CN1448399A - Synthetic method of 24-methylene-cholesterol-5-alkenyl-3 beta, 19-glycol - Google Patents
Synthetic method of 24-methylene-cholesterol-5-alkenyl-3 beta, 19-glycol Download PDFInfo
- Publication number
- CN1448399A CN1448399A CN 03114287 CN03114287A CN1448399A CN 1448399 A CN1448399 A CN 1448399A CN 03114287 CN03114287 CN 03114287 CN 03114287 A CN03114287 A CN 03114287A CN 1448399 A CN1448399 A CN 1448399A
- Authority
- CN
- China
- Prior art keywords
- ketone
- courage steroid
- alkene
- acetoxyl group
- obtains
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000010189 synthetic method Methods 0.000 title claims description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 18
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000004593 Epoxy Substances 0.000 claims abstract description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 230000007062 hydrolysis Effects 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- 239000007787 solid Substances 0.000 claims description 29
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 238000010898 silica gel chromatography Methods 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 claims description 7
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 claims description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 claims description 7
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 239000012312 sodium hydride Substances 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 claims description 7
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 claims description 7
- 229940032091 stigmasterol Drugs 0.000 claims description 7
- 235000016831 stigmasterol Nutrition 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- JNMIXMFEVJHFNY-UHFFFAOYSA-M methyl(triphenyl)phosphanium;iodide Chemical compound [I-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 JNMIXMFEVJHFNY-UHFFFAOYSA-M 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000005286 illumination Methods 0.000 claims description 5
- 239000011261 inert gas Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 claims description 4
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 235000012204 lemonade/lime carbonate Nutrition 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 238000010719 annulation reaction Methods 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 2
- CASUWPDYGGAUQV-UHFFFAOYSA-M potassium;methanol;hydroxide Chemical compound [OH-].[K+].OC CASUWPDYGGAUQV-UHFFFAOYSA-M 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 229930014626 natural product Natural products 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- XLVMMFHWIROLGG-HSIBUNQISA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methyl-5-oxoheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound C1C=C2C[C@@H](OC(C)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCC(=O)C(C)C)[C@@]1(C)CC2 XLVMMFHWIROLGG-HSIBUNQISA-N 0.000 abstract 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 abstract 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 abstract 2
- VMWFJQWTOGCZJN-XZRIDVCPSA-N (6r)-6-[(3s,8s,9s,10s,13r,14s,17r)-3-hydroxy-10-(hydroxymethyl)-13-methyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylheptan-3-one Chemical compound C1C=C2C[C@@H](O)CC[C@]2(CO)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCC(=O)C(C)C)[C@@]1(C)CC2 VMWFJQWTOGCZJN-XZRIDVCPSA-N 0.000 abstract 1
- 230000002421 anti-septic effect Effects 0.000 abstract 1
- 230000000259 anti-tumor effect Effects 0.000 abstract 1
- 238000007142 ring opening reaction Methods 0.000 abstract 1
- 230000001131 transforming effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 241001395157 Litophyton Species 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- WOOKNJANWWBKHW-UHFFFAOYSA-N (3beta)-24-methylcholesta-5,24(28)-diene-3,19-diol Natural products C1C=C2CC(O)CCC2(CO)C2C1C1CCC(C(C)CCC(=C)C(C)C)C1(C)CC2 WOOKNJANWWBKHW-UHFFFAOYSA-N 0.000 description 1
- WOOKNJANWWBKHW-CGMUPKQHSA-N (3s,8r,9r,10s,13r,14r,17r)-10-(hydroxymethyl)-13-methyl-17-[(2r)-6-methyl-5-methylideneheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(CO)[C@H]2[C@H]1[C@H]1CC[C@H]([C@H](C)CCC(=C)C(C)C)[C@@]1(C)CC2 WOOKNJANWWBKHW-CGMUPKQHSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- WOOKNJANWWBKHW-TURLQYGPSA-N 24-methylene-cholest-5-en-3beta,19-diol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(CO)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCC(=C)C(C)C)[C@@]1(C)CC2 WOOKNJANWWBKHW-TURLQYGPSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 201000005443 oral cavity cancer Diseases 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Abstract
The synthesis process of natural product 24-methene-cholest-5-ene-3beta,19-diol (Litoserol) with antitumor and antiseptic activity includes the steps of: synthesis of 3beta-acetoxy-cholest-5-ene-24-one with easy-to-obtain stigmacholest; reaction of 3beta-acetoxy-cholest-5-ene-24-one with N-bromoacetamide in the catalysis of water solution of perchloric acid to produce 3beta-acetoxy-cholest-5alpha-bromo-6beta-hydroxy-24-one; photoannulation reaction to produce 3beta-acetoxy-cholest-5alpha-bromo-6, 19-epoxy-24-one; epoxy ring-opening reaction to produce 3beta-acetoxy-cholest-5-ene-19-hydroxy-24-one; hydrolysis to produce 3beta, 19-dihydroxy-cholest5-ene-24-one; and final transforming the carbonyl group in 24-th place of branch chain into methane to obtain the destination product. The present invention has total yield of 9.3 %.
