CN101054383A - Bromodihydroartemisinin and preparation method thereof - Google Patents

Bromodihydroartemisinin and preparation method thereof Download PDF

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CN101054383A
CN101054383A CNA2006101441863A CN200610144186A CN101054383A CN 101054383 A CN101054383 A CN 101054383A CN A2006101441863 A CNA2006101441863 A CN A2006101441863A CN 200610144186 A CN200610144186 A CN 200610144186A CN 101054383 A CN101054383 A CN 101054383A
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bromine
bromodihydroartemisiand
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CN100480250C (en
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石雁羽
程志鹏
梁隆
祝华军
李明验
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Sichuan Kelun Pharmaceutical Co Ltd
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Abstract

The present invention relates to bromodihydro arteannuin and also provides its preparation method which comprise the following steps: dissolving dihydro arteannuin in protecting solvent of bromination reaction, adding bromine or bromide under 0-40 degree, stirring 10-200min, filtering, washing with bromine removing solution, Collecting organic layer, dehydrating the organic layer, then vacuum concentrating of organic layer. using normal hexane for recrystallization, obtaining final product. In vitro anticancer test prove that bromodihydro arteannuin possess good anticancer effect.

Description

Bromodihydroartemisiand and preparation method thereof
Technical field
The present invention relates to chemical field, specifically, relate to Bromodihydroartemisiand and preparation method thereof.
Background technology
Malignant tumour is one of serious disease that endangers at present people's life health.Show about 1,000 ten thousand people of the annual morbidity of whole world cancer, dead about 7,000,000 people according to The World Health Organization's statistical information.Tumour is a kind of complex system disease of general, and operation and radiotherapy can only solve local problem.Chemicals is being killed aspect the tumour cell, and suitable effect is arranged, but serious limitation is arranged: one, toxic side effect is too big, and many cancer patientss die from tumour, but die from the toxic side effect of chemicals.Two, resistance height.After the drug use several years, render a service obviously and descend, for reaching original effect, clinically have to strengthen dose, thereby produce stronger toxic side effect, scientist also has to research and develop one and another new drug.Seeking the anticancer active constituent that toxicity is low, curative effect is high from natural animal and plant just becomes one of focus of home and abroad scientific worker research in recent years, and wherein representative medicine is as taxol, camptothecine, golden larch, Squamocin A etc.But, present natural drug extract shortcoming also clearly: the firstth, action target spot is single; The secondth, the resistance problem still exists, and the 3rd is that toxic side effect is still very strong.
A breakthrough job is: the Lai Xiangli of Washington, DC university professor and assistant thereof confirm that in isolated experiment the Artemisinin that refines has the ability of magical kill cancer cell from the herbal medicine argy wormwood." it is not only effective, and selectivity is very strong.Cancer cells there is very high toxicity, but very little to Normocellular influence.”(US 55578637)
Artemisinin is the distinctive yellow Artemisinin of China, as medicinal existing history in 3000, as the specific medicament for the treatment of malaria the history in 32 years is also arranged in China.The mechanism that Artemisinin can be controlled malaria is, it can with the iron phase mutual effect of the intravital high density of plasmodium.When Artemisinin and iron phase chance, chemical reaction takes place thereupon, emit a large amount of charge atoms, the chemist is called " free group ".Free group makes it to be separated from each other and kills single plasmodium cell with the attack cells film.
Before 7 years, the bad professor of the U.S. begins to imagine same mechanism necessarily also can act on cancer: need a large amount of ironys ability repetition DNAs during the cancer cell division, so the irony content of cancer cells is more high than normal cell.Find that after deliberation cancer cells is than the high 5-15 of normal cell iron content times, high reaches 50 times, and the highest leukaemia cancer cell reaches 1000 times unexpectedly.Professor Lai claims: " it is not only effective, and selectivity is very strong.Cancer cells there is very high toxicity, but very little to Normocellular influence." it might become nontoxic efficient anticarcinogen.
This supposition has obtained extensive support in clinical experiment: some groups of breast cancer cells contacted with Transferrins,iron complexes with the normal breast cell, and after 8 hours, only remaining 25% cancer cells.After past 16 hours, nearly all cancer cells is all dead, and normal cell is unaffected.For example a dog that suffers from serious osteocarcinoma can not walk, and is accepting under the treatment that Artemisinin is aided with iron, just recovers fully in 5 days.
Artemisinin has following several big advantage as cancer therapy drug: curative effect is better, broad spectrum anticancer, and healing time is short; Specificity is strong, have no side effect; Not radiotherapy, not chemotherapy, the treatment no pain; Expense is low, also can be used as prophylactic.But its drug effect still chemicalses such as Zorubicin not as large usage quantity on the present market is strong, has limited application clinically.
Summary of the invention
The derivative that the purpose of this invention is to provide the Artemisinin that a kind of anticancer effect is good, toxicity is low.
In order to realize purpose of the present invention, the invention provides Bromodihydroartemisiand, its general structure is as follows:
Figure A20061014418600041
The present invention also provides a kind of preparation method of Bromodihydroartemisiand; comprise the steps: dihydroarteannuin added in the protection solvent of bromination reaction and dissolve; add bromine or bromide down in 0～40 ℃; stir after 10～200 minutes; filter; add and remove the bromine solutions washing; collected organic layer; organic layer dehydration back concentrating under reduced pressure; the normal hexane recrystallization; that is, wherein 0.1mol dihydroarteannuin adding 500～1000ml protection solvent and 10～150ml remove bromine solutions, and the 0.1mol dihydroarteannuin adds bromine or bromide 0.1～1mol.
