CN111704645B - Application of descimidine reagent in synthesis of Ocotillol type saponin derivative key intermediate - Google Patents
Application of descimidine reagent in synthesis of Ocotillol type saponin derivative key intermediate Download PDFInfo
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- CN111704645B CN111704645B CN202010367823.3A CN202010367823A CN111704645B CN 111704645 B CN111704645 B CN 111704645B CN 202010367823 A CN202010367823 A CN 202010367823A CN 111704645 B CN111704645 B CN 111704645B
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- RQBNSDSKUAGBOI-UHFFFAOYSA-N 17-[5-(2-hydroxypropan-2-yl)-2-methyloxolan-2-yl]-4,4,8,10,14-pentamethyl-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-ol Chemical compound O1C(C(C)(O)C)CCC1(C)C1C(CCC2C3(CCC4C(C)(C)C(O)CCC42C)C)C3(C)CC1 RQBNSDSKUAGBOI-UHFFFAOYSA-N 0.000 title claims description 24
- RQBNSDSKUAGBOI-GGWQMWHBSA-N Ocotillol Natural products O1[C@@H](C(C)(O)C)CC[C@@]1(C)[C@@H]1[C@@H](CC[C@H]2[C@]3(CC[C@H]4C(C)(C)[C@@H](O)CC[C@@]42C)C)[C@@]3(C)CC1 RQBNSDSKUAGBOI-GGWQMWHBSA-N 0.000 title claims description 23
- RQBNSDSKUAGBOI-VVGBCXFDSA-N Ocotillol II Natural products O1[C@H](C(C)(O)C)CC[C@@]1(C)[C@@H]1[C@@H](CC[C@H]2[C@]3(CC[C@H]4C(C)(C)[C@@H](O)CC[C@@]42C)C)[C@@]3(C)CC1 RQBNSDSKUAGBOI-VVGBCXFDSA-N 0.000 title claims description 23
- 239000003153 chemical reaction reagent Substances 0.000 title claims description 23
- FHICGHSMIPIAPL-HDYAAECPSA-N [2-[3-[6-[3-[(5R,6aS,6bR,12aR)-10-[6-[2-[2-[4,5-dihydroxy-3-(3,4,5-trihydroxyoxan-2-yl)oxyoxan-2-yl]ethoxy]ethyl]-3,4,5-trihydroxyoxan-2-yl]oxy-5-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydropicene-4a-carbonyl]peroxypropyl]-5-[[5-[8-[3,5-dihydroxy-4-(3,4,5-trihydroxyoxan-2-yl)oxyoxan-2-yl]octoxy]-3,4-dihydroxy-6-methyloxan-2-yl]methoxy]-3,4-dihydroxyoxan-2-yl]propoxymethyl]-5-hydroxy-3-[(6S)-6-hydroxy-2,6-dimethylocta-2,7-dienoyl]oxy-6-methyloxan-4-yl] (2E,6S)-6-hydroxy-2-(hydroxymethyl)-6-methylocta-2,7-dienoate Chemical compound C=C[C@@](C)(O)CCC=C(C)C(=O)OC1C(OC(=O)C(\CO)=C\CC[C@](C)(O)C=C)C(O)C(C)OC1COCCCC1C(O)C(O)C(OCC2C(C(O)C(OCCCCCCCCC3C(C(OC4C(C(O)C(O)CO4)O)C(O)CO3)O)C(C)O2)O)C(CCCOOC(=O)C23C(CC(C)(C)CC2)C=2[C@@]([C@]4(C)CCC5C(C)(C)C(OC6C(C(O)C(O)C(CCOCCC7C(C(O)C(O)CO7)OC7C(C(O)C(O)CO7)O)O6)O)CC[C@]5(C)C4CC=2)(C)C[C@H]3O)O1 FHICGHSMIPIAPL-HDYAAECPSA-N 0.000 title claims description 4
- 230000015572 biosynthetic process Effects 0.000 title description 4
- 238000003786 synthesis reaction Methods 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000007800 oxidant agent Substances 0.000 claims abstract description 13
- 230000001590 oxidative effect Effects 0.000 claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 6
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 44
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 21
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 21
- 239000004593 Epoxy Substances 0.000 claims description 15
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 13
- DOAJFZJEGHSYOI-UHFFFAOYSA-N (20S,24S)-epoxydammarane-3,12,25-triol Natural products O1C(C(C)(O)C)CCC1(C)C1C(C(O)CC2C3(CCC4C(C)(C)C(O)CCC42C)C)C3(C)CC1 DOAJFZJEGHSYOI-UHFFFAOYSA-N 0.000 claims description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- 235000010265 sodium sulphite Nutrition 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 238000001514 detection method Methods 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 abstract description 20