Description
Technical field
The present invention relates to have natural product 24-methylene radical-courage steroid-5-alkene-3 β of remarkable physiologically active, 19-glycol (24-methylene-cholest-5-en-3 β, 19-diol; Litosterol) artificial synthesis.
Background technology
24-methylene radical-courage steroid-5-alkene-3 β, (structure is suc as formula shown in the I for the 19-glycol, hereinafter to be referred as formula I compound) at first be that people such as Kazuo IGUCHI separate from the soft coral Litophyton viridis of ocean and obtain (Kazuo IGUCHI, Shuichi SAITOH, Yasuji YAMADA, Chem.Pharm.Bull., 1989,37,2553-2554), this natural product all has powerful poisoning ability, ED to human body rectum cancer cell, human body lung carcinoma cell, human oral cavity cancer cells and muroid lymphocytic cancer cell
50Value is respectively 1.76,1.31,1.10 and 0.45 μ g/mL (ED
50≤ 4.0 μ g/mL significantly suppress, Chang-Yih Duh, and Shang-Kwei Wang, Mei-Jen Chu et al., J.Nat.Prod., 1998,61,1022-1024); And has a significant anti-mycotic activity (MICs can suppress the growth of 90% H37Rv pulmonary tuberculosis cell when being 3.13 μ g/mL), simultaneously because its toxicity is low, be an ideal drug candidate (Khalid A.El Sayed, Piotr Bartyzel, Xiaoyu Shen, et al., Tetrahedron, 2000,56,949-953).
24-methylene radical-courage steroid-5-alkene-3 β, the content of 19-glycol in marine organisms is atomic, Kazuo IGUCHI etc. is divided into from 6.5kg soft coral Litophyton viridis from obtaining this compound of 18mg, and the halobiontic quantity of this kind is few, so directly utilize marine organisms to be difficult to satisfy the demand of society now as this compound of raw material separation and Extraction.
Summary of the invention
The purpose of this invention is to provide a kind of Synthetic 2 4-methylene radical-courage steroid-5-alkene-3 β, the method for 19-glycol.
Method of the present invention is with the synthetic 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone (III) that obtains of the Stigmasterol (II) that is easy to get, react under high chloro acid solution's catalysis with N-bromo ethanamide again and generate 3 β-acetoxyl group-courage steroid-5 α-bromo-6 beta-hydroxies-24-ketone (IV), then generate 3 β-acetoxyl group-courage steroid-5 α-bromo-6 by the illumination annulation, 19-epoxy-24-ketone (V), then epoxy addition generates 3 β-acetoxyl group-courage steroid-5-alkene-19-hydroxyl-24-ketone (VI), then hydrolysis generates 3 β, 19-dihydroxyl-courage steroid-5-alkene-24-ketone (VII), at last 24 carbonyls on the side chain are changed into methylene radical, obtain purpose product (formula I compound).Overall yield 14%.The process of reaction is shown below:
The concrete steps of the inventive method are as follows:
(1). with Stigmasterol (II) according to existent method (JianGuo Cui, LongMei Zeng, Jing Yu Su et al., Steroids, 2001,66,33-38) the synthetic 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone (III) that obtains;
(2). III is dissolved in the dioxane (consumption is generally and just dissolves III or many slightly), be chilled to 10~15 ℃, (concentration is 5%~10%wt to the high chloro acid solution of adding catalytic amount, consumption is 1%~5%mole) of III, lucifuge adds the N-bromo ethanamide of 1~1.4 times of weight in batches in 30~40 minutes, room temperature continued stirring reaction 30~40 minutes, add the sodium sulfite aqueous solution stopped reaction, dichloromethane extraction, removal of solvent under reduced pressure obtains a white solid, silica gel column chromatography, recrystallizing methanol obtain 3 β-acetoxyl group-courage steroid-5 α-bromo-6 beta-hydroxies-24-ketone (IV);
