2-iodo-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester (I
G-1);
2-cyano group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester (I
G-2);
2-chloro-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester (I
G-3);
2-bromo-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester (I
G-4);
2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester (I
G-5);
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester (I
G-6);
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid, ethyl ester (I
G-7);
2-acetoxy-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester (I
G-8);
3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-1);
N-methyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-2);
N-ethyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-3);
3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acyl piperazine (I
H-4);
2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-5);
N-methyl-2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-6);
N-ethyl-2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-7);
2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acyl piperazine (I
H-8);
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-9);
N-methyl-2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-10);
N-ethyl-2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-11);
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acyl piperazine (I
H-12);
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acyl imidazoles (I
H-13);
3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
i);
2-iodo-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
j);
2-cyano group-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
k);
2-chloro-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
M-1);
2-bromo-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
M-2);
2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
N-1);
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
o);
2-hydroxyl-3-oxo-30-three benzyloxies-18 β-volatile oil-1,12-diene (I
q);
2,30-dihydroxyl-3-oxo-18 β-volatile oil-1,12-diene (I
Y-1);
2-hydroxyl-3-oxo-30-acetoxyl group-18 β-volatile oil-1,12-diene (I
Z-1).
The compound code name that relates in the following pharmacological evaluation is equal to the pairing compound of code name herein.
Described compound comprises all conformers, optically active isomer and the racemic modification of general formula (I) compound, diastereomer and tautomer and steric isomer, and the mixture of any above-mentioned form.
Another object of the present invention is to provide the preparation method of compound shown in the general formula (I), it is characterized in that:
A) work as R
2Be CO
2During H; the preparation method of general formula (I) compound is: glycyrrhetinic acid makes 3 beta-hydroxies-18 β-volatile oil-12-alkene-30-acid (II) through the Clemmensen reduction; II and adjacent iodoxy phenylformic acid (IBX) heated oxide generate 3-oxo-18 β-volatile oil-1; 12-diene-30-acid (III); III makes 2-iodo-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I with the elemental iodine reaction under pyridine catalysis
a), I
aReact with fluorosulfonyl difluoroacetic acid methyl esters with the cuprous cyanide reaction or under cuprous iodide catalysis, make 2-cyano group-3-oxo-18 β-volatile oil-1 respectively, 12-diene-30-acid (I
b) and 2-trifluoromethyl-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I
c); III gets 1 through hydrogen peroxide oxidation, 2-epoxy-3-oxo-18 β-volatile oil-12-alkene-30-acid (IV), IV and haloid acid (HX) or sodium alkoxide (R
3ONa) reaction makes 2-halogen-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I respectively
d) and 2-alkoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I
e), I
eGenerate 2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-acid (V), V and alkanoic acid anhydride ((R with hydrochloric acid reaction
3CO)
2O) reaction makes 2-alkanoyloxy-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I
f); Its synthetic route is as follows:
Wherein, X represents F, Cl, Br, R
3Definition as described in the claim 1-3;
Preparation formula (III) compound is characterised in that solvent is selected from dimethyl sulfoxide (DMSO) (DMSO), dimethyl formamide (DMF), N-Methyl pyrrolidone (NMP) or ethyl acetate; Temperature of reaction is 60-120 ℃; Reaction times is 3-24 hour;
B) work as R
2Be CO
2R
4Or C (O) NR
5R
6The time, the preparation method of general formula (I) compound is: with formula (III) and the formula (I that a) makes
a-I
f) compound is raw material, under the alkalescence effect with halohydrocarbon (R
4X) reaction or generate behind the acyl chlorides again and corresponding aminated compounds (HNR with chloride reagent reaction
5R
6) reaction, make ester compound (I respectively
g) and amides (I
h); Its synthetic route is as follows:
Wherein, R
1, R
4, R
5And R
6Definition as described in the claim 1-3;
Preparation formula (I
h) time, chloride reagent is selected from oxalyl chloride, sulfur oxychloride or phosphorus trichloride;
C) work as R
2During for CN, the preparation method of general formula (I) compound is: with b) 3-oxo-18 β-volatile oil-1 of making, 12-diene-30-methane amide (I
H-1) be raw material, under the dehydrated reagent effect, make 3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
i); With reference to synthetic method a), I
iUnder pyridine catalysis, make 2-iodo-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I with the iodine reaction
j), I
jReact with fluorosulfonyl difluoroacetic acid methyl esters with the cuprous cyanide reaction or under cuprous iodide catalysis, make 2-cyano group-3-oxo-18 β-volatile oil-1 respectively, 12-diene-30-nitrile (I
k) and 2-trifluoromethyl-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
l); I
iMake 1 with the hydrogen peroxide reaction, 2-epoxy group(ing)-3-oxo-18 β-volatile oil-12-alkene-30-nitrile (VI), VI and haloid acid (HX) reaction makes 2-halogen-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
m); VI and sodium alkoxide (R
3ONa) reaction makes 2-alkoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
n), I
nUnder the hydrochloric acid effect, generate 2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
o), I
oWith alkanoic acid anhydride ((R
3CO)
2O) reaction makes 2-alkanoyloxy-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
p); Its synthetic route is as follows:
Wherein, X is F, Cl or Br, R
3Definition as described in the claim 1-3;
Preparation formula (I
i) time, dehydrated reagent is selected from trifluoroacetic anhydride, diacetyl oxide, phosphorus oxychloride or phosphorus trichloride;
D) work as R
2Be CH
2OH, CH
2OC (Ph)
3Or CH
2OC (O) R
4The time, the preparation method of general formula (I) compound is: II makes 3 beta-hydroxies-18 β-volatile oil-12-alkene-30-alcohol (VII) through the Lithium Aluminium Hydride reduction, VII and triphenylmethyl chloride reaction generate 3 beta-hydroxies-30-three benzyloxies-18 β-volatile oil-12-alkene (VIII), VIII makes 3-oxo-30-three benzyloxies-18 β-volatile oil-12-alkene (IX) through IBX oxidation under room temperature, IX makes 2-hydroxyl-3-oxo-30-three benzyloxies-18 β-volatile oil-1,12-diene (I through the potassium tert.-butoxide oxidation
q), I
qWith alkanoic acid anhydride ((R
3CO)
2O) reaction makes 2-alkanoyloxy-3-oxo-30-three benzyloxies-18 β-volatile oil-1,12-diene (I
r); Its synthetic route is as follows:
VIII and IBX heated oxide generate 3-oxo-30-three benzyloxies-18 β-volatile oil-1,12-diene (I
s); With reference to synthetic method a), I
sUnder pyridine catalysis, make 2-iodo-3-oxo-30-three benzyloxies-18 β-volatile oil-1,12-diene (I with the elemental iodine reaction
t), I
tReact with fluorosulfonyl difluoroacetic acid methyl esters with the cuprous cyanide reaction or under cuprous iodide catalysis, make 2-cyano group-3-oxo-30-three benzyloxies-18 β-volatile oil-1 respectively, 12-diene (I
u) and 2-trifluoromethyl-3-oxo-30-three benzyloxies-18 β-volatile oil-1,12-diene (I
v); I
sGet 1 through hydrogen peroxide oxidation, 2-epoxy-3-oxo-30-three benzyloxies-18 β-volatile oil-12-alkene (X), X and haloid acid (HX) or sodium alkoxide (R
3ONa) reaction makes 2-halogen-3-oxo-30-three benzyloxies-18 β-volatile oil-1,12-diene (I respectively
w) and 2-alkoxyl group-3-oxo-30-three benzyloxies-18 β-volatile oil-1,12-diene (I
x); Its synthetic route is as follows:
Formula (I
q-I
x) compound and hydrochloric acid and Glacial acetic acid react under room temperature and make formula (I
y) compound; Formula (I
q-I
x) compound and hydrochloric acid and organic acid (R
4CO
2H) back flow reaction makes formula (I
z) compound; Its synthetic route is as follows:
Wherein, X is F, Cl or Br, R
1, R
3And R
4Definition as described in the claim 1-3;
Preparation formula (III) compound is characterised in that solvent is selected from DMSO, and temperature of reaction is 85 ℃, and the reaction times is 4h.