Described protection solvent is preferably methylene dichloride, chloroform, tetracol phenixin, Nitromethane 99Min., dimethyl formamide, acetate or acetonitrile.
The described bromine solutions that removes is preferably sodium thiosulfate solution, sodium bicarbonate aqueous solution, aqueous sodium carbonate, sodium chloride aqueous solution or water.
Preferably add Manganse Dioxide, silico-aluminate or cuprous halide during bromination reaction; Or the tungsten lamp direct irradiation, to play catalytic effect.
Anticancer experiment in vitro shows that described Bromodihydroartemisiand has the good antitumor effect.
Description of drawings
Fig. 1 Bromodihydroartemisiand schematic arrangement.
Fig. 2 Bromodihydroartemisiand schematic arrangement.
The infrared spectrum of Fig. 3 Bromodihydroartemisiand.
The mass spectrogram of Fig. 4 Bromodihydroartemisiand.
Embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
9g dihydroarteannuin and 300ml acetonitrile mix, and under 40 ℃ of temperature, import bromine water 2ml, the bromine water conduit will go deep into the bottom of reactant, stir simultaneously, so that reactant fully contacts with bromine water, after 50 minutes, in reaction mixture, add the hypo solution of 9ml 10%, collect organic phase, add the sodium hydrogen carbonate solution of 60ml 10% again, add the ethyl acetate collected organic layer, organic layer with anhydrous sodium sulfate dehydration after concentrating under reduced pressure become crystallization, drying obtains Bromodihydroartemisiand, for the block crystallization of little Huang, get white, needle-shaped crystals with the normal hexane recrystallization.
IRv KBr max：1745，1115，831，881cm -1。The infrared spectrum of Bromodihydroartemisiand is seen Fig. 3, compares with the dihydroarteannuin infrared spectrum, bromine peaks such as many 995.6,690.5,649.8.Characteristic peak has: the oxo bridge peak value was 831 in Artemisinin was distinctive.
The mass-spectrometric data of Bromodihydroartemisiand sees Table 1.The mass spectrum report shows that the isotropic substance phenomenon is arranged, and bromine has isotropic substance, but former dihydroarteannuin does not have; Molecular ion peak m/z 363 conforms to the Bromodihydroartemisiand molecular weight.
The mass-spectrometric data of table 1 Bromodihydroartemisiand
M/z intensity relative intensity (%) m/z intensity relative intensity (%) m/z intensity relative intensity (%) m/z intensity relative intensity (%)
29 1126 1.72 30 54 .08 34 42 .06 37 65 .1
39 48 .07 41 998 1.52 42 97 .15 43 65535 100
44 1137 1.73 45 1404 2.14 46 1421 2.17 47 332 .51
53 378 .58 54 153 .23 55 5834 8.9 56 158 .24
57 2822 4.31 58 3081 4.7 59 1496 2.28 60 507 .77
61 291 .44 66 42 .06 67 2607 3.98 68 565 .86
69 6164 9.41 70 102 .16 71 17209 26.26 72 1417 2.16
73 81 .12 74 121 .18 76 72 .11 77 101 .15
79 2397 3.66 80 10733 16.38 81 11505 17.56 82 9367 14.29
83 4530 6.91 84 2468 3.77 85 2944 4.49 86 167 .25
87 337 .51 91 932 1.42 92 134 .2 93 10251 15.64
94 1742 2.66 95 10107 15.42 96 1156 1.76 97 6798 10.37
99 741 1.11 99 1716 2.62 100 407 .62 101 330 .5
103 69 .11 104 73 .11 105 6284 9.59 106 866 1.32
107 10181 15.54 108 1468 2.24 109 8669 13.23 110 1774 2.71
111 3641 5.56 112 635 .97 113 2661 4.06 114 188 .29
115 244 .37 116 88 .13 117 425 .65 118 84 .13
119 5719 8.73 120 1236 1.89 121 31587 48.2 122 4790 7.31
123 5460 8.33 124 1760 2.69 125 3540 5.4 126 396 .6
127 431 .66 128 62 .09 129 638 .97 130 96 .15
131 2546 3.88 132 1003 1.53 133 12822 19.57 134 1858 2.84
135 7732 11.8 136 1204 1.84 137 7154 10.92 138 2301 3.51
139 3471 5.3 140 315 .48 141 481 .73 142 171 .26
143 525 .8 144 298 .45 145 1308 2 146 423 .65
147 4093 6.25 148 919 1.4 149 8480 12.94 150 2556 3.9
151 8104 12.37 152 1038 1.58 153 483 .74 154 97 .15
155 467 .71 156 493 .75 157 928 1.42 158 817 1.25
159 2317 3.54 160 2407 3.67 161 11117 16.96 162 5379 8.21
163 8433 12.87 164 1805 2.75 165 9586 14.63 166 1687 2.57
167 3805 5.81 168 168 .26 169 214 .33 170 127 .19