- 239000000543 intermediate Substances 0.000 abstract description 5
- 239000001397 quillaja saponaria molina bark Substances 0.000 abstract description 3
- 229930182490 saponin Natural products 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 2
- 150000007949 saponins Chemical class 0.000 abstract description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 abstract 3
- 238000012805 post-processing Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 23
- 229930182494 ginsenoside Natural products 0.000 description 14
- 229940089161 ginsenoside Drugs 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 9
- 230000003647 oxidation Effects 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000006227 byproduct Substances 0.000 description 7
- -1 saponin amide Chemical class 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000002158 endotoxin Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 229920006008 lipopolysaccharide Polymers 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000001179 sorption measurement Methods 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229940049937 Pgp inhibitor Drugs 0.000 description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000002748 glycoprotein P inhibitor Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 description 1
- QTQGHKVYLQBJLO-UHFFFAOYSA-N 4-methylbenzenesulfonate;(4-methyl-1-oxo-1-phenylmethoxypentan-2-yl)azanium Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.CC(C)CC(N)C(=O)OCC1=CC=CC=C1 QTQGHKVYLQBJLO-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 206010069351 acute lung injury Diseases 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229960001401 hydrocortisone sodium succinate Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
本发明提供戴斯马丁试剂在合成Ocotillol型皂苷衍生物关键中间体中的应用，所述应用的方法为：(一)式(1‑R)或式(1‑S)所示的(20S,24R/24S)‑环氧达玛烷‑3β,12β,25‑三醇与戴斯马丁试剂按照物质的量之比为1:1～1.2反应制备得到相应的式(2‑R)或式(2‑S)所示的(20S,24R/24S)‑环氧‑25‑羟基‑3β‑羟基‑达玛烷‑3‑酮；(二)式(1‑R)或式(1‑S)所示的(20S,24R/24S)‑环氧达玛烷‑3β,12β,25‑三醇与戴斯马丁试剂按照物质的量之比为1:2～3反应制备得到相应的式(3‑R)或式(3‑S)所示的(20S,24R/24S)‑环氧‑25‑羟基‑达玛烷‑3,12‑二酮。本发明采用DMP为氧化剂，后处理方便，选择性高，收率好，在低用量情况下单氧化产物收率高达96％，在高用量情况下双氧化产物收率达90％以上。The present invention provides the application of Dess-Martin reagent in synthesizing key intermediates of Ocotilol-type saponin derivatives, and the method for the application is: (1) (20S, 24R/24S)-Damarane-epoxy-3β, 12β, 25-triol and Dess-Martin reagent according to the ratio of substance amount to 1:1～1.2 to prepare corresponding formula (2-R) or formula ( (20S, 24R/24S)-epoxy-25-hydroxy-3β-hydroxy-dammarane-3-ketone shown in 2-S); (two) formula (1-R) or formula (1-S) Shown (20S, 24R/24S)-Damarane-3β, 12β, 25-triol and Dess-Martin reagent according to the ratio of the amount of substances are 1:2～3 reaction preparation to obtain the corresponding formula (3 -R) or (20S,24R/24S)-epoxy-25-hydroxy-dammarane-3,12-dione represented by formula (3-S). The invention adopts DMP as the oxidant, and has convenient post-processing, high selectivity and good yield. The yield of mono-oxidation product is as high as 96% under the condition of low dosage, and the yield of double-oxidation product is over 90% under the condition of high dosage.
