CN103664782A - Isocorydine derivative as well as preparation method and application thereof - Google Patents

Isocorydine derivative as well as preparation method and application thereof Download PDF

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CN103664782A
CN103664782A CN201210340250.0A CN201210340250A CN103664782A CN 103664782 A CN103664782 A CN 103664782A CN 201210340250 A CN201210340250 A CN 201210340250A CN 103664782 A CN103664782 A CN 103664782A
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CN103664782B (en
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柳军玺
邸多隆
刘言娟
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Lanzhou Institute of Chemical Physics LICP of CAS
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    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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Abstract

The invention discloses an isocorydine derivative as well as a preparation method and an application thereof. By virtue of two-step organic synthesis and conversion, a chemical structure of a natural product isocorydine is modified to prepare the isocorydine derivative with a formula I, wherein R in the formula I is one of NH2, N(CH3)2 and OH. A compound structure is confirmed by NMR (Nuclear Magnetic Resonance) and HRESIMS (High Resolution Electrospray Ionization Mass Spectroscopy); a cell pharmacological activity experiment proves that the compounds with the formula I have better cytotoxicity, and are applied as drugs for chemical-prevention and treatment drugs of tumors. The formula I is shown in the specification.

Description

ICD derivative and its preparation method and application
Technical field
The present invention relates to the semi-synthetic conversion of natural organic-compound, belong to Synthetic Organic Chemistry field, concretely, the present invention relates to that a kind of to take ICD (English name isocorydine) be raw material, by chemical conversion, the derivative of a series of ICDs of synthetic preparation, this compounds is studied by experiment and is shown to have good cytotoxic activity, can be used as cancer therapy drug.
Background technology
Aporphine alkaloid is the class in morphinane alkaloid, this Alkaloid is extensively present in the plant of 20Ge section more than 100 genus, comprises Magnoliaceae, Menispermaceae, Euphorbiaceae, Lauraceae, Loganiaceae, annonaceae, Aristolochiaceae, Berberidaceae, papaveracease, Ranunculaceae, Rutaceae etc.Aporphine alkaloid has many-sided pharmaceutical activity, comprises anti-oxidant, anti-platelet aggregation, anticancer, anticonvulsion, spasmolytic, anti-malarial, protozoacide, anti-poliovirus, cytotoxicity, anti-parkinson etc.This class natural product and their synthesis of derivatives are the guides that development can be treated the medicine of various diseases.
ICD is a kind of typical aporphine alkaloid, it be present in menispermaceous plants white line potato ( stephania brachyandradiets) piece root, bloodroot corydalis ( corydalis tuberosadC), in stem tuber, be also present in the other plant of multiple not equal genus simultaneously.
Slenderstalk dicranostigma herb ( dicranostigma leptopodum), have another name called Hong Maocao, baldhead spend, rein in the horse back (Shaanxi), biennial or perennial herb, produce northwestern Yunnan Province, western Sichuan, southern Tibet, East of Qinghai Province, SOUTH OF GANSU to the southeast, Qinling Mountains in Shaanxi north slope, Southern Shanxi Province, the west and south, Hebei and the northwestward, Henan.Careless slope and the roadside of being born in height above sea level 400-2900 rice, ridge, the top of a wall, roof are also common.Root and herb are medicinal, the effect such as that herb has is clearing heat and detoxicating, swelling and pain relieving, desinsection; Control toothache due to pathogenic wind-fire, pharyngolaryngitis, tonsillitis, lymphoid tuberculosis, the favus of the scalp, sore furuncle mange, ulcer.
Natural product chemistry composition Study shows mainly to contain the luxuriant and rich with fragrance class morphinane alkaloid of Ah flutterring (if pass unimpeded in slenderstalk dicranostigma herb, slenderstalk dicranostigma herb chemical composition and tissue morphology research. pharmaceutical analysis magazine, 1982,2,273-277.), this Alkaloid mostly has analgesia, calmness and the effect of adrenergic receptor sample, and part of compounds has antitumour activity.
Contriver is in to the screening study of papaveracease slenderstalk dicranostigma herb platymiscium slenderstalk dicranostigma herb chemical composition and anticancer active constituent, find to contain in this plant a large amount of ICDs, poor (the Liu Junxi of its antitumour activity although its content is abundant, slenderstalk dicranostigma herb alkaloids chemical constitution study, herbal medicine, 2011,42,1056-1058.).2000, in the research of Wright CW etc., find that ICD does not have cytotoxicity (Wright CW, In vitro antiplasmodial, antiamoebic to KB cell, and cytotoxic activities of some monomeric isoquinoline alkaloids j Nat Prod, 2000,63,1638-1640.).In the research of You etc., find that ICD does not all have cytotoxic activity (You M, (-)-Roemerine, an aporphine alkaloid to series of human tumor cell line annona-senegalensisthat reverses the multidrug-resistance phenotype with cultured-cells, j Nat Prod-lloydia,1995,58,598-604).
In contriver's anti-cancer active compound screening study in early stage, by semi-synthetic, ICD is carried out to structure of modification, the Isocorydione obtaining (isocorydione), its antitumour activity has obtained obvious improvement (number of patent application: 201110085388.6,201110085389.0).As can be seen here, this compounds is by the derivative and transformation of chemical structure, its biological activity can be significantly improved, the lipid of this compounds can significantly be taken on a new look simultaneously, based on this application's patent, aporphine alkaloid is carried out the derivatize transformation of chemical structure, obtain a series of compounds with better antitumour activity and suitable lipid.
The same with other drug molecule, between the pharmacologically active of aporphine alkaloid and its mother nucleus structure and substituting group, exist close relationship.The research such as Tran finds that 1,2-methylene-dioxy substituting group has very important impact for the cytotoxicity of aporphine alkaloid.The cytotoxicity in most cases with the compound of this functional group is better than the not compound of this functional group far away.In addition, the aporphine derivative of the upper oxidation of N is than other compounds with identical parent nucleus, cytotoxicity low (Tran TD, Chemical investigation of drug-like compounds from the Australian tree, neolitsea dealbata. bioorg Med Chem Lett, 2010,20,5859-5863.).Generally the N on aporphine alkaloid B ring is quaternized is disadvantageous to cytotoxicity later, the N of tertiary amine is to favourable (the Silva EC of its antitumour activity, The antitumoral, trypanocidal and antileishmanial activities of extract and alkaloids isolated from duguetia furfuracea. phytomed, 2009,16,1059-1063.).
Summary of the invention
The object of the present invention is to provide a kind of ICD derivative and its preparation method and application.
Existing to the research of aporphine alkaloid structure activity relationship mainly for A, B and C ring, the present invention is mainly D ring C 8the impact of the derivatize transformation of position on its antitumour activity.The present invention transforms by two step organic syntheses, natural product ICD is carried out to the modification of chemical structure, obtains ICD derivative.
A chemical derivative for ICD, shown in I:
Formula I
In its Chinese style I, R is NH 2, N (CH 3) 2, OH, in a kind of.
A synthetic method for ICD derivative formula I, is characterized in that synthesizing by following steps:
Steps A: by the mixing acid of nitric acid and sulfuric acid, N-chlorosuccinimide, a kind of in N-bromosuccinimide joins in the organic solvent solution of ICD, at-40 ℃-20 ℃, stirring reaction 1-5 h, there is the substitution reaction of ICD, after reacting completely, reaction solution is added in frozen water, with buck regulator solution meta-alkalescence, chloroform extraction, reclaims solvent, and product purification obtains steps A reaction product;
Step B: by the hydrogen under palladium-carbon catalyst catalysis, a kind of in dimethylamino, piperazine and sodium hydroxide adds in the solution of A step reaction product,-20 ℃-20 ℃, under 0-2 Mpa pressure,, there is chemical reaction in stirring reaction 1-5 h, after reacting completely, reclaim solvent, reactant carries out purifying, obtains target compounds of formula I.
Mixing acid in the present invention be nitric acid with sulfuric acid by volume for the volume ratio of 1:1-1:2 is mixed composition.
Purification process in the present invention is column chromatography purification process, liquid-liquid extraction purification process or recrystallization method.
Organic solvent in steps A of the present invention is chloroform, methylene dichloride, 1, a kind of in 2-ethylene dichloride, ethyl acetate, ethanol, methyl alcohol, benzene, toluene and acetone.
Solution in step B of the present invention is chloroform, methylene dichloride, 1, a kind of in 2-ethylene dichloride, ethyl acetate, ethanol, methyl alcohol, acetone and water.
ICD derivative in the present invention all proves target compound by NMR, HRESI-MS and multiple spectroscopy means.
Formula I ICD derivative provided by the invention, shows to have stronger inhibition growth of human tumor cells effect by cell in vitro activity experiment, has good cytotoxic activity, can be used as the chemoprophylaxis of tumour and the application of medicine.
The invention has the advantages that:
Chemical structure by ICD is transformed, raising by a relatively large margin the antitumour activity of this compounds, also improved the lipid of this compounds simultaneously, improved the one-tenth property of medicine of this compounds;
By structure of modification of the present invention, obtain the analogue of a series of ICDs, enriched the structure storehouse of aporphine alkaloid, for the drug screening of this compounds provides a large amount of lead compounds;
The natural product ICD of take derives as raw material carries out structure, has retained the chiral centre of natural product, has reduced the production cost of compou nd synthesis, and technique is simple, and raw material is easy to get.
Embodiment
For a better understanding of the present invention, by following examples, describe, but this patent is not limited in embodiment:
Synthesizing of the amino ICD of embodiment 1:8-:
In A, 6 g ICDs, add 200 mL chloroforms and 200 mL methylene dichloride, dissolve the solution that obtains ICD, be cooled to-30 ℃; Under vigorous stirring, to the mixing acid nitrating agent that is added dropwise to 1.48 mL nitrosonitric acids and the 1.48 mL vitriol oils in above-mentioned solution and is made into, stir 90 min stopped reaction; Reaction solution is poured in 200 mL frozen water, with ammoniacal liquor, the pH value of above-mentioned reaction product is adjusted to 8 left and right, 300 mL chloroform extractions three times, merge organic phase, reclaim organic solvent, and silica gel column chromatography separating and extracting thing obtains 4 g 8-nitro ICDs;
Figure 710149DEST_PATH_IMAGE002
8-nitro ICD: yellow powder shape solid, HR-ESI-MS m/z[387.1565 M+H] +(calculated value C 20h 23n 2o 6be 387.1551), 1h-NMR (400 MHz, CDCl 3): 6.76 (1H, s, H-3), 3.00 (2H, m, H-4), 2.40-2.48 (2H, j=17.2,2.8 Hz, H-4), 2.68-2.72 (2H, dd, j=17.2,2.8Hz, H-5), 3.67 (1H, dd, j=14.4,3.2 Hz, H-6 a), 3.00-3.21 (2H, m, H-7), 7.52 (1H, s, H-9), 3.46 (3H, s, N-CH 3), 3.71 (3H, s, 1-OCH 3), 3.96 (3H, s, 2-OCH 3), 3.90 (3H, s, 10-OCH 3); 13c-NMR (100 MHz, CDCl 3): 142.3 (C-1), 128.0 (C-1a), 130.2 (C-1b), 151.4 (C-2), 112.1 (C-3), 127.5 (C-3a), 29.1 (C-4), 52.6 (C-5), 62.4 (C-6a), 31.0 (C-7), 121.3 (C-7a), 141.8 (C-8), 107.1 (C-9), 148.8 (C-10), 148.7 (C-11), 123.8 (C-11a), 61.6 (1-OCH 3), 56.3 (2-OCH 3), 55.9 (11-OCH 3), 43.9 (N-CH 3).
B, 4 g 8-nitro ICDs add 450 mL dehydrated alcohols in hydrogenation autoclave, induction stirring makes to dissolve, in above-mentioned solution, add the Pd/C hydro-reduction catalyzer that 4 g content are 10%, in autoclave, pass into hydrogen, 0.3MPa pressure, stirring at normal temperature is reacted stopped reaction after 2.5 h; By reaction solution decompress filter, decompression and solvent recovery, silica gel column chromatography is separated, obtains amino ICD 3.4 g of 8-.
Figure 208126DEST_PATH_IMAGE003
The amino ICD of 8-has following spectroscopy data: brown ceramic powder shape solid, HR-ESI-MS m/z[357.1816 M+H] +(calculated value C 20h 25n 2o 4be 357.1809); 1h-NMR (400 MHz, CDCl 3): 6.60 (1H, s, H-3), 3.00 (2H, m, H-4), 2.43 (2H, m, H-5), 3.00 (1H, m, H-6 a), 2.88 (1H, dd, j=16.4,2.0 Hz, H-7), 2.60 (1H, dd, j=16.4,2.0 Hz, H-7), 4.35 (2H, brs, 8-NH 2), 6.34 (1H, s, H-9), 2.51 (3H, s, N-CH 3), 3.56 (3H, s, 1-OCH 3), 3.79 (3H, s, 2-OCH 3), 3.76 (3H, s, 10-OCH 3); 13c-NMR (100 MHz, CDCl 3): 142.2 (C-1), 125.9 (C-1a), 128.9 (C-1b), 151.2 (C-2), 113.0 (C-3), 127.6 (C-3a), 29.2 (C-4), 52.2 (C-5), 62.2 (C-6a), 36.6 (C-7), 120.6 (C-7a), 135.4 (C-8), 102.0 (C-9), 149.2 (C-10), 136.9 (C-11), 110.7 (C-11a), 62.8 (1-OCH 3), 55.8 (2-OCH 3), 55.4 (11-OCH 3), 43.9 (N-CH 3).
Synthesizing of embodiment 2:8-piperazinyl ICD:
In A, 3 g ICDs, add 150 mL Glacial acetic acid, dissolve the solution that obtains ICD, be cooled to 7 ℃; Under vigorous stirring, in above-mentioned solution, add 1.178 gN-chlorosuccinimides, stir 2 h stopped reaction; Reaction solution is poured in 200 mL frozen water, with ammoniacal liquor, the pH value of above-mentioned reaction product is adjusted to 8 left and right, 200 mL chloroform extractions three times, merge organic phase, reclaim organic solvent, and silica gel column chromatography separating and extracting thing obtains 2 g 8-chloro ICDs;
Figure 42090DEST_PATH_IMAGE004
8-chloro ICD: yellow powder shape solid, HR-ESI-MS m/z[375.2060 M+H] +(calculated value C 20h 22clNO 4be 375.1237); 1h-NMR (400 MHz, CDCl 3): 6.74 (1H, s, H-3), 2.31-2.31 (2H, m, H-4), 2.91-2.95 (2H, m, H-5), 3.06 (1H, m, H-6a), (2.67-2.69 2H, m, H-7), (7.50 1H, s, H-9), 2.38 (3H, s, N-CH 3), 3.60 (3H, s, 1-OCH 3), 3.85 (3H, s, 2-OCH 3), 3.79 (3H, s, 10-OCH 3); 13c-NMR (100 MHz, CDCl 3): 142.1 (C-1), 128.5 (C-1a), 130.1 (C-1b), 151.2 (C-2), 112.0 (C-3), 127.4 (C-3a), 29.6 (C-4), 52.5 (C-5), 62.3 (C-6a), 30.9 (C-7), 121.2 (C-7a), 141.7 (C-8), 107.0 (C-9), 148.3 (C-10), 148.7 (C-11), 123.7 (C-11a), 61.5 (1-OCH 3), 56.3 (2-OCH 3), 55.9 (11-OCH 3), 43.9 (N-CH 3).
In B, 3 g 8-chloro ICD 600 mL DMF, add 4.14 g Piperazine anhydrous, be warming up to 150 ℃ from 40 in 1.5 h, mechanical stirring reaction, decompression and solvent recovery, silica gel column chromatography separating and extracting thing obtains 0.5 g 8-piperazinyl ICD;
Figure 55046DEST_PATH_IMAGE005
8-piperazinyl ICD: brown ceramic powder shape solid, HR-ESI-MS m/z[426.4321 M+H] +(calculated value C 24h 32n 3o 4be 425.2315); 1h-NMR (400 MHz, CDCl 3): 6.74 (1H, s, H-3), 2.31-2.31 (2H, m, H-4), 2.91-2.95 (2H, m, H-5), 3.06 (1H, m, H-6a), (2.67-2.69 2H, m, H-7), (7.50 1H, s, H-9), 2.38 (3H, s, N-CH 3), 3.60 (3H, s, 1-OCH 3), 3.85 (3H, s, 2-OCH 3), 3.79 (3H, s, 10-OCH 3), 2.78 (2H, m, H-1 '), 3.47 (2H, m, H-2 '); 13c-NMR (100 MHz, CDCl 3): 142.1 (C-1), 128.5 (C-1a), 130.1 (C-1b), 151.2 (C-2), 112.0 (C-3), 127.4 (C-3a), 29.6 (C-4), 52.5 (C-5), 62.3 (C-6a), 30.9 (C-7), 121.2 (C-7a), 141.7 (C-8), 107.0 (C-9), 148.3 (C-10), 148.7 (C-11), 123.7 (C-11a), 61.5 (1-OCH 3), 56.3 (2-OCH 3), 55.9 (11-OCH 3), 43.9 (N-CH 3), 60.4 (C-1 '), 70.7 (C-2 ').
Synthesizing of embodiment 3:8-dimethylamino ICD
In A, 3 g ICDs, add 150 mL Glacial acetic acid, dissolve the solution that obtains ICD, be cooled to 7 ℃; Under vigorous stirring, in above-mentioned solution, add 1.178 gN-chlorosuccinimides, stir 2 h stopped reaction; Reaction solution is poured in 200 mL frozen water, with ammoniacal liquor, the pH value of above-mentioned reaction product is adjusted to 8 left and right, 200 mL chloroform extractions three times, merge organic phase, reclaim organic solvent, and silica gel column chromatography separating and extracting thing obtains 2 g 8-chloro ICDs;
Figure 937551DEST_PATH_IMAGE006
b,in 3 g 8-chloro ICD 600 mL DMF, add 4.14 mL dimethylamine, be warming up to 100 ℃ from 40 ℃ in 1.5 h, mechanical stirring reaction, decompression and solvent recovery, silica gel column chromatography separating and extracting thing obtains the 8-dimethylamino ICD of 0.5 g;
Figure 290035DEST_PATH_IMAGE007
8-dimethylamino ICD: brown ceramic powder shape solid, HR-ESI-MS m/z[384.2035 M+H] +(calculated value C 22h 28n 2o 4be 384.2049); 1h-NMR (400 MHz, CDCl 3): 6.74 (1H, s, H-3), 2.31-2.31 (2H, m, H-4), 2.91-2.95 (2H, m, H-5), 3.06 (1H, m, H-6a), (2.67-2.69 2H, m, H-7), (7.50 1H, s, H-9), 2.38 (3H, s, N-CH 3), 3.60 (3H, s, 1-OCH 3), 3.85 (3H, s, 2-OCH 3), 3.79 (3H, s, 10-OCH 3), 2.78 (6H, s, N-CH 3); 13c-NMR (100 MHz, CDCl 3): 142.1 (C-1), 128.5 (C-1a), 130.1 (C-1b), 151.2 (C-2), 112.0 (C-3), 127.4 (C-3a), 29.6 (C-4), 52.5 (C-5), 62.3 (C-6a), 30.9 (C-7), 121.2 (C-7a), 141.7 (C-8), 107.0 (C-9), 148.3 (C-10), 148.7 (C-11), 123.7 (C-11a), 61.5 (1-OCH 3), 56.3 (2-OCH 3), 55.9 (11-OCH 3), 43.9 (N-CH 3), 40.3 (N-CH 3).
Synthesizing of embodiment 4:8-hydroxyl ICD
In A, 3 g ICDs, add 150 mL Glacial acetic acid, dissolve the solution that obtains ICD, be cooled to 7 ℃; Under vigorous stirring, in above-mentioned solution, add 1.178 gN-chlorosuccinimides, stir 2 h stopped reaction; Reaction solution is poured in 200 mL frozen water, with ammoniacal liquor, the pH value of above-mentioned reaction product is adjusted to 8 left and right, 200 mL chloroform extractions three times, merge organic phase, reclaim organic solvent, and silica gel column chromatography separating and extracting thing obtains 2 g 8-chloro ICDs;
A, 3.4 g 8-chlorine ICDs are added in 250 mL water, dissolve, add the NaOH of 1.335 g, stirring reaction 1 h in ice bath, 200 mL 1,2 ethylene dichloride extracting twice, reclaim organic solvent, silica gel column chromatography separating and extracting thing obtains the 8-hydroxyl ICD of 0.85 g.
8-hydroxyl ICD: brown ceramic powder shape solid, HR-ESI-MS m/z[357.1534 M+H] +(calculated value C 20h 21nO 5be 357.1576); 1h-NMR (400 MHz, CDCl 3): 6.67 (1H, s, H-3), 5.88 (1H, s, H-9), 3.84 (3H, s, 1-OCH 3), 3.82 (3H, s, 10-OCH 3), 3.79 (3H, s, 2-OCH 3), 2.46 (3H, s, N-CH 3), 3.34 (1H, m, H-6a), 3.00 (2H, m, H-5), 2.42 (1H, m, H-4), 2.85 (1H, dd, j=16.4 Hz, H-7), 2.60 (1H, dd, j=16.4 Hz, H-7); 13c-NMR (100 MHz, CDCl 3): 140.8 (C-1), 127.9 (C-1a), 121.4 (C-1b), 151.8 (C-2), 114.3 (C-3), 128.4 (C-3a), 28.4 (C-4), 53.3 (C-5), 61.3 (C-6a), 25.6 (C-7), 185.5 (C-8), 106.1 (C-9), 160.1 (C-10), 180.2 (C-11), 127.8 (C-11a), 60.9 (1-OCH 3), 56.3 (2-OCH 3), 55.7 (10-OCH 3), 43.9 (N-CH 3).
The amino ICD of embodiment 5:8-and the Vitro Cytotoxicity of 8-hydroxyl ICD to cancer cells
5.1 prepare human cancer cell strain HepG2(human liver cancer cell), 7901(stomach cancer cell), A549(human lung carcinoma cell) suspension: 0.25% tryptic digestion, is made into 8 * 10 with nutrient solution 4individual cell/mL cell suspension; Inoculating cell: every hole 100L is inoculated in 96 orifice plates;
5.2 precultures: 37 ℃, 5%CO 2and cultivate 24h under saturated humidity;
5.3 by the amino ICD of 8-and 8-hydroxyl ICD: press finite concentration dosing, and every hole 100L, each concentration is established three and is answered holes.37 ℃, 5%CO 2and under saturated humidity, 24h is cultivated in continuation;
After 5.4 24 h, take out culture plate, every hole adds trichoroacetic acid(TCA) (TCA) 50 fixed cells of 50% (mass/volume), and the final concentration of TCA is 10%, is added on the liquid level of every hole, in 4 ℃ of refrigerators, places 1h, deionized water wash 5 times of each hole of culture plate, remove TCA, after air drying, every hole adds 0.4% SRB100 L, under room temperature, place 10 ~ 30 min, discard in each hole and with 1% acetic acid, wash 5 times after liquid, remove unconjugated dyestuff, after air drying, with pH, be 10.5, 10 mmol/L tri methylol amino methanes dissolve, 5 min vibrate on oscillator plate, under enzyme-linked immunosorbent assay instrument 490 nm wavelength, measure OD value, with blank, return to zero, obtained growth of tumour cell inhibiting rate is defined as to the extracorporeal inhibiting rate of medicine to tumour cell, measure the IC of ICD derivative 50, the results are shown in Table 1.
The amino ICD of table 1 srb assay mensuration 8-and 8-hydroxyl ICD are for the IC of cancer cells 50value (g/mL)
Cell strain (title) Amino ICD (the IC of 8- 50） 8-hydroxyl ICD (IC 50）
HepG2(human liver cancer cell) 20.0 7.25
A549(human lung carcinoma cell) 2.68 3.05
7901(stomach cancer cell) 5.27 4.98

Claims (7)

1. a chemical derivative for ICD, shown in I:
Formula I
In its Chinese style I, R is NH 2, N (CH 3) 2, OH, in a kind of.
2. a preparation method for the chemical derivative of ICD as claimed in claim 1, is characterized in that synthesizing by following steps:
Steps A: by the mixing acid of nitric acid and sulfuric acid, N-chlorosuccinimide, a kind of in N-bromosuccinimide joins in the organic solvent solution of ICD, at-40 ℃-20 ℃, stirring reaction 1-5 h, there is the substitution reaction of ICD, after reacting completely, reaction solution is added in frozen water, with buck regulator solution meta-alkalescence, chloroform extraction, reclaims solvent, and product purification obtains steps A reaction product;
Step B: by the hydrogen under palladium-carbon catalyst catalysis, a kind of in dimethylamino, piperazine and sodium hydroxide adds in the solution of A step reaction product,-20 ℃-20 ℃, under 0-2 Mpa pressure,, there is chemical reaction in stirring reaction 1-5 h, after reacting completely, reclaim solvent, reactant carries out purifying, obtains target compounds of formula I.
3. method as claimed in claim 2, it is characterized in that mixing acid be nitric acid with sulfuric acid by volume for the volume ratio of 1:1-1:2 is mixed composition.
4. method as claimed in claim 2, is characterized in that purification process is column chromatography purification process, liquid-liquid extraction purification process or recrystallization method.
5. method as claimed in claim 2, is characterized in that the organic solvent in steps A is chloroform, methylene dichloride, 1, a kind of in 2-ethylene dichloride, ethyl acetate, ethanol, methyl alcohol, benzene, toluene and acetone.
6. method as claimed in claim 2, is characterized in that the solution in step B is chloroform, methylene dichloride, 1, a kind of in 2-ethylene dichloride, ethyl acetate, ethanol, methyl alcohol, acetone and water.
7. the chemical derivative of ICD as claimed in claim 1, is characterized in that the chemical derivative of ICD is as chemoprophylaxis and the medicine of tumour.
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CN105315208A (en) * 2014-07-17 2016-02-10 中国科学院兰州化学物理研究所 Aporphine type alkaloid and preparation method thereof
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