171 325 .5 172 294 .15 173 2124 3.24 171 752 1.15
175 3854 5.88 176 647 .99 177 4799 7.32 178 12161 18.56
179 9506 14.51 180 1638 2.5 181 1125 1.72 182 137 .21
183 486 .71 184 96 .15 185 485 .74 186 366 .56
187 1268 1.93 188 274 .42 189 2196 3.35 190 698 1.07
191 1915 2.92 192 5091 7.77 193 8844 13.51 194 3286 5.01
195 4068 6.21 196 648 .99 197 136 .21 198 152 .23
199 421 .64 200 484 .74 201 228 .35 202 2160 3.3
203 884 1.35 204 1655 2.53 205 469 .72 206 1706 2.6
207 430 .66 208 4469 6.82 209 1659 2.53 210 5103 7.79
211 1196 1.82 212 835 1.27 213 420 .64 214 522 .8
215 444 .68 216 939 1.43 217 620 .95 218 1801 2.75
219 4296 6.56 220 8135 12.41 221 1278 1.95 222 6697 10.22
223 958 1.46 224 724 1.1 225 296 .45 226 214 .33
227 334 .51 228 354 .54 229 4062 6.2 230 779 1.19
231 3816 5.82 232 833 1.27 233 11411 17.41 234 2249 3.43
235 1877 2.86 236 752 1.15 237 3421 5.22 238 736 1.12
239 252 .38 240 100 .15 241 530 .81 242 92 .14
243 588 .9 244 351 .54 245 179 .27 246 528 .81
247 1174 1.79 248 513 .78 249 726 1.11 250 2767 4.22
251 1037 1.58 252 157 .24 253 4585 7 254 675 1.03
255 181 .28 256 283 .43 257 306 .47 258 302 .46
259 2028 3.09 260 238 .36 261 1374 2.1 262 225 .34
263 43 .07 264 177 .27 265 220 .34 266 1235 1.88
267 168 .26 268 56 .09 269 468 .71 270 51 .08
271 394 .6 272 21773 33.22 273 3458 5.28 274 19774 30.17
275 3268 4.99 276 399 .61 279 66 .1 280 298 .45
281 149 .23 282 255 .39 283 155 .24 284 108 .16
286 59 .09 287 1063 1.62 288 102 .16 289 696 1.06
290 156 .24 291 134 .2 292 156 .24 293 160 .24
291 286 .44 295 207 .32 296 99 .15 297 150 .21
298 108 .16 299 78 .12 300 149 .23 301 648 .99
302 201 .31 303 552 .84 304 444 .68 305 93 .14
307 79 .12 308 149 .23 309 100 .15 310 93 .14
312 83 .13 313 745 1.14 314 168 .26 315 614 .94
316 904 1.38 317 198 .3 318 468 .71 319 192 .29
322 45 .07 325 56 .09 326 166 .25 327 302 .46
328 399 .61 329 272 .42 330 4301 6.56 331 540 .82
332 3956 6.04 333 572 .87 334 73 .11
Chemical name be 6-Br-(3R, 5aS, 6R, 8aS, 9R, 12S, 12aR)-octahydro-3-methyl-3,6,9 trimethylammoniums-3,12-bridging oxygen-12H-pyrans is [4,3-j]-1 also, 2-benzo two thiophenes are put down-10 (3H) alcohol.
No uv-absorbing.Be dissolved in chloroform, acetone, ethyl acetate and dissolve in ethanol, ether, be slightly soluble in cold sherwood oil and benzene, water insoluble.
Molecular formula: C15H24O5Br, molecular weight: 363
Colourless needle crystal, fusing point: 102 ℃ (decomposition).
Bromine content is 22.54% in the oxygen flask combustion method mensuration Bromodihydroartemisiand, conforms to the Bromodihydroartemisiand bromine content.
Bromodihydroartemisiand monocrystalline-X diffracting spectrum has confirmed described structure, and its data see Table 2～8.
Table 2. crystallography and crystalline structure refine data Crystal data and structure refinement
Empirical formula C 15H 23O 5Br
Formula weight Temperature Wavelength Crystal system，space group Unit cell dimensions Volume Z，Calculated density Absorption coefficient F(000) Crystal size Theta range for data collection Limiting indices Reflections collected/unique Completeness to theta＝27.47 Absorption correction Max.and min.transmission 363.24 153(2)K 0.71073A Monoclinic，P2(1) a＝9.9163(4)A alpha＝90deg. b＝6.1621(4)A beta＝92.347(1)deg. c＝12.7071(5)A gamma＝90deg. 775.82(7)A^3 2.1.555Mg/m^3 2.668mm^-1 376 0.64×0.30×0.25mm 3.21to 27.47deg. -12＜＝h＜＝12，-8＜＝k＜＝7，-16＜＝1＜＝16 7512/3278[R(int)＝0.0629] 99.8％ Empirical 0.5552 and 0.2800
Refinement method Data/restraints/parameters Goodness-of-fit on F^2 Final R indices[I＞2sigma(I)] R indices(all data) Absolute structure parameter Extinction coefficient Largest diff.peak and hole Full-matrix least-squares on F^2 3278/1/195 0.951 R1＝0.0318，wR2＝0.0748 R1＝0.0329，wR2＝0.0755 0.009(7) 0.036(4) 0.438and-0.703e.A^-3
Table 3 non-hydrogen atom coordinate and effective homogeneity thermal parameter Atomic coordinates (x 10^4) andequivalent isotropic displacement parameters thereof (A^2 * 10^3).