Description
Technical Field
The invention relates to an application of a dessamidine reagent in synthesizing an Ocotillol saponin derivative key intermediate.
Background
In tumor treatment, multidrug resistance is a problem to be solved urgently, and one of promising strategies is to find a novel P-glycoprotein inhibitor, wherein the main metabolic component of the natural product ginsenoside in the body is Ocotillol type ginsenoside. Patent CN109021058A introduces a synthesis method of an Ocotillol ginsenoside amide derivative, and in vitro cytotoxicity experiments and research on anti-drug resistance reversion capability, verapamil is used as a positive control, and the research shows that the Ocotillol ginsenoside amide derivative is a potential P-glycoprotein inhibitor and has good drug resistance reversion activity.
The latest synthetic route for the Ocotillol type saponin amide derivatives is as follows
In the above route, (24R/24S) Ocotillol ginsenoside shown in formula 1 is reacted under the oxidation of PPC to obtain (24R/24S) C-3 mono-oxidized Ocotillol ginsenoside shown in formula 2, then the obtained product is reacted with hydroxylamine hydrochloride to obtain C-3 oximinolated Ocotillol ginsenoside, and then the obtained product is reacted with ammonium acetate and sodium cyanoborohydride to obtain C-3 aminated Ocotillol ginsenoside, a series of linear alkyl compounds and aromatic compounds, and finally the obtained product is subjected to peptide-forming condensation reaction to obtain the Ocotillol ginsenoside amide derivative.
Wherein (24R/24S) Ocotillol ginsenoside shown in formula 1 is reacted under the oxidation of PPC to obtain (20S,24R/S) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in formula 2, PCC is used as an oxidant in the reaction, the selectivity of the oxidant is poor, the highest yield of the reaction is 85% as described in patent CN109021058A, and the yield of byproducts (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-diketone is high and low. The catalyst is easy to form sticky with a product after reaction, is difficult to separate, can extract the product by using a solvent after being subjected to suction filtration and adsorption by using kieselguhr, and can influence the yield of the product.
Disclosure of Invention
In view of the poor selectivity of the oxidant selected for selective oxidation, the easy formation of sticky and difficult separation with the product after reaction, and the need of suction filtration and adsorption with diatomite, the invention provides a new method, which selects DMP oxidant, and the like, and has good selective oxidation, safety and high efficiency, and better solubility with the product of oxidation of ocotilol type ginsenoside in a series of organic solvents. The catalyst has high selectivity and no influence on subsequent reaction, and has no influence on the activity of the final product, namely the Ocotillol type ginsenoside derivative.
The invention mainly solves the technical problem of providing an oxidation method which is simple to operate, mild in reaction conditions and high in selectivity and is used for preparing key intermediates of the Ocotillol type ginsenoside derivatives.
In order to solve the problems, the technical scheme adopted by the invention is as follows:
the application of descimidine reagent in the synthesis of key intermediates of Ocotillol type saponin derivatives is one of the following two methods:
(20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in formula (1-R) or (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in formula (1-S) and a deshimaladine reagent (DMP reagent) are subjected to oxidation reaction according to the mass ratio of 1: 1-1.2 to prepare corresponding (20S,24R) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in formula (2-R) or (20S,24S) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in formula (2-S).
The reaction formula is shown as follows:
(II) carrying out oxidation reaction on (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-R) or (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in the formula (1-S) and a dessimutan reagent (DMP reagent) according to the mass ratio of 1: 2-3 to prepare corresponding (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in the formula (3-R) or (20S,24S) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in the formula (3-S).
The reaction formula is shown as follows
Because chiral isomers exist, R or S configuration raw materials respectively correspondingly prepare R or S configuration products, and the preparation methods of the two isomers are written together in an OR mode for convenience of description.
Specifically, in the method (I), the (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in the formula (1-R) reacts with DMP according to the mass ratio of 1: 1-1.2 to prepare (20S,24R) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in the formula (2-R);
reacting (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in formula (1-S) with DMP according to the mass ratio of 1: 1-1.2 to prepare (20S,24S) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in formula (2-S).
