CN101148437A - Biinomenine derivative connected with C-C bond, preparation method and application thereof - Google Patents

Biinomenine derivative connected with C-C bond, preparation method and application thereof Download PDF

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CN101148437A
CN101148437A CNA2007101346488A CN200710134648A CN101148437A CN 101148437 A CN101148437 A CN 101148437A CN A2007101346488 A CNA2007101346488 A CN A2007101346488A CN 200710134648 A CN200710134648 A CN 200710134648A CN 101148437 A CN101148437 A CN 101148437A
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disinomenine
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CN101148437B (en
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李建新
邓张双
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Nanjing University
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Abstract

The present invention discloses one kind of sinomenine derivative connected in C-C mode and its preparation process and antiphlogistic and antotumor effects. The sinomenine derivative is prepared with sinomenine as the parent material and through C-C connection in the place 1 biologically and/or chemically. The sinomenine derivative has, the pharmcodynamical experiment shows, high antiphlogistic and antotumor bioactivity, and possesses latent medicinal application foreground.

Description

Disinomenine derivative, preparation method and application thereof that carbon carbon mode connects
One, technical field
The present invention relates to a kind of compound and preparation method thereof, the disinomenine derivative that specifically a kind of carbon carbon mode connects and using microbe transform and (or) chemosynthesis prepares the method for this Sinomenine derivate.The compound that the present invention also provides has potential medicinal application prospect in the antitumor field of anti-inflammatory.
Two, background technology
Tuduranine (sinomenine) be from menispermaceous plants Stem of Orientoine and hair sinomenium acutum rhizome, extract be applied to treating rheumatism and rheumatoid arthritis clinically, the most effective alkaloids medicament of diseases such as arthroncus has pharmacological actions such as significant anti-inflammatory, analgesia, step-down and anti-cerebral ischemia.
Transform by structure tuduranine, seek novel structure, active Sinomenine derivate more efficiently is present research focus, and to the structure of modification of tuduranine C ring research emphasis especially.(CN.1687070A CN.1687065A) synthesizes the Sinomenine derivate that the C ring is connected with pyrazine ring and five-membered ring to Yao Zhujun.(Acta Pharmaceutica Sinica such as Ye Xianrong, 2004,39 (3), 180-183) tuduranine C ring is carried out modification and obtained series compound, and adopt mouse acetic acid twisting method to carry out the active animal test, find that compound 7-methoxyl group-dihydro tuduranine analgesic activities is better than tuduranine.CN.1800164A modifies and obtains a series of derivatives equally to Kukoline C ring, this derivative has stronger anti-inflammatory and antalgic activity, can be used for preparing the medicine of treatment rheumatic arthritis and heart disorder aspect.
The Sinomenine structure-modified D ring that occurs in equally; Chinese patent CN.1785976A, CN.1785977A and CN1962638A have reported N-alkyl diversine and preparation method thereof respectively, and a class 17-sulfonyl diversine and preparation method thereof and a class have the tuduranine compound and the method for making of dextral C circle lacking of morphinan skeleton.
Up-to-date working out now to the modification of tuduranine A ring 1-position carbon, CN.1948291A has synthesized a class 1-substituted amine methyl diversine derivative, and patent CN.187634A introduces aldehyde radical and hydroxyethyl respectively on 1 on A ring.
Make a general survey of above-mentioned document, the research of A ring in the tuduranine being carried out structure of modification is less, and utilizes the method for microbial transformation that the report that tuduranine carries out structure of modification is not reported so far.
Three, summary of the invention
First purpose of the present invention is to disclose the disinomenine derivative that a class carbon-carbon bond connects; Second purpose of the present invention is to disclose the preparation method of this analog derivative; The 3rd purpose of the present invention is to disclose the pharmaceutical use of this compounds at anti-inflammatory and anti-tumor aspect.