U(eq)is defined as one third of the trace of the orthogonalized Uij tensor.
U(eq) x y z
Br O(1) O(2) O(3) O(4) O(5) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) 7554(1) 2706(2) 3400(2) 1743(2) 3953(2) 6011(2) 2350(3) 893(2) 648(2) 1463(2) 2947(2) 3379(2) 4840(2) 4884(3) 3912(3) 2480(3) 5811(2) 5204(2) 6209(3) 1501(3) 747(3) 2868(1) 8059(3) 7125(2) 4845(3) 4486(2) 3777(3) 4142(4) 4627(4) 6751(4) 6968(4) 3958(4) 4747(3) 4055(4) 1695(4) 1347(4) 1789(4) 4409(4) 3400(3) 6789(4) 1316(5) 8277(4) 7356(1) 6749(1) 7690(1) 6151(1) 5819(1) 5204(1) 8518(2) 8141(2) 7553(2) 6559(2) 6553(2) 7668(2) 7984(2) 8409(2) 9283(2) 8913(2) 7061(2) 6045(2) 6902(2) 9785(2) 5700(2) 28(1) 19(1) 17(1) 20(1) 18(1) 27(1) 18(1) 22(1) 22(1) 20(1) 15(1) 14(1) 16(1) 21(1) 23(1) 23(1) 17(1) 18(1) 22(1) 36(1) 29(1)
Table 4. bond distance and bond angle Bond lengths[A] and angles[deg]
Br-C(11) O(1)-C(4) O(1)-O(2) O(2)-C(6) O(3)-C(5) O(3)-C(4) O(4)-C(12) O(4)-C(5) O(5)-C(12) O(5)-H(5O) C(1)-C(2) C(1)-C(10) C(1)-C(6) C(1)-H(1) C(2)-C(3) C(2)-H(2A) C(2)-H(2B) C(3)-C(4) C(3)-H(3A) C(3)-H(3B) C(4)-C(15) C(5)-C(6) C(5)-H(5) C(6)-C(7) C(7)-C(8) C(7)-C(11) C(7)-H(7) C(8)-C(9) C(8)-H(8A) C(8)-H(8B) C(9)-C(10) C(9)-H(9A) C(9)-H(9B) C(10)-C(14) C(10)-H(10) C(11)-C(12) C(11)-C(13) C(12)-H(12) C(13)-H(13A) 1.995(2) 1.416(3) 1.473(2) 1.466(2) 1.391(3) 1.439(3) 1.429(3) 1.431(2) 1.381(2) 0.8400 1.533(4) 1.538(3) 1.561(3) 1.0000 1.522(3) 0.9900 0.9900 1.532(3) 0.9900 0.9900 1.512(3) 1.543(3) 1.0000 1.547(3) 1.551(3) 1.563(3) 1.0000 1.516(3) 0.9900 0.9900 1.503(4) 0.9900 0.9900 1.531(3) 1.0000 1.533(3) 1.534(3) 1.0000 0.9800
C(13)-H(13B) C(13)-H(13C) C(14)-H(14A) C(14)-H(14B) C(14)-H(14C) C(15)-H(15A) C(15)-H(15B) C(15)-H(15C) C(4)-O(1)-O(2) C(6)-O(2)-O(1) C(5)-O(3)-C(4) C(12)-O(4)-C(5) C(12)-O(5)-H(5O) C(2)-C(1)-C(10) C(2)-C(1)-C(6) C(10)-C(1)-C(6) C(2)-C(1)-H(1) C(10)-C(1)-H(1) C(6)-C(1)-H(1) C(3)-C(2)-C(1) C(3)-C(2)-H(2A) C(1)-C(2)-H(2A) C(3)-C(2)-H(2B) C(1)-C(2)-H(2B) H(2A)-C(2)-H(2B) C(2)-C(3)-C(4) C(2)-C(3)-H(3A) C(4)-C(3)-H(3A) C(2)-C(3)-H(3B) C(4)-C(3)-H(3B) H(3A)-C(3)-H(3B) O(1)-C(4)-O(3) O(1)-C(4)-C(15) O(3)-C(4)-C(15) O(1)-C(4)-C(3) O(3)-C(4)-C(3) C(15)-C(4)-C(3) O(3)-C(5)-O(4) O(3)-C(5)-C(6) O(4)-C(5)-C(6) O(3)-C(5)-H(5) O(4)-C(5)-H(5) C(6)-C(5)-H(5) O(2)-C(6)-C(5) 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 109.11(15) 111.68(15) 113.57(17) 112.66(15) 109.5 110.5(2) 111.87(18) 113.7(2) 106.7 106.7 106.7 116.8(2) 108.1 108.1 108.1 108.1 107.3 113.63(19) 108.8 108.8 108.8 108.8 107.7 108.27(19) 104.44(19) 108.43(18) 112.72(17) 109.51(18) 113.2(2) 106.40(16) 114.58(17) 110.62(17) 108.4 108.4 108.4 109.62(16)