Specifically, in the second method, the (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in the formula (1-R) reacts with DMP according to the mass ratio of 1: 2-3 to prepare (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in the formula (3-R); reacting (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in formula (1-S) with DMP according to the mass ratio of 1: 2-3 to obtain (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in formula (3-S).
The reaction principle of DMP is: the first step is that hydroxyl at C-3 position of the Ocotillol type ginsenoside is replaced with one acetoxyl group of DMP, and the second step is that when the other acetoxyl group is separated, the proton of the carbon atom linked with the alcoholic hydroxyl group is transferred to the acetoxyl group, and simultaneously the hydroxyl group is oxidized into corresponding ketone, and the reaction process not only completely avoids the occurrence of transition reaction, but also has quite high chemical selectivity.
The inventor finds through a large number of experiments that the selectivity of the mono-oxidation product and the di-oxidation product can be controlled by adjusting the dosage ratio of DMP, when the dosage ratio of DMP to the raw material is 1-1.2: 1, the mono-oxidation product is generated with high selectivity, the yield is over 90%, and when the dosage ratio of DMP to the raw material is 2-3: 1, the di-oxidation product is generated with high selectivity, the yield is over 93%.
Further, it is preferable that the ratio of the amounts of the (20S,24R) -epoxy dammarane-3 β,12 β, 25-triol represented by the formula (1-R) or the (20S,24S) -epoxy dammarane-3 β,12 β, 25-triol represented by the formula (1-S) to the DMP is 1:1 to 1.1, the compound represented by the formula (2-R) is (20S,24R) -epoxy-25-hydroxy-3 β -hydroxy-dammarane-3-one or the compound represented by the formula (2-S) is (20S,24S) -epoxy-25-hydroxy-3 β -hydroxy-dammarane-3-one, and the yield is 94% or more.
The initial reaction temperature of the invention is controlled below 0 ℃, generally between-5 ℃ and 0 ℃, preferably between-5 ℃ and 0 ℃ for 1 to 2 hours, and then the temperature is raised to room temperature for 3 to 5 hours.
In the reaction of the invention, sodium bicarbonate is added to adjust the pH, and the mass ratio of the DMP reagent to the sodium bicarbonate is 1: 1.2-3.
In the reaction of the invention, a proper amount of tertiary butanol is added to promote the oxidation reaction and is used as a cosolvent of an oxidant. The volume of the tert-butyl alcohol is generally 0.2-1 mL/mmol based on the amount of the substance of the dessimutan reagent (DMP).
The reaction of the invention adopts dichloromethane as solvent. The volume usage amount of the dichloromethane is generally 8-15 mL/mmol, preferably 10-15 mL/mmol, based on the amount of (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol represented by formula (1-R) or (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol represented by formula (1-S).
Specifically, the method of the present invention is preferably operated by the following steps:
the application method (I): feeding (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-R) or (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-S) and an oxidant desimadine reagent (DMP reagent) according to the mass ratio of 1: 1-1.2, reacting for 1 hour in an ice bath at-5-0 ℃ by taking dichloromethane as a solvent under the action of sodium bicarbonate and tert-butyl alcohol at normal temperature for 3-5 hours, and after the TLC detection reaction is completed, carrying out post-treatment on the reaction solution to correspondingly prepare (20S,24R) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in a formula (2-R) or (20S shown in a formula (2-S), 24S) -epoxy-25-hydroxy-3 β -hydroxy-dammaran-3-one.
The application method (II): feeding (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-R) or (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-S) and an oxidant desimadine reagent (DMP reagent) according to the mass ratio of 1: 2-3, reacting for 1 hour at the temperature of-5-0 ℃ in an ice bath by using dichloromethane as a solvent under the action of sodium bicarbonate and tert-butyl alcohol, reacting for 3-5 hours at normal temperature, performing TLC detection reaction completely, and performing post-treatment on a reaction solution to correspondingly prepare (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in a formula (3-R) or (20S,24S) -epoxy-25-hydroxy-dammarane-3 shown in a formula (3-S), 12-diketones.
