CN101985445A - Method for preparing coptisine from coptis mixed alkaloid based on common basic structural characteristic - Google Patents
Method for preparing coptisine from coptis mixed alkaloid based on common basic structural characteristic Download PDFInfo
- Publication number
- CN101985445A CN101985445A CN 201010519053 CN201010519053A CN101985445A CN 101985445 A CN101985445 A CN 101985445A CN 201010519053 CN201010519053 CN 201010519053 CN 201010519053 A CN201010519053 A CN 201010519053A CN 101985445 A CN101985445 A CN 101985445A
- Authority
- CN
- China
- Prior art keywords
- coptisine
- tetrahydrochysene
- mixed biologic
- coptis
- biologic alkali
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing coptisine from coptis mixed alkaloid based on common basic structural characteristic. The coptisine is synthesized by using the coptis mixed alkaloid consisting of berberine, coptisine, palmatine and jateorhizine which have the same isoquinoline ring structure, and by performing reductive hydrogenation, hydroxylation of methoxy group and methylenedioxy group, cyclization of ortho-oxhydryl group and oxidative hydrogenation, wherein the total yield can reach 16 percent. Compared with the conventional method for preparing the coptisine, the method is simple and convenient, and easy to operate and eliminates the purification step of the raw material during the synthesis of medicaments. By the method, the rough mixed total alkali with indefinite medicinal effect dispersion and low purity is converted into monomer coptisine with high antibacterial specificity and activity. The method is easy and convenient to operate, low in cost and wide in application prospect, is suitable for batch production of the coptisine, can provide reference idea for research on conversion of main components of other Chinese herbal medicines which have similar structures, and has great guidance significance for the improvement on the utilization value of the traditional Chinese medicine and the development and preparation of new medicaments.
Description
Technical field
The present invention relates to a kind of method for preparing coptisine based on the coptis mixed biologic alkali of common basic structural feature.
Background technology
Coptis mixed biologic alkali is that the isoquinoline 99.9 ring with identical that extracts from the Chinese medicine coptis is an agent structure, and with methoxyl group, methylene-dioxy, hydroxyl are the mixed biologic alkali of 2,3,9,10 replacements, comprise palmatine and jateorhizine, Berberine and coptisine.Wherein research and most widely used be Berberine.And the coptisine that has hypoglycemic, antitumor, immunomodulatory, antisepsis and anti-inflammation and improve multiple pharmacological effect such as cardiovascular because of content in the coptis is extremely low, has then limited its further research and using.Coptisine is light yellow needle crystal in ethanol, the utmost point is water-soluble slightly, is slightly soluble in ethanol, is dissolved in alkali.There is report to confirm that the effectiveness of its anti-saccharomyces carlsbergensis bacterium is also stronger than Berberine, palmatine and palmatine.It also is better than Berberine for anti-HT29 cell and LoVo cell activity.
The scientific research personnel has carried out multinomial research to coptisine synthetic, and experimental data shows, no matter is complete synthesis coptisine or is converted into coptisine by Berberine, and the synthetic yield of coptisine all has much room for improvement.Maria
[1]Deng through four-step reaction Berberine is converted into coptisine, and synthetic coptisine and natural coptisine are carried out evaluating drug effect, find that synthetic coptisine has stronger cytotoxic activity for anti-HT29 cell strain and LoVo cell strain, but lower to the toxicity of L1210 cell strain.And this experiment at first needs to obtain the Berberine of purifying, and the total recovery of last synthetic coptisine only is 11%.Chen Shuai
[2]Deng with 2, the 3-dimethoxy benzaldehyde is a starting raw material, through demethylation, cyclization, contract and the hydrochloric acid coptisine has been synthesized in 5 step reaction such as closed loop, total recovery 9.9%, but because 2, the 3-dimethoxy benzaldehyde is under 48% HBr, make the too short or temperature of the reaction time through the high temperature demethylation and cross the low by product of taking off a methyl that all generates easily, temperature is crossed the low product that closes ring that only generates easily in the process of cyclization in addition, the too high by product of taking off an aldehyde radical that then generates easily again of temperature, difficult control of temperature, therefore complete synthesis coptisine step is many, yield is low, has only theory significance.
More than 1500 yuan of at present commercially available 20 milligrams of need of coptisine monomers standard substance are monomeric 3 times of Berberines.By the chemically modified means blended coptis biology total alkali is converted into the monomer coptisine, do not need complicated purification and separate, on the basis that transforms, the content of coptisine then depends on the content of total alkali in the coptis, the content of Berberine reaches 5～8% in the coptis, adding other biological alkali, is 8% to calculate as the content by total alkali, also is higher than in the coptis self coptisine far away even transformation efficiency is the coptisine of 50% gained.Find total alkali easy realization, that transformation efficiency is high to be converted into the method and the rule of monomer coptisine, will help improving the development and application of pharmaceutical use He its series product of the Chinese medicine coptis, and provide referential thinking for the utilization of other herbal medicine.
(reference [1] Maria Laura Colombo, Carlo Bugatti, Andrea Moss, etal.Cytotoxicity evaluation of natural coptisine and synthesis of Coptisinefrom berberine[J] .Il Farmaco, 2001,56:403-409.
[2]CHEN?Shuai，TONG?YUAN-feng，et?al.Total?Synthesis?of?CoptisineHydrochloride[J].Chinese?Journal?of?Synthetic?Chemistry，2009，4：512-513.)
Summary of the invention
In order to solve the problem that prior art exists, the purpose of this invention is to provide and a kind ofly prepare the method for coptisine, directly be translated into the productive rate that coptisine significantly improves coptisine under the condition of purifying without complexity by coptis mixed biologic alkali based on the coptis mixed biologic alkali of common basic structure.
A kind of method for preparing coptisine based on the coptis mixed biologic alkali of common basic structure provided by the invention, described coptis mixed biologic alkali is that the isoquinoline 99.9 ring with identical that extracts from the Chinese medicine coptis is an agent structure, with methoxyl group, methylene-dioxy, hydroxyl is 2,3,9, the mixed biologic alkali of 10 replacements comprises palmatine, jateorhizine, Berberine and coptisine; The general structure (I) of coptis mixed biologic alkali is as follows:
In the structural formula (I), the structural formula of palmatine is formula a, and wherein R1 is-CH3, and R2 is-CH3 that R3 is-CH3 that R4 is-CH3;
In the structural formula (I), the jateorhizine structural formula is formula b, and wherein R1 is-H, and R2 is-CH3 that R3 is-CH3 that R4 is-CH3;
The Berberine structural formula is formula c, R1+R2=-CH2-wherein, and R3 is-CH3 that R4 is-CH3;
The coptisine structural formula is formula d, R1+R2=-CH2-wherein, R3+R4=-CH2-;
1) preparation of tetrahydrochysene coptis mixed biologic alkali
General formula (II) structure of tetrahydrochysene coptis mixed biologic alkali is as follows:
In the general formula (II), R1, R2, R3, R4 respectively with the general formula (I) of above-mentioned coptis mixed biologic alkali in consistent;
Is aqueous ethanolic solution heating for dissolving to the 80 ℃ backflow of 70%-90% with coptis mixed biologic alkali with the ethanol massfraction, and the concentration of coptis mixed biologic alkali in aqueous ethanolic solution is 0.02-0.04g/mL; Add the catalyzer Anhydrous potassium carbonate then, the mass ratio of catalyst levels and coptis mixed biologic alkali is 1.6-4: 1; Then, every interval 5min adds the sodium borohydride of equivalent totally for three times respectively, and the mass ratio of described sodium borohydride total amount and coptis mixed biologic alkali is 0.12-0.60: 1; Suction filtration behind room temperature reaction 4-8h leaches insolubles, and insolubles gets tetrahydrochysene coptis mixed biologic alkali (II) through the benzene recrystallization; Be followed successively by 356.1 through its molecular weight of mass spectrometric detection; 342.1; 340.1; 324.1, be defined as coptis mixed biologic alkali palmatine, jateorhizine, Berberine and coptisine hydrogenation after product.
2) preparation of tetrahydrochysene tetrahydroxy coptisine
The molecular structural formula (III) of tetrahydrochysene tetrahydroxy coptisine is as follows:
The tetrahydrochysene coptis mixed biologic alkali that step 1) is obtained dissolves with methylene dichloride, and the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.02-0.04g/mL;-40 ℃ of speed with 0.17 ml/min in system, dripping concentration is the dichloromethane solution of 1mol/L boron tribromide, and the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 4-10: 1; After being warming up to stirring at room reaction 12-24h then, at room temperature add the methyl alcohol cancellation immediately, suction filtration leaches insolubles through the ether recrystallization, gets tetrahydrochysene tetrahydroxy coptisine (III); Detecting its molecular weight through mass spectrum and hydrogen nuclear magnetic resonance is 300.2, and molecular formula is [C
17H
18NO
4]
+, determine that compound is a tetrahydrochysene tetrahydroxy coptisine.