Preparation formula (I
h) compound is characterised in that chloride reagent is selected from oxalyl chloride.
Preparation formula (I
i) compound is characterised in that dehydrated reagent is selected from trifluoroacetic anhydride.
Further purpose of the present invention is to provide a kind of general formula of the present invention (I) compound of significant quantity and pharmaceutical composition of pharmaceutically acceptable carrier or auxiliary material of containing.
A further object of the present invention provides the application of general formula (I) compound in preparation medicine for treating tumor thing, especially treats the application in liver cancer, colorectal carcinoma, prostate cancer and the carcinoma of the pancreas medicine.
The compounds of this invention can with other antitumor drug for example alkylating agent (as endoxan or cis-platinum), antimetabolite (as 5 FU 5 fluorouracil or hydroxyurea), topoisomerase enzyme inhibitor (as camptothecine), mitotic inhibitor (as taxol or vinealeucoblastine(VLB)), DNA intercalating agent (as Zorubicin) combined utilization, in addition can also with the radiotherapy combined utilization.These other antitumor drugs or radiotherapy can give simultaneously or at different time with The compounds of this invention.Thereby these combination therapys can produce synergy helps to improve result of treatment.
The pharmacological experimental method and the result of The compounds of this invention anti-tumor activity are as follows:
Adopt sulphonyl rhodamine B (SRB) protein staining method to estimate the antiproliferative activity of The compounds of this invention to 4 kinds of human cancer cell strains.Srb assay has been widely used in screening anti-tumor medicine.Positive control drug is CDODA-Me and 2-cyano group-3,12-dioxo volatile oil-1,9 (11)-diene-28-carboxylate methyl ester (CDDO-Me).Wherein, CDODA-Me is aforementioned Enoxolone derivative; CDDO-Me is the compound with good anti-inflammatory and anti-tumor activity that is obtained by pentacyclic triterpene natural product-Oleanolic Acid structure of modification, is in the II phase clinical development stage under at present, is used for the treatment of tumour and diabetic nephropathy.
Human cancer cell strain: liver cancer cell SMMC-7721, colon cancer cell HCT116, prostate cancer cell PC3, pancreatic cancer cell BxPC-3.
Experimental technique: the cell that will be in logarithmic phase is seeded to 96 well culture plates by proper density, every hole 100 μ L after the overnight incubation, add the drug effect 72h of different concns, each concentration is established three multiple holes, and establishes contrast of physiological saline solvent and acellular zeroing hole.After effect finishes, the attached cell nutrient solution that inclines adds 10% trichoroacetic acid(TCA) (100 μ L/ hole) in 4 ℃ of fixing 1h, uses distilled water flushing subsequently five times, after treating at room temperature drying, every hole adds SRB solution (4mg/mL is dissolved in 1% glacial acetic acid) 100 μ L, hatch dyeing 15min under the room temperature after, with five unconjugated SRB of flush away of 1% glacial acetic acid flushing, after the drying, every hole adds 10mM Tris solution 100 μ L under the room temperature, and the VERSMax microplate reader is measured the optical density(OD) (OD value) under the 560nm wavelength.Calculate inhibiting rate, experimental result is as shown in table 1.
Table 1 part of compounds of the present invention is to tumor cell proliferation inhibition rate % (10
-4μ M)
The pharmacological results shows, The compounds of this invention has in various degree restraining effect to humanized's tumor cell proliferation, wherein, the anti-tumor activity of majority of compounds is better than the lead compound glycyrrhetinic acid, and the part of compounds activity is better than positive control drug CDODA-Me and CDDO-Me.
Embodiment
In order further to illustrate the present invention, provide a series of embodiment below, these embodiment are illustrative fully, they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.The used glycyrrhetinic acid of the present invention is available from Xi'an Fu Jie Bioisystech Co., Ltd, content＞98%.
Embodiment 1
The preparation of 3 beta-hydroxies-18 β-volatile oil-12-alkene-30-acid (II)
Mercury chloride (3.60g 13.3mmol) is dissolved in 50mL 5% hydrochloric acid soln, and the adding zinc powder (18g, 0.28mol), stirring at room 30min, the layer that anhydrates that inclines washs zinc amalgam (10mL * 3) with dioxane.In freshly prepd zinc amalgam, add glycyrrhetinic acid (4.0g, dioxane solution 8.51mmol) (60mL) slowly drips the 15mL concentrated hydrochloric acid, drip off room temperature reaction 3h, the most of solvent of pressure reducing and steaming in 30 minutes, add water 200mL, fully stirred 30 minutes suction filtration, Glacial acetic acid recrystallization, dry, white needles powder 3.32g, yield 75%, mp＞300 ℃.
3-oxo-18 β-volatile oil-1, the preparation of 12-diene-30-acid (III)
(4.56g 10mmol) is dissolved among the 60mL DMSO II, adds IBX (11.2g, 40mmol), stir down and slowly be warming up to 85 ℃, reaction 4h, add water 200mL, ethyl acetate extraction (80mL * 3) is used 5% sodium bicarbonate (30mL * 3), saturated aqueous common salt (30mL * 3) washing successively, anhydrous sodium sulfate drying, concentrate, drying, recrystallization from ethyl acetate/petroleum ether get white solid 3.40g, yield 74%, 277～279 ℃ of mp.
2-iodo-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I
a) preparation
(1.0g 2.2mmol) is dissolved among the anhydrous THF of 30mL III, adds iodine (1.7g successively, 6.6mmol) and pyridine (0.7g, 8.6mmol), back flow reaction 48h, be cooled to room temperature, add 50mL 10% sodium sulfite solution, ethyl acetate extraction (50mL * 3), saturated common salt water washing (30mL * 3), concentrate, (ethyl acetate: sherwood oil=1: 8 (V: V)) gets white solid 0.85g to column chromatography, yield 68.5%, 137～141 ℃ of mp.
ESI-MS?577.3[M-H]
-；
IR(KBr，cm
-1)v：3429，3329，2960，2935，2863，1726，1666，1585，1452，1384，1345，1219，1192，1161，1085，1022，993，963，827；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.802(s，3H，CH
3)，1.039(s，3H，CH
3)，1.131(s，6H，2×CH
3)，1.169(s，3H，CH
3)，1.215(s，3H，CH
3)，1.254(s，3H，CH
3)，5.347(brs，1H，C
12-H)，7.824(s，1H，C
1-H).
Embodiment 2
2-cyano group-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I
b) preparation
I
a(0.35g 0.61mmol) is dissolved in the 20mL N-Methyl pyrrolidone (NMP), and (110mg, 1.21mmol), 140 ℃ of reactions of temperature 2h is cooled to room temperature in keeping, and adds 50mL 10%FeCl to add CuCN
3The aqueous solution is separated out gray solid, suction filtration, drying, column chromatography (ethyl acetate: sherwood oil=1: 8 (V: V)), white solid 220mg, yield 76%, mp＞300 ℃.
ESI-MS?476.4[M-H]
-；
IR(KBr，cm
-1)v：3428，2955，2933，2868，2236，1695，1460，1385，1231，1180，972，817，617；?
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.879(s，3H，CH
3)，1.065(s，3H，CH
3)，1.073(s，3H，CH
3)，1.155(s，6H，2×CH
3)，1.163(s，3H，CH
3)，1.224(s，3H，CH
3)，1.228(s，3H，CH
3)，5.375(brs，1H，C
12-H)，7.752(s，1H，C
1-H).
Embodiment 3
1, the preparation of 2-epoxy-3-oxo-18 β-volatile oil-12-alkene-30-acid (IV)
(0.90g 2.0mmol) is dissolved among the 30mL THF III, adds 2M sodium hydroxide solution 8mL, drip the methanol solution 15mL of hydrogen peroxide (6mL, 30%), dropwise in 10 minutes, stirring at room 12h, the most of solvent of pressure reducing and steaming adds 50mL 5% aqueous hydrochloric acid, separate out solid, suction filtration, drying, column chromatography (sherwood oil: ethyl acetate=10: 1 (V: V)), get white solid 0.78g, yield 84%, 206～208 ℃ of mp.
