CN1296009A - Arteannuin derivant containing azacyclic radical and preparation process thereof - Google Patents
Arteannuin derivant containing azacyclic radical and preparation process thereof Download PDFInfo
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- CN1296009A CN1296009A CN 99124012 CN99124012A CN1296009A CN 1296009 A CN1296009 A CN 1296009A CN 99124012 CN99124012 CN 99124012 CN 99124012 A CN99124012 A CN 99124012A CN 1296009 A CN1296009 A CN 1296009A
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- nitrogen heterocycle
- artemisinin derivative
- nitrogen
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- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 229960004191 artemisinin Drugs 0.000 title abstract description 7
- 241001597008 Nomeidae Species 0.000 title 1
- 229930191701 arteannuin Natural products 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 6
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 claims description 14
- 229960002521 artenimol Drugs 0.000 claims description 13
- 229930016266 dihydroartemisinin Natural products 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- -1 acetyl Dihydroartemisinin Chemical compound 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 235000015320 potassium carbonate Nutrition 0.000 claims description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical group FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- IGEBZMMCKFUABB-KPHNHPKPSA-N artemisitene Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)C4=C IGEBZMMCKFUABB-KPHNHPKPSA-N 0.000 claims description 4
- 239000012964 benzotriazole Substances 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 240000001851 Artemisia dracunculus Species 0.000 claims description 3
- IGEBZMMCKFUABB-UHFFFAOYSA-N Artemisitene Natural products O1C(OO2)(C)CCC3C(C)CCC4C32C1OC(=O)C4=C IGEBZMMCKFUABB-UHFFFAOYSA-N 0.000 claims description 3
- 239000004593 Epoxy Substances 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 229960002970 artemotil Drugs 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 150000003852 triazoles Chemical class 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 150000001556 benzimidazoles Chemical group 0.000 claims description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 2
- 150000002475 indoles Chemical group 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 241000894007 species Species 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- 239000000463 material Substances 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 3
- 150000004030 azacyclic compounds Chemical class 0.000 abstract 3
- 206010061218 Inflammation Diseases 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 abstract 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 abstract 1
- 150000004216 artemisine derivatives Chemical class 0.000 abstract 1
- 201000011510 cancer Diseases 0.000 abstract 1
- 230000036039 immunity Effects 0.000 abstract 1
- 230000004054 inflammatory process Effects 0.000 abstract 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 abstract 1
- 244000045947 parasite Species 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229930101531 artemisinin Natural products 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- 240000000011 Artemisia annua Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 1
- GUOVBFFLXKJFEE-UHFFFAOYSA-N 2h-benzotriazole-5-carboxylic acid Chemical compound C1=C(C(=O)O)C=CC2=NNN=C21 GUOVBFFLXKJFEE-UHFFFAOYSA-N 0.000 description 1
- 235000001405 Artemisia annua Nutrition 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 125000005426 adeninyl group Chemical group N1=C(N=C2N=CNC2=C1N)* 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- MXJIHEXYGRXHGP-UHFFFAOYSA-N benzotriazol-1-ylmethanol Chemical compound C1=CC=C2N(CO)N=NC2=C1 MXJIHEXYGRXHGP-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002423 protozoacide Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention relates to a kind of artemisine derivative containing azacyclic group and its preparation method. It is characterized by that it uses acetyl dihydrogen artemisine (or trifluoroacetyl dihydrogen artemisine, methine artemisine, dihydrogen artemisine, beta-bromoarteether, 2,3-epoxyartemisic propyl ether) and azacyclic compound (or azacyclic compound containing carboxyl group and azacyclic compound containing hydroxyl group) to make them produce reaction to produce said invented product with the medical actions of resisting protozoon, resisting cancer, regulating immunity, relieving inflammation and destroying parasites, etc.
Description
The present invention relates to condensed ring system and contain the heterogeneous ring compound of aerobic nitrogen-atoms as heterocyclic atom, is artemisinin derivative that contains Azacyclyl and preparation method thereof specifically.
Artemisinin is the antimalarial effective ingredient of Chinese medicine sweet wormwood (plant Artemisia annua Artemisia annua L), and treatment resistant malaria and characteristics quick-acting, low toxicity are arranged.Scientist has prepared the derivative of a large amount of Artemisinins both at home and abroad, and wherein the artemisinin derivative of nitrogen heterocycle has following report:
(1) in the formula,
A-J.Lin etc. prepared the artemisinin derivative (J.Med.Chem.1990,33,2610) that minority has structural formula (one).