The structural characterization data are as follows: fusing point: 309-310 ℃;
1H NMR (400MHz, CD
3OD) δ: 3.04 (2H, m, He-5), 3.17 (1H .m, He-13), 3.37 (2H, m, Ha-5), 3.77 (1H, m, Ha-13), 3.57 (1H, m, H-14), 4.41 (1H, d, J=16Hz, Ha-8), 4.78 (2H, m, H-6), 4.83 (1H, d, J=16Hz, He-8), 6.74 (1H, s, H-4), 6.76 (1H, d, J=8.4Hz, H-12), 6.89 (1H, d, J=8.4Hz, H-11), 6.90 (1H, s, H-1); ESI-MS m/z:300.1
3) preparation of Tetrahydrocoptisine
(IV) is as follows for the molecular structural formula of Tetrahydrocoptisine:
With rapid 2) the tetrahydrochysene tetrahydroxy coptisine that obtains dissolves with anhydrous dimethyl formamide, the concentration of tetrahydrochysene tetrahydroxy coptisine in anhydrous dimethyl formamide is 0.02-0.04g/mL, add catalyzer cesium fluoride (CsF), the mass ratio of described catalyzer cesium fluoride and tetrahydrochysene tetrahydroxy coptisine is 1.6-4: 1, system is heated to 60 ℃, speed dripping bromine methyl chloride with 0.17 ml/min in system reacts, and the mol ratio of described bromochloromethane and tetrahydrochysene tetrahydroxy coptisine is 2-10: 1; Temperature of reaction is brought up to 95-120 ℃ of reaction 24-48h; Then system is cooled to room temperature, suction filtration, filtrate decompression concentrate dark solid, with its with water dissolution after, use extracted with diethyl ether, merge organic layer, concentrate yellow solid, through re-crystallizing in ethyl acetate, must Tetrahydrocoptisine (IV); Detecting its molecular weight through electrospray ionization mass spectrum and hydrogen nuclear magnetic resonance is 324.1, and molecular formula is [C
19H
18NO
4]
+, determine that compound is a Tetrahydrocoptisine.
The structural characterization data are as follows: fusing point: 198-199 ℃;
1H NMR (400MHz, CD
3OD) δ: 2.64 (2H, m, H-5), 2.82 (1H, m, Ha-13), 3.13 (2H, m, H-6), 3.23 (1H, m, H-13), 3.54 (1H, d, J=8.2Hz, Ha-8), 3.57 (1H, d, J=8.0Hz, H-14), 4.09 (1H, d, J=8.2Hz, He-8), 5.92 (2H, s ,-OCH
2O-), 5.95 (2H, s ,-OCH
2O-), 6.56 (1H, s, H-4), 6.67 (1H, d, J=8.0Hz, H-11), 6.62 (1H, d, J=8.0Hz, H-12), 6.80 (1H, s, H-1); ESI-MS m/z:324.1.
4) preparation of coptisine
The molecular structural formula of coptisine is suc as formula shown in the d:
Formula d
With rapid 3) Tetrahydrocoptisine (IV) that obtains is the ebullient mixing solutions dissolving of 2: 1 ethanol and acetate with volume ratio, the concentration of Tetrahydrocoptisine in mixing solutions is 0.02-0.04g/mL, add catalyst acetic acid sodium, the mass ratio of described catalyst acetic acid sodium and Tetrahydrocoptisine is 1.6-4: 1, system is heated to 50 ℃, speed with 0.17 ml/min in system drips the ethanolic soln that is dissolved with iodine, the mol ratio of described iodine and Tetrahydrocoptisine is 2-4: 1, the concentration of iodine in ethanol is 0.02-0.06g/mL, the mixture stirred overnight at room temperature, leach throw out,, get coptisine through acetone recrystallization.Detecting its molecular weight through electrospray ionization mass spectrum and hydrogen nuclear magnetic resonance is 320.1, and molecular formula is [C
19H
14NO
4]
+, determine that compound is a coptisine.
The structural characterization data are as follows: fusing point＞300 ℃;
1H NMR (400MHz, CD
3OD) δ: 3.26 (2H, m, H-6), 4.76 (2H, m, H-5), 6.05 (2H, s ,-OCH
2O-), 6.41 (2H, s ,-OCH
2O-), 6.90 (1H, s, H-4), 7.61 (1H, s, H-1), 7.76 (1H, d, J=8.2Hz, H-12), 7.80 (1H, d, J=8.2Hz, H-11), 8.68 (1H, m, H-13), 9.66 (1H, s, H-8); ESI-MSm/z:320.1.
Beneficial effect: the invention discloses a kind of method for preparing coptisine based on the coptis mixed biologic alkali of common basic structural feature, has coptis mixed biologic alkali that Berberine, coptisine, palmatine and the jateorhizine of common isoquinoline 99.9 ring structure form through the reduction hydrogenation, methoxyl group, the hydroxylation of methylene-dioxy, the cyclization of vicinal hydroxyl groups and oxydehydrogenation four-step reaction have synthesized coptisine, and total recovery can reach 16%.Method of the present invention is more simple and easy to operate than the preparation method of traditional coptisine, has saved the purification step of raw material during medicine is synthetic.The present invention without the purification of complexity with separate, and improved the productive rate of coptisine greatly.
The present invention disperses the thick mixing total alkali not clear, that purity is low to be converted into antibiotic high-specificity, active strong monomer coptisine the efficacy of a drug.Working method is easy, cost is lower, is fit to the batch process of coptisine, has broad application prospects, and can be Study on Transformation that other herbal medicine contain the main component of the similar structures thinking of offering reference, have better guide significance for utility value that improves Chinese medicine and development initiative new drug.
Comparing, by the Berberine of purifying, only is 11% through the total recovery of the last synthetic coptisine of hydroxylation, cyclization and oxydehydrogenation of shortening, methoxyl group and methylene-dioxy; With 2, the 3-dimethoxy benzaldehyde is a starting raw material, through demethylation, ring and, contract and the total recoverys of 5 steps reaction synthetic hydrochloric acid coptisine such as closed loop are 9.9%; But because 2, the 3-dimethoxy benzaldehyde is under 48% HBr, make the too short or temperature of the reaction time through the high temperature demethylation and cross the low by product of taking off a methyl that all generates easily, temperature is crossed the low product that closes ring that only generates easily in the process of cyclization in addition, the too high by product of taking off an aldehyde radical, the difficult control of temperature of then generating easily again of temperature.Therefore the step of complete synthesis coptisine is more, and yield is lower.
Description of drawings
Fig. 1 is a coptis mixed biologic alkali hydrogenation mass spectrum.
Fig. 2 is a tetrahydrochysene tetrahydroxy coptisine mass spectrum.
Fig. 3 is a tetrahydrochysene tetrahydroxy coptisine
1H NMR figure.
Fig. 4 is the Tetrahydrocoptisine mass spectrum.
Fig. 5 is coptisine electrospray ionization mass spectrum figure.
Embodiment
Embodiment 1: the preparation of tetrahydrochysene coptis mixed biologic alkali
Take by weighing coptis mixed biologic alkali 1g in the 100ml three-necked bottle, adding 25ml ethanol massfraction is 70% aqueous ethanolic solution heating for dissolving to 80 ℃ backflow, the concentration of coptis mixed biologic alkali in aqueous ethanolic solution is 0.04g/mL, add Anhydrous potassium carbonate 1.6g, the mass ratio of Anhydrous potassium carbonate and coptis mixed biologic alkali is 1.6: 1, it is that the sodium borohydride of 0.12g reacts that every then interval 5min divides three equivalent to add total amount, the mass ratio of described sodium borohydride and coptis mixed biologic alkali is 0.12: 1, suction filtration behind stirring at room reaction 4h, leach insolubles, insolubles gets tetrahydrochysene coptis mixed biologic alkali 0.83g through the benzene recrystallization, and yield is 84%.
Embodiment 2: the preparation of tetrahydrochysene coptis mixed biologic alkali
Take by weighing coptis mixed biologic alkali 1g in the 100ml three-necked bottle, adding 40ml ethanol massfraction is 80% aqueous ethanolic solution heating for dissolving to 80 ℃ backflow, the concentration of coptis mixed biologic alkali in aqueous ethanolic solution is 0.025g/mL, add Anhydrous potassium carbonate 3g, the mass ratio of Anhydrous potassium carbonate and coptis mixed biologic alkali is 3: 1, dividing three each 5min equivalent at interval to add total amount then is that the sodium borohydride of 0.3g reacts, the mass ratio of described sodium borohydride and coptis mixed biologic alkali is 0.3: 1, suction filtration behind stirring at room reaction 6h, leach insolubles, insolubles gets tetrahydrochysene coptis mixed biologic alkali 0.88g through the benzene recrystallization, and yield is 87%.