ESI-MS?486.3[M+NH
4]
+；503.6[M+Cl]
-；
IR(KBr，cm
-1)v：3426，2941，2870，1701，1458，1384，1333，1317，1261，1231，1167，1030，928，880，827，816，671；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.791(s，3H，CH
3)，1.021(s，3H，CH
3)，1.065(s，3H，2×CH
3)，1.110(s，3H，CH
3)，1.135(s，3H，CH
3)，1.177(s，3H，CH
3)，1.215(s，3H，CH
3)，3.382(d，1H，C
1-H，J＝4.1Hz)，3.521(d，1H，C
2-H，J＝4.2Hz)，5.339(brs，1H，C
12-H).
2-chloro-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I
D-1) preparation
IV (0.15g 0.321mmol) is dissolved in the 10mL acetate, adds concentrated hydrochloric acid 1mL, and stirring at room 10h adds water 30mL, separates out white solid, suction filtration, and drying gets white solid 120mg, yield 76.9%, 230～233 ℃ of mp.
ESI-MS?487.3[M+H]
+；
IR(KBr，cm
-1)v：2922，2862，1600，1697，1458，1383，1321，1226，1179，1101，964，925，815，761，673；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.830(s，3H，CH
3)，1.056(s，3H，CH
3)，1.168(s，3H，CH
3)，1.223(s，6H，2×CH
3)，1.244(s，6H，2×CH
3)，5.372(brs，1H，C
12-H)，7.238(s，1H，C
1-H).
Embodiment 4
2-bromo-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I
D-2) preparation
IV (0.20g 0.427mmol) is dissolved in the 20mL acetate, adds 48% hydrobromic acid solution 1mL, and under the lucifuge condition, stirring at room 4h adds water 50mL, separates out white solid, suction filtration, and drying gets white solid 210mg, yield 92.6%, 178～181 ℃ of mp.
ESI-MS?531.3[M+H]
+；
IR(KBr，cm
-1)v：3890，3734，3671，3408，3196，2941，2866，1692，1604，1460，1383，1323，1257，1225，1161，1094，1024，932，804，750，669；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.830(s，3H，CH
3)，1.053(s，3H，CH
3)，1.172(s，3H，CH
3)，1.223(s，6H，2×CH
3)，1.235(s，6H，2×CH
3)，5.372(brs，1H，C
12-H)，7.501(s，1H，C
1-H).
Embodiment 5
2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I
E-1) preparation
IV (0.30g, (0.72g is 31.3mmol) among the solution 30mL 0.64mmol) to be dissolved in sodium methylate-methyl alcohol, back flow reaction 48h, the most of solvent of pressure reducing and steaming adds 20% hydrochloric acid down in ice bath and transfers pH to 2, separate out white solid, suction filtration is washed to neutrality, drying, column chromatography (ethyl acetate: sherwood oil=1: 10 (V: V)), get white solid 160mg, yield 51.9%, 154～156 ℃ of mp.
ESI-MS?483.3[M+H]
+；481.4[M-H]
-；
IR(KBr，cm
-1)v：3392，2953，2934，2868，1728，1699，1678，1624，1460，1384，1312，1220，1165，1092，1028，972，758，669；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.835(s，3H，CH
3)，1.059(s，3H，CH
3)，1.152(s，3H，CH
3)，1.190(s，3H，CH
3)，1.206(s，3H，CH
3)，1.217(s，6H，2×CH
3)，3.568(s，3H，OCH
3)，5.387(brs，1H，C
12-H)，5.980(s，1H，C
1-H).
Embodiment 6
2-iodo-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester (I
G-1) preparation
I
a(0.24g 0.41mmol) is dissolved among the 15mL DMF, adds Carbon Dioxide clock (70mg successively, 0.51mmol) and methyl iodide (70mg, 0.50mmol), stirring at room 12h, add water 20mL, ethyl acetate extraction (20mL * 3), 5% sodium sulfite solution washing (20mL * 3), saturated common salt water washing (20mL * 3), anhydrous sodium sulfate drying concentrates, column chromatography (ethyl acetate: sherwood oil=1: 60 (V: V)), get white solid 180mg, yield 85.7%, 221～224 ℃ of mp.
ESI-MS?593.3[M+H]
+；
IR(KBr，cm
-1)v：3429，3329，2964，2935，2860，1726，1676，1585，1452，1381，1317，1219，1192，1161，1085，1022，993，963，827，785，700，673，603，490；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.855(s，3H，CH
3)，1.039(s，3H，CH
3)，1.138(s，6H，2×CH
3)，1.166(s，3H，CH
3)，1.204(s，3H，CH
3)，1.253(s，3H，CH
3)，3.697(s，3H，OCH
3)，5.347(brs，1H，C
12-H)，7.819(s，1H，C
1-H).
Embodiment 7
2-cyano group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester (I
G-2) preparation
With reference to I
G-1The preparation method, by I
bMake faint yellow solid with iodomethane reaction, yield 82%, 261～263 ℃ of mp.
ESI-MS?509.2[M+NH
4]
+；
IR(KBr，cm
-1)v：3422，2974，2937，2864，2230，1722，1684，1458，1383，1223，1194，1163，1084，995，980，827，767，669；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.789(s，3H，CH
3)，1.065(s，3H，CH
3)，1.141(s，3H，CH
3)，1.153(s，6H，2×CH
3)，1.196(s，3H，CH
3)，1.222(s，3H，CH
3)，3.701(s，3H，OCH
3)，5.346(brs，1H，C
12-H)，7.762(s，1H，C
1-H).
Embodiment 8
2-chloro-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester (I
G-3) preparation
With reference to I
G-1The preparation method, by I
D-1Make white solid with iodomethane reaction, yield 91%, 244～247 ℃ of mp.
ESI-MS?501.3[M+H]
+；518.4[M+NH
4]
+；
IR(KBr，cm
-1)v：3431，3387，2968，2939，2860，1728，1681，1063，1451，1429，1385，1330，1260，1219，1192，1163，1101，1082，1022，808，765，673；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.790(s，3H，CH
3)，1.049(s，3H，CH
3)，1.136(s，3H，CH
3)，1.162(s，3H，CH
3)，1.220(s，3H，CH
3)，1.242(s，3H，CH
3)，1.276(s，3H，CH
3)，3.696(s，3H，OCH
3)，5.344(brs，1H，C
12-H)，7.237(s，1H，C
2-OH).
Embodiment 9
2-bromo-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester (I
G-4) preparation
With reference to I
G-1The preparation method, by I
D-2Make white solid with iodomethane reaction, yield 90%, 249～251 ℃ of mp.
ESI-MS?545.2[M+H]
+；
IR(KBr，cm
-1)v：3430，3343，2966，2931，2861，1726，1680，1597，1456，1383，1321，1260，1192，1161，1090，1022，798，673，607；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.790(s，3H，CH
3)，1.048(s，3H，CH
3)，1.138(s，3H，CH
3)，1.169(s，3H，CH
3)，1.218(s，3H，CH
3)，1.233(s，3H，CH
3)，1.257(s，3H，CH
3)，3.696(s，3H，OCH
3)，5.347(brs，1H，C
12-H)，7.500(s，1H，C
1-H).
Embodiment 10
2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester (I
G-5) preparation
With reference to I
G-1The preparation method, by I
E-1Make white solid with iodomethane reaction, yield 89%, 95～98 ℃ of mp.
ESI-MS?497.3[M+H]
+；
IR(KBr，cm
-1)v：3412，3392，2949，2866，1728，1680，1624，1458，1384，1315，1219，1192，1159，1090，1030，977，763，669；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.801(s，3H，CH
3)，1.055(s，3H，CH
3)，1.139(s，3H，CH
3)，1.149(s，6H，2×CH
3)，1.180(s，6H，2×CH
3)，3.566(s，1H，OCH
3)，3.694(s，3H，COOCH
3)，5.369(brs，1H，C
12-H)，5.984(s，1H，C
1-H).