(2) XR=heterocyclic radical such as base in the formula (adeninyl, thymine base, the cytosine(Cyt) base, uracil base and they have R
2The base that replaces) and triazole
Base and they have CONH
2Or R
2The base that replaces;
R
2=hydroxyl, alkoxyl group (C
1-C
4), alkyl (C
1-C
4), carboxyl, ester group (COOCH
3, COOC
2H
5), acetamido (NHCOCH
3) nitro, and halogen (F, Cl, Br, I) and Dihydroartemisinin base etc.
Above compound can be referring to Chinese patent 94113982.4.
For excavating the artemisinin derivative potential biological activity of a class nitrogen heterocycle, the present invention has done further research work on the basis of Chinese patent 94113982.4, and purpose provides this analog derivative and preparation method thereof.
The artemisinin derivative of nitrogen heterocycle of the present invention can be used following general formula:
Het is replacement or unsubstituted triazole species in the formula, benzotriazole category, benzimidazoles, indoles, and substituting group can be a carboxyl, ester group, acyl group, alkoxyl group, lower alkyl alkyl (C
1-C
3), hydroxyl, methylol etc.
Q representative in the following structural formula
Wave molding (～) is represented C
11Or C
12The β of position replaces or/and α replaces
Straight line (-) is represented C
11Or C
12The β of position replaces
Dotted line (...) represent C
11Or C
12The α of position replaces
The preparation method of artemisinin derivative of the present invention divide following several
1、
Acetyl Dihydroartemisinin (IV) or trifluoroacetyl Dihydroartemisinin (V) react with nitrogen heterocyclic in organic solvent, and generate in the reaction in the presence of an acidic catalyst (boron trifluoride ethyl ether complex, trifluoroacetic acid, tosic acid etc.).
2、
Press literature method (F.E1-Feraly etc., J.Nat.Prod.53 (1): 66,1990) Artemisinin is converted into Artemisitene (VI), then with nitrogen heterocyclic generation addition reaction.During reaction, can add alkaline matter (as salt of wormwood, triethylamine, sodium hydride etc.), also not add sometimes and can react.
3、
Dihydroartemisinin (VII) reacts in the presence of dicyclohexylcarbodiimide with the nitrogen heterocyclic that contains carboxyl, generates ester compound
4、
Dihydroartemisinin (VII) exists down at an acidic catalyst (boron trifluoride ethyl ether complex, iron trichloride, trifluoroacetic acid, tosic acid, hydrochloric acid etc.) with the nitrogen heterocyclic that contains hydroxyl, generates ether compound
Beta-bromo arteether (VIII) generates with nitrogen heterocyclic (as salt of wormwood, triethylamine, pyridine etc.) reaction in the presence of alkaline matter.
2,3-epoxy wormwood artemisia propyl ether (IX) generates ether compound with nitrogen heterocyclic reacting by heating in organic solvent
Above synthetic method, except that 2, can be referring to the detailed description in Chinese patent ZL93112454.9 and 94113982.4.
The artemisinin derivative of nitrogen heterocycle of the present invention is through preliminary pharmacological screening, finds that protozoacide is arranged, effects such as anticancer, immunomodulatory, anti-inflammatory, desinsection, and its biological activity sees also table 1
The present invention is further elaborated by following embodiment, but does not limit the scope of the invention
Embodiment 1 preparation
Dihydroartemisinin (VII) 10mmol is added in the 200ml methylene dichloride, add trifluoroacetic anhydride 20mmol in 0-5 ℃ of reaction, make Dihydroartemisinin trifluoro-acetate (V), add 1,2 again, 4-triazole 15mmol continues reaction, follow the tracks of with thin-layer chromatography, after reacting completely, reaction solution is poured in the frozen water, tell organic layer, use NaHCO
3Water liquid washes, washes, dry, concentrate, residue obtains three kinds of products through silica gel column chromatography separating purification, their physical constant and productive rate see Table 2 sequence number 1-3
Embodiment 2 preparations
Artemisitene (VI) 10mmol and benzoglyoxaline 1.5mmol are dissolved in tetrahydrofuran (THF) 15ml, after adding salt of wormwood 2mmol again, reflux to react completely, the pressure reducing and steaming tetrahydrofuran (THF), use the methylene dichloride dissolution residual substance, wash with water again, dry, concentrate, residue is through silica gel column chromatography separating purification, assign to two products, their physical constant and productive rate see Table 2 sequence numbers 21 and 22.