Embodiment 3: the preparation of tetrahydrochysene coptis mixed biologic alkali
Take by weighing coptis mixed biologic alkali 1g in the 100ml three-necked bottle, adding 50ml ethanol massfraction is 90% aqueous ethanolic solution, with aqueous ethanolic solution heating for dissolving to the 80 ℃ backflow of coptis mixed biologic alkali, the concentration of coptis mixed biologic alkali in aqueous ethanolic solution is 0.02g/mL, add Anhydrous potassium carbonate 4g, the mass ratio of Anhydrous potassium carbonate and coptis mixed biologic alkali is 4: 1, dividing three each 5min equivalent at interval to add total amount then is that the sodium borohydride of 0.6g reacts, the mass ratio of sodium borohydride and coptis mixed biologic alkali is 0.6: 1, in stirring at room reaction 8h, suction filtration after reaction finishes, leach insolubles, insolubles gets tetrahydrochysene coptis mixed biologic alkali 0.84g through the benzene recrystallization, and yield is 85%.
Embodiment 4: the preparation of tetrahydrochysene coptis mixed biologic alkali
Take by weighing coptis mixed biologic alkali 1g in the 100ml three-necked bottle, adding 25ml ethanol massfraction is 80% aqueous ethanolic solution heating for dissolving to 80 ℃ backflow, the concentration of coptis mixed biologic alkali in aqueous ethanolic solution is 0.04g/mL, add Anhydrous potassium carbonate 1.6g, the mass ratio of Anhydrous potassium carbonate and coptis mixed biologic alkali is 1.6: 1, it is that the sodium borohydride of 0.12g reacts that every then interval 5min divides three equivalent to add total amount, the mass ratio of described sodium borohydride and coptis mixed biologic alkali is 0.12: 1, suction filtration behind stirring at room reaction 4h, leach insolubles, insolubles gets tetrahydrochysene coptis mixed biologic alkali 0.79g through the benzene recrystallization, and yield is 80%.
Embodiment 5: the preparation of tetrahydrochysene coptis mixed biologic alkali
Take by weighing coptis mixed biologic alkali 1g in the 100ml three-necked bottle, adding 25ml ethanol massfraction is 90% aqueous ethanolic solution heating for dissolving to 80 ℃ backflow, the concentration of coptis mixed biologic alkali in aqueous ethanolic solution is 0.04g/mL, add Anhydrous potassium carbonate 1.6g, the mass ratio of Anhydrous potassium carbonate and coptis mixed biologic alkali is 1.6: 1, it is that the sodium borohydride of 0.12g reacts that every then interval 5min divides three equivalent to add total amount, the mass ratio of described sodium borohydride and coptis mixed biologic alkali is 0.12: 1, suction filtration behind stirring at room reaction 4h, leach insolubles, insolubles gets tetrahydrochysene coptis mixed biologic alkali 0.80g through the benzene recrystallization, and yield is 79%.
Embodiment 6: the preparation of tetrahydrochysene coptis mixed biologic alkali
Take by weighing coptis mixed biologic alkali 1g in the 100ml three-necked bottle, adding 40ml ethanol massfraction is 70% aqueous ethanolic solution heating for dissolving to 80 ℃ backflow, the concentration of coptis mixed biologic alkali in aqueous ethanolic solution is 0.025g/mL, add Anhydrous potassium carbonate 4.0g, the mass ratio of Anhydrous potassium carbonate and coptis mixed biologic alkali is 4.0: 1, it is that the sodium borohydride of 0.12g reacts that every then interval 5min divides three equivalent to add total amount, the mass ratio of described sodium borohydride and coptis mixed biologic alkali is 0.12: 1, suction filtration behind stirring at room reaction 4h, leach insolubles, insolubles gets tetrahydrochysene coptis mixed biologic alkali 0.82g through the benzene recrystallization, and yield is 81%.
Embodiment 7: the preparation of tetrahydrochysene coptis mixed biologic alkali
Take by weighing coptis mixed biologic alkali 1g in the 100ml three-necked bottle, adding 40ml ethanol massfraction is 80% aqueous ethanolic solution heating for dissolving to 80 ℃ backflow, the concentration of coptis mixed biologic alkali in aqueous ethanolic solution is 0.025g/mL, add Anhydrous potassium carbonate 4.0g, the mass ratio of Anhydrous potassium carbonate and coptis mixed biologic alkali is 4.0: 1, it is that the sodium borohydride of 0.3g reacts that every then interval 5min divides three equivalent to add total amount, the mass ratio of described sodium borohydride and coptis mixed biologic alkali is 0.3: 1, suction filtration behind stirring at room reaction 4h, leach insolubles, insolubles gets tetrahydrochysene coptis mixed biologic alkali 0.88g through the benzene recrystallization, and yield is 87%.
Embodiment 8: the preparation of tetrahydrochysene coptis mixed biologic alkali
Take by weighing coptis mixed biologic alkali 1g in the 100ml three-necked bottle, adding 40ml ethanol massfraction is 90% aqueous ethanolic solution heating for dissolving to 80 ℃ backflow, the concentration of coptis mixed biologic alkali in aqueous ethanolic solution is 0.025g/mL, add Anhydrous potassium carbonate 4.0g, the mass ratio of Anhydrous potassium carbonate and coptis mixed biologic alkali is 4.0: 1, it is that the sodium borohydride of 0.3g reacts that every then interval 5min divides three equivalent to add total amount, the mass ratio of described sodium borohydride and coptis mixed biologic alkali is 0.3: 1, suction filtration behind stirring at room reaction 6h, leach insolubles, insolubles gets tetrahydrochysene coptis mixed biologic alkali 0.86g through the benzene recrystallization, and yield is 85%.
Embodiment 9: the preparation of tetrahydrochysene coptis mixed biologic alkali
Take by weighing coptis mixed biologic alkali 1g in the 100ml three-necked bottle, adding 50ml ethanol massfraction is 70% aqueous ethanolic solution heating for dissolving to 80 ℃ backflow, the concentration of coptis mixed biologic alkali in aqueous ethanolic solution is 0.02g/mL, add Anhydrous potassium carbonate 1.6g, the mass ratio of Anhydrous potassium carbonate and coptis mixed biologic alkali is 1.6: 1, it is that the sodium borohydride of 0.6g reacts that every then interval 5min divides three equivalent to add total amount, the mass ratio of described sodium borohydride and coptis mixed biologic alkali is 0.6: 1, suction filtration behind stirring at room reaction 4h, leach insolubles, insolubles gets tetrahydrochysene coptis mixed biologic alkali 0.81g through the benzene recrystallization, and yield is 80%.
Embodiment 10: the preparation of tetrahydrochysene coptis mixed biologic alkali
Take by weighing coptis mixed biologic alkali 1g in the 100ml three-necked bottle, adding 50ml ethanol massfraction is 80% aqueous ethanolic solution heating for dissolving to 80 ℃ backflow, the concentration of coptis mixed biologic alkali in aqueous ethanolic solution is 0.02g/mL, add Anhydrous potassium carbonate 3.0g, the mass ratio of Anhydrous potassium carbonate and coptis mixed biologic alkali is 3: 1, it is that the sodium borohydride of 0.6g reacts that every then interval 5min divides three equivalent to add total amount, the mass ratio of described sodium borohydride and coptis mixed biologic alkali is 0.6: 1, suction filtration behind stirring at room reaction 6h, leach insolubles, insolubles gets tetrahydrochysene coptis mixed biologic alkali 0.84g through the benzene recrystallization, and yield is 83%.
Embodiment 11: the preparation of tetrahydrochysene coptis mixed biologic alkali
Take by weighing coptis mixed biologic alkali 1g in the 100ml three-necked bottle, adding 40ml ethanol massfraction is 80% aqueous ethanolic solution heating for dissolving to 80 ℃ backflow, the concentration of coptis mixed biologic alkali in aqueous ethanolic solution is 0.025g/mL, add Anhydrous potassium carbonate 3g, the mass ratio of Anhydrous potassium carbonate and coptis mixed biologic alkali is 3: 1, it is that the sodium borohydride of 0.3g reacts that each then 5min at interval divides three equivalent to add total amount, the mass ratio of described sodium borohydride and coptis mixed biologic alkali is 0.3: 1, suction filtration behind stirring at room reaction 4h, leach insolubles, insolubles gets tetrahydrochysene coptis mixed biologic alkali 0.88g through the benzene recrystallization, and yield is 87%.
Embodiment 12: the preparation of tetrahydrochysene coptis mixed biologic alkali
Take by weighing coptis mixed biologic alkali 1g in the 100ml three-necked bottle, adding 50ml ethanol massfraction is 90% aqueous ethanolic solution, with aqueous ethanolic solution heating for dissolving to the 80 ℃ backflow of coptis mixed biologic alkali, the concentration of coptis mixed biologic alkali in aqueous ethanolic solution is 0.02g/mL, add Anhydrous potassium carbonate 4g, the mass ratio of Anhydrous potassium carbonate and coptis mixed biologic alkali is 4: 1, it is that the sodium borohydride of 0.3g reacts that each then 5min at interval divides three equivalent to add total amount, the mass ratio of sodium borohydride and coptis mixed biologic alkali is 0.3: 1, in stirring at room reaction 4h, suction filtration after reaction finishes, leach insolubles, insolubles gets tetrahydrochysene coptis mixed biologic alkali 0.83g through the benzene recrystallization, and yield is 82%.