The reaction solution post-treatment steps of the invention are as follows: adding saturated sodium bicarbonate and sodium sulfite aqueous solution into the reaction solution to adjust the pH, extracting with ethyl acetate, washing the organic phase with sodium bicarbonate and saturated saline solution respectively, drying with anhydrous sodium sulfate, filtering, concentrating, separating by silica gel column chromatography, and eluting to obtain the target product.
The objective product was washed with an aqueous sodium sulfite solution in order to remove acetic acid and iodine as by-products.
The (20S,24S) -epoxy-25-hydroxy-dammarane-3, 12-dione shown in formula (3-R) or (20S,24S) -epoxy-25-hydroxy-dammarane-3, 12-dione shown in formula (3-S) prepared by the invention is a new compound, and can be used for continuously synthesizing a new Ocotillol type esterified derivative in the following process, and has anti-inflammatory activity. The method comprises the following specific steps: selectively reducing the (20S,24S) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in the formula (3-R) or the (20S,24S) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in the formula (3-S) with sodium borohydride to selectively reduce the carbonyl at the 3-position into hydroxy, and respectively and correspondingly preparing (20S,24R) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-12-ketone shown in the formula (4-R) or (20S,24S) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-12-ketone shown in the formula (4-S); then carrying out esterification reaction with amino acid derivatives shown in formula (7) to respectively and correspondingly prepare the protection group-containing Ocotillol type esterified derivatives shown in formula (5-R) or formula (5-S). The protection group-containing Ocotillol esterified derivative represented by the formula (5-R) or (5-S) is subjected to deprotection reaction to obtain the Ocotillol esterified derivative represented by the formula (6-R) or (6-S). The protection group-containing Ocotillol esterified derivative shown in the formula (5-R) or the formula (5-S) and the Ocotillol esterified derivative shown in the formula (6-R) or the formula (6-S) have anti-inflammatory activity, can be used for preparing anti-inflammatory drugs or anti-inflammatory drug compositions, and further can be used for preparing drugs or drug compositions for treating and preventing diseases related to acute lung injury, sepsis and the like.
Wherein R is1Is hydrogen, C1-C4 alkyl, phenyl, benzyl, p-hydroxybenzyl, -RaCOORb、-RaORb、-RaNHRcor-RaSRd；R2Is tert-butyloxycarbonyl (Boc), fluorenyl-methoxycarbonyl (Fmoc) or benzyl (Bn); r3Is H or C1-C4 alkyl; or R1、R3Connecting with N to form a ring to form N-tetrahydropyrrole;
R1in, RaIs C1-C4 alkylene; rbH, Bn or tBu; rcH, Boc or Fmoc; rdIs H or methyl;
preferably R1Is hydrogen, isopropyl, benzyl, - (CH)2)2-COOH、-CH2-COOH、-(CH2)2-COO-tBu or-CH2-COO-tBu；
Preferably R2Is Boc; preferably R3Is H.
The invention has the beneficial effects that:
DMP is adopted as an oxidant, so that the selectivity is high, the yield is good, the mono-oxidation product can be prepared with high selectivity under the condition of low dosage, the yield is up to 96%, and the di-oxidation product can be prepared with high selectivity under the condition of high dosage, and the yield is up to more than 90%.
And the oxidant and the product after the reaction do not produce sticky substances, the post-treatment operation is simple, acid by-products generated by oxidation can be removed through washing and the like, the separation is easier, and the product loss is reduced.
Detailed Description
The technical solution of the present invention is further described with specific examples, but the scope of the present invention is not limited thereto.