(3). the product IV in the previous step or white solid are dissolved in benzene/cyclohexane, and (volume ratio is 1/3~1/2, consumption is generally and just dissolves IV or many slightly) in the mixed solvent, the lead tetra-acetate that adds 5~10 times of weight, the iodine of 1~1.2 times of weight, the lime carbonate of 2~3 times of weight, illumination reaction is 5~7 hours under the protection of inert gas, cooling back sherwood oil and ethyl acetate extraction, removal of solvent under reduced pressure obtains a light yellow solid, silica gel column chromatography, recrystallizing methanol obtains 3 β-acetoxyl group-courage steroid-5 α-bromo-6,19-epoxy-24-ketone (V);
(4). the product V in the previous step or light yellow solid be dissolved in 95% the ethanol (general consumption is for just dissolving V or many slightly), the zinc powder that adds 3~5 times of weight, stirring and refluxing 5~7 hours, cooled and filtered is removed zinc powder, removal of solvent under reduced pressure obtains a light yellow solid, silica gel column chromatography, recrystallizing methanol obtain 3 β-acetoxyl group-courage steroid-5-alkene-19-hydroxyl-24-ketone (VI);
(5). product VI in the previous step or light yellow solid are dissolved in the tetrahydrofuran (THF) (general consumption is for just dissolving VI or many slightly), adding concentration is the potassium hydroxide methanol solution (consumption of potassium hydroxide is 1~3 times of VI weight) of 2~3%wt, reflux 10~15 minutes, cooling back removal of solvent under reduced pressure, ethyl acetate extraction, removal of solvent under reduced pressure obtain a light yellow solid, silica gel column chromatography, recrystallizing methanol obtains 3 β, 19-dihydroxyl-courage steroid-5-alkene-24-ketone (VII);
(6). under protection of inert gas; anhydrous dimethyl sulfoxide solution (5mg/mL~10mg/mL) be heated to 70~80 ℃ to stir 35~45 minutes with sodium hydride; be cooled to the methyl triphenyl phosphonium iodide or the methyltriphenylphosphonium bromide (usually with a small amount of anhydrous dimethyl sulfoxide dissolving) that add 5~8 times of sodium hydride weight after the room temperature; stir after 10~15 minutes; product VII in the previous step of 0.5~1.0 times of sodium hydride weight of adding (usually with a small amount of anhydrous dimethyl sulfoxide dissolving); be warming up to 70~80 ℃ of stirring reactions 1~2 hour; add the frozen water stopped reaction after being cooled to room temperature; extracted with diethyl ether; removal of solvent under reduced pressure obtains a light yellow solid; silica gel column chromatography; recrystallizing methanol obtains purpose product 24-methylene radical-courage steroid-5-alkene-3 β, 19-glycol (formula I compound).
The inventive method as starting raw material, obtains 24-methylene radical-courage steroid-5-alkene-3 β through the reaction of ten steps is synthetic first with the Stigmasterol (II) that is easy to get, 19-glycol (I), and overall yield reaches 14%.
The inventive method is at synthetic 3 β of 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone (III), adopt unique reaction conditions and post-treating method in the process of 19-dihydroxyl-courage steroid-5-alkene-24-ketone (VII), intermediate product (the IV of four-step reaction, V, VI) can not separate purification and be directly used in next step reaction, avoided separating some unnecessary loss in the purification process, can obtain higher relatively productive rate (improving 4%), such treatment process has more actual production and is worth.
Embodiment
The invention will be further described by the following examples.