Embodiment 13: the preparation of tetrahydrochysene tetrahydroxy coptisine
The tetrahydrochysene coptis mixed biologic alkali that is made by embodiment 1-12 that takes by weighing 1g dissolves with the 50ml methylene dichloride, the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.02g/mL, in-40 ℃ of dichloromethane solutions that in system, contain the 1mol/L boron tribromide with the speed dropping 12ml of 0.17 ml/min, the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 4: 1, temperature is transferred to stirring at room reaction 12h, after finishing, reaction at room temperature adds the methyl alcohol cancellation, suction filtration, leach insolubles through the ether recrystallization, get tetrahydrochysene tetrahydroxy coptisine 0.80g, yield is 91%.
Embodiment 14: the preparation of tetrahydrochysene tetrahydroxy coptisine
The tetrahydrochysene coptis mixed biologic alkali that is made by embodiment 1-12 that takes by weighing 1g dissolves with the 50ml methylene dichloride, the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.02g/mL, in-40 ℃ of dichloromethane solutions that in system, contain the 1mol/L boron tribromide with the speed dropping 24ml of 0.17 ml/min, the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 8: 1, temperature is transferred to stirring at room reaction 12h, after finishing, reaction at room temperature adds the methyl alcohol cancellation, suction filtration, leach insolubles through the ether recrystallization, get tetrahydrochysene tetrahydroxy coptisine 0.79g, yield is 80%.
Embodiment 15: the preparation of tetrahydrochysene tetrahydroxy coptisine
The tetrahydrochysene coptis mixed biologic alkali that is made by embodiment 1-12 that takes by weighing 1g dissolves with the 50ml methylene dichloride, the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.02g/mL, in-40 ℃ of dichloromethane solutions that in system, contain the 1mol/L boron tribromide with the speed dropping 30ml of 0.17 ml/min, the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 10: 1, temperature is transferred to stirring at room reaction 12h, after finishing, reaction at room temperature adds the methyl alcohol cancellation, suction filtration, leach insolubles through the ether recrystallization, get tetrahydrochysene tetrahydroxy coptisine 0.82g, yield is 93%.
Embodiment 16: the preparation of tetrahydrochysene tetrahydroxy coptisine
The tetrahydrochysene coptis mixed biologic alkali that is made by embodiment 1-12 that takes by weighing 1g dissolves with the 40ml methylene dichloride, the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.025g/mL, in-40 ℃ of dichloromethane solutions that in system, contain the 1mol/L boron tribromide with the speed dropping 12ml of 0.17 ml/min, the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 4: 1, temperature is transferred to stirring at room reaction 18h, after finishing, reaction at room temperature adds the methyl alcohol cancellation, suction filtration, leach insolubles through the ether recrystallization, get tetrahydrochysene tetrahydroxy coptisine 0.78g, yield is 89%.
Embodiment 17: the preparation of tetrahydrochysene tetrahydroxy coptisine
The tetrahydrochysene coptis mixed biologic alkali that is made by embodiment 1-12 that takes by weighing 1g dissolves with the 40ml methylene dichloride, the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.025g/mL, in-40 ℃ of dichloromethane solutions that in system, contain the 1mol/L boron tribromide with the speed dropping 24ml of 0.17 ml/min, the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 8: 1, temperature is transferred to stirring at room reaction 18h, after finishing, reaction at room temperature adds the methyl alcohol cancellation, suction filtration, leach insolubles through the ether recrystallization, get tetrahydrochysene tetrahydroxy coptisine 0.85g, yield is 96%.
Embodiment 18: the preparation of tetrahydrochysene tetrahydroxy coptisine
The tetrahydrochysene coptis mixed biologic alkali that is made by embodiment 1-12 that takes by weighing 1g dissolves with the 40ml methylene dichloride, the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.025g/mL, in-40 ℃ of dichloromethane solutions that in system, contain the 1mol/L boron tribromide with the speed dropping 30ml of 0.17 ml/min, the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 10: 1, temperature is transferred to stirring at room reaction 18h, after finishing, reaction at room temperature adds the methyl alcohol cancellation, suction filtration, leach insolubles through the ether recrystallization, get tetrahydrochysene tetrahydroxy coptisine 0.84g, yield is 95%.
Embodiment 19: the preparation of tetrahydrochysene tetrahydroxy coptisine
The tetrahydrochysene coptis mixed biologic alkali that is made by embodiment 1-12 that takes by weighing 1g dissolves with the 25ml methylene dichloride, the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.04g/mL, in-40 ℃ of dichloromethane solutions that in system, contain the 1mol/L boron tribromide with the speed dropping 12ml of 0.17 ml/min, the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 4: 1, temperature is transferred to stirring at room reaction 24h, after finishing, reaction at room temperature adds the methyl alcohol cancellation, suction filtration, leach insolubles through the ether recrystallization, get tetrahydrochysene tetrahydroxy coptisine 0.79g, yield is 90%.
Embodiment 20: the preparation of tetrahydrochysene tetrahydroxy coptisine
The tetrahydrochysene coptis mixed biologic alkali that is made by embodiment 1-12 that takes by weighing 1g dissolves with the 25ml methylene dichloride, the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.04g/mL, in-40 ℃ of dichloromethane solutions that in system, contain the 1mol/L boron tribromide with the speed dropping 24ml of 0.17 ml/min, the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 8: 1, temperature is transferred to stirring at room reaction 24h, after finishing, reaction at room temperature adds the methyl alcohol cancellation, suction filtration, leach insolubles through the ether recrystallization, get tetrahydrochysene tetrahydroxy coptisine 0.87g, yield is 98%.
Embodiment 21: the preparation of tetrahydrochysene tetrahydroxy coptisine
The tetrahydrochysene coptis mixed biologic alkali that is made by embodiment 1-12 that takes by weighing 1g dissolves with the 25ml methylene dichloride, the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.04g/mL, in-40 ℃ of dichloromethane solutions that in system, contain the 1mol/L boron tribromide with the speed dropping 30ml of 0.17 ml/min, the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 10: 1, temperature is transferred to stirring at room reaction 24h, after finishing, reaction at room temperature adds the methyl alcohol cancellation, suction filtration, leach insolubles through the ether recrystallization, get tetrahydrochysene tetrahydroxy coptisine 0.80g, yield is 91%.
Embodiment 22: the preparation of tetrahydrochysene tetrahydroxy coptisine
The tetrahydrochysene coptis mixed biologic alkali that is made by embodiment 1-12 that takes by weighing 1g dissolves with the 50ml methylene dichloride, the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.02g/mL, in-40 ℃ of dichloromethane solutions that in system, contain the 1mol/L boron tribromide with the speed dropping 24ml of 0.17 ml/min, the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 8: 1, temperature is transferred to stirring at room reaction 18h, after finishing, reaction at room temperature adds the methyl alcohol cancellation, suction filtration, leach insolubles through the ether recrystallization, get tetrahydrochysene tetrahydroxy coptisine 0.80g, yield is 91%.
Embodiment 23: the preparation of tetrahydrochysene tetrahydroxy coptisine
The tetrahydrochysene coptis mixed biologic alkali that is made by embodiment 1-12 that takes by weighing 1g dissolves with the 50ml methylene dichloride, the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.02g/mL, in-40 ℃ of dichloromethane solutions that in system, contain the 1mol/L boron tribromide with the speed dropping 30ml of 0.17 ml/min, the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 10: 1, temperature is transferred to stirring at room reaction 24h, after finishing, reaction at room temperature adds the methyl alcohol cancellation, suction filtration, leach insolubles through the ether recrystallization, get tetrahydrochysene tetrahydroxy coptisine 0.84g, yield is 95%.
Embodiment 24: the preparation of tetrahydrochysene tetrahydroxy coptisine
The tetrahydrochysene coptis mixed biologic alkali that is made by embodiment 1-12 that takes by weighing 1g dissolves with the 40ml methylene dichloride, the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.025g/mL, in-40 ℃ of dichloromethane solutions that in system, contain the 1mol/L boron tribromide with the speed dropping 24ml of 0.17 ml/min, the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 8: 1, temperature is transferred to stirring at room reaction 12h, after finishing, reaction at room temperature adds the methyl alcohol cancellation, suction filtration, leach insolubles through the ether recrystallization, get tetrahydrochysene tetrahydroxy coptisine 0.82g, yield is 93%.
Embodiment 25: the preparation of tetrahydrochysene tetrahydroxy coptisine
The tetrahydrochysene coptis mixed biologic alkali that is made by embodiment 1-12 that takes by weighing 1g dissolves with the 40ml methylene dichloride, the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.025g/mL, in-40 ℃ of dichloromethane solutions that in system, contain the 1mol/L boron tribromide with the speed dropping 30ml of 0.17 ml/min, the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 10: 1, temperature is transferred to stirring at room reaction 24h, after finishing, reaction at room temperature adds the methyl alcohol cancellation, suction filtration, leach insolubles through the ether recrystallization, get tetrahydrochysene tetrahydroxy coptisine 0.86g, yield is 97%.