Example 1
Taking a compound (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol (50mg, 0.10mmol) and sodium bicarbonate (16mg, 0.20mmol) in a 25mL eggplant-shaped bottle, adding a rotor, adding 1mL of dichloromethane, stirring and dissolving, adding dessimidine (DMP, 53mg, 0.12mmol) in ice bath at 0 ℃, adding 30 mu L of tert-butyl alcohol to accelerate the dissolution of DMP, reacting for 1 hour, removing the ice bath, and reacting for 4 hours at normal temperature. After confirming completion of the reaction by TLC, saturated aqueous sodium bicarbonate and sodium sulfite solution were added to the reaction system to adjust pH and stirred for half an hour. The organic phase was washed with 20mL of sodium bicarbonate and 20mL of saturated saline solution, and then combined into a flask, and the flask was filled with anhydrous sodium sulfate, dried, left for 20 minutes, filtered, and concentrated. Separating by using a 200-300-mesh silica gel column, wherein the used eluent sequentially comprises petroleum ether: ethyl acetate 10:1 → 8:1 → 6:1 → 5:1, and elution gave 45mg of (20S,24R) -epoxy-25-hydroxy-3 β -hydroxy-dammarane-3-one in 90% yield and 4mg of by-product (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-dione in 9% yield.
Example 2
Taking the compound (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol (513mg, 1.1mmol) and sodium bicarbonate (231mg, 2.75mmol) to a 25mL eggplant-shaped bottle, adding a rotor, adding 11mL of dichloromethane, stirring and dissolving, adding dessimutane (DMP, 548mg, 1.2mmol) at 0 ℃ in an ice bath, adding 300 mu L of tert-butyl alcohol to accelerate the dissolution of the DMP, reacting for 1 hour, removing the ice bath, and reacting for 4 hours at normal temperature. After confirming completion of the reaction by TLC, saturated aqueous sodium bicarbonate and sodium sulfite solution were added to the reaction system to adjust pH and stirred for half an hour. The organic phase was washed with 50mL of sodium bicarbonate and 50mL of saturated saline solution, respectively, and then combined into a flask, the flask bottom was covered with anhydrous sodium sulfate, dried, left for 20 minutes, filtered, and concentrated. Separating by using a 200-300-mesh silica gel column, wherein the used eluent sequentially comprises petroleum ether: after elution with ethyl acetate 10:1 → 8:1 → 6:1 → 5:1, (20S,24S) -epoxy-25-hydroxy-3 β -hydroxy-dammarane-3-one was obtained in 482mg, yield 95%, and by-product (20S,24S) -epoxy-25-hydroxy-dammarane-3, 12-dione in 12mg, yield 2%.
Example 3
Taking a compound (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol (722mg, 1.5mmol) and sodium bicarbonate (327mg, 3.9mmol) to be placed in a 50mL eggplant-shaped bottle, adding a rotor, adding 16mL of dichloromethane, stirring and dissolving, adding dessimidine (DMP, 771mg, 1.6mmol) to be added with 800 mu L of tert-butyl alcohol to accelerate the dissolution of the DMP at the temperature of 0 ℃ under ice bath, reacting for 1 hour, removing the ice bath, and reacting for 4 hours at normal temperature. After confirming completion of the reaction by TLC, saturated aqueous sodium bicarbonate and sodium sulfite solution were added to the reaction system to adjust pH and stirred for half an hour. The organic phase was washed with 100mL of sodium bicarbonate and 100mL of saturated saline solution, and then combined into a flask, and the flask was filled with anhydrous sodium sulfate, dried, left for 20 minutes, filtered, and concentrated. Separating by using a 200-300-mesh silica gel column, wherein the used eluent sequentially comprises petroleum ether: the ethyl acetate eluted (20S,24R) -epoxy-25-hydroxy-3 β -hydroxy-dammarane-3-one in 96% yield and (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-dione in 3% yield (10: 1 → 8:1 → 6:1 → 5: 1).
Example 4
Taking the compound (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol (73mg,0.15mmol) and sodium bicarbonate (77mg, 0.91mmol) to a 25mL eggplant-shaped bottle, adding a rotor, adding 1.5mL of dichloromethane, stirring and dissolving, adding dessimutane (DMP, 162mg, 0.34mmol) at 0 ℃ in an ice bath, adding 200 mu L of tert-butyl alcohol to accelerate the dissolution of the DMP, and removing the ice bath after reacting for 1 hour and reacting at normal temperature. Completion of the reaction was confirmed by TLC after 4 hours of reaction. Saturated aqueous sodium bicarbonate and sodium sulfite solution were added to the reaction system to adjust the pH and stirred for half an hour. Extracting with 90mL ethyl acetate for three times, washing the organic phase with 30mL sodium bicarbonate and 30mL saturated saline solution respectively, mixing to the conical flask, spreading anhydrous sodium sulfate on the bottom of the conical flask for drying, standing for 20 min, filtering, and concentrating. Separating by using a 200-300-mesh silica gel column, wherein the used eluent sequentially comprises petroleum ether: elution with ethyl acetate (10: 1 → 6:1 → 4:1 → 2: 1) gave 66mg of (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-dione in 93% yield.
The various amounts of DMP reagent and product yields are shown in table 1 below:
table 1:
comparative example 1
Dissolving the compound (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol (821mg, 1.72mmol) in dichloromethane (20mL), adding PCC (pyridinium chlorochromate, 389mg, 1.80mmol) on an ice bath, slowly raising the temperature to room temperature and stirring for 15 hours, then completely reacting, carrying out post-treatment, filtering and concentrating in a funnel by using cotton, carrying out suction filtration and adsorption concentration again by using kieselguhr, removing viscous PCC, and washing the sample by using dichloromethane for multiple times. Column chromatography gave (20S,24R) -epoxy-25-hydroxy-3 β -hydroxy-dammarane-3-one (689mg, 1.45mmol, 84% yield), and by-product (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-dione (70mg, 0.14mmol, 8.1% yield).
The comparative example shows that the post-treatment of the PCC after the reaction is troublesome, the viscous PCC needs to be removed by suction filtration and adsorption of diatomite, the reaction selectivity is not high, and the yield of the target product is low.
The applicant also studied the reaction for preparing the double oxidation product by oxidizing PCC, and found that the selectivity is very poor, and under the condition that the dosage of PCC is increased by 6 times, the yield of the double oxidation product is only about 60%, and a large amount of by-products which are not completely oxidized are generated, so that the practicability is not achieved.
Example 5
Example of use of (20S,24R) -epoxy-25-hydroxy-3-one-dammaran-12-one prepared in example 4
(20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-dione (214mg, 0.45mmol), sodium borohydride (34mg, 0.91mmol) was dissolved in isopropanol (6.5mL) and stirred at room temperature for 24 h. Quenching reaction with water, extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography to obtain (20S,24R) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-12-one (180mg, 0.38mmol, 83.7% yield)
(20S,24R) -epoxy-25-hydroxy-3 β -hydroxy-dammaran-12-one (33mg, 0.07mmol), N-Boc-2-valine (27mg, 0.08 mmol 1) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 40mg, 0.21mmol) were dissolved in anhydrous dichloromethane (0.6mL), 4-dimethylaminopyridine (DMAP, 3mg, 0.03mmol) was added under argon protection in an ice bath and slowly warmed to room temperature and stirred for 24 h. Quenching the reaction with water, extracting with dichloromethane, drying the combined organic phases over anhydrous sodium sulfate, concentrating, and performing column chromatography to give (20S,24R) -epoxy-25-hydroxy-3 β -O- (N-Boc-valyl) -dammaran-12-one (28mg, 0.04mmol, 57% yield)
Nuclear magnetic resonance spectrum:1H NMR(400MHz,CHCl3)δ4.98(d,J＝9.2Hz,1H),4.49(dd,J＝11.3,4.9Hz,1H),4.19(dd,J＝9.2,4.1Hz,1H),3.67(dd,J＝8.7,6.1Hz,1H),2.87(d,J＝9.5Hz,1H),2.54(td,J＝10.7,4.5Hz,1H),2.18(d,J＝8.0Hz,2H),1.86-1.46(m,19H),1.42(s,9H),1.23(s,3H),1.18(d,J＝3.9Hz,6H),1.08(d,J＝1.6Hz,6H),0.96(d,J＝6.9Hz,3H),0.93(s,3H),0.87(s,3H),0.85(s,3H),0.74(s,3H).