Embodiment 3 preparations
Dihydroartemisinin (VII) 1.4mmol and 5-carboxy benzotriazole 2mmol are dissolved among the methylene dichloride 30ml, add dicyclohexylcarbodiimide 3mmol and dimethylamino pyridine 4mg stirring reaction at room temperature, thin-layer chromatography is followed the trail of, after reaction finishes, filter, filtrate water is washed, dry, concentrated, residue purification by silica gel column chromatography, and the physical constant of product and productive rate see Table 2 sequence numbers 18.
Embodiment 4 preparations
Dihydroartemisinin (VII) 2mmol and 1-methylol benzotriazole 3mmol are dissolved in dichloromethane solution, stirring at room, splash into 3 of boron trifluoride ethyl ether complexs, continue to be stirred to reaction and finish, reaction solution is washed with sodium bicarbonate aqueous solution, washing, dry, concentrate, resistates uses column chromatography purifying, first-class part is I (Het=1-benzotriazole base, the α body), productive rate 40%, its physical constant see Table 2 sequence numbers 7.Second stream part is ether compound III (X=-O-CH
2-, Het=1-benzotriazole base) productive rate 11%, its physical constant sees Table 2 sequence numbers 17.
Embodiment 5 preparations
β bromo arteether (VIII) 2mmol, benzoglyoxaline 4mmol, salt of wormwood 0.4g mixes with acetonitrile 20ml, stirring heating (60 ℃) to react completely, filtration, filtrate concentrate, residue uses column chromatography purifying, and the physical constant of product and productive rate see Table 2 sequence numbers 16.
Embodiment 6 preparations
2,3-epoxy wormwood artemisia propyl ether (IX) 2mmol is dissolved in 15ml acetone, is heated with stirring to 50 ℃ of reactions, and after reaction finished, aftertreatment was the same, and product is an amorphous solid, and its physical constant and productive rate see Table 2 sequence numbers 20.
The biologically active of the artemisinin derivative of table 1 nitrogen heterocycle
The artemisinin derivative of table 2 nitrogen heterocycle 
Claims (11)
1, the artemisinin derivative of a class nitrogen heterocycle is characterized in that the general formula of this class artemisinin derivative is as follows:
Het is for replacing or unsubstituted triazole species in the formula, and benzotriazole category, benzimidazoles, indoles substituting group can be carboxyls, ester group, acyl group, alkoxyl group, lower alkyl alkyl (C
1～C
3), hydroxyl, methylol
2, the preparation method of the artemisinin derivative of a class nitrogen heterocycle according to claim 1 is characterized in that: when this analog derivative is
During type, in the presence of an acidic catalyst, react generation by acetyl Dihydroartemisinin or trifluoroacetyl Dihydroartemisinin and nitrogen heterocyclic.
3, the preparation method of the artemisinin derivative of nitrogen heterocycle according to claim 1 is characterized in that: when this analog derivative is
The time, by Artemisitene and nitrogen heterocyclic having/no alkaline material in the presence of heating (30 ℃-solvent boiling point) reaction generate.
4, the preparation method of the artemisinin derivative of nitrogen heterocycle according to claim 1 is characterized in that: when this analog derivative is
The time, in the presence of dicyclohexylcarbodiimide (DCC), react generation by Dihydroartemisinin and the nitrogen heterocyclic that contains carboxyl.
5, the preparation method of the artemisinin derivative of nitrogen heterocycle according to claim 1 is characterized in that: when this analog derivative is
The time, in the presence of an acidic catalyst, react generation by Dihydroartemisinin and the nitrogen heterocyclic that contains hydroxyl.
6, the preparation method of the artemisinin derivative of nitrogen heterocycle according to claim 1 is characterized in that: when this analog derivative is
The time, in the presence of alkaline matter, react generation by Beta-bromo arteether and nitrogen heterocyclic.
7, the preparation method of the artemisinin derivative of nitrogen heterocycle according to claim 1 is characterized in that: when this analog derivative is
The time, by 2,3-epoxy wormwood artemisia propyl ether and nitrogen heterocyclic heat (30 ℃-solvent boiling point) reaction and generate in organic solvent.
8, the preparation method of the artemisinin derivative of a class nitrogen heterocycle according to claim 2 is characterized in that used an acidic catalyst is a boron trifluoride ethyl ether complex, trifluoroacetic acid, tosic acid.
9, the preparation method of the artemisinin derivative of a class nitrogen heterocycle according to claim 3 is characterized in that described alkaline matter is a salt of wormwood, triethylamine, sodium hydride.