Embodiment 26: the preparation of tetrahydrochysene tetrahydroxy coptisine
The tetrahydrochysene coptis mixed biologic alkali that is made by embodiment 1-12 that takes by weighing 1g dissolves with the 25ml methylene dichloride, the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.04g/mL, in-40 ℃ of dichloromethane solutions that in system, contain the 1mol/L boron tribromide with the speed dropping 24ml of 0.17 ml/min, the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 8: 1, temperature is transferred to stirring at room reaction 12h, after finishing, reaction at room temperature adds the methyl alcohol cancellation, suction filtration, leach insolubles through the ether recrystallization, get tetrahydrochysene tetrahydroxy coptisine 0.85g, yield is 96%.
Embodiment 27: the preparation of tetrahydrochysene tetrahydroxy coptisine
The tetrahydrochysene coptis mixed biologic alkali that is made by embodiment 1-12 that takes by weighing 1g dissolves with the 25ml methylene dichloride, the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.04g/mL, in-40 ℃ of dichloromethane solutions that in system, contain the 1mol/L boron tribromide with the speed dropping 30ml of 0.17 ml/min, the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 10: 1, temperature is transferred to stirring at room reaction 18h, after finishing, reaction at room temperature adds the methyl alcohol cancellation, suction filtration, leach insolubles through the ether recrystallization, get tetrahydrochysene tetrahydroxy coptisine 0.82g, yield is 93%.
Embodiment 28: the preparation of Tetrahydrocoptisine
The tetrahydrochysene tetrahydroxy coptisine that is made by embodiment 13-27 that takes by weighing 1g dissolves with the 50ml anhydrous dimethyl formamide, the concentration of tetrahydrochysene tetrahydroxy coptisine in anhydrous dimethyl formamide is 0.02g/mL, add the 1.6g cesium fluoride, the mass ratio of cesium fluoride and tetrahydrochysene tetrahydroxy coptisine is 1.6: 1, be heated 60 ℃, the bromochloromethane that drips 0.4ml with the speed of 0.17 ml/min in system reacts, the mol ratio of bromochloromethane and tetrahydrochysene tetrahydroxy coptisine is 2: 1, temperature of reaction is risen to 95 ℃, stirring reaction 24h, the system for the treatment of is cooled to room temperature, suction filtration, filtrate decompression concentrate dark solid, with its with water dissolution after, use extracted with diethyl ether, merge organic layer concentrate yellow solid, through re-crystallizing in ethyl acetate, get Tetrahydrocoptisine 0.30g, yield is 28%.
Embodiment 29: the preparation of Tetrahydrocoptisine
The tetrahydrochysene tetrahydroxy coptisine that is made by embodiment 13-27 that takes by weighing 1g dissolves with the 40ml anhydrous dimethyl formamide, the concentration of tetrahydrochysene tetrahydroxy coptisine in anhydrous dimethyl formamide is 0.02g/mL, add the 1.6g cesium fluoride, the mass ratio of cesium fluoride and tetrahydrochysene tetrahydroxy coptisine is 1.6: 1, be heated 60 ℃, the bromochloromethane that drips 0.4ml with the speed of 0.17 ml/min in system reacts, the mol ratio of bromochloromethane and tetrahydrochysene tetrahydroxy coptisine is 2: 1, temperature of reaction is risen to 95 ℃, stirring reaction 24h, the system for the treatment of is cooled to room temperature, suction filtration, filtrate decompression concentrate dark solid, with its with water dissolution after, use extracted with diethyl ether, merge organic layer concentrate yellow solid, through re-crystallizing in ethyl acetate, get Tetrahydrocoptisine 0.33g, yield is 30%.
Embodiment 30: the preparation of Tetrahydrocoptisine
The tetrahydrochysene tetrahydroxy coptisine that is made by embodiment 13-27 that takes by weighing 1g dissolves with the 25ml anhydrous dimethyl formamide, the concentration of tetrahydrochysene tetrahydroxy coptisine in anhydrous dimethyl formamide is 0.02g/mL, add the 1.6g cesium fluoride, the mass ratio of cesium fluoride and tetrahydrochysene tetrahydroxy coptisine is 1.6: 1, be heated 60 ℃, the bromochloromethane that drips 0.4ml with the speed of 0.17 ml/min in system reacts, the mol ratio of bromochloromethane and tetrahydrochysene tetrahydroxy coptisine is 2: 1, temperature of reaction is risen to 95 ℃, stirring reaction 24h, the system for the treatment of is cooled to room temperature, suction filtration, filtrate decompression concentrate dark solid, with its with water dissolution after, use extracted with diethyl ether, merge organic layer concentrate yellow solid, through re-crystallizing in ethyl acetate, get Tetrahydrocoptisine 0.30g, yield is 28%.
Embodiment 31: the preparation of Tetrahydrocoptisine
The tetrahydrochysene tetrahydroxy coptisine that is made by embodiment 13-27 that takes by weighing 1g dissolves with the 50ml anhydrous dimethyl formamide, the concentration of tetrahydrochysene tetrahydroxy coptisine in anhydrous dimethyl formamide is 0.02g/mL, add the 3g cesium fluoride, the mass ratio of cesium fluoride and tetrahydrochysene tetrahydroxy coptisine is 3: 1, be heated 60 ℃, the bromochloromethane that drips 1.2ml with the speed of 0.17 ml/min in system reacts, the mol ratio of bromochloromethane and tetrahydrochysene tetrahydroxy coptisine is 6: 1, temperature of reaction is risen to 110 ℃, stirring reaction 36h, the system for the treatment of is cooled to room temperature, suction filtration, filtrate decompression concentrate dark solid, with its with water dissolution after, use extracted with diethyl ether, merge organic layer concentrate yellow solid, through re-crystallizing in ethyl acetate, get Tetrahydrocoptisine 0.35g, yield is 32%.
Embodiment 32: the preparation of Tetrahydrocoptisine
The tetrahydrochysene tetrahydroxy coptisine that is made by embodiment 13-27 that takes by weighing 1g dissolves with the 40ml anhydrous dimethyl formamide, the concentration of tetrahydrochysene tetrahydroxy coptisine in anhydrous dimethyl formamide is 0.025g/mL, add the 3g cesium fluoride, the mass ratio of cesium fluoride and tetrahydrochysene tetrahydroxy coptisine is 3: 1, be heated 60 ℃, the bromochloromethane that drips 1.2ml with the speed of 0.17 ml/min in system reacts, the mol ratio of bromochloromethane and tetrahydrochysene tetrahydroxy coptisine is 6: 1, temperature of reaction is risen to 110 ℃, stirring reaction 48h, the system for the treatment of is cooled to room temperature, suction filtration, filtrate decompression concentrate dark solid, with its with water dissolution after, use extracted with diethyl ether, merge organic layer concentrate yellow solid, through re-crystallizing in ethyl acetate, get Tetrahydrocoptisine 0.22g, yield is 20%.
Embodiment 33: the preparation of Tetrahydrocoptisine
The tetrahydrochysene tetrahydroxy coptisine that is made by embodiment 13-27 that takes by weighing 1g dissolves with the 25ml anhydrous dimethyl formamide, the concentration of tetrahydrochysene tetrahydroxy coptisine in anhydrous dimethyl formamide is 0.04g/mL, add the 3g cesium fluoride, the mass ratio of cesium fluoride and tetrahydrochysene tetrahydroxy coptisine is 3: 1, be heated 60 ℃, the bromochloromethane that drips 1.2ml with the speed of 0.17 ml/min in system reacts, the mol ratio of bromochloromethane and tetrahydrochysene tetrahydroxy coptisine is 6: 1, temperature of reaction is risen to 110 ℃, stirring reaction 48h, the system for the treatment of is cooled to room temperature, suction filtration, filtrate decompression concentrate dark solid, with its with water dissolution after, use extracted with diethyl ether, merge organic layer concentrate yellow solid, through re-crystallizing in ethyl acetate, get Tetrahydrocoptisine 0.30g, yield is 28%.
Embodiment 34: the preparation of Tetrahydrocoptisine
The tetrahydrochysene tetrahydroxy coptisine that is made by embodiment 13-27 that takes by weighing 1g dissolves with the 50ml anhydrous dimethyl formamide, the concentration of tetrahydrochysene tetrahydroxy coptisine in anhydrous dimethyl formamide is 0.02g/mL, add the 4g cesium fluoride, the mass ratio of cesium fluoride and tetrahydrochysene tetrahydroxy coptisine is 4: 1, be heated 60 ℃, the bromochloromethane that drips 2ml with the speed of 0.17 ml/min in system reacts, the mol ratio of bromochloromethane and tetrahydrochysene tetrahydroxy coptisine is 10: 1, temperature of reaction is risen to 120 ℃, stirring reaction 48h, the system for the treatment of is cooled to room temperature, suction filtration, filtrate decompression concentrate dark solid, with its with water dissolution after, use extracted with diethyl ether, merge organic layer concentrate yellow solid, through re-crystallizing in ethyl acetate, get Tetrahydrocoptisine 0.35g, yield is 32%.