O(2)-C(6)-C(7) C(5)-C(6)-C(7) O(2)-C(6)-C(1) C(5)-C(6)-C(1) C(7)-C(6)-C(1) C(6)-C(7)-C(8) C(6)-C(7)-C(11) C(8)-C(7)-C(11) C(6)-C(7)-H(7) C(8)-C(7)-H(7) C(11)-C(7)-H(7) C(9)-C(8)-C(7) C(9)-C(8)-H(8A) C(7)-C(8)-H(8A) C(9)-C(8)-H(8B) C(7)-C(8)-H(8B) H(8A)-C(8)-H(8B) C(10)-C(9)-C(8) C(10)-C(9)-H(9A) C(8)-C(9)-H(9A) C(10)-C(9)-H(9B) C(8)-C(9)-H(9B) H(9A)-C(9)-H(9B) C(9)-C(10)-C(14) C(9)-C(10)-C(1) C(14)-C(10)-C(1) C(9)-C(10)-H(10) C(14)-C(10)-H(10) C(1)-C(10)-H(10) C(12)-C(11)-C(13) C(12)-C(11)-C(7) C(13)-C(11)-C(7) C(12)-C(11)-Br C(13)-C(11)-Br C(7)-C(11)-Br O(5)-C(12)-O(4) O(5)-C(12)-C(11) O(4)-C(12)-C(11) O(5)-C(12)-H(12) O(4)-C(12)-H(12) C(11)-C(12)-H(12) C(11)-C(13)-H(13A) C(11)-C(13)-H(13B) H(13A)-C(13)-H(13B) 104.96(17) 111.95(16) 103.58(17) 113.27(17) 112.74(17) 111.2(2) 111.42(17) 112.49(18) 107.1 107.1 107.1 112.20(19) 109.2 109.2 109.2 109.2 107.9 111.48(19) 109.3 109.3 109.3 109.3 108.0 111.0(2) 109.8(2) 111.7(2) 108.1 108.1 108.1 111.80(17) 110.05(17) 113.71(17) 105.80(14) 104.72(16) 110.34(14) 106.93(16) 111.32(18) 106.66(16) 110.6 110.6 110.6 109.5 109.5 109.5
C(11)-C(13)-H(13C) H(13A)-C(13)-H(13C) H(13B)-C(13)-H(13C) C(10)-C(14)-H(14A) C(10)-C(14)-H(14B) H(14A)-C(14)-H(14B) C(10)-C(14)-H(14C) H(14A)-C(14)-H(14C) H(14B)-C(14)-H(14C) C(4)-C(15)-H(15A) C(4)-C(15)-H(15B) H(15A)-C(15)-H(15B) C(4)-C(15)-H(15C) H(15A)-C(15)-H(15C) H(15B)-C(15)-H(15C) 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5
Symmetry transformations used to generate equivalent atoms：
Table 5 anisotropic parameters Anisotropic displacement parameters (the .The anisotropic displacement factor exponent takes the form:-2pi^2[h^2a*^2U11+...+2h ka*b*U12 of A^2 * 10^3)]
U11 U22 U33 U23 U13 U12
Br O(1) O(2) O(3) O(4) O(5) C(1) C(2) C(3) C(4) C(5) C(6) C(7) 15(1) 19(1) 21(1) 17(1) 18(1) 26(1) 17(1) 17(1) 15(1) 18(1) 14(1) 15(1) 17(1) 31(1) 18(1) 13(1) 22(1) 22(1) 31(1) 20(1) 27(1) 22(1) 19(1) 17(1) 13(1) 16(1) 38(1) 20(1) 17(1) 20(1) 13(1) 24(1) 16(1) 22(1) 28(1) 23(1) 15(1) 14(1) 15(1) 0(1) 4(1) 0(1) -4(1) 0(1) -7(1) -4(1) -1(1) -2(1) -2(1) -1(1) -3(1) -3(1) 0(1) 1(1) -1(1) -2(1) 4(1) 11(1) 7(1) 7(1) 5(1) 2(1) 1(1) 4(1) 1(1) 3(1) 0(1) -1(1) 1(1) 0(1) 1(1) 0(1) -2(1) 0(1) 2(1) 0(1) -3(1) -2(1)
C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) 21(1) 31(2) 27(1) 13(1) 19(1) 20(1) 40(2) 28(1) 18(1) 22(1) 23(1) 17(1) 18(1) 20(1) 38(2) 30(2) 24(1) 17(1) 19(1) 21(1) 18(1) 25(1) 33(1) 29(1) 2(1) 5(1) 2(1) -3(1) -3(1) -3(1) 11(1) 5(1) 1(1) 2(1) 8(1) 1(1) 4(1) 5(1) 17(1) -1(1) 1(1) -1(1) -4(1) 0(1) 1(1) -5(1) -2(1) 6(1)
Table 6. hydrogen coordinate and isotropy thermal parameter Hydrogen coordinates thereof (* 10^4) and isotropicdisplacement parameters (A^2 * 10^3).
x y z U(eq)
H(5O) H(1) H(2A) H(2B) H(3A) H(3B) H(5) H(7) H(8A) H(8B) H(9A) H(9B) H(10) H(12) H(13A) H(13B) H(13C) H(14A) 6047 2553 578 324 882 -325 2847 5159 4656 5812 3987 4159 2252 5054 5410 6887 6585 1614 2651 5101 3424 4620 7972 6868 2344 5023 681 1358 -169 2320 799 1808 7628 6879 7381 2411 4834 9139 7676 8763 8033 7353 6572 8575 7824 8676 9537 9880 8308 6140 6674 6364 7567 10341 32 21 26 26 26 26 18 19 25 25 28 28 28 22 26 26 26 44
H(14B) H(14C) H(15A) H(15B) H(15C) 1691 572 1337 522 -84 -126 1358 8437 9714 7528 10082 9492 5105 5972 5464 44 44 35 35 35
Table 7. torsional angle data Torsion angles[deg].