Embodiment 1:
(1). Stigmasterol is reacted synthetic obtain 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone, overall yield 63% according to the method for " JianGuo Cui, LongMei Zeng, Jing Yu Su et al., Steroids, 2001,66,33-38 " through five steps;
(2) .3 β-acetoxyl group-courage steroid-5-alkene-24-ketone 300mg is dissolved in the 3mL dioxane solution, after being cooled to 10 ℃ with ice-water bath, add 0.15mL high chloro acid solution (concentration is 7%wt), lucifuge adds 300mg N-bromo ethanamide, divide eight times and add, add in 40 minutes.Remove cryostat, room temperature continues to stir 40 minutes, adds rare cold sodium sulfite aqueous solution 20mL, and dichloromethane extraction four times merges organic phase, washes with water successively, and 5% sodium bicarbonate aqueous solution is washed, and saturated common salt is washed to neutrality, anhydrous sodium sulfate drying.Filter, removal of solvent under reduced pressure obtains a white solid, this solid is directly used in the next step, or separate with silica gel column chromatography (the petrol ether/ethyl acetate volume ratio is 5/1 wash-out), recrystallizing methanol obtains colourless acicular crystal 3 β-acetoxyl group-courage steroid-5 α-bromo-6 beta-hydroxies-24-ketone, fusing point: 128~130 ℃.
(3). the white solid 100mg that obtains in the step (2) is dissolved in the mixed solvent of 50mL benzene/cyclohexane (volume ratio is 1: 3); add the 600mg lead tetraacetate fast; 120mg iodine, 250mg lime carbonate, under protection of inert gas with two 300 watts incandescent-lamp bulb illumination reflux 5 hours.Behind the cool to room temperature, filter, white filter residue washs with sherwood oil and ethyl acetate repeatedly, merging filtrate, and 5% sodium bicarbonate aqueous solution is washed secondary, and saturated common salt is washed to neutrality, anhydrous sodium sulfate drying.Filter, removal of solvent under reduced pressure obtains a light yellow solid, this solid is directly used in next step reaction, or separate with silica gel column chromatography (the petrol ether/ethyl acetate volume ratio is 7/1 wash-out), recrystallizing methanol obtains colourless acicular crystal 3 β-acetoxyl group-courage steroid-5 α-bromo-6,19-epoxy-24-ketone, fusing point: 139~141 ℃.
(4). the light yellow solid 100mg that obtains in the step (3) is dissolved in the ethanolic soln of 15mL95%, add zinc powder 350mg, stirring and refluxing 5 hours, be cooled to the room temperature after-filtration, solid is washed repeatedly with ethanol, merge organic phase, removal of solvent under reduced pressure obtains a light yellow solid, this solid is directly used in next step reaction, or separate with silica gel column chromatography (the petrol ether/ethyl acetate volume ratio is 5/1 wash-out), recrystallizing methanol obtains colourless acicular crystal 3 β-acetoxyl group-courage steroid-5-alkene-19-hydroxyl-24-ketone, fusing point: 132~133 ℃.
(5). the light yellow solid 100mg that obtains in the step (4) is dissolved in the 20mL tetrahydrofuran solution, adds 6mL methanol solution (containing 3%wt potassium hydroxide), reflux 15 minutes.Be cooled to room temperature, removal of solvent under reduced pressure obtains a yellow solid, the ethyl acetate dilution, and saturated common salt is washed to neutrality, anhydrous sodium sulfate drying.Filter, removal of solvent under reduced pressure, the light yellow solid that obtains separates with silica gel column chromatography (sherwood oil/acetone volume ratio is 4/1 wash-out), and recrystallizing methanol obtains colourless acicular crystal 3 β, 19-dihydroxyl-courage steroid-5-alkene-24-ketone 74mg, fusing point: 155~156 ℃.Above four-step reaction overall yield is 29%.
(6). reaction flask cleans with argon gas earlier, under argon gas atmosphere, add sodium hydride (55%-65%) 80mg then,, add anhydrous dimethyl sulfoxide 5mL behind the decompressing and extracting sherwood oil with exsiccant sherwood oil (30-60 ℃) washing 3 times, 70~80 ℃ of stirring reactions 40 minutes, a yellow-green soln.After question response liquid is reduced to room temperature, add the methyl triphenyl phosphonium iodide 400mg that is dissolved in the 3mL methyl-sulphoxide, solution becomes aureus, continue to stir after 10 minutes, add 3 β be dissolved in the 1mL methyl-sulphoxide, 19-dihydroxyl-courage steroid-5-alkene-24-ketone 25mg was 70~80 ℃ of stirring reactions 1 hour.After treating that temperature is reduced to room temperature, add 15mL cold water, with extracted with diethyl ether four times, diethyl ether solution washes with water to neutrality, boil off solvent, the lurid solid that obtains, the latter separates with silica gel column chromatography (sherwood oil/acetone volume ratio is 3/1 wash-out), and recrystallizing methanol obtains the purpose product 18mg of colourless needle-like crystalline form.Fusing point: 166~167 ℃.Productive rate 74%, the ten steps reaction overall yield initial from Stigmasterol is 14%.