The present invention seeks to be achieved through the following technical solutions:
Sinomenine derivate is the disinomenine derivative that class A ring connects with the C-C key among the present invention, and has stereoselectivity.Structural formula is as follows:
Figure A20071013464800071
In the formula: R 4=H, OH (α and β);
(I) work as R 2, R 3=
Figure A20071013464800072
R 1=ethyl, propyl group, butyl, sec.-propyl, straight-chain alkyls such as allyl group; Or cyclopentyl, cyclohexyl, cyclic hydrocarbon group such as suberyl; Or β-fluoro ethyl, cyclopropyl methyl, cyclobutylmethyl, phenmethyl, picolyl, furfuryl, beta-phenyl ethyl, α-Jia Jibianji, alkoxy methyl, substituting groups such as pyrazoles methyl.Or R 1=R 5S (OO)-wherein R 5=methyl, ethyl, propyl group, the alkyl of trifluoromethyl and substituted hydrocarbon radical, phenyl and substituting group;
(II) work as R 2, R 3=
Figure A20071013464800073
R 1=CH 3, H, R 5Be carbonyl or hydroxyl;
(III) work as R 2, R 3=
Figure A20071013464800081
R 1＝CH 3，
R 5, R 6=
Figure A20071013464800082
R 7, R 8, R 9, R 10=H, C 1-14Saturated and unsaturated alkyl, F, Cl, Br, I ,-OH ,-NH 2,-OCH 3,-OC 2H 5,-NO 2,-CN ,-CF 3, COOCH 3, COPh, COOH, Ph are phenyl;
(IV) work as R 2, R 3=
Figure A20071013464800083
R 1=CH 3, R 6, R 7=C 1-14Alkane and unsaturated alkyl, R 5=H, O, S, C 1-10Alkyl, have 1-3 substituting group or be not with substituent five yuan or hexavalent aromatic ring, nitrogen heterocyclic ring, oxygen heterocyclic ring and sulfur heterocyclic ring, described substituting group is C 1-10Alkyl, halogen, C 1-14Alkyl or contain fluoroalkyl, nitro, itrile group, methoxyl group or alkyl, two keys of representative or singly-bound;
(V) work as R 2, R 3=
R 3=H, CH 3, acid amides, sulphonamide, heterocycle etc.; R 5=C 1-20Saturated or unsaturated alkyl)
(VI) work as R 2, R 3=
Figure A20071013464800085
R 3=H, CH 3, acid amides, sulphonamide, heterocycle etc.; R 5=O ,-OH ,-NH 2, NHCONH 2, NHCOPh, C 1-20Aromatic hydrocarbons or aliphatic group, R 6=C 1-20Saturated or unsaturated alkyl;
(VII) work as R 2, R 3=
Figure A20071013464800092
R 3=H, CH 3, acid amides, sulphonamide, heterocycle etc.; R 5=C 1-20Saturated or unsaturated alkyl;
Above-mentioned carbon carbon mode connects the disinomenine derivative preparation method, and its preparation process is as follows:
1) strains separation: field sampling, the dilution coating separates selective screening, 0 ℃ of preservation of strain inclined plane.
2) preparation of bioconversion product: activate 7 days slant strains, be transferred in the fermention medium, at 25 ℃, cultivated 4 days on the shaking table of 150r/min, add the tuduranine hydrochloride, final concentration≤400 μ g/ml, similarity condition continues to cultivate second kind of substrate of adding after 1 day down, final concentration≤400 μ g/ml, the same terms continue down to cultivate 4 days, stop to cultivate; With filtering fermentation liquor, filtrate is used NH 4OH regulates pH value 8～9, repeatedly extracts combined dichloromethane extraction liquid, anhydrous Na SO with methylene dichloride 4Drying is filtered, and the rotation solvent evaporated gets converted product;
3) separation of bioconversion product: adopting the chromatography column of filling is silicagel column, and chromatographic solution is 100: 0～50: 50V/V chloroform-methanol mixed solution.