C(4)-O(1)-O(2)-C(6) C(10)-C(1)-C(2)-C(3) C(6)-C(1)-C(2)-C(3) C(1)-C(2)-C(3)-C(4) O(2)-O(1)-C(4)-O(3) O(2)-O(1)-C(4)-C(15) O(2)-O(1)-C(4)-C(3) C(5)-O(3)-C(4)-O(1) C(5)-O(3)-C(4)-C(15) C(5)-O(3)-C(4)-C(3) C(2)-C(3)-C(4)-O(1) C(2)-C(3)-C(4)-O(3) C(2)-C(3)-C(4)-C(15) C(4)-O(3)-C(5)-O(4) C(4)-O(3)-C(5)-C(6) C(12)-O(4)-C(5)-O(3) C(12)-O(4)-C(5)-C(6) O(1)-O(2)-C(6)-C(5) O(1)-O(2)-C(6)-C(7) O(1)-O(2)-C(6)-C(1) O(3)-C(5)-C(6)-O(2) O(4)-C(5)-C(6)-O(2) O(3)-C(5)-C(6)-C(7) O(4)-C(5)-C(6)-C(7) 46.0(2) -169.74(18) -41.9(3) 58.4(3) -73.45(18) 171.17(15) 47.8(2) 33.0(2) 145.80(19) -90.2(2) -93.4(2) 27.2(3) 148.3(2) -94.27(19) 28.3(2) -171.03(16) 63.9(2) 13.7(2) 134.11(15) -107.45(16) -53.1(2) 67.1(2) -169.19(18) -48.9(2)
O(3)-C(5)-C(6)-C(1) O(4)-C(5)-C(6)-C(1) C(2)-C(1)-C(6)-O(2) C(10)-C(1)-C(6)-O(2) C(2)-C(1)-C(6)-C(5) C(10)-C(1)-C(6)-C(5) C(2)-C(1)-C(6)-C(7) C(10)-C(1)-C(6)-C(7) O(2)-C(6)-C(7)-C(8) C(5)-C(6)-C(7)-C(8) C(1)-C(6)-C(7)-C(8) O(2)-C(6)-C(7)-C(11) C(5)-C(6)-C(7)-C(11) C(1)-C(6)-C(7)-C(11) C(6)-C(7)-C(8)-C(9) C(11)-C(7)-C(8)-C(9) C(7)-C(8)-C(9)-C(10) C(8)-C(9)-C(10)-C(14) C(8)-C(9)-C(10)-C(1) C(2)-C(1)-C(10)-C(9) C(6)-C(1)-C(10)-C(9) C(2)-C(1)-C(10)-C(14) C(6)-C(1)-C(10)-C(14) C(6)-C(7)-C(11)-C(12) C(8)-C(7)-C(11)-C(12) C(6)-C(7)-C(11)-C(13) C(8)-C(7)-C(11)-C(13) C(6)-C(7)-C(11)-Br C(8)-C(7)-C(11)-Br C(5)-O(4)-C(12)-O(5) C(5)-O(4)-C(12)-C(11) C(13)-C(11)-C(12)-O(5) C(7)-C(11)-C(12)-O(5) 62.0(3) -177.77(17) 73.0(2) -160.88(19) -45.7(3) 80.5(2) -174.10(18) -48.0(2) 158.35(15) -82.80(19) 46.3(2) -75.30(19) 43.5(2) 172.65(17) -52.6(2) -178.40(19) 60.1(3) 177.0(2) -59.1(2) -179.75(18) 53.4(2) -56.2(2) 176.9(2) -49.9(2) 75.7(2) 76.4(2) -158.0(2) -166.33(14) -40.7(2) 171.11(16) -69.7(2) 49.8(2) 177.17(18)
Br-C(11)-C(12)-O(5) C(13)-C(11)-C(12)-O(4) C(7)-C(11)-C(12)-O(4) Br-C(11)-C(12)-O(4) -63.63(18) -66.5(2) 60.9(2) -179.93(13)
Symmetry transformations used to generate equivalent atoms：
Table 8. hydrogen bond data Hydrogen bonds[A and deg.].
D-H...A d(D-H) d(H...A) d(D...A) ＜(DHA)
O(5)-H(5O)...O(4)#1 0.84 2.12 2.947(2) 168.6
Symmetry transformations used to generate equivalent atoms：#1-x+1，y-1/2，-z+1
Embodiment 2
1.5g dihydroarteannuin and 50ml dimethyl formamide mix, and import bromine 0.3ml down in 25 ℃, after 5 minutes, the hypo solution that in reaction mixture, adds 15ml 10%, collect organic phase, add the sodium hydrogen carbonate solution of 30ml 10% again, add the ethyl acetate collected organic layer, organic layer with anhydrous sodium sulfate dehydration after concentrating under reduced pressure become crystallization, crystal washs with normal hexane, leaches crystallization, drying, obtain Bromodihydroartemisiand, be the block crystallization of little Huang.Get white, needle-shaped crystals with the normal hexane recrystallization.