Embodiment 2:
With reference to the method for implementing 1, wherein:
The consumption of N-bromo ethanamide is 400mg in the step (2);
The consumption of lead tetraacetate is 900mg in the step (3), and the reaction times is 7 hours;
The consumption of zinc powder is 500mg in the step (4), and the reaction times is 7 hours;
The consumption of methanol solution (containing 3%wt potassium hydroxide) is 10mL in the step (5);
The consumption of methyl triphenyl phosphonium iodide is 600mg in the step (6);
Other condition is identical with enforcement 1, is come to the same thing.
Embodiment 3:
With reference to the method for enforcement 1 and embodiment 2, wherein, step (6) replaces methyl triphenyl phosphonium iodide with the equivalent methyltriphenylphosphonium bromide respectively, and other condition is identical, is come to the same thing.
Purpose product (24-methylene radical-courage steroid-5-alkene-3 β, 19-glycol) structural identification:
Fusing point: 166~167 ℃, bibliographical information is 165~166 ℃
Specific rotatory power: [α]
20 D=-24 ° of (c, 0.125, CHCl
3), bibliographical information is-25.8 ° of (c, 0.24, CHCl
3)
Ultimate analysis: C:79.95, H:11.23, C
28H
46O
2Calculated value: C:81.10, H:11.18
FAB-MS: M
++1=415
IR: 3394,3082,2957,2936,2869,1642,1466,1378,1054,964,888v/cm
-1
1HNMR(CDCl
3):?0.737(s,3H,18-CH
3),0.947(d,J=6.5Hz,3H,H-21),1.014(d,J=2.5Hz,3H,H-26),
1.028(d,J=2.5Hz,3H,H-27),3.573(m,1H,H-3),3.610(d,J=11.5Hz,1H,H-19a),
3.821(d,J=11.5Hz,1H,H-19b),4.652(brs,1H,H-28a),4.711(brs,1H,H-28b),
5.747(brd,J=5.0Hz,1H,H-6)
13CNMR(CDCl
3):156.88(C),135.56(C),127.40(CH),105.94(CH
2),71.38(CH),62.75(CH
2),
57.68(CH),56.00(CH),50.41(CH),42.59(C),42.35(CH
2),41.55(C),40.07(CH
2),
35.76(CH),34.71(CH
2),33.82(CH),33.44(CH),33.36(CH
2),32.00(CH
2),
31.25(CH
2),31.01(CH
2),28.22(CH
2),24.08(CH
2),22.00(CH
3),21.87(CH
3),
21.81(CH
2),18.70(CH
3),12.22(CH
3)
Claims (4)
1. 24-methylene radical-courage steroid-5-alkene-3 β, the synthetic method of 19-glycol, it is characterized in that with the synthetic 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone that obtains of Stigmasterol, react under high chloro acid solution's catalysis with N-bromo ethanamide again and generate 3 β-acetoxyl group-courage steroid-5 α-bromo-6 beta-hydroxies-24-ketone, then generate 3 β-acetoxyl group-courage steroid-5 α-bromo-6 by the illumination annulation, 19-epoxy-24-ketone, then epoxy addition generates 3 β-acetoxyl group-courage steroid-5-alkene-19-hydroxyl-24-ketone, then hydrolysis generates 3 β, 19-dihydroxyl-courage steroid-5-alkene-24-ketone, at last 24 carbonyls on the side chain are changed into methylene radical, obtain the purpose product.