Embodiment 35: the preparation of Tetrahydrocoptisine
The tetrahydrochysene tetrahydroxy coptisine that is made by embodiment 13-27 that takes by weighing 1g dissolves with the 40ml anhydrous dimethyl formamide, the concentration of tetrahydrochysene tetrahydroxy coptisine in anhydrous dimethyl formamide is 0.025g/mL, add the 4g cesium fluoride, the mass ratio of cesium fluoride and tetrahydrochysene tetrahydroxy coptisine is 4: 1, be heated 60 ℃, the bromochloromethane that drips 2ml with the speed of 0.17 ml/min in system reacts, the mol ratio of bromochloromethane and tetrahydrochysene tetrahydroxy coptisine is 10: 1, temperature of reaction is risen to 120 ℃, stirring reaction 48h, the system for the treatment of is cooled to room temperature, suction filtration, filtrate decompression concentrate dark solid, with its with water dissolution after, use extracted with diethyl ether, merge organic layer concentrate yellow solid, through re-crystallizing in ethyl acetate, get Tetrahydrocoptisine 0.27g, yield is 25%.
Embodiment 36: the preparation of Tetrahydrocoptisine
The tetrahydrochysene tetrahydroxy coptisine that is made by embodiment 13-27 that takes by weighing 1g dissolves with the 25ml anhydrous dimethyl formamide, the concentration of tetrahydrochysene tetrahydroxy coptisine in anhydrous dimethyl formamide is 0.04g/mL, add the 4g cesium fluoride, the mass ratio of cesium fluoride and tetrahydrochysene tetrahydroxy coptisine is 4: 1, be heated 60 ℃, the bromochloromethane that drips 2ml with the speed of 0.17 ml/min in system reacts, the mol ratio of bromochloromethane and tetrahydrochysene tetrahydroxy coptisine is 10: 1, temperature of reaction is risen to 120 ℃, stirring reaction 48h, the system for the treatment of is cooled to room temperature, suction filtration, filtrate decompression concentrate dark solid, with its with water dissolution after, use extracted with diethyl ether, merge organic layer concentrate yellow solid, through re-crystallizing in ethyl acetate, get Tetrahydrocoptisine 0.31g, yield is 29%.
Embodiment 37: the preparation of Tetrahydrocoptisine
The tetrahydrochysene tetrahydroxy coptisine that is made by embodiment 13-27 that takes by weighing 1g dissolves with the 50ml anhydrous dimethyl formamide, the concentration of tetrahydrochysene tetrahydroxy coptisine in anhydrous dimethyl formamide is 0.02g/mL, add the 3g cesium fluoride, the mass ratio of cesium fluoride and tetrahydrochysene tetrahydroxy coptisine is 3: 1, be heated 60 ℃, the bromochloromethane that drips 0.4ml with the speed of 0.17 ml/min in system reacts, the mol ratio of bromochloromethane and tetrahydrochysene tetrahydroxy coptisine is 2: 1, temperature of reaction is risen to 110 ℃, stirring reaction 48h, the system for the treatment of is cooled to room temperature, suction filtration, filtrate decompression concentrate dark solid, with its with water dissolution after, use extracted with diethyl ether, merge organic layer concentrate yellow solid, through re-crystallizing in ethyl acetate, get Tetrahydrocoptisine 0.35g, yield is 32%.
Embodiment 38: the preparation of Tetrahydrocoptisine
The tetrahydrochysene tetrahydroxy coptisine that is made by embodiment 13-27 that takes by weighing 1g dissolves with the 40ml anhydrous dimethyl formamide, the concentration of tetrahydrochysene tetrahydroxy coptisine in anhydrous dimethyl formamide is 0.025g/mL, add the 4g cesium fluoride, the mass ratio of cesium fluoride and tetrahydrochysene tetrahydroxy coptisine is 4: 1, be heated 60 ℃, the bromochloromethane that drips 1.2ml with the speed of 0.17 ml/min in system reacts, the mol ratio of bromochloromethane and tetrahydrochysene tetrahydroxy coptisine is 6: 1, temperature of reaction is risen to 110 ℃, stirring reaction 24h, the system for the treatment of is cooled to room temperature, suction filtration, filtrate decompression concentrate dark solid, with its with water dissolution after, use extracted with diethyl ether, merge organic layer concentrate yellow solid, through re-crystallizing in ethyl acetate, get Tetrahydrocoptisine 0.28g, yield is 27%.
Embodiment 39: the preparation of Tetrahydrocoptisine
The tetrahydrochysene tetrahydroxy coptisine that is made by embodiment 13-27 that takes by weighing 1g dissolves with the 25ml anhydrous dimethyl formamide, the concentration of tetrahydrochysene tetrahydroxy coptisine in anhydrous dimethyl formamide is 0.04g/mL, add the 1.6g cesium fluoride, the mass ratio of cesium fluoride and tetrahydrochysene tetrahydroxy coptisine is 1.6: 1, be heated 60 ℃, the bromochloromethane that drips 2ml with the speed of 0.17 ml/min in system reacts, the mol ratio of bromochloromethane and tetrahydrochysene tetrahydroxy coptisine is 10: 1, temperature of reaction is risen to 120 ℃, stirring reaction 36h, the system for the treatment of is cooled to room temperature, suction filtration, filtrate decompression concentrate dark solid, with its with water dissolution after, use extracted with diethyl ether, merge organic layer concentrate yellow solid, through re-crystallizing in ethyl acetate, get Tetrahydrocoptisine 0.31g, yield is 29%.
Embodiment 40: the preparation of coptisine
The Tetrahydrocoptisine that is made by embodiment 28-39 that takes by weighing 1g is 2: 1 ethanol and acetic acid mixed solution dissolving with 50ml ebullient volume ratio, the concentration of Tetrahydrocoptisine in mixing solutions is 0.02g/mL, add the 1.6g sodium-acetate, the mass ratio of sodium-acetate and Tetrahydrocoptisine is 1.6: 1.System is heated to 50 ℃, speed with 0.17 ml/min in system drips the 75ml ethanolic soln that is dissolved with 1.5g iodine, and the mol ratio of iodine and Tetrahydrocoptisine is 2: 1, and the concentration of iodine in ethanol is 0.02g/mL, the mixture stirred overnight at room temperature leaches throw out.Through acetone recrystallization, get coptisine 0.58g, yield is 59%.
Embodiment 41: the preparation of coptisine
The Tetrahydrocoptisine that is made by embodiment 28-39 that takes by weighing 1g is 2: 1 ethanol and acetic acid mixed solution dissolving with 40ml ebullient volume ratio, the concentration of Tetrahydrocoptisine in mixing solutions is 0.025g/mL, add the 1.6g sodium-acetate, the mass ratio of sodium-acetate and Tetrahydrocoptisine is 1.6: 1.System is heated to 50 ℃, speed with 0.17 ml/min in system drips the 75ml ethanolic soln that is dissolved with 1.5g iodine, and the mol ratio of iodine and Tetrahydrocoptisine is 2: 1, and the concentration of iodine in ethanol is 0.02g/mL, the mixture stirred overnight at room temperature leaches throw out.Through acetone recrystallization, get coptisine 0.62g, yield is 63%.
Embodiment 42: the preparation of coptisine
The Tetrahydrocoptisine that is made by embodiment 28-39 that takes by weighing 1g is 2: 1 ethanol and acetic acid mixed solution dissolving with 25ml ebullient volume ratio, the concentration of Tetrahydrocoptisine in mixing solutions is 0.04g/mL, add the 1.6g sodium-acetate, the mass ratio of sodium-acetate and Tetrahydrocoptisine is 1.6: 1.System is heated to 50 ℃, speed with 0.17 ml/min in system drips the 75ml ethanolic soln that is dissolved with 1.5g iodine, and the mol ratio of iodine and Tetrahydrocoptisine is 2: 1, and the concentration of iodine in ethanol is 0.02g/mL, the mixture stirred overnight at room temperature leaches throw out.Through acetone recrystallization, get coptisine 0.59g, yield is 60%.
Embodiment 43: the preparation of coptisine
The Tetrahydrocoptisine that is made by embodiment 28-39 that takes by weighing 1g is 2: 1 ethanol and acetic acid mixed solution dissolving with 50ml ebullient volume ratio, the concentration of Tetrahydrocoptisine in mixing solutions is 0.02g/mL, add the 3g sodium-acetate, the mass ratio of sodium-acetate and Tetrahydrocoptisine is 3: 1.System is heated to 50 ℃, speed with 0.17 ml/min in system drips the 58ml ethanolic soln that is dissolved with 2.3g iodine, and the mol ratio of iodine and Tetrahydrocoptisine is 3: 1, and the concentration of iodine in ethanol is 0.04g/mL, the mixture stirred overnight at room temperature leaches throw out.Through acetone recrystallization, get coptisine 0.61g, yield is 62%.