10, the preparation method of the artemisinin derivative of a class nitrogen heterocycle according to claim 5 is characterized in that used an acidic catalyst is a boron trifluoride ethyl ether complex, iron trichloride, trifluoroacetic acid, tosic acid, hydrochloric acid.
11, the preparation method of the artemisinin derivative of a class nitrogen heterocycle according to claim 6 is characterized in that used alkaline matter is a salt of wormwood, triethylamine, pyridine.
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| CN99124012A CN1105722C (en) | 1999-11-12 | 1999-11-12 | Arteannuin derivant containing azacyclic radical and preparation process thereof |
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| CN99124012A CN1105722C (en) | 1999-11-12 | 1999-11-12 | Arteannuin derivant containing azacyclic radical and preparation process thereof |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003048167A1 (en) * | 2001-12-06 | 2003-06-12 | Ufc Limited | Trioxane derivatives |
| WO2007009388A1 (en) * | 2005-07-22 | 2007-01-25 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Water-soluble artemisinin derivatives, their preparation methods, the pharmaceutical compositions and the use thereof |
| WO2010032165A2 (en) * | 2008-09-19 | 2010-03-25 | North-West University | Prodrugs of artemisinin |
| CN102675337A (en) * | 2012-05-21 | 2012-09-19 | 中国人民解放军第三军医大学 | Dihydroarteannuin derivatives and application thereof |
| WO2012111025A3 (en) * | 2011-02-14 | 2012-10-11 | Council Of Scientific & Industrial Research | 1,2,3-triazole containing artemisinin compounds and process for preparation thereof |
| CN103664982A (en) * | 2013-12-06 | 2014-03-26 | 湖南科源生物制品有限公司 | Arteannuin analogs and preparation method thereof |
| CN103664985A (en) * | 2013-12-12 | 2014-03-26 | 华东理工大学 | Stereoselectivity preparation method of beta-hydroxy sweet wormwood herb alkyl ether |
| US8889730B2 (en) | 2012-04-10 | 2014-11-18 | Pfizer Inc. | Indole and indazole compounds that activate AMPK |
| CN105503898A (en) * | 2015-11-16 | 2016-04-20 | 中国人民解放军第三军医大学 | Nitrogen-heterocycle-containing artemisinin derivative and preparation method thereof |
| US9394285B2 (en) | 2013-03-15 | 2016-07-19 | Pfizer Inc. | Indole and indazole compounds that activate AMPK |
| CN110448551A (en) * | 2019-08-23 | 2019-11-15 | 西南大学 | Dihydroqinghaosu is preparing the application in anti-angiogenic medicaments |
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| CN102603768A (en) * | 2012-03-07 | 2012-07-25 | 广州牌牌生物科技有限公司 | Method of using macroporous resin to separate and purify artemisinin |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1049435C (en) * | 1994-11-09 | 2000-02-16 | 中国科学院上海药物研究所 | Artemisin derivative containg phenyl and hetero cyclic radical, and mfg. method thereof |
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| WO2007009388A1 (en) * | 2005-07-22 | 2007-01-25 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Water-soluble artemisinin derivatives, their preparation methods, the pharmaceutical compositions and the use thereof |
| US8129426B2 (en) | 2005-07-22 | 2012-03-06 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Water-soluble artemisinin derivatives, their preparation methods, the pharmaceutical compositions and the use thereof |
| WO2010032165A2 (en) * | 2008-09-19 | 2010-03-25 | North-West University | Prodrugs of artemisinin |
| WO2010032165A3 (en) * | 2008-09-19 | 2010-11-18 | North-West University | Prodrugs of artemisinin |
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| CN103664982A (en) * | 2013-12-06 | 2014-03-26 | 湖南科源生物制品有限公司 | Arteannuin analogs and preparation method thereof |
| CN103664985A (en) * | 2013-12-12 | 2014-03-26 | 华东理工大学 | Stereoselectivity preparation method of beta-hydroxy sweet wormwood herb alkyl ether |
| CN103664985B (en) * | 2013-12-12 | 2015-12-09 | 华东理工大学 | Stereoselective preparation method of β-hydroxyartemisinic ether |
| CN105503898A (en) * | 2015-11-16 | 2016-04-20 | 中国人民解放军第三军医大学 | Nitrogen-heterocycle-containing artemisinin derivative and preparation method thereof |
| CN110448551A (en) * | 2019-08-23 | 2019-11-15 | 西南大学 | Dihydroqinghaosu is preparing the application in anti-angiogenic medicaments |
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