2. method according to claim 1 is characterized in that concrete steps are:
(1). with Stigmasterol II according to the synthetic 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone III that obtains of existent method;
(2). III is dissolved in the dioxane solution, be chilled to 10~15 ℃, the high chloro acid solution who adds catalytic amount, lucifuge adds the N-bromo ethanamide of 1~1.4 times of weight in batches in 30~40 minutes, and room temperature continued stirring reaction 30~40 minutes, the sodium sulfite aqueous solution stopped reaction, dichloromethane extraction, removal of solvent under reduced pressure obtains a white solid, silica gel column chromatography, and recrystallizing methanol obtains 3 β-acetoxyl group-courage steroid-5 α-bromo-6 beta-hydroxies-24-ketone IV;
(3). product IV in the previous step or white solid are dissolved in the mixed solvent of benzene/cyclohexane=1/3~1/2 volume ratio, the lead tetra-acetate that adds 5~10 times of weight, the iodine of 1~1.2 times of weight, the lime carbonate of 2~3 times of weight, illumination reaction is 5~7 hours under the protection of inert gas, cooling back sherwood oil and ethyl acetate extraction, removal of solvent under reduced pressure obtains a light yellow solid, silica gel column chromatography, recrystallizing methanol obtain 3 β-acetoxyl group-courage steroid-5 α-bromo-6,19-epoxy-24-ketone V;
(4). the product V in the previous step or light yellow solid be dissolved in 95% the ethanolic soln, the zinc powder that adds 3~5 times of weight, stirring and refluxing 5~7 hours, cooled and filtered, removal of solvent under reduced pressure obtains a light yellow solid, silica gel column chromatography, recrystallizing methanol obtain 3 β-acetoxyl group-courage steroid-5-alkene-19-hydroxyl-24-ketone VI;
(5). product VI in the previous step or light yellow solid are dissolved in the tetrahydrofuran solution, and adding concentration is the potassium hydroxide methanol solution of 2~3%wt, and the consumption of potassium hydroxide is 1~3 times of VI weight; Reflux 10~15 minutes, cooling back removal of solvent under reduced pressure, ethyl acetate extraction, removal of solvent under reduced pressure obtains a light yellow solid, silica gel column chromatography, recrystallizing methanol obtains 3 β, 19-dihydroxyl-courage steroid-5-alkene-24-ketone VII;
(6). under protection of inert gas; the anhydrous dimethyl sulfoxide solution of 5mg/mL~10mg/mL sodium hydride is heated to 70~80 ℃ of stirrings 35~45 minutes; be cooled to the methyl triphenyl phosphonium iodide or the methyltriphenylphosphonium bromide that add 5~8 times of sodium hydride weight after the room temperature; stir after 10~15 minutes; product VII in the previous step of 0.5~1.0 times of sodium hydride weight of adding; be warming up to 70~80 ℃ of stirring reactions 1~2 hour; add the frozen water stopped reaction after being cooled to room temperature; extracted with diethyl ether; removal of solvent under reduced pressure obtains a light yellow solid; silica gel column chromatography, recrystallizing methanol obtain purpose product 24-methylene radical-courage steroid-5-alkene-3 β, 19-glycol.
3. method according to claim 2, the concentration that it is characterized in that used high chloro acid solution in the step (2) is 5%~10%wt, consumption is 1%~5%mole of III.