Embodiment 11
2-hydroxyl-3-oxo-18 β-volatile oil-1, the preparation of 12-diene-30-carboxylic acid (V)
I
E-1(0.10g 0.21mmol) is dissolved in the 20mL acetate, adds 5% dilute hydrochloric acid 5mL, backflow 2h, be cooled to room temperature, add water 20mL, suction filtration, column chromatography (ethyl acetate: sherwood oil=1: 8 (V: V)), get white solid 70mg, yield 72.2%, 146～149 ℃ of mp.
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester (I
G-6) preparation
With reference to I
G-1The preparation method, make white solid by V and iodomethane reaction, yield 91%, 143～146 ℃ of mp.
ESI-MS?483.3[M+H]
+；500.3[M+NH
4]
+；
IR(KBr，cm
-1)v：3443，2972，2943，2866，1730，1667，1641，1456，1410，1383，1257，1217，1192，1161，1085，1057，991，972，881，825，761，671，536，511；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.794(s，3H，CH
3)，1.040(s，3H，CH
3)，1.135(s，9H，3×CH
3)，1.306(s，3H，CH
3)，1，346(s，3H，CH
3)，3.695(s，3H，OCH
3)，5.330(brs，1H，C
12-H)，5.919(s，1H，C
1-H)，6.364(s，1H，C
2-OH).
Embodiment 12
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid, ethyl ester (I
G-7) preparation
With reference to I
G-1The preparation method, make white solid, yield 84%, 126～128 ℃ of mp by the reaction of V and monobromethane.
ESI-MS?497.4[M+H]
+；
IR(KBr，cm
-1)v：3441，2959，2870，1726，1667，1460，1385，1316，1254，1219，1159，1088，1026，976，868，806，767，673；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.793(s，3H，CH
3)，1.042(s，3H，CH
3)，1.127(s，3H，CH
3)，1.136(s，3H，CH
3)，1.234(s，3H，CH
3)，1.254(s，3H，CH
3)，1.298(s，3H，CH
3)，4.092～4.231(m，2H，OCH
2)，5.315(brs，1H，C
12-H)，5.923(s，1H，C
1-H)，6.365(s，1H，C
2-OH).
Embodiment 13
2-acetoxy-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester (I
G-8) preparation
I
G-6(0.25g 0.52mmol) is dissolved in the 10mL diacetyl oxide, backflow 8h, cooling adds water 20mL, separates out solid, suction filtration, column chromatography (ethyl acetate: sherwood oil=1: 40 (V: V)), white solid 150mg, yield 55.1%, mp158～160 ℃.
ESI-MS?525.4[M+H]
+；
IR(KBr，cm
-1)v：3439，3389，3346，29242862，1764，1730，1682，1458，1375，1217，1161，1082，1037，984，827，671，601，509，465；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.790(s，3H，CH
3)，1.050(s，3H，CH
3)，1.136(s，3H，CH
3)，1.152(s，6H，2×CH
3)，1.220(s，3H，CH
3)，1.264(s，3H，CH
3)，2.211(s，3H，COCH
3)，3.695(s，3H，OCH
3)，5.329(brs，1H，C
12-H)，6.695(s，1H，C
1-H)，5.979(s，1H，C
2-OH).
Embodiment 14
3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-1) preparation
III (2.5g 5.53mmol) is dissolved in the 50mL methylene dichloride, drips the dichloromethane solution 15mL of oxalyl chloride (2.5mL), finish for 30 minutes, and stirring at room 12h, oxalyl chloride that pressure reducing and steaming is excessive and solvent, drying gets the acyl chlorides intermediate; It is dissolved in the 50mL methylene dichloride, feeds exsiccant NH
3To reaction system pH to 11～12, continue to stir 1h, concentrate, (ethyl acetate: sherwood oil=1: 5 (V: V)) gets white solid 2.2g, yield 88.0%, 228～231 ℃ of mp to column chromatography.
ESI-MS?452.4[M+H]
+；486.4[M+Cl]
-；
IR(KBr，cm
-1)v：3446，3358，3202，2953，2926，2870，1667，1611，1456，1385，1361，1285，1246，1196，1159，1099，1028，926，826，752，665；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.824(s，3H，CH
3)，1.060(s，3H，CH
3)，1.109(s，3H，CH
3)，1.168(s，9H，3×CH
3)，1.191(s，3H，CH
3)，5.358(brs，1H，C
12-H)，5.715(brs，2H，NH
2)，5.812(d，1H，C
1-H，J＝10.1Hz)，7.042(d，1H，C
2-H，J＝10.1Hz).
Embodiment 15
N-methyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-2) preparation
With reference to I
H-1The preparation method, make faint yellow solid, yield 90.8%, 276～278 ℃ of mp by the reaction of III and methylamine gas.
ESI-MS?466.6[M+H]
+；464.5[M-H]
-；510.3[M+Cl]
-；
IR(KBr，cm
-1)v：3412，2943，2866，1659，1530，1462，1385，1248，1157，1101，1026，826，667，586；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.805(s，3H，CH
3)，1.055(s，3H，CH
3)，1.108(s，6H，2×CH
3)，1.164(s，6H，2×CH
3)，1.191(s，3H，CH
3)，2.847(d，3H，NCH
3，J＝4.5Hz)，5.358(brs，1H，C
12-H)，5.633(brs，1H，NH)，5.811(d，1H，C
1-H，J＝9.9Hz)，7.045(d，1H，C
1-H，J＝10.2Hz).
Embodiment 16
N-ethyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-3) preparation
With reference to I
H-1The preparation method, make faint yellow solid by III and ethamine gas reaction, yield 80.2%, 249～251 ℃ of mp.
ESI-MS?480.5[M+H]
+；510.3[M+Cl]
-；
IR(KBr，cm
-1)v：3414，2972，2945，2920，2868，1655，1520，1466，1383，1240，1157，1101，827，669，586；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.805(s，3H，CH
3)，1.055(s，3H，CH
3)，1.108(s，6H，2×CH
3)，1.164(s，6H，2×CH
3)，1.191(s，3H，CH
3)，3.262～3.394(m，2H，NCH
2)，5.348(brs，1H，C
12-H)，5.586(brs，1H，NH)，5.810(d，1H，C
1-H，J＝10.2Hz)，7.043(d，1H，C
1-H，J＝10.2Hz).
Embodiment 17
3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acyl piperazine (I
H-4) preparation
With reference to I
H-1The preparation method, make white powder, yield 32.6%, 133～135 ℃ of mp by the reaction of III and Piperazine anhydrous.
ESI-MS?520.5[M+H]
+；
IR(KBr，cm
-1)v：3422，3399，2947，2864，2859，1738，1668，1629，1460，1412，1383，1246，1099，1022，824，665；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.815(s，3H，CH
3)，1.043(s，3H，CH
3)，1.146(s，3H，CH
3)，1.159(s，3H，CH
3)，1.189(s，3H，CH
3)，1.225(s，6H，2×CH
3)，3.178(brs，4H，2×CH
2N)，3.654(brs，1H，NH)，3.963(brs，4H，2×CH
2NCO)，5.342(brs，1H，C
12-H)，5.989(d，1H，C
1-H，J＝10.1Hz)，7.061(d，1H，C
1-H，J＝10.2Hz).
Embodiment 18
2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-5) preparation
With reference to I
H-1The preparation method, by I
E-1Make faint yellow solid with ammonia gas react, yield 89%, 126～129 ℃ of mp.