lipopolysaccharide (LPS) -induced NO release levels in RAW264.7 cells were measured using Griess reagent. RAW264.7 cells were treated with 1X106Individual cells/well were seeded in 96-well plates and cultured for 1 hour; then LPS (1ug/mL) is used for stimulating and molding, and after the cells are treated by derivatives with 20uM concentration and positive drugs (hydrocortisone sodium succinate) for 24 hours, the amount of NO generated is determined by detecting the nitrite level by using Griess reagent (Beyotime, China); the absorbance of the sample at 540nm (OD540) was then measured in a microplate reader (spectra maxm 3); wherein the blank group is LPS-free and drug-treated group; the control group is a LPS-stimulated molding group but no compound treatment group;
NO inhibition ═ 100% for [ control (OD540) -compound (OD540) ]/[ control (OD540) -blank (OD540) ];
the NO inhibition rate of (20S,24R) -epoxy-25-hydroxy-3 beta-O- (N-Boc-valyl ester) -dammarane-12 ketone is 41%, compared with the control group, P is less than 0.001, and the inhibition rate of the positive drug group is improved by 4 times by 10%.
Claims (5)
1. A method for synthesizing an Ocotillol saponin derivative key intermediate by using a temastine reagent as an oxidizing agent is characterized in that the method is one of the following two methods:
(I) feeding (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-R) or (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-S) and an oxidant descimycin reagent according to the mass ratio of 1: 1-1.2, reacting for 1-2 hours in an ice bath at-5-0 ℃ by taking dichloromethane as a solvent under the action of sodium bicarbonate and tert-butyl alcohol at normal temperature for 3-5 hours, carrying out TLC detection reaction, and carrying out post-treatment on the reaction solution to obtain (20S,24R) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in a formula (2-R) or (20S) shown in a formula (2-S), 24S) -epoxy-25-hydroxy-3 β -hydroxy-dammaran-3-one; the reaction formula is shown as follows:
(II) feeding (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-R) or (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-S) and an oxidant desimadine reagent according to the mass ratio of 1: 2-3, reacting for 1 hour at the normal temperature for 3-5 hours at the ice bath of-5-0 ℃ by using dichloromethane as a solvent under the action of sodium bicarbonate and tert-butyl alcohol, carrying out TLC detection reaction completely, carrying out post-treatment on the reaction liquid to correspondingly prepare (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in a formula (3-R) or (20S,24S) -epoxy-25-hydroxy-dammarane-3 shown in a formula (3-S), a 12-diketone; the reaction formula is shown as follows:
2. the method according to claim 1, wherein in the method (one), the ratio of the amounts of the (20S,24R) -epoxydammarane-3 β,12 β, 25-triol represented by the formula (1-R) or the (20S,24S) -epoxydammarane-3 β,12 β, 25-triol represented by the formula (1-S) to the amount of the dessimutan reagent is 1:1 to 1.1.
3. The method according to claim 1, wherein the ratio of the amount of dessimutant reagent to the amount of sodium bicarbonate is 1:1.2 to 3.
4. The method according to claim 1, wherein the tert-butanol is used in a volume of 0.2 to 1mL/mmol based on the amount of the substance of the dessimutant reagent.
5. The method according to claim 1, wherein the post-treatment step of the reaction solution comprises: adding saturated sodium bicarbonate and sodium sulfite aqueous solution into the reaction solution to adjust the pH, extracting with ethyl acetate, washing the organic phase with sodium bicarbonate and saturated saline solution respectively, drying with anhydrous sodium sulfate, filtering, concentrating, separating by silica gel column chromatography, and eluting to obtain the target product.
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| CN103965281A (en) * | 2013-01-31 | 2014-08-06 | 上海中药创新研究中心 | Protopanaxadiol derivative, preparation method and application thereof |
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| CN103965281A (en) * | 2013-01-31 | 2014-08-06 | 上海中药创新研究中心 | Protopanaxadiol derivative, preparation method and application thereof |
| CN109021058A (en) * | 2018-09-12 | 2018-12-18 | 烟台大学 | With active ocotillol type sapogenin derivative of tumor drug resistance reversal and its preparation method and application |
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