Above-mentioned steps 1) bioconversion strain in comprises: fungal strain Antrodiella semisupina and belong to bacterial strain, monochromatic rainbow conk Coriolus unicolor together and belong to bacterial strain, peroxidase Peroxidase or laccase Laccase together.
The present invention also provides carbon carbon mode to connect the chemical preparation process of disinomenine derivative, it is characterized in that in reaction flask, adding tuduranine, be dissolved in the methyl alcohol, add excessive Manganse Dioxide, the stirring at room reaction, the supernatant liquor concentrating under reduced pressure is got in centrifugation, get brown oil, separate obtaining product through silica gel column chromatography with chloroform-methanol 15: 1V/V;
Perhaps: in reaction flask, add the tuduranine hydrochloride, soluble in water, add excessive potassium permanganate solution, stirring at room, TLC detection reaction process, during reaction terminating, adding ammoniacal liquor adjusting pH value is 8.0-9.0, uses dichloromethane extraction, the organic phase anhydrous sodium sulfate drying, drying under reduced pressure gets yellow oil.Through silica gel column chromatography with chloroform-methanol 15: 1V/V separate product.
The also claimed carbon carbon of the present invention mode connects the application of disinomenine derivative at preparation treatment inflammation medicine, and in the application for preparing antitumor drug.
Organic solvent of the present invention includes but not limited to methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, Pentyl alcohol, primary isoamyl alcohol, hexalin, Bian alcohol, methylene dichloride, chloroform, 1,2-ethylene dichloride, tetracol phenixin, ether, tetrahydrofuran (THF), benzene,toluene,xylene, acetone, butanone, second cyanogen, N, dinethylformamide, ethyl acetate etc.
Four, Figure of description
Fig. 1 is the kapillary microreactor.
Five, embodiment
Following experiment and embodiment are used to further specify but are not limited to the present invention.
Embodiment 1:
Carbon carbon connects the stereoselectivity biosynthesizing of disinomenine, and its synthetic route is:
Figure A20071013464800101
Strains A ntrodiella semisupina is on slant medium, in 25 ℃ cultivate 7 days after, the 2L that is inoculated into the bacterium of going out transforms in the substratum, cultivate on the shaking table 4 days (25 ℃, 150r/min), add the tuduranine hydrochloride by 0.1 μ m millipore filtration, adding concentration is 250 μ g/ml, and similarity condition continues to cultivate 4 days down.Conversion fluid is through filtering, and mycelia is with the distilled water drip washing of a small amount of pH 6.0, merge the back altogether filtrate 2100ml, with ammoniacal liquor adjusting pH value 8～9, and repeatedly extract combined dichloromethane extraction liquid, anhydrous sodium sulfate drying with methylene dichloride, filter, the rotation solvent evaporated gets pressed powder 450mg.Converted product separates through silicagel column (300-400 order), and leacheate is a chloroform: methyl alcohol=2: 1 gets disinomenine 100mg, productive rate 20%.Disinomenine A (1): fusing point 220-222 ℃, [α] 25 D=+12.9 ° of (c=0.45, CH3OH) .UV (λ Max, CH 3OH): 252nm (ε, 16626) .EI-MS m/z:656[25.1%, M +], 641[100.0% ,], 598[17.4%], 192[12.1%].
Hydrogen spectrum (solvent is Chloroform-d): 6.00 (1H, s, 2-H), 3.75 (3H, s, 3-OCH 3), 2.49 (1H, d, J=15.6Hz, 5-H), 4.41 (1H, d, J=15.6Hz, 5-H), 3.51 (3H, s, 7-OCH 3), 5.43 (1H, d, J=2.4Hz, 8-H), 3.08 (brt, J=4.0Hz, 9-H), 2.42 (1H, dd, J=18.6,5.3Hz, 10-H), 2.32 (1H, brd, J=18.6Hz, 10-H), 2.99 (1H, brs, 14-H), 2.02 (1H, dt, J=12.2,3.4Hz, 15-H), 1.91 (1H, td, J=12.2,3.4Hz, 15-H), 2.57 (1H, ddd, J=12.0,4.3,2.1Hz, 16-H), 2.16 (td, J=12.0,3.4Hz, 16-H), 2.35 (3H, s, 17-N-CH 3).In addition half from 1 ' to 17 ' identical to 17 with 1.
Carbon spectrum (solvent is Chloroform-d): 130.7 (C-1), 110.7 (C-2), 144.8 (C-3), 56.0 (C-3-OCH 3), 143.8 (C-4), 49.3 (C-5), 193.8 (C-6), 152.5 (C-7), 54.8 (C-7-OCH 3), 115.0 (C-8), 56.4 (C-9), 23.9 (C-10), 127.8 (C-11), 123.3 (C-12), 40.9 (C-13), 45.8 (C-14), 35.9 (C-15), 47.2 (C-16), 43.0 (C-17-NCH 3).In addition half from 1 ' to 17 ' identical to 17 with 1.
Embodiment 2:
Carbon carbon connects the stereoselectivity biosynthesizing of two denitrification methyl diversines, and its synthetic route is:
Figure A20071013464800111
Its method is removed the first tuduranine with embodiment 1 but substrate is N-, obtains denitrification methyl disinomenine 100mg, productive rate 20%.
Remove first disinomenine A (3): positive ion ESI-MS m/z 609[M+H] +
Hydrogen spectrum (solvent is Chloroform-d): 6.30 (1H, s, 2-H), 3.75 (3H, s, 3-OCH3), 2.51 (1H, d, J=15.6Hz, 5-H), 4.37 (1H, d, J=15.6Hz, 5-H), 3.49 (3H, s, 7-OCH3), 5.38 (1H, d, J=2.4Hz, 8-H), 3.36 (brt, J=4.0Hz, 9-H), 2.75 (1H, dd, J=18.4,5.6Hz, 10-H), 2.19 (1H, brd, J=18.4Hz, 10-H), 2.90 (1H, brs, 14-H), 2.02 (1H, brd, J=12.2Hz, 15-H), 1.72 (1H, td, J=13.0,3.9Hz, 15-H), 2.85 (1H, dd, J=13.0,3.9Hz, 16-H), 2.60 (1H, td, J=13.0,3.9Hz, 16-H).In addition half from 1 ' to 17 ' identical to 17 with 1.
Carbon spectrum (solvent is Chloroform-d): 131.0 (C-1), 110.4 (C-2), 145.1 (C-3), 56.0 (C-3-OCH3), 143.8 (C-4), 49.7 (C-5), 193.8 (C-6), 152.3 (C-7), 54.8 (C-7-OCH3), 114.5 (C-8), 49.4 (C-9), 32.4 (C-10), 127.6 (C-11), 122.9 (C-12), 41.6 (C-13), 46.3 (C-14), 36.3 (C-15), 39.4 (C-16).In addition half from 1 ' to 17 ' identical to 17 with 1.
Disinomenine A (1) data are seen embodiment 1.
Embodiment 3:
Carbon carbon connects the chemosynthesis of disinomenine, and its synthetic route is:
Figure A20071013464800121
Method A: in reaction flask, add tuduranine 200mg (0.61mmol), be dissolved in the 20ml methyl alcohol, add Manganse Dioxide 1g (11.5mmol), stirring at room reaction 48h.The supernatant liquor concentrating under reduced pressure is got in centrifugation, gets brown oil.Through silica gel column chromatography (chloroform-methanol 15: 1V/V) separate whitening compound 1 (about 60%) and 6 (about 40%).
Method B: in reaction flask, add tuduranine hydrochloride 200mg (0.61mmol), be dissolved in the 20ml water, add 50mM potassium permanganate solution 10ml, stirring at room, TLC detection reaction process.During reaction terminating, adding ammoniacal liquor adjusting pH value is 8.0-9.0, uses the 100ml dichloromethane extraction, the organic phase anhydrous sodium sulfate drying, and drying under reduced pressure gets yellow oil.Through silica gel column chromatography (chloroform-methanol 15: 1V/V) separate whitening compound 1 (about 60%) and 6 (about 40%).
Method C: tuduranine hydrochloride and the potassium permanganate solution solution of preparing 0.1-10mg/mL respectively, press shown in Fig. 1 (kapillary microreactor), utilize the kapillary microreactor, it is 8.0-9.0 that the reaction stream fluid adds ammoniacal liquor adjusting pH value, use dichloromethane extraction, the organic phase anhydrous sodium sulfate drying, drying under reduced pressure gets yellow oil.Through silica gel column chromatography with 15: 1 V/V of chloroform-methanol separate product.Utilize microreactor can improve the productive rate of reaction.
Above-mentioned chemical reaction is to improve the yield (1 about 92% and 6 about 8%) of active compound 1 between the 5.5-7.0 in the pH value.
Disinomenine B (6): EI-MS m/z:656[25.1%, M +].
Hydrogen spectrum (solvent is Chloroform-d): 6.45 (1H, s, 2-H), 3.81 (3H, s, 3-OCH 3), 2.51 (1H, d, J=15.7Hz, 5-H), 4.43 (1H, d, J=15.7Hz, 5-H), 3.51 (3H, s, 7-OCH 3), 5.27 (1H, d, J=1.3Hz, 8-H), 3.03-3.15 (overlapped, 9-H), 1.83 (1H, dd, J=18.7,5.1Hz, 10-H), 2.53 (1H, brd, J=18.7Hz, 10-H), 3.03-3.15 (overlapped, 14-H), 2.03 (1H, m, 15-H), 1.97 (1H, td, J=12.7,4.0Hz, 15-H), 2.66 (1H, brd, J=11.2Hz, 16-H), 2.13 (td, J=11.2,2.6Hz, 16-H), 2.36 (3H, s, 17-NCH 3).In addition half from 1 ' to 17 ' identical to 17 with 1.
Carbon spectrum (solvent is Chloroform-d): 130.8 (C-1), 109.5 (C-2), 145.2 (C-3), 56.1 (C-3-OCH 3), 144.0 (C-4), 48.9 (C-5), 193.6 (C-6), 152.5 (C-7), 54.5 (C-7-OCH 3), 114.0 (C-8), 56.5 (C-9), 22.6 (C-10), 127.5 (C-11), 122.9 (C-12), 40.4 (C-13), 45.0 (C-14), 35.3 (C-15), 47.4 (C-16), 42.8 (C-17-NCH 3).In addition half from 1 ' to 17 ' identical to 17 with 1.
The anti-inflammatory action of Sinomenine derivate (seeing attached list 1):
The anti-inflammatory action of subordinate list 1 Sinomenine derivate
Compound Hu IL-6 detects water (pg/ml) in the enchylema
Blank 107.8
Sinomenine 98.7
1 80.9
3 71.6
6 115.8
Get synovial cell SW982 and cultivate, culture density 5 * 10 in 24 porose discs 4/ hole, with CGM (wherein replacing FBS with 0.2%BSA) displacement nutrient solution, behind the 24h, (final concentration is 10 to add testing drug again behind the 24h -5Mol/L), behind the 24h, (contain 0.2% BSA and 10 with the L-15 of 10ng/ml 1L-1 β -5The testing drug of mol/L) displacement nutrient solution continues to get nutrient solution Human IL-6 test kit detection behind the cultivation 48h.The results are shown in Table 1, show that bioconversion product has stronger cellular inflammation factor restraining effect.