ESI-MS?482.4[M+H]
+；516.4[M+Cl]
-；
IR(KBr，cm
-1)v：3433，3360，3200，2955，2926，2862，1674，1663，1620，1460，1385，1238，1089，972，804，663；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.828(s，3H，CH
3)，1.058(s，3H，CH
3)，1.151(s，3H，CH
3)，1.170(s，3H，CH
3)，1.189(s，6H，2×CH
3)，1.206(s，3H，CH
3)，3.566(s，3H，OCH
3)，5.133(brs，1H，NH)，5.374(brs，1H，C
12-H)，5.622(brs，1H，NH)，5.974(s，1H，C
1-H).
Embodiment 19
N-methyl-2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-6) preparation
With reference to I
H-1The preparation method, by I
E-1Make faint yellow solid, yield 92%, 229～231 ℃ of mp with the methylamine gas reaction.
ESI-MS?496.4[M+H]
+；530.6[M+Cl]
-；
IR(KBr，cm
-1)v：3435，2957，2918，1676，1657，1628，1521，1462，1383，1236，1157，1096，974，837，760，667；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.809(s，3H，CH
3)，1.053(s，3H，CH
3)，1.108(s，3H，CH
3)，1.150(s，3H，CH
3)，1.185(s，6H，2×CH
3)，1.204(s，3H，CH
3)，2.844(d，3H，NHCH
3，J＝4.5Hz)，3.567(s，3H，OCH
3)，5.380(brs，1H，C
12-H)，5.618(brs，1H，NH)，5.978(s，1H，C
1-H).
Embodiment 20
N-ethyl-2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-7) preparation
With reference to I
H-1The preparation method, by I
E-1Make faint yellow solid with the ethamine gas reaction, yield 91%, 223～225 ℃ of mp.
ESI-MS?510.4[M+H]
+；544.6[M+Cl]
-；
IR(KBr，cm
-1)v：3410，3244，3171，2970，2947，2870，1740，1682，1651，1616，1520，1474，1452，1379，1292，1234，1122，1084，1028，968，883，783，756，669；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.809(s，3H，CH
3)，1.054(s，3H，CH
3)，1.105(s，3H，CH
3)，1.151(s，3H，CH
3)，1.186(s，6H，2×CH
3)，1.204(s，3H，CH
3)，3.268～3.386(m，2H，NCH
2)，3.566(s，3H，OCH
3)，5.364(brs，1H，C
12-H)，5.569(brs，1H，NH)，5.978(s，1H，C
1-H).
Embodiment 21
2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acyl piperazine (I
H-8) preparation
With reference to I
H-1The preparation method, by I
E-1Make white solid, yield 93%, 166～168 ℃ of mp with the Piperazine anhydrous reaction.
ESI-MS?551.5[M+H]
+；585.6[M+Cl]
-；
IR(KB?r，cm
-1)v：3665，3421，3400，3269，3206，2949，2868，2725，2636，2486，2355，2317，1680，?1636，1460，1410，1383，1307，1244，1199，1132，1090，972，831，802，756，719，661，523；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.812(s，3H，CH
3)，1.048(s，3H，CH
3)，1.151(s，3H，CH
3)，1.164(s，3H，CH
3)，1.191(s，3H，CH
3)，1.210(s，6H，2×CH
3)，3.167(brs，4H，2×CH
2N)，3.576(s，3H，OCH
3)，3.643(brs，1H，NH)，3.953(brs，4H，2×CH
2NCO)，5.382(brs，1H，C
12-H)，5.989(s，1H，C
1-H).
Embodiment 22
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-9) preparation
With reference to I
H-1The preparation method, make white solid by V and ammonia gas react, yield 90%, 230～233 ℃ of mp.
ESI-MS?468.4[M+H]
+；502.5[M+Cl]
-；
IR(KBr，cm
-1)v：3437，3373，3248，2957，2928，2868，1710，1657，1602，1462，1389，1284，1244，1167，1051，1030，976，667；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.828(s，3H，CH
3)，1.058(s，3H，CH
3)，1.151(s，3H，CH
3)，1.170(s，3H，CH
3)，1.189(s，6H，2×CH
3)，1.206(s，3H，CH
3)，5.133(brs，1H，NH)，5.374(brs，1H，C
12-H)，5.622(brs，1H，NH)，5.974(s，1H，C
1-H)，6.358(s，1H，C
2-OH).
Embodiment 23
N-methyl-2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-10) preparation
With reference to I
H-1The preparation method, make white solid, yield 92%, 274～279 ℃ of mp by the reaction of V and methylamine gas.
ESI-MS?482.4[M+H]
+；526.3[M+Cl]
-；
IR(KBr，cm
-1)v：3379，3206，3171，2947，1665，1628，1537，1466，1395，1246，1041，842，752，669；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.800(s，3H，CH
3)，1.039(s，3H，CH
3)，1.106(s，3H，CH
3)，1.137(s，3H，CH
3)，1.145(s，3H，CH
3)，1.234(s，3H，CH
3)，1.254(s，3H，CH
3)，2.848(d，3H，NCH
3，J＝4.5Hz)，5.331(brs，1H，C
12-H)，5.644(brs，1H，NH)，5.935(s，1H，C
1-H)，6.552(s，1H，C
2-OH).
Embodiment 24
N-ethyl-2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides (I
H-11) preparation
With reference to I
H-1The preparation method, make white solid by V and ethamine gas reaction, yield 87%, 266～269 ℃ of mp.
ESI-MS?496.5[M+H]
+；530.6[M-Cl]
-；
IR(KBr，cm
-1)v：3395，3161，2934，2870，2719，1667，1622，1537，1468，1451，1377，1288，1249，1047，842，796，756，667，627；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.801(s，3H，CH
3)，1.041(s，3H，CH
3)，1.104(s，3H，CH
3)，1.138(s，3H，CH
3)，1.149(s，3H，CH
3)，1.235(s，3H，CH
3)，1.255(s，3H，CH
3)，3.285～3.379(m，2H，NCH
2)，5.317(brs，1H，C
12-H)，5.587(brs，1H，NH)，5.933(s，1H，C
1-H)，6.551(s，1H，C
2-OH).
Embodiment 25
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acyl piperazine (I
H-12) preparation
With reference to I
H-1The preparation method, make white solid, yield 64%, 133～136 ℃ of mp by the reaction of V and Piperazine anhydrous.
ESI-MS?537.5[M+H]
+；
IR(KB?r，cm
-1)v：3553，3430，3113，2931，2861，1732，1665，1634，1460，1406，1250，1188，1094，1044，1026，976，947，804，667，583，530；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.812(s，3H，CH
3)，1.048(s，3H，CH
3)，1.151(s，3H，CH
3)，1.164(s，3H，CH
3)，1.191(s，3H，CH
3)，1.210(s，6H，2×CH
3)，3.167(brs，4H，2×CH
2N)，3.643(brs，1H，NH)，3.953(brs，4H，2×CH
2NCO)，5.382(brs，1H，C
12-H)，5.989(s，1H，C
1-H)，6.293(s，1H，C
2-OH).
Embodiment 26
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acyl imidazoles (I
H-13) preparation
With reference to I
H-1The preparation method, make white solid, yield 42%, 99～102 ℃ of mp by the reaction of V and imidazoles.
ESI-MS?519.3[M+H]
+；
IR(KBr，cm
-1)v：3553，3395，3233，3154，2957，2866，1728，1713，1664，1653，1537，1520，1508，1221，1132，1064，1020，935，810，756，665，523；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.799(s，3H，CH
3)，1.019(s，3H，CH
3)，1.135(s，3H，CH
3)，1.155(s，3H，CH
3)，1.235(s，3H，CH
3)，1.245(s，3H，CH
3)，1.436(s，3H，CH
3)，5.220(brs，1H，C
12-H)，6.354(s，1H，C
1-H)，7.083(s，1H，＝CH)，7.580(s，1H，＝CH)，8.306(s，1H，NCH＝N).
Embodiment 27
3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
i) preparation
I
H-1(2.6g, 5.74mmol) be dissolved in the 60mL methylene dichloride, (2.42g, methylene dichloride 11.5mmol) (10mL) solution dripped complete in 10 minutes to drip trifluoroacetic anhydride, room temperature reaction 2h, concentrate, (ethyl acetate: sherwood oil=1: 40 (V: V)) gets white solid 1.5g to column chromatography, yield 60.2%, 194～197 ℃ of mp.
ESI-MS?434.4[M+H]
+；
IR(KBr，cm
-1)v：3412，2964，2931，2868，2226，1659，1456，1385，1254，1159，1098，1028，928，826，716，578；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.794(s，3H，CH
3)，1.000(s，3H，CH
3)，1.051(s，3H，CH
3)，1.065(s，3H，CH
3)，1.077(s，3H，CH
3)，1.104(s，3H，CH
3)，1.115(s，3H，CH
3)，2.327～2.415(m，1H，C
2-H)，2.503～2.617(m，1H，C
2-H)，3.688(s，3H，CH
3)，5.298(brs，1H，C
12-H).
Embodiment 28
2-iodo-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
j) preparation
With reference to I
aThe preparation method, by Compound I
iMake white solid, yield 73.3%, 213～216 ℃ of mp with the iodine reaction.
ESI-MS?560.2[M+H]
+；
IR(KBr，cm
-1)v：3619，3555，3445，3437，2969，2926，2866，2230，1678，1460，1383，1325，1093，792，661；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.912(s，3H，CH
3)，1.060(s，3H，CH
3)，1.132(s，3H，CH
3)，1.169(s，3H，CH
3)，1.199(s，3H，CH
3)，1.214(s，3H，CH
3)，1.352(s，3H，CH
3)，5.423(s，1H，C
12-H)，7.805(s，1H，C
1-H).
Embodiment 29
2-cyano group-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
k) preparation
With reference to I
bThe preparation method, by I
jMake white powder, yield 52.6%, 237～241 ℃ of mp with the cuprous cyanide reaction.
ESI-MS?476.4[M+NH
4]
+；493.7[M+Cl]
-；
IR(KBr，cm
-1)v：3619，3555，3445，3437，2969，2926，2866，2230，1678，1460，1383，1325，1093，792，661；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.915(s，3H，CH
3)，1.060(s，3H，CH
3)，1.132(s，3H，CH
3)，1.169(s，3H，CH
3)，1.199(s，3H，CH
3)，1.214(s，3H，CH
3)，1.352(s，3H，CH
3)，5.423(brs，1H，C
12-H)，7.805(s，1H，C
1-H).
Embodiment 30
1, the preparation of 2-epoxy group(ing)-3-oxo-18 β-volatile oil-12-alkene-30-nitrile (VI)
With reference to the preparation method of IV, by I
iMake white solid, yield 79.6%, 239～241 ℃ of mp with the hydrogen peroxide reaction.
ESI-MS?467.3[M+NH
4]
+；
IR(KBr，cm
-1)v：3393，2926，2868，1699，1636，1460，1389，1254，1161，1078，1026，934，887，810，762，716，667；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.914(s，3H，CH
3)，1.000(s，3H，CH
3)，1.017(s，3H，CH
3)，1.042(s，3H，CH
3)，1.112(s，3H，CH
3)，1.178(s，3H，CH
3)，1.352(s，3H，CH
3)，3.380(d，1H，C
1-H，J＝4.5Hz)，3.507(d，1H，C
2-H，J＝4.5Hz)，5.413(brs，1H，C
12-H).
2-chloro-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
M-1) preparation
With reference to I
D-1The preparation method, make white solid, yield 78.9%, 198～201 ℃ of mp by the reaction of VI and concentrated hydrochloric acid.
ESI-MS?468.3[M+H]
+；
IR(KBr，cm
-1)v：3393，3241，2974，2931，2866，2227，1685，1458，1383，1329，1251，1099，1026，966，937，856，812，662，646；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.845(s，3H，CH
3)，0.999(s，3H，CH
3)，1.057(s，3H，CH
3)，1.097(s，3H，CH
3)，1.151(s，3H，CH
3)，1.182(s，3H，CH
3)，1.281(s，3H，CH
3)，5.349(brs，1H，C
12-H)，7.160(s，1H，C
1-H).
Embodiment 31
2-bromo-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
M-2) preparation;
With reference to I
D-1The preparation method, make white solid, yield 66.1%, 218～220 ℃ of mp by the reaction of VI and 48% Hydrogen bromide.
ESI-MS?512.3[M+H]
+；514.3[M+H+2]
+；
IR(KBr，cm
-1)v：3399，2972，2926，2864，2227，1681，1456，1383，1327，1096，1026，964，936，800，661，627；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.845(s，3H，CH
3)，0.997(s，3H，CH
3)，1.061(s，3H，CH
3)，1.102(s，3H，CH
3)，1.148(s，3H，CH
3)，1.172(s，3H，CH
3)，1.283(s，3H，CH
3)，5.351(brs，1H，C
12-H)，7.423(s，1H，C
1-H).
Embodiment 32
2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
N-1) preparation
With reference to I
E-1The preparation method, make white solid, yield 87%, 196～199 ℃ of mp by the reaction of VI and sodium methylate.
ESI-MS?464.4[M+H]
+；
IR(KBr，cm
-1)v：3399，3358，2976，2928，2862，2228，1685，1620，1460，1383，1236，1125，1090，1026，974，829，806，664；
1H-NMR(300MHz，CDC1
3)，δ(ppm)：0.837(s，3H，CH
3)，1.003(s，3H，CH
3)，1.071(s，3H，CH
3)，1.082(s，3H，CH
3)，1.119(s，3H，CH
3)，1.143(s，3H，CH
3)，1.279(s，3H，CH
3)，3.501(s，3H，OCH
3)，5.364(brs，1H，C
12-H)，5.899(s，1H，C
1-H).
Embodiment 33
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
o) preparation
With reference to the preparation method of V, by I
N-1Make white solid, yield 77.7%, 199～201 ℃ of mp.
ESI-MS?450.3[M+H]
+；
IR(KB?r，cm
-1)v：3424，2963，2924，2866，2231，1663，1456，1395，1292，1234，1126，1088，1055，1033，976，947，856，795，758，661，617，576；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.845(s，3H，CH
3)，0.990(s，3H，CH
3)，1.037(s，3H，CH
3)，1.067(s，3H，CH
3)，1.162(s，3H，CH
3)，1.191(s，3H，CH
3)，1.276(s，3H，CH
3)，5.339(brs，1H，C
12-H)，5.871(s，1H，C
1-H)，6.282(s，1H，C
2-OH).
Embodiment 34
The preparation of 3 beta-hydroxies-18 β-volatile oil-12-alkene-30-alcohol (VII)
(3g 6.58mmol) among molten and the anhydrous THF of 40mL, adds LiAlH to II in batches
4(1.75g 46.1mmol), slowly is warming up to backflow, reaction 2h is chilled to room temperature, adds 5% dilute hydrochloric acid cancellation in reaction solution, ethyl acetate extraction (40mL * 3), saturated common salt water washing (20mL * 3), anhydrous sodium sulfate drying concentrates, dry, get white solid 2.71g, yield 93%, 239～241 ℃ of mp.
The preparation of 3 beta-hydroxy 30-, three benzyloxies-18 β-volatile oil-12-alkene (VIII)
VII (0.80g, 1.81mmol) be dissolved in the 60mL methylene dichloride, add trityl chloride (2.5g successively, 9.05mmol), DMAP (0.23g, 1.89mmol), triethylamine (0.2mL), back flow reaction 24h, column chromatography (ethyl acetate: sherwood oil=1: 10 (V: V)), get white solid 0.77g, yield 62.1%, 102～104 ℃ of mp.
The preparation of 3-oxo-30-three benzyloxies-18 β-volatile oil-12-alkene (IX)
(0.6g 0.88mmol) is dissolved among the 20mL DMSO VIII, adds IBX (0.31g, 1.1mmol), stirring at room 12h adds water 30mL, ethyl acetate extraction (30mL * 3), 5% sodium bicarbonate aqueous solution washing (20mL * 3), saturated common salt water washing (20mL * 3), anhydrous sodium sulfate drying, concentrate, get white solid, yield 95.3%, 194～196 ℃ of mp.
IR(KBr，cm
-1)v：3452，2935，2879，1660，1432，1398，1060，995，759，711，624；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.958(s，3H，CH
3)，1.048(s，6H，2×CH
3)，1.075(s，3H，CH
3)，1.089(s，3H，CH
3)，1.128(s，3H，CH
3)，1.255(s，3H，CH
3)，2.373～2.544(m，2H，C
2-H)，2.927(dd，2H，CH
2O，J＝8.6，19.4Hz)，5.052(brs，1H，C
12-H)，7.197～7.322(m，7H)，7.470(d，8H，J＝8.0Hz).
2-hydroxyl-3-oxo-30-three benzyloxies-18 β-volatile oil-1,12-diene (I
q) preparation
IX (0.20g 0.29mmol) is dissolved in the 30mL trimethyl carbinol, be warming up to 45 ℃ after, (0.66g 5.89mmol), reacts 2.5h in 40～45 ℃ to add potassium tert.-butoxide, be cooled to room temperature, add 5% dilute hydrochloric acid and transfer pH to 4, the most of solvent of pressure reducing and steaming, separate out white solid, suction filtration, drying gets white solid 110mg, yield 54.2%, 128～130 ℃ of mp.
IR(KBr，cm
-1)v：3433，3059，2922，2861，1707，1659，1454，1393，1227，1065，756，704，632，530；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.767(s，3H，CH
3)，0.796(s，3H，CH
3)，0.954(s，3H，CH
3)，1.100(s，3H，CH
3)，1.126(s，3H，CH
3)，1.214(s，3H，CH
3)，1.252(s，3H，CH
3)，1.994(d，1H，C
18-H，J＝14.1Hz)，2.285(s，1H，C
9-H)，2.391(d，1H，C
18-H，J＝14.0Hz)，2.936(s，2H，CH
2O)，5.653(d，1H，C
11-H，J＝10.8Hz)，5.957(s，1H，C
1-H)，6.463(d，1H，C
12-H，J＝8.6Hz)，6.354(s，1H，C
1-H)，6.590(s，1H，C
2-OH)，7.239(m，9H)，7.471(d，6H).
Embodiment 35
2,30-dihydroxyl-3-oxo-18 β-volatile oil-1,12-diene (I
Y-1) preparation
I
q(380mg, 0.55mmol) be dissolved in 30mL acetate, add 3mL 5% hydrochloric acid, room temperature reaction 2h, add water 20mL, ethyl acetate extraction (30mL * 3) is used 5% sodium bicarbonate aqueous solution (20mL * 3), saturated aqueous common salt (20mL * 3) washing, anhydrous sodium sulfate drying successively, concentrate, column chromatography gets white solid 160mg, yield 64.5%.
mp?204～207℃；
ESI-MS?513.4[M+H]
+，588.5[M+Cl]
-；
IR(KBr，cm
-1)v：3507，3431，3283，2951，2870，1659，1458，1391，1294，1234，1033，976，837，797，758，667；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.844(s，3H，CH
3)，0.905(s，3H，CH
3)，1.040(s，3H，CH
3)，1.135(s，3H，CH
3)，1.151(s，3H，CH
3)，1.233(s，3H，CH
3)，1.251(s，3H，CH
3)，3.530(dd，2H，CH
2O，J＝10.8，22.7Hz)，5.250(brs，1H，C
12-H)，5.936(s，1H，C
1-H)，6.357(s，1H，C
2-OH).
Embodiment 36
2-hydroxyl-3-oxo-30-acetoxyl group-18 β-volatile oil-1,12-diene (I
Z-1) preparation
I
q(80mg 0.12mmol) is dissolved in the 20mL acetate, adds 3mL 5% hydrochloric acid, back flow reaction 2h, add water 30mL, ethyl acetate extraction (30mL * 3) is used 5% sodium bicarbonate aqueous solution (20mL * 3), saturated aqueous common salt (20mL * 3) washing successively, anhydrous sodium sulfate drying, concentrate, (ethyl acetate: sherwood oil=1: 30 (V: V)) gets white solid 15mg to column chromatography, yield 28.8%, 152～154 ℃ of mp.
IR(KB?r，cm
-1)v：3433，3059，2922，2861，1454，1393，1227，1065，756，671，536，511；ESI-MS?451.3[M+H]
+；449.3[M-H]
-；
1H-NMR(300MHz，CDCl
3)，δ(ppm)：0.843(s，3H，CH
3)，0.913(s，3H，CH
3)，1.038(s，3H，CH
3)，1.136(s，6H，2×CH
3)，1.233(s，3H，CH
3)，1.246(s，3H，CH
3)，1.251(s，3H，CH
3)，2.080(s，3H，COCH
3)，3.997(s，2H，OCH
2)，5.229(brs，1H，C
12-H)，5.923(s，1H，C
1-H)，6.357(s，1H，C
2-OH).
Claims (10)
1. have 1, Enoxolone derivative or its pharmacy acceptable salt of 12-diene-3-ketone skeleton shown in the general formula (I):
Wherein:
R
1Represent hydrogen atom, halogen atom, cyano group, hydroxyl, trifluoromethyl, sulfydryl, nitro, amino, C
1-C
6Alkyl, C
1-C
6Alkylamino, OR
3Or OC (O) R
3
R
2Represent CN, CH
2OC (Ph)
3, CO
2H, CO
2R
4, CH
2OH, CH
2OC (O) R
4Or C (O) NR
5R
6
R
3Represent C
1-C
6Alkyl;
R
4Represent C
1-C
6Alkyl or C
6-C
10Aromatic base, wherein said aromatic base can be randomly be selected from following group and replace with one or more: halogen atom, nitro, cyano group, amino or hydroxyl;
R
5And R
6Can be identical or different, represent hydrogen atom, C
1-C
6Alkyl or R
1And R
2Form 5-7 unit heterocyclic group with the nitrogen-atoms that connects with them, this heterocyclic group can randomly comprise other heteroatoms of one or more O of being selected from, S, N or NH, and this heterocyclic group can randomly be replaced to five replacements by following identical or different substituting group list, and described substituting group comprises: halogen atom, hydroxyl, nitro, cyano group, amino, C
1-C
6Alkyl or C
1-C
6Alkoxyl group;
Wherein, except following formula (a-c) compound:
2. Enoxolone derivative according to claim 1 or its pharmacy acceptable salt is characterized in that:
R
1Represent H, OH, Cl, Br, I, CN, OR
3Or OC (O) R
3
R
2Represent CN, CH
2OC (Ph)
3, CO
2H, CO
2R
4, CH
2OH, CH
2OC (O) R
4Or C (O) NR
5R
6
R
3Represent CH
3
R
4Represent CH
3Or C
2H
5
NR
5R
6Represent NH
2, piperazinyl or imidazolyl.
3. glycyrrhetinic acid acid derivative according to claim 1 or its pharmacy acceptable salt is characterized in that, described compound is selected from:
2-iodo-3-oxo-18 β-volatile oil-1,12-diene-30-acid;
2-cyano group-3-oxo-18 β-volatile oil-1,12-diene-30-acid;
2-chloro-3-oxo-18 β-volatile oil-1,12-diene-30-acid;
2-bromo-3-oxo-18 β-volatile oil-1,12-diene-30-acid;
2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-acid;
2-iodo-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester;
2-cyano group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester;
2-chloro-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester;
2-bromo-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester;
2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester;
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester;
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid, ethyl ester;
2-acetoxy-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester;
3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides;
N-methyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides;
N-ethyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides;
3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acyl piperazine;
2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides;
N-methyl-2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides;
N-ethyl-2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides;
2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acyl piperazine;
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides;
N-methyl-2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides;
N-ethyl-2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acid amides;
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acyl piperazine;
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-carboxylic acyl imidazoles;
3-oxo-18 β-volatile oil-1,12-diene-30-nitrile;
2-iodo-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile;
2-cyano group-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile;
2-chloro-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile;
2-bromo-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile;
2-methoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile;
2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile;
2-hydroxyl-3-oxo-30-three benzyloxies-18 β-volatile oil-1, the 12-diene;
2,30-dihydroxyl-3-oxo-18 β-volatile oil-1,12-diene;
2-hydroxyl-3-oxo-30-acetoxyl group-18 β-volatile oil-1, the 12-diene.
4. the preparation method of the described Enoxolone derivative of claim 1-3 is characterized in that:
A) work as R
2Be CO
2During H; the preparation method of general formula (I) compound is: glycyrrhetinic acid makes 3 beta-hydroxies-18 β-volatile oil-12-alkene-30-acid (II) through the Clemmensen reduction; II and adjacent iodoxy phenylformic acid (IBX) heated oxide generate 3-oxo-18 β-volatile oil-1; 12-diene-30-acid (III); III makes 2-iodo-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I with the elemental iodine reaction under pyridine catalysis
a), I
aReact with fluorosulfonyl difluoroacetic acid methyl esters with the cuprous cyanide reaction or under cuprous iodide catalysis, make 2-cyano group-3-oxo-18 β-volatile oil-1 respectively, 12-diene-30-acid (I
b) and 2-trifluoromethyl-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I
c); III gets 1 through hydrogen peroxide oxidation, 2-epoxy-3-oxo-18 β-volatile oil-12-alkene-30-acid (IV), IV and haloid acid (HX) or sodium alkoxide (R
3ONa) reaction makes 2-halogen-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I respectively
d) and 2-alkoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I
e), I
eGenerate 2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-acid (V), V and alkanoic acid anhydride ((R with hydrochloric acid reaction
3CO)
2O) reaction makes 2-alkanoyloxy-3-oxo-18 β-volatile oil-1,12-diene-30-acid (I
f); Its synthetic route is as follows:
Wherein, X represents F, Cl, Br, R
3Definition as described in the claim 1-3;
Preparation formula (III) compound is characterised in that solvent is selected from dimethyl sulfoxide (DMSO) (DMSO), dimethyl formamide (DMF), N-Methyl pyrrolidone (NMP) or ethyl acetate; Temperature of reaction is 60-120 ℃; Reaction times is 3-24 hour;
B) work as R
2Be CO
2R
4Or C (O) NR
5R
6The time, the preparation method of general formula (I) compound is: with formula (III) and the formula (I that a) makes
a-I
f) compound is raw material, under the alkalescence effect with halohydrocarbon (R
4X) reaction or generate behind the acyl chlorides again and corresponding aminated compounds (HNR with chloride reagent reaction
5R
6) reaction, make ester compound (I respectively
g) and amides (I
h); Its synthetic route is as follows:
Wherein, R
1, R
4, R
5And R
6Definition as described in the claim 1-3;
Preparation formula (I
h) time, chloride reagent is selected from oxalyl chloride, sulfur oxychloride or phosphorus trichloride;
C) work as R
2During for CN, the preparation method of general formula (I) compound is: with b) 3-oxo-18 β-volatile oil-1 of making, 12-diene-30-methane amide (I
H-1) be raw material, under the dehydrated reagent effect, make 3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
i); With reference to synthetic method a), I
iUnder pyridine catalysis, make 2-iodo-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I with the iodine reaction
j), I
jReact with fluorosulfonyl difluoroacetic acid methyl esters with the cuprous cyanide reaction or under cuprous iodide catalysis, make 2-cyano group-3-oxo-18 β-volatile oil-1 respectively, 12-diene-30-nitrile (I
k) and 2-trifluoromethyl-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
l); I
iMake 1 with the hydrogen peroxide reaction, 2-epoxy group(ing)-3-oxo-18 β-volatile oil-12-alkene-30-nitrile (VI), VI and haloid acid (HX) reaction makes 2-halogen-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
m); VI and sodium alkoxide (R
3ONa) reaction makes 2-alkoxyl group-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
n), I
nUnder the hydrochloric acid effect, generate 2-hydroxyl-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
o), I
oWith alkanoic acid anhydride ((R
3CO)
2O) reaction makes 2-alkanoyloxy-3-oxo-18 β-volatile oil-1,12-diene-30-nitrile (I
p); Its synthetic route is as follows:
Wherein, X is F, Cl or Br, R
3Definition as described in the claim 1-3;
Preparation formula (I
i) time, dehydrated reagent is selected from trifluoroacetic anhydride, diacetyl oxide, phosphorus oxychloride or phosphorus trichloride;
D) work as R
2Be CH
2OH, CH
2OC (Ph)
3Or CH
2OC (O) R
4The time, the preparation method of general formula (I) compound is: II makes 3 beta-hydroxies-18 β-volatile oil-12-alkene-30-alcohol (VII) through the Lithium Aluminium Hydride reduction, VII and triphenylmethyl chloride reaction generate 3 beta-hydroxies-30-three benzyloxies-18 β-volatile oil-12-alkene (VIII), VIII makes 3-oxo-30-three benzyloxies-18 β-volatile oil-12-alkene (IX) through IBX oxidation under room temperature, IX makes 2-hydroxyl-3-oxo-30-three benzyloxies-18 β-volatile oil-1,12-diene (I through the potassium tert.-butoxide oxidation
q), I
qWith alkanoic acid anhydride ((R
3CO)
2O) reaction makes 2-alkanoyloxy-3-oxo-30-three benzyloxies-18 β-volatile oil-1,12-diene (I
r); Its synthetic route is as follows:
VIII and IBX heated oxide generate 3-oxo-30-three benzyloxies-18 β-volatile oil-1,12-diene (I
s); With reference to synthetic method a), I
sUnder pyridine catalysis, make 2-iodo-3-oxo-30-three benzyloxies-18 β-volatile oil-1,12-diene (I with the elemental iodine reaction
t), I
tReact with fluorosulfonyl difluoroacetic acid methyl esters with the cuprous cyanide reaction or under cuprous iodide catalysis, make 2-cyano group-3-oxo-30-three benzyloxies-18 β-volatile oil-1 respectively, 12-diene (I
u) and 2-trifluoromethyl-3-oxo-30-three benzyloxies-18 β-volatile oil-1,12-diene (I
v); I
sGet 1 through hydrogen peroxide oxidation, 2-epoxy-3-oxo-30-three benzyloxies-18 β-volatile oil-12-alkene (X), X and haloid acid (HX) or sodium alkoxide (R
3ONa) reaction makes 2-halogen-3-oxo-30-three benzyloxies-18 β-volatile oil-1,12-diene (I respectively
w) and 2-alkoxyl group-3-oxo-30-three benzyloxies-18 β-volatile oil-1,12-diene (I
x); Its synthetic route is as follows:
Formula (I
q-I
x) compound and hydrochloric acid and Glacial acetic acid react under room temperature and make formula (I
y) compound; Formula (I
q-I
x) compound and hydrochloric acid and organic acid (R
4CO
2H) back flow reaction makes formula (I
z) compound; Its synthetic route is as follows:
Wherein, X is F, Cl or Br, R
1, R
3And R
4Definition as described in the claim 1-3.
5. method according to claim 4, preparation formula (III) compound is characterised in that solvent is selected from DMSO, and temperature of reaction is 85 ℃, and the reaction times is 4h.
6. method according to claim 4, preparation formula (I
h) compound is characterised in that chloride reagent is selected from oxalyl chloride.
7. method according to claim 4, preparation formula (I
i) compound is characterised in that dehydrated reagent is selected from trifluoroacetic anhydride.
8. pharmaceutical composition is gone up the described general formula of claim 1 (I) compound of significant quantity and pharmaceutically acceptable carrier or auxiliary material by treatment and is formed.
9. the described general formula of claim 1 (I) compound or its pharmacy acceptable salt are in the purposes of preparation in the antitumor drug.
10. the purposes of claim 9, described tumor disease is liver cancer, colorectal carcinoma, prostate cancer, carcinoma of the pancreas.
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