Embodiment 44: the preparation of coptisine
The Tetrahydrocoptisine that is made by embodiment 28-39 that takes by weighing 1g is 2: 1 ethanol and acetic acid mixed solution dissolving with 40ml ebullient volume ratio, the concentration of Tetrahydrocoptisine in mixing solutions is 0.025g/mL, add the 3g sodium-acetate, the mass ratio of sodium-acetate and Tetrahydrocoptisine is 3: 1.System is heated to 50 ℃, speed with 0.17 ml/min in system drips the 58ml ethanolic soln that is dissolved with 2.3g iodine, and the mol ratio of iodine and Tetrahydrocoptisine is 3: 1, and the concentration of iodine in ethanol is 0.04g/mL, the mixture stirred overnight at room temperature leaches throw out.Through acetone recrystallization, get coptisine 0.60g, yield is 61%.
Embodiment 45: the preparation of coptisine
The Tetrahydrocoptisine that is made by embodiment 28-39 that takes by weighing 1g is 2: 1 ethanol and acetic acid mixed solution dissolving with 25ml ebullient volume ratio, the concentration of Tetrahydrocoptisine in mixing solutions is 0.04g/mL, add the 3g sodium-acetate, the mass ratio of sodium-acetate and Tetrahydrocoptisine is 3: 1.System is heated to 50 ℃, speed with 0.17 ml/min in system drips the 58ml ethanolic soln that is dissolved with 2.3g iodine, and the mol ratio of iodine and Tetrahydrocoptisine is 3: 1, and the concentration of iodine in ethanol is 0.04g/mL, the mixture stirred overnight at room temperature leaches throw out.Through acetone recrystallization, get coptisine 0.57g, yield is 58%.
Embodiment 46: the preparation of coptisine
The Tetrahydrocoptisine that is made by embodiment 28-39 that takes by weighing 1g is 2: 1 ethanol and acetic acid mixed solution dissolving with 50ml ebullient volume ratio, the concentration of Tetrahydrocoptisine in mixing solutions is 0.02g/mL, add the 4g sodium-acetate, the mass ratio of sodium-acetate and Tetrahydrocoptisine is 4: 1.System is heated to 50 ℃, speed with 0.17 ml/min in system drips the 50ml ethanolic soln that is dissolved with 3g iodine, and the mol ratio of iodine and Tetrahydrocoptisine is 4: 1, and the concentration of iodine in ethanol is 0.06g/mL, the mixture stirred overnight at room temperature leaches throw out.Through acetone recrystallization, get coptisine 0.58g, yield is 59%.
Embodiment 47: the preparation of coptisine
The Tetrahydrocoptisine that is made by embodiment 28-39 that takes by weighing 1g is 2: 1 ethanol and acetic acid mixed solution dissolving with 40ml ebullient volume ratio, the concentration of Tetrahydrocoptisine in mixing solutions is 0.025g/mL, add the 4g sodium-acetate, the mass ratio of sodium-acetate and Tetrahydrocoptisine is 4: 1.System is heated to 50 ℃, speed with 0.17 ml/min in system drips the 50ml ethanolic soln that is dissolved with 3g iodine, and the mol ratio of iodine and Tetrahydrocoptisine is 4: 1, and the concentration of iodine in ethanol is 0.06g/mL, the mixture stirred overnight at room temperature leaches throw out.Through acetone recrystallization, get coptisine 0.54g, yield is 55%.
Embodiment 48: the preparation of coptisine
The Tetrahydrocoptisine that is made by embodiment 28-39 that takes by weighing 1g is 2: 1 ethanol and acetic acid mixed solution dissolving with 25ml ebullient volume ratio, the concentration of Tetrahydrocoptisine in mixing solutions is 0.04g/mL, add the 4g sodium-acetate, the mass ratio of sodium-acetate and Tetrahydrocoptisine is 4: 1.System is heated to 50 ℃, speed with 0.17 ml/min in system drips the 50ml ethanolic soln that is dissolved with 3g iodine, and the mol ratio of iodine and Tetrahydrocoptisine is 4: 1, and the concentration of iodine in ethanol is 0.06g/mL, the mixture stirred overnight at room temperature leaches throw out.Through acetone recrystallization, get coptisine 0.63g, yield is 64%.
Embodiment 49: the preparation of coptisine
The Tetrahydrocoptisine that is made by embodiment 28-39 that takes by weighing 1g is 2: 1 ethanol and acetic acid mixed solution dissolving with 25ml ebullient volume ratio, the concentration of Tetrahydrocoptisine in mixing solutions is 0.04g/mL, add the 4g sodium-acetate, the mass ratio of sodium-acetate and Tetrahydrocoptisine is 4: 1.System is heated to 50 ℃, speed with 0.17 ml/min in system drips the 115ml ethanolic soln that is dissolved with 2.3g iodine, and the mol ratio of iodine and Tetrahydrocoptisine is 3: 1, and the concentration of iodine in ethanol is 0.02g/mL, the mixture stirred overnight at room temperature leaches throw out.Through acetone recrystallization, get coptisine 0.52g, yield is 53%.
Embodiment 50: the preparation of coptisine
The Tetrahydrocoptisine that is made by embodiment 28-39 that takes by weighing 1g is 2: 1 ethanol and acetic acid mixed solution dissolving with 50ml ebullient volume ratio, the concentration of Tetrahydrocoptisine in mixing solutions is 0.02g/mL, add the 3g sodium-acetate, the mass ratio of sodium-acetate and Tetrahydrocoptisine is 3: 1.System is heated to 50 ℃, speed with 0.17 ml/min in system drips the 25ml ethanolic soln that is dissolved with 1.5g iodine, and the mol ratio of iodine and Tetrahydrocoptisine is 2: 1, and the concentration of iodine in ethanol is 0.06g/mL, the mixture stirred overnight at room temperature leaches throw out.Through acetone recrystallization, get coptisine 0.58g, yield is 59%.
Claims (5)
1. one kind prepares the method for coptisine based on the coptis mixed biologic alkali of common basic structural feature, it is characterized in that may further comprise the steps:
1) coptis mixed biologic alkali generates tetrahydrochysene coptis mixed biologic alkali through the reduction hydrogenation;
2) methoxyl group of tetrahydrochysene coptis mixed biologic alkali, methylene-dioxy generates tetrahydrochysene tetrahydroxy coptisine through hydroxylation;
3) tetrahydrochysene tetrahydroxy coptisine generates Tetrahydrocoptisine through cyclization;
4) Tetrahydrocoptisine oxydehydrogenation generates coptisine;
Described coptis mixed biologic alkali is that the isoquinoline 99.9 ring with identical that extracts from the Chinese medicine coptis is an agent structure, with methoxyl group, and methylene-dioxy, hydroxyl is 2,3,9, the mixed biologic alkali of 10 replacements comprises palmatine and jateorhizine, Berberine and coptisine; The general structure (I) of coptis mixed biologic alkali is as follows:
In the structural formula (I), the structural formula of palmatine is formula a, and wherein R1 is-CH3, and R2 is-CH3 that R3 is-CH3 that R4 is-CH3;
In the structural formula (I), the jateorhizine structural formula is formula b, and wherein R1 is-H, and R2 is-CH3 that R3 is-CH3 that R4 is-CH3;
In the structural formula (I), the Berberine structural formula is formula b, R1+R2=-CH2-wherein, and R3 is-CH3 that R4 is-CH3;
Formula c
In the structural formula (I), the coptisine structural formula is formula c, R1+R2=-CH2-wherein, and R3, R4 are-CH2-.
2. according to claim 1-as kind to prepare the method for coptisine, it is characterized in that described 1 based on the coptis mixed biologic alkali of common basic structural feature) coptis mixed biologic alkali is as follows through the step that the reduction hydrogenation generates tetrahydrochysene coptis mixed biologic alkali:
General formula (II) structure of tetrahydrochysene coptis mixed biologic alkali is as follows:
In the general formula (II), R1, R2, R3, R4 respectively with the general formula (I) of the coptis mixed biologic alkali of claim 1 in consistent;
Is aqueous ethanolic solution heating for dissolving to the 80 ℃ backflow of 70%-90% with coptis mixed biologic alkali with the ethanol massfraction, and the concentration of coptis mixed biologic alkali in aqueous ethanolic solution is 0.02-0.04g/mL; Add the catalyzer Anhydrous potassium carbonate then, the mass ratio of catalyst levels and coptis mixed biologic alkali is 1.6-4: 1; Then, every interval 5min adds the sodium borohydride of equivalent totally for three times respectively, and the mass ratio of described sodium borohydride total amount and coptis mixed biologic alkali is 0.12-0.60: 1; Suction filtration behind room temperature reaction 4-8h leaches insolubles, and insolubles gets tetrahydrochysene coptis mixed biologic alkali through the benzene recrystallization.
3. a kind of method for preparing coptisine based on the coptis mixed biologic alkali of common basic structural feature according to claim 1, it is characterized in that, described 2) methoxyl group of tetrahydrochysene coptis mixed biologic alkali, methylene-dioxy is as follows through the step that hydroxylation generates tetrahydrochysene tetrahydroxy coptisine:
The molecular structural formula (III) of tetrahydrochysene tetrahydroxy coptisine is as follows:
The tetrahydrochysene coptis mixed biologic alkali that claim 2 is obtained dissolves with methylene dichloride, and the concentration of tetrahydrochysene coptis mixed biologic alkali in methylene dichloride is 0.02-0.04g/mL;-40 ℃ of speed with 0.17 ml/min in system, dripping concentration is the dichloromethane solution of 1mol/L boron tribromide, and the mol ratio of described boron tribromide and tetrahydrochysene coptis mixed biologic alkali is 4-10: 1; After being warming up to stirring at room reaction 12-24h then, at room temperature add the methyl alcohol cancellation immediately, suction filtration leaches insolubles through the ether recrystallization, gets tetrahydrochysene tetrahydroxy coptisine.