The antitumor action of Sinomenine derivate (seeing attached list 2):
The antitumor action of subordinate list 2 Sinomenine derivates
Compound Inhibiting rate (%) to lung tumor cell BGC Inhibiting rate (%) to tumor cell of liver 7721
Blank 0 0
Sinomenine 0.5 3.5
1 12.7 7.6
3 4.0 3.2
6 11.3 10.3
Get lung tumor cell BGC and tumor cell of liver 7721 in 96 hole culture plates (nutrient solution contains 10% tire calf serum), culture density 1 * 10 4/ hole, (final concentration is 10 to add testing drug -5Mol/L), behind the cultivation 48h, the PBS solution (5mg/ml) that every hole adds 10 μ l MTT continued to hatch 4 hours, stopped cultivating, and careful the suction abandoned culture supernatant in the hole.Every hole adds 150ul DMSO, vibrates 10 minutes, and crystallisate fully melts.Select the 570nm wavelength, measure each hole absorbance value on the enzyme linked immunological monitor, the record result calculates tumor control rate.As table 2, show that compound 1,2,6 compares tuduranine with 9, tumour cell there is stronger restraining effect.

Claims (6)

1. disinomenine derivative that carbon carbon mode connects, general formula is:
Figure A2007101346480002C1
In the formula:
R 4=H or OH (α and β);
R 2，R 3＝
Figure A2007101346480002C2
R 1=ethyl, propyl group, butyl, sec.-propyl, straight-chain alkyls such as allyl group; Or cyclopentyl, cyclohexyl, cyclic hydrocarbon group such as suberyl; Or β-fluoro ethyl, cyclopropyl methyl, cyclobutylmethyl, phenmethyl, picolyl, furfuryl, beta-phenyl ethyl, α-Jia Jibianji, alkoxy methyl, substituting groups such as pyrazoles methyl.Or R 1=R 5S (OO)-wherein R 5=methyl, ethyl, propyl group, the alkyl of trifluoromethyl and substituted hydrocarbon radical, phenyl and substituting group;
Or: R 2, R 3=
R 1=CH 3, H, R 5Be carbonyl or hydroxyl;
Or: R 2, R 3=
Figure A2007101346480002C4
R 5，R 6＝
R 7, R 8, R 9, R 10=H, C 1-14Saturated and unsaturated alkyl, F, Cl, Br, I ,-OH ,-NH 2,-OCH 3,-OC 2H 5,-NO 2,-CN ,-CF 3, COOCH 3, COPh, COOH, Ph are phenyl;
Or: R 2, R 3=
Figure A2007101346480003C2
R 1=CH 3, R 6, R 7=C 1-14Alkane and unsaturated alkyl, R 5=H, O, S, C 1-10Alkyl, have 1-3 substituting group or be not with substituent five yuan or hexavalent aromatic ring, nitrogen heterocyclic ring, oxygen heterocyclic ring and sulfur heterocyclic ring, described substituting group is C 1-10Alkyl, halogen, C 1-14Alkyl or contain fluoroalkyl, nitro, itrile group, methoxyl group or alkyl, two keys of representative or singly-bound;
Or: R 2, R 3=
Figure A2007101346480003C3
R 3=H, CH 3, acid amides, sulphonamide, heterocycle etc.; R 5=C 1-20Saturated or unsaturated alkyl) or: R 2, R 3=
Figure A2007101346480003C4
R 3=H, CH 3, acid amides, sulphonamide, heterocycle etc.; R 5=O ,-OH ,-NH 2, NHCONH 2, NHCOPh, C 1-20Aromatic hydrocarbons or aliphatic group, R 6=C 1-20Saturated or unsaturated alkyl;
Or: R 2, R 3=
Figure A2007101346480004C1
R 3=H, CH 3, acid amides, sulphonamide, heterocycle; R 5=C 1-20Saturated or unsaturated alkyl.
2. the described carbon carbon of claim 1 mode connects the biological preparation method of disinomenine derivative, it is characterized in that preparation process is as follows:
1) strains separation: field sampling, the dilution coating separates selective screening, 0 ℃ of preservation of strain inclined plane.