Embodiment 3
1.5g dihydroarteannuin and 50ml acetate mix, and in the common 0.3ml of 0 ℃ of following bromine water, stir stirring reaction after 200 minutes, add entry and stir debrominate, the collected organic layer concentrating under reduced pressure becomes crystallization, crystal washs with normal hexane, leach crystallization, drying obtains Bromodihydroartemisiand, drying gets white, needle-shaped crystals.
Embodiment 4
Reactor N 2Drying adds 0.1mol dihydroarteannuin and 1000ml chloroform, and dissolving adds 15g MnO 2, stir evenly, and under 30 ℃ of temperature, import liquid bromine 0.1mol, stir simultaneously, after 60 minutes, the filtering reaction thing, the sodium thiosulfate solution that adds 1000ml 10% in filtrate washs collected organic layer.Organic layer with anhydrous sodium sulfate dehydration after concentrating under reduced pressure become white crystals, crystal washs with normal hexane, leaches crystallization, drying obtains Bromodihydroartemisiand, is white, needle-shaped crystals.
Embodiment 5
Reactor N 2Drying adds 0.1mol dihydroarteannuin and 1000ml tetracol phenixin, dissolving; Add 14g MnO2, stir evenly.And under 20 ℃ of temperature, import the liquid bromine, carry out stirring reaction simultaneously.After 200 minutes, the filtering reaction thing.Filtrate is taken off residual bromine, collected organic layer with the water agitator treating of 3000ml.Organic layer with anhydrous sodium sulfate dehydration after concentrating under reduced pressure become white crystals, crystal washs with normal hexane, leaches crystallization, drying obtains Bromodihydroartemisiand, is white, needle-shaped crystals.
Embodiment 6
Reactor N 2Drying adds 0.1mol dihydroarteannuin and 1500ml acetonitrile, dissolving.Under 30 ℃, import liquid bromine 0.15mol, stir simultaneously.Under the photochemical catalysis of 1000W halogen lamp, reacted 6 hours.The sodium thiosulfate solution washing that in reactant, adds 30ml10%, collected organic layer.The sodium hydrogen carbonate solution washing that adds 100ml10% again, collected organic layer.Organic layer with anhydrous sodium sulfate dehydration after concentrating under reduced pressure become white crystals, crystal washs with normal hexane, leaches crystallization, drying obtains Bromodihydroartemisiand, is white, needle-shaped crystals.
Embodiment 7
15g dihydroarteannuin and 500ml phosgene mix, and dissolving adds 14g MnO 2, stir evenly.And under 40 ℃ of temperature, import liquid bromine 3ml altogether, stir simultaneously.After 90 minutes, the filtering reaction thing, filtrate is refining once with chloroform again.Become white crystals with concentrating under reduced pressure behind the anhydrous sodium sulfate dehydration, crystal washs with normal hexane, leaches crystallization, and drying obtains Bromodihydroartemisiand, is white, needle-shaped crystals.
Embodiment 8
Container fills N 2After, add 15g dihydroarteannuin and 500ml chloroform and mix, add aluminosilicate catalyst, and under about 30 ℃ of temperature, import the miscellany of bromine and air, stir simultaneously, after 200 minutes, filter, filtrate decompression distill crude product.Add chloroform again, become the white, needle-shaped crystals of Bromodihydroartemisiand with concentrating under reduced pressure behind the anhydrous sodium sulfate dehydration.
The research of experimental example Bromodihydroartemisiand anti tumor activity in vitro
1. material
1.1 cell strain
Human hepatoma cell strain-HepG2 is available from U.S. ATCC;
Human lung carcinoma cell line-A549 is available from Shanghai cell institute of the Chinese Academy of Sciences.
1.2 substratum
Dulbecco’s Modified Eagle Medium(DMEM)：GIBCOBRL，Cat
NO：12100-038，
RPMI 1640：GIBCOBRL，Cat NO：430-1800EB，
Fetal Bovines Serum：Hyclone，Cat NO：CH30160.03
GIBCOBRL，Cat NO：27250-018。
1.3 be subjected to test product
Bromodihydroartemisiand: white powder, molecular-weight average 320.
Assistant agent: white powder, continent Rong Dong, lot number 20041116.
Transfer factor: white crystalline powder, molecular-weight average 79000 is available from sigma.
2. method
2.1 cell cultures
HepG2 and A549 cell routine respectively are incubated among 10%FBS/DMEM and the 10%FBS/RPMI 1640, change liquid in 2～3 days.
2.2 medicine preparation
Pipette transfer factor, assistant agent, Bromodihydroartemisiand with 100,000/electronic balance precision, wherein transfer factor, assistant agent directly are dissolved in the degerming of cell culture medium after-filtration, transfer factor C o=17.6nM, assistant agent C o=5mg/L; And after Bromodihydroartemisiand is dissolved in DMSO earlier, be diluted to desired concn with cell culture medium again, filtration sterilization, C o=6.4mg/L.Prepared than dilution by low by the different concns of test product.