4. according to claim 1ly a kind ofly preparing the method for coptisine, it is characterized in that described 3 based on the coptis mixed biologic alkali of common basic structural feature) tetrahydrochysene tetrahydroxy coptisine is as follows through the step that cyclization generates Tetrahydrocoptisine:
(IV) is as follows for the molecular structural formula of Tetrahydrocoptisine:
The tetrahydrochysene tetrahydroxy coptisine that claim 3 is obtained dissolves with anhydrous dimethyl formamide, the concentration of tetrahydrochysene tetrahydroxy coptisine in anhydrous dimethyl formamide is 0.02-0.04g/mL, add the catalyzer cesium fluoride, the mass ratio of described catalyzer cesium fluoride and tetrahydrochysene tetrahydroxy coptisine is 1.6-4: 1, system is heated to 60 ℃, speed dripping bromine methyl chloride with 0.17 ml/min in system reacts, and the mol ratio of described bromochloromethane and tetrahydrochysene tetrahydroxy coptisine is 2-10: 1; Temperature of reaction is brought up to 95-120 ℃ of reaction 24-48h; Then system is cooled to room temperature, suction filtration, filtrate decompression concentrate dark solid, with its with water dissolution after, use extracted with diethyl ether, merge organic layer, concentrate yellow solid, through re-crystallizing in ethyl acetate, must Tetrahydrocoptisine.
5. according to claim 1ly a kind ofly preparing the method for coptisine, it is characterized in that described 4 based on the coptis mixed biologic alkali of common basic structural feature) to generate the step of coptisine as follows in Tetrahydrocoptisine oxydehydrogenation:
The molecular structural formula of coptisine is suc as formula shown in the d:
Formula d
With claim 4) the Tetrahydrocoptisine volume ratio that obtains is the ebullient mixing solutions dissolving of 2: 1 ethanol and acetate, the concentration of Tetrahydrocoptisine in mixing solutions is 0.02-0.04g/mL, add catalyst acetic acid sodium, the mass ratio of described catalyst acetic acid sodium and Tetrahydrocoptisine is 1.6-4: 1, system is heated to 50 ℃, speed with 0.17 ml/min in system drips the ethanolic soln that is dissolved with iodine, the mol ratio of described iodine and Tetrahydrocoptisine is 2-4: 1, the concentration of iodine in ethanol is 0.02-0.06g/mL, the mixture stirred overnight at room temperature, leach throw out,, get coptisine through acetone recrystallization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010519053 CN101985445A (en) | 2010-10-26 | 2010-10-26 | Method for preparing coptisine from coptis mixed alkaloid based on common basic structural characteristic |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010519053 CN101985445A (en) | 2010-10-26 | 2010-10-26 | Method for preparing coptisine from coptis mixed alkaloid based on common basic structural characteristic |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101985445A true CN101985445A (en) | 2011-03-16 |
Family
ID=43709845
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010519053 Pending CN101985445A (en) | 2010-10-26 | 2010-10-26 | Method for preparing coptisine from coptis mixed alkaloid based on common basic structural characteristic |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101985445A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102285982A (en) * | 2011-08-30 | 2011-12-21 | 聊城大学 | Method for separating and purifying monomer compounds from Chinese medicinal herb golden thread |
| CN102408424A (en) * | 2011-09-28 | 2012-04-11 | 长春工业大学 | Method for preparing Palmatine by utilizing hybrid coptis total alkaloid with isoquinoline structure |
| CN103622958A (en) * | 2012-08-25 | 2014-03-12 | 北京以岭药业有限公司 | Application of tetrahydroproberberine compounds to prepare antidepressants |
| CN105330708A (en) * | 2015-11-13 | 2016-02-17 | 中国科学院化学研究所 | Tetrahydropalmatine derivative and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101590044A (en) * | 2008-05-29 | 2009-12-02 | 北京卓越同创药物研究院 | The pharmaceutical usage of berberine |
| CN101597287A (en) * | 2009-04-20 | 2009-12-09 | 云南植物药业有限公司 | The synthetic method of a kind of Fibrauretin and berberine |
-
2010
- 2010-10-26 CN CN 201010519053 patent/CN101985445A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101590044A (en) * | 2008-05-29 | 2009-12-02 | 北京卓越同创药物研究院 | The pharmaceutical usage of berberine |
| CN101597287A (en) * | 2009-04-20 | 2009-12-09 | 云南植物药业有限公司 | The synthetic method of a kind of Fibrauretin and berberine |
Non-Patent Citations (2)
| Title |
|---|
| 《Il Farmaco》 20010701 Maria Laura Colombo等 Cytotoxicity evaluation of natural coptisine and synthesis of coptisine from berberine 第405-406 1-5 第56卷, * |
| 《中国优秀硕士学位论文全文数据库，医药卫生科技辑》 20081130 刘卫涛 小檗碱衍生物的制备及其神经营养活性研究 第21页 2 , * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102285982A (en) * | 2011-08-30 | 2011-12-21 | 聊城大学 | Method for separating and purifying monomer compounds from Chinese medicinal herb golden thread |
| CN102408424A (en) * | 2011-09-28 | 2012-04-11 | 长春工业大学 | Method for preparing Palmatine by utilizing hybrid coptis total alkaloid with isoquinoline structure |
| CN103622958A (en) * | 2012-08-25 | 2014-03-12 | 北京以岭药业有限公司 | Application of tetrahydroproberberine compounds to prepare antidepressants |
| CN103622958B (en) * | 2012-08-25 | 2017-05-24 | 北京以岭药业有限公司 | Application of tetrahydroproberberine compounds to prepare antidepressants |
| CN105330708A (en) * | 2015-11-13 | 2016-02-17 | 中国科学院化学研究所 | Tetrahydropalmatine derivative and preparation method and application thereof |
| CN105330708B (en) * | 2015-11-13 | 2018-11-13 | 中国科学院化学研究所 | Tetrahydropalmatine derivatives and preparation method thereof, purposes |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Grundon | Quinoline, quinazoline, and acridone alkaloids | |
| CN101985445A (en) | Method for preparing coptisine from coptis mixed alkaloid based on common basic structural characteristic | |
| CN102977161A (en) | Method for chemically synthesising gastrodin | |
| CN102617649A (en) | 1-ferrocenyl-4-N-phenothiazinyl acrylketone and preparation method thereof | |
| CN102180914A (en) | Preparation method of 2-deoxidizing-D-glucose | |
| CN102250102A (en) | Alpha(beta)quinoline-oligopolycthylene glycol phthalocyanine zinc and preparation method thereof | |
| CN106117197A (en) | A kind of method being prepared 2,3,9,10 4 butoxy protoberberines by Rhizoma Coptidis mixed biologic alkali | |
| CN103319356A (en) | One-step green synthesis process of antimalarial raw material benflumetol | |
| CN101195602B (en) | 1-deoxidization nojiri toxin derivant, production method and uses thereof | |
| CN104177301B (en) | A kind of preparation method of dexrazoxane | |
| CN101003535A (en) | Alpha hydroxy - alpha phenyl phenylacetic acid 8 - aza dicyclo [3. 2. 1] - 3 heptyl ester, midbody compound, and preparation method | |
| CN102408424A (en) | Method for preparing Palmatine by utilizing hybrid coptis total alkaloid with isoquinoline structure | |
| CN102633808B (en) | Manufacturing method for deoxypodophyllotoxin | |
| CN114736212A (en) | Furo [3,2-b ] indole derivative and synthetic method and application thereof | |
| Lacroix et al. | Absolute configuration of 2′(R)-acetylmontrifoline and 2′(R)-montrifoline, furoquinolines from the fruits of Teclea nobilis | |
| CN103275078A (en) | Method for industrial production of moxifloxacin side chain | |
| CN103788110B (en) | A kind of take arteannuinic acid as the method that Artemisinin prepared by raw material | |
| CN103739608B (en) | The residue utilizing sweet wormwood to extract Artemisinin prepares the method for Artemisinin | |
| CN101798284A (en) | Azepine brazilin compound and synthesis method thereof | |
| CN108484623B (en) | Camptothecin derivative and preparation method and application thereof | |
| CN105859621A (en) | Difluoromethylene phenanthridine derivative and preparation method thereof | |
| CN101314587B (en) | Preparation for midbody of Irinotecan and preparation for Irinotecan | |
| CN105418499A (en) | Preparation method of acridine compound | |
| CN105646517A (en) | Preparation methods of natural product Hirtellanine B and derivatives thereof and application of natural product Hirtellanine B and derivatives thereof in preparation of drug for treating tumor | |
| CN108947999A (en) | The high-efficiency synthesis method of hydroquinidine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20110316 |