2) preparation of bioconversion product: activate 7 days slant strains, be transferred in the fermention medium, at 25 ℃, cultivated 4 days on the shaking table of 150r/min, add the tuduranine hydrochloride, final concentration≤400 μ g/ml, similarity condition continues to cultivate second kind of substrate of adding after 1 day down, final concentration≤400 μ g/ml, the same terms continue down to cultivate 4 days, stop to cultivate; With filtering fermentation liquor, filtrate is used NH 4OH regulates pH value 8～9, repeatedly extracts combined dichloromethane extraction liquid, anhydrous Na SO with methylene dichloride 4Drying is filtered, and the rotation solvent evaporated gets converted product;
3) separation of bioconversion product: adopting the chromatography column of filling is silicagel column, and chromatographic solution is 100: 0～50: 50V/V chloroform-methanol mixed solution.
3. carbon carbon mode according to claim 2 connects the biological preparation method of disinomenine derivative, it is characterized in that the bioconversion strain in the step 1) comprises: fungal strain Antrodiella semisupina and belong to bacterial strain, monochromatic rainbow conk Coriolus unicolor together and belong to bacterial strain, peroxidase Peroxidase or laccase Laccase together.
4. the described carbon carbon of claim 1 mode connects the chemical preparation process of disinomenine derivative, it is characterized in that in reaction flask, adding tuduranine, be dissolved in the methyl alcohol, add excessive Manganse Dioxide, the stirring at room reaction, the supernatant liquor concentrating under reduced pressure is got in centrifugation, get brown oil, separate obtaining product through silica gel column chromatography with chloroform-methanol 15: 1V/V;
Perhaps: in reaction flask, add the tuduranine hydrochloride, soluble in water, add excessive potassium permanganate solution, stirring at room, TLC detection reaction process, during reaction terminating, adding ammoniacal liquor adjusting pH value is 8.0-9.0, uses dichloromethane extraction, the organic phase anhydrous sodium sulfate drying, drying under reduced pressure gets yellow oil.Through silica gel column chromatography with chloroform-methanol 15: 1V/V separate product.
Perhaps: prepare tuduranine hydrochloride and the potassium permanganate solution solution of 0.1-10mg/mL respectively, by the kapillary microreactor, it is 8.0-9.0 that the reaction stream fluid adds ammoniacal liquor adjusting pH value, use dichloromethane extraction, the organic phase anhydrous sodium sulfate drying, drying under reduced pressure gets yellow oil.Through silica gel column chromatography with chloroform-methanol 15: 1V/V separate product.Utilize microreactor can improve the productive rate of reaction.
Above-mentioned chemical reaction is to improve the yield of active compound 1 between the 5.5-7.0 in the pH value.
5. the described carbon carbon of claim 1 mode connects the application of disinomenine analog derivative in preparation treatment inflammation medicine.
6. the described carbon carbon of claim 1 mode connects the application of disinomenine analog derivative in the preparation antitumor drug.
CN2007101346488A 2007-11-05 2007-11-05 Biinomenine derivative connected with C-C bond, preparation method and application thereof Expired - Fee Related CN101148437B (en)

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Cited By (4)

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WO2011098035A1 (en) 2010-02-10 2011-08-18 中国科学院上海有机化学研究所 Sinomenine derivatives, synthetic methods and uses thereof
CN106539797A (en) * 2016-10-14 2017-03-29 上海交通大学医学院 Application of the Sinomenine derivate in treatment multiple myeloma medicine is prepared
CN112274514A (en) * 2019-07-24 2021-01-29 中国医学科学院药物研究所 Application of sinomenine compound in preparing medicine for preventing or treating glioma
CN114387856A (en) * 2020-10-05 2022-04-22 蒙家英 Micro-drug chemical experiment and chemical examination integrated teaching method

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