All in facing with preceding fresh preparation, every hole adds 50 μ L to the solution of transfer factor, assistant agent, Bromodihydroartemisiand.
2.3 cytotoxicity test method
HepG2 that takes the logarithm vegetative period and A549 cell are after the ordinary method digestion, with 8 * 10 3Density be inoculated in 24 porocyte culture plates.Behind the inoculation 24h, add the assistant agent of transfer factor, corresponding dosage respectively respectively by table 1,2, hatch 8h.The Bromodihydroartemisiand that adds each dosage, drug effect are after 72 hours, and the ordinary method cell counting the results are shown in Table 9,10.
3. result
Table 9 Bromodihydroartemisiand is to human hepatoma cell strain-HepG2 anti tumor activity in vitro
Group Sample number Drug dose Cells survival rate (%)
Transfer factor (nM) Assistant agent (mg/L) Bromodihydroartemisiand (nM)
Blank 4 - - - 100.0±9.1
Transfer factor 4 880 0.25 - 44.7±5.6
Bromodihydroartemisiand 4 880 0.25 1000 23.3±5.3
4 880 0.05 200 32.7±14.1
4 880 0.01 40 31.3±10.6
4 880 0.002 8 41.6±3.6
Annotate: assistant agent: Bromodihydroartemisiand=250ng: 1nM
Table 10 Bromodihydroartemisiand is to human lung carcinoma cell line-A549 anti tumor activity in vitro
Group Sample number Drug dose Cells survival rate (%)
Transfer factor (nM) Assistant agent (mg/L) Bromodihydroartemisiand (nM)
Blank 4 - - - 100.0±14.9
Transfer factor 4 880 0.25 - 59.0±9.8
Bromodihydroartemisiand 4 880 0.25 1000 17.4±7.5
4 880 0.025 100 39.0±5.2
4 880 0.0025 10 58.2±5.2
4 880 0.00025 1 59.0±13.0
Annotate: assistant agent: Bromodihydroartemisiand=250ng: 1nM
This experiment shows that Bromodihydroartemisiand all has very obvious in-vitro anti-tumor activity to human hepatoma cell strain-HepG2 and human lung carcinoma cell line-A549, to the IC of HepG2 and A549 cell 50Difference＜8nM and 31.6nM.

Claims (6)

1, Bromodihydroartemisiand, its structural formula is as follows:
Figure A2006101441860002C1
2, a kind of preparation method of Bromodihydroartemisiand; comprise the steps: dihydroarteannuin added in the protection solvent of bromination reaction and dissolve, add bromine or bromide down in 0～40 ℃, stir after 10～200 minutes; filter; add and remove the bromine solutions washing, collected organic layer, organic layer dehydration back concentrating under reduced pressure; the normal hexane recrystallization; that is, wherein 0.1mol dihydroarteannuin adding 500～1000ml protection solvent and 10～150ml remove bromine solutions, and bromine or bromide add-on are 0.1～1mol.
3, preparation method as claimed in claim 2 is characterized in that, described protection solvent is methylene dichloride, chloroform, tetracol phenixin, Nitromethane 99Min., dimethyl formamide, acetate or acetonitrile.
4, preparation method as claimed in claim 2 is characterized in that, the described bromine solutions that removes is sodium thiosulfate solution, sodium bicarbonate aqueous solution, aqueous sodium carbonate, sodium chloride aqueous solution or water.
5, as the arbitrary described preparation method of claim 2～4, it is characterized in that, add Manganse Dioxide, silico-aluminate or cuprous bromide during bromination reaction.
6, as the arbitrary described preparation method of claim 2～4, it is characterized in that tungsten lamp direct irradiation during bromination reaction.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102727522A (en) * 2011-04-08 2012-10-17 石雁羽 Compound double-release capsule preparation composed of bromodihydroartemisinin and Fe<2+> agent
CN104086560A (en) * 2014-07-03 2014-10-08 唐心建 Halogenated artemisinin mother nucleus, halogenated artemisinin derivatives, halogenated dihydroartemisinin and halogenated decarbonylation artemisinin and medical use thereof
CN107011356A (en) * 2017-06-08 2017-08-04 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 A kind of synthetic method of AHA
TWI685345B (en) * 2018-08-29 2020-02-21 王俊傑 Artemisia extracts for inhibiting lung cancer cells

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CN1295231C (en) * 2005-01-12 2007-01-17 四川科伦药业股份有限公司 Bromo-dihydroartemisine

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102727522A (en) * 2011-04-08 2012-10-17 石雁羽 Compound double-release capsule preparation composed of bromodihydroartemisinin and Fe<2+> agent
CN102727522B (en) * 2011-04-08 2013-09-25 石雁羽 Compound double-release capsule preparation composed of bromodihydroartemisinin and Fe<2+> agent
CN104086560A (en) * 2014-07-03 2014-10-08 唐心建 Halogenated artemisinin mother nucleus, halogenated artemisinin derivatives, halogenated dihydroartemisinin and halogenated decarbonylation artemisinin and medical use thereof
CN107011356A (en) * 2017-06-08 2017-08-04 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 A kind of synthetic method of AHA
TWI685345B (en) * 2018-08-29 2020-02-21 王俊傑 Artemisia extracts for inhibiting lung cancer cells

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