4. according to claim 2 or 3 described methods, it is characterized in that methyl triphenyl phosphonium iodide or methyltriphenylphosphonium bromide used in the step (6), and VII, respectively with adding again after the anhydrous dimethyl sulfoxide dissolving.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 03114287 CN1448399A (en) | 2003-04-24 | 2003-04-24 | Synthetic method of 24-methylene-cholesterol-5-alkenyl-3 beta, 19-glycol |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 03114287 CN1448399A (en) | 2003-04-24 | 2003-04-24 | Synthetic method of 24-methylene-cholesterol-5-alkenyl-3 beta, 19-glycol |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1448399A true CN1448399A (en) | 2003-10-15 |
Family
ID=28684103
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN 03114287 Pending CN1448399A (en) | 2003-04-24 | 2003-04-24 | Synthetic method of 24-methylene-cholesterol-5-alkenyl-3 beta, 19-glycol |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN1448399A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007076656A1 (en) * | 2005-12-31 | 2007-07-12 | Sun Yat-Sen University | METHOD FOR SYNTHESIS OF CHOLEST-5-EN-3β,19-DIHYDROXY-24-ONE AND ITS DERIVATIVES |
CN100436474C (en) * | 2005-12-31 | 2008-11-26 | 中山大学 | Process for synthesizing cholester-3 bata, 5 alpha, 6 bata, 19-tetrahydroxy-24-one and derivative |
CN100436475C (en) * | 2005-12-31 | 2008-11-26 | 中山大学 | Process for synthesizing cholester-5-ylene-3bata-hydroxy-24-one and derivative |
-
2003
- 2003-04-24 CN CN 03114287 patent/CN1448399A/en active Pending
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007076656A1 (en) * | 2005-12-31 | 2007-07-12 | Sun Yat-Sen University | METHOD FOR SYNTHESIS OF CHOLEST-5-EN-3β,19-DIHYDROXY-24-ONE AND ITS DERIVATIVES |
CN100410270C (en) * | 2005-12-31 | 2008-08-13 | 中山大学 | Synthesis method of cholesterol-5-olefin-3 beta,19-dihydroxy-24-ketone and derivative |
CN100436474C (en) * | 2005-12-31 | 2008-11-26 | 中山大学 | Process for synthesizing cholester-3 bata, 5 alpha, 6 bata, 19-tetrahydroxy-24-one and derivative |
CN100436475C (en) * | 2005-12-31 | 2008-11-26 | 中山大学 | Process for synthesizing cholester-5-ylene-3bata-hydroxy-24-one and derivative |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1035820C (en) | Process for the preparation of chlorosulafate and sulfamate derivatives of 2,3:4,5-bis-0-(1-methylethylidene)-beta-D-fructoryranose and(1-methylcyclohexyl)methanol | |
KR19980018088A (en) | Stereoselective Preparation of 4-acetoxyazetidinone | |
CN1617875A (en) | Crystalline cefdinir potassium dihydrate | |
CN108675976A (en) | A kind of halogenated glucose carbon glycosides of 6- and its preparation method and application | |
CN1699395A (en) | Process for preparing perdnisolone derivatives by one-pot method | |
CN1448399A (en) | Synthetic method of 24-methylene-cholesterol-5-alkenyl-3 beta, 19-glycol | |
CN1448400A (en) | Synthetic method of 24-methylene-cholesterol-3 beta, 5 alpha, 6 beta,19-tetraalcohol | |
JPH07316188A (en) | Production of oleanolic acid derivative | |
CN1388807A (en) | Penicillin crystal and process for producing the same | |
CN1189152A (en) | Process for producing of enantiomerically-pure azetidein-2-carboxylic acid | |
CN1583781A (en) | Synthesis of 3 beta, 7 beta, 19-tricarboxy-5-ene-cholestane | |
DE3618538A1 (en) | OPTICALLY ACTIVE CARBACYCLIN INTERMEDIATES AND METHOD FOR THE PRODUCTION THEREOF | |
CN1583782A (en) | Synthesis of 24-submethyl-cholesterol-5-ene-3 beta, 7 beta, 19-trialcohol | |
JPH085866B2 (en) | Novel aconitine compounds and analgesic / anti-inflammatory agents | |
CN1114612C (en) | Process for synthesizing long-acting rapin lactones | |
CN1027976C (en) | Synthetizing technique of analogue of rape lactone | |
CN113683650A (en) | Preparation method of beta-D- (1,4) -mannuronic acid oligosaccharide and intermediate thereof | |
CN1269827C (en) | Method for synthesizing iridium (III) triacetylacetonate | |
CN1202110C (en) | Yiseman derivative and its preparation method | |
CN1249046C (en) | Method for producing L-(R) propylidene glycerin | |
CN1235907C (en) | Syntehsis method plant sterol or/and plant steroid alkanol-beta-D-glucoside compound | |
CN1256341C (en) | Synthesis of rhodiola glycoside compound | |
FR2498607A1 (en) | NEW PROCESS FOR THE PREPARATION OF 17A-HYDROXY 17B-HYDROXYACETYL STEROIDS, CORRESPONDING INTERMEDIATE PRODUCTS AND FINAL PRODUCTS OBTAINED | |
CN1228340C (en) | Method for purifying 20(S)-camptothecin | |
JP3682291B2 (en) | Method for producing oleanolic acid derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |