CN100389123C - Synthesis of 26-bromo-16, 22-dioxy-cholesterol compounds - Google Patents
Synthesis of 26-bromo-16, 22-dioxy-cholesterol compounds Download PDFInfo
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- CN100389123C CN100389123C CNB2006100292522A CN200610029252A CN100389123C CN 100389123 C CN100389123 C CN 100389123C CN B2006100292522 A CNB2006100292522 A CN B2006100292522A CN 200610029252 A CN200610029252 A CN 200610029252A CN 100389123 C CN100389123 C CN 100389123C
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- China
- Prior art keywords
- compound
- oac
- acetic acid
- bromo
- hydrogen bromide
- Prior art date
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- 238000003786 synthesis reaction Methods 0.000 title abstract description 20
- 230000015572 biosynthetic process Effects 0.000 title abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 12
- 150000003431 steroids Chemical class 0.000 claims abstract description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- -1 methoxymethylene Chemical group 0.000 claims description 15
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 claims description 12
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 claims description 12
- 229940125782 compound 2 Drugs 0.000 claims description 10
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 8
- 230000003647 oxidation Effects 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- WIERHVRLMSNHPH-NOIOWZGKSA-N (3S,8S,9S,10R,13S,14S,17R)-17-[(2S)-7-bromo-6-methyl-3-oxoheptan-2-yl]-3-hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,17-dodecahydrocyclopenta[a]phenanthren-16-one Chemical class BrCC(CCC([C@H]([C@H]1C(C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)=O)C)=O)C WIERHVRLMSNHPH-NOIOWZGKSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 6
- NWMIYTWHUDFRPL-UHFFFAOYSA-N sapogenin Natural products COC(=O)C1(CO)C(O)CCC2(C)C1CCC3(C)C2CC=C4C5C(C)(O)C(C)CCC5(CCC34C)C(=O)O NWMIYTWHUDFRPL-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 5
- 229940125904 compound 1 Drugs 0.000 claims description 5
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
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- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
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- 238000010189 synthetic method Methods 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
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- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 17
- MPXTYZZFIJTPPA-UHFFFAOYSA-N 3beta,16beta,17alpha-trihydroxycholest-5-en-22-one 16-O-(2-O-(4-methoxybenzoyl)-beta-D-xylopyranosyl)-(1-3)-(2-O-acetyl-alpha-arabinopyranoside) Natural products C1=CC(OC)=CC=C1C(=O)OC1C(OC2C(C(OC3C(C4(C)CCC5C6(C)CCC(O)CC6=CCC5C4C3)(O)C(C)C(=O)CCC(C)C)OCC2O)OC(C)=O)OCC(O)C1O MPXTYZZFIJTPPA-UHFFFAOYSA-N 0.000 abstract description 10
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- 238000009776 industrial production Methods 0.000 abstract description 2
- MPXTYZZFIJTPPA-MKQTXCTDSA-N [(2s,3r,4s,5r)-2-[(2s,3r,4s,5s)-3-acetyloxy-2-[[(3s,8r,9s,10r,13s,14s,16s,17s)-3,17-dihydroxy-10,13-dimethyl-17-[(2s)-6-methyl-3-oxoheptan-2-yl]-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-16-yl]oxy]-5-hydroxyoxan-4-yl]oxy-4,5-dihydro Chemical compound C1=CC(OC)=CC=C1C(=O)O[C@H]1[C@H](O[C@@H]2[C@H]([C@H](O[C@@H]3[C@]([C@@]4(C)CC[C@@H]5[C@@]6(C)CC[C@H](O)CC6=CC[C@H]5[C@@H]4C3)(O)[C@H](C)C(=O)CCC(C)C)OC[C@@H]2O)OC(C)=O)OC[C@@H](O)[C@@H]1O MPXTYZZFIJTPPA-MKQTXCTDSA-N 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
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- 239000000243 solution Substances 0.000 description 21
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- MPXTYZZFIJTPPA-JOQRFCRPSA-N [(2s,3r,4s,5r)-2-[(2s,3r,4s,5s)-3-acetyloxy-2-[[(3r,8s,9r,10r,13s,14r,16r,17s)-3,17-dihydroxy-10,13-dimethyl-17-[(2s)-6-methyl-3-oxoheptan-2-yl]-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-16-yl]oxy]-5-hydroxyoxan-4-yl]oxy-4,5-dihydro Chemical compound C1=CC(OC)=CC=C1C(=O)O[C@H]1[C@H](O[C@@H]2[C@H]([C@H](O[C@H]3[C@]([C@@]4(C)CC[C@H]5[C@@]6(C)CC[C@@H](O)CC6=CC[C@@H]5[C@H]4C3)(O)[C@H](C)C(=O)CCC(C)C)OC[C@@H]2O)OC(C)=O)OC[C@@H](O)[C@@H]1O MPXTYZZFIJTPPA-JOQRFCRPSA-N 0.000 description 9
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 235000016547 Ornithogalum umbellatum Nutrition 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
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- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Abstract
The present invention relates to the synthesis process of 26-bromo-16, 22-dioxy-cholesterol compounds. Under the action of hydrogen bromide-acetic solution, steroid E/F ketal spiro compound is ring opening reacted and has its 26 site bromized to obtain 26-bromo-16, 22-dioxy-cholesterol compounds. The 26-bromo-16, 22-dioxy-cholesterol compounds may be debrominated to obtain cholest compounds, which may be further synthesized into OSW-1 aglycones and their analogs. The synthesis process of the present invention has convenient operation and is suitable for industrial production.
Description
Technical Field
The invention relates to a synthetic method of 26-bromo-16, 22-dioxo-cholesterol compound, namely, a 16-bit oxidation product of steroid sapogenin or derivatives thereof reacts with hydrogen bromide-acetic acid solution to obtain a series of steroid E/F ring-opened 26-bromo compounds; the compound is debrominated to obtain 16, 22-dioxo-cholesterol compound which can be further synthesized into OSW-1 and analogues thereof.
Technical Field
The star-of-Bethlehem saponin (OSW-1) is a saponin with cholesterol skeleton separated from the underground bulb of Ornithogalum saunderside, which is a very green ornamental plant native to south Africa, and has strong killing power to various malignant tumor cells, and the efficacy is 10-100 times higher than that of several anticancer drugs such as Mitomycin (Mitomycin), Adriamycin (Adriamycin), Taxol (Taxol) and the like which are clinically used at present. More importantly, although OSW-1 has good activity against many malignant tumor cells, it has little toxicity to normal lung cells (IC)501500nM) (see Phytochemistry, 1992, 31, 3969; bioorg.&Med.chem.lett.1997, 7, 633) with the following specific structure:
because OSW-1 has extremely strong anticancer activity and a unique chemical structure, and plant resources containing the compound are few, chemical synthesis of the compound has attracted extensive attention. However, most groups have synthesized OSW-1 aglycone starting from dehydroepiandrosterone (see tetra. Lett.1998, 39, 1099; J. org.chem.1999, 64, 202; J. arm.chem.Soc.2002, 124, 6576; CarbohydrateRes.2002, 337), whereas dehydroepiandrosterone is obtained by six-step degradation of natural Diosgenin (Diosgenin) with a total yield of 25-50% (see J.am.chem.Soc.1940, 62, 3350; J.org.chem.1956, 21, 520).
Tabanese et al, using diosgenin (diosgenin) as a starting material, fully utilize the complete carbon skeleton of steroidal sapogenin to synthesize rhodea ornata saponin (OSW-1) (CN 02145066.8; tetra. Lett.2003, 44, 9375; CN 200610026473.4) and pennogenin (CN 02150907.7; Chinese Science in China Ser.B Chemistry, 2004, 47, 142), respectively, and reported synthetic routes are as follows:
synthesis of OSW-1:
as can be seen from the above synthetic routes, the synthesis of the diketone compound A from diosgenin requires reduction to open the F ring and then oxidation to open the E ring, while the synthesis of the diketone compound B requires oxidation to open only the E/F ring; the operation for synthesizing the diketone compound A is complicated, the transformation can be complete only by repeated oxidation and separation, and the diketone compound B can be obtained from the diosgenin with the total yield of more than 70 percent; in order to synthesize both natural products OSW-1 and pennogenin more efficiently, Tianweisheng et al have integrated two synthetic routes to convert a derivative compound D of diketone B, which is easy to prepare in large quantities, into a derivative compound C of diketone A, which is difficult to prepare in large quantities (see CN 200610025917.2):
however, the above route is long, the operation is complicated, the total yield is low, and the method is not favorable for mass production of the compound C.
The synthesis of 26-bromo-16, 22-dioxo-cholesterol compounds was also reported by agravin et al, but with a relatively low efficiency (see CN 02150907.7):
26-bromo-16, 22-dioxo-cholesterol compounds 26-bromine can be removed by literature methods to obtain cholesteric compound A and its analogues (see J.Med.chem.1984, 27, 1690; tetra.Lett.1994, 35, 935).
The invention starts from the 16-site oxidation product of the steroid sapogenin or the derivative thereof, and can conveniently prepare the 26-bromo-16, 22-dioxo-cholesterol compound which can be further used for synthesizing the compound A and the analogue thereof, thereby realizing the accumulation of the amount of key compounds in the route for synthesizing the OSW-1.
Disclosure of Invention
The invention aims to provide a method for synthesizing 26-bromo-16, 22-dioxo-cholesterol compounds.
The synthesis method of the 26-bromo-16, 22-dioxo-cholesterol compound comprises the following steps:
dissolving a 16-site oxidation product 1 of the steroid sapogenin or the derivative thereof in an aprotic solvent, acetic acid or a mixed solvent of the aprotic solvent and the acetic acid, adding a hydrogen bromide-acetic acid solution, and stirring the mixture at a reflux temperature of-20 ℃ for 0.5-24 h to obtain a 26-bromo-16, 22-dioxo-cholesterol compound 2, wherein the molar ratio of the compound 1 to the hydrogen bromide is 1: 1-10; the hydrogen bromide-acetic acid solution is an acetic acid solution containing 1-50% of hydrogen bromide; the aprotic solvent is dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane (dioxane), benzene, toluene, acetonitrile or a mixed solvent thereof;
the structural formulas of the compounds 1 and 2 are shown as follows:
wherein MOM is methoxymethylene, Bn is benzyl, PMB is p-methoxybenzyl, THP is tetrahydropyranyl, Tr is trityl, Ac is acetyl, Bz is benzoyl, Piv is pivaloyl, TMS is trimethylsilyl, TES is triethylsilyl, TBS is t-butyldimethylsilyl, TBDPS is t-butyldiphenylsilyl, and X is halogen.
Compound 2 cholesteric Compound A and its analogues can be synthesized by literature methods (see J.Med.chem.1984, 27, 1690; tetra.Lett.1994, 35, 935) to achieve accumulation of the amount of key compounds in the synthetic OSW-1 route. .
The invention starts from the 16-position oxidation product of the steroid sapogenin or the derivative thereof, and conveniently prepares the 26-bromo-16, 22-dioxo-cholesterol compound, thereby not only having simple and convenient operation, but also being suitable for industrial production and having great superiority compared with the prior method. OSW-1 aglycone and analogues thereof can be conveniently synthesized by the methods of the literature references (see CN 02145066.8; CN 200610025917.2; CN 200610026473.4).
Detailed description of the invention
The following detailed description will help to understand the present invention, but does not limit the content of the present invention.
Compounds 1a, 1d, 1e, 1f, 1g of the invention were synthesized according to the methods described in the references (see CN 02150907.7; tetra. Lett.1994, 35, 935).
EXAMPLE 1 Synthesis of Compounds 1b and 1c
1.861g of Compound 1a are dissolved in 50ml of absolute ethanol, 0.411g of NH are added4Cl (2.6eq.) and 0.966g zinc powder (5.0eq.) were refluxed for 0.5h, the fluorescence spot disappeared and the reaction was good. Filtering with diatomite, washing the filter cake with anhydrous ethanol, spin-drying the filtrate, and separating by flash column chromatography (PE: EA is 40: 1-10: 1) to obtain 1b0.139g (10.0%) of compound and 1c 1.314g (89.0%).
Compound 1 b: c29H44O4；FW 472；mp 150℃；
1H-NMR(CDCl3，300 MHz)δ：5.39(1H，d，J＝4.8Hz，6-H)，4.63-4.57(1H，m，3-H)，3.61-3.56(3H，m，26-H and 16-OH)，1.03(3H，s，19-Me)，1.01(3H，d，J＝6.9Hz，21-Me)，0.83(3H，d，J＝6.3Hz，27-Me)，0.76(3H，s，18-Me)；
MS(EI)：454(M+-18，11.1％)，43(100％).
Compound 1 c: c31H48O5；FW 500；mp 145-148℃；
1H-NMR(CDCl3，300 MHz)δ：5.38(1H，d，J＝4.8Hz，6-H)，4.62-4.50(1H，m，3-H)，3.70-3.36(4H，m，26-H and 16-OCH 2 CH3)，2.03(3H，s，OAc)，1.21(3H，t，J＝7.2Hz，16-OCH2 CH 3 )，1.03(3H，s，19-Me)，1.01(3H，d，J＝6.6Hz，21-Me)，0.81(3H，d，J＝7.8Hz，27-Me)，0.78(3H，s，18-Me).
EXAMPLE 2 Synthesis of Compound 2a
0.5g of Compound 1a is taken in 5ml of CH2Cl2Dissolving, adding 0.2ml 30% hydrogen bromide-acetic acid solution, reacting at room temperature, tracking by TLC until the reaction is completed, taking about 2h, and adding saturated NaHCO3Quenching the solution, aqueous phase with CH2Cl2Extracting, washing the combined organic phase with saturated brine, anhydrous Na2SO4Drying, filtering and concentrating the crude product, and separating by column chromatography to obtain 0.415g of compound 2a (76% yield).
Compound 2 a: c29H43Br3O4；FW 692；
1H-NMR(CDCl3，300 MHz)δ：5.50(1H，t，J＝5.4Hz，6-H)，4.83(1H，m，3-H)，3.43(2H，d，J＝5.2Hz，26-H)，2.03(3H，s，OAc)，1.04(6H，S，18，19-CH3)；
IR v：2946，1736，1377，1242，1029 cm-1.
EXAMPLE 3 Synthesis of Compound 2b
The method comprises the following steps: synthesis of Compound 2b from Compound 1b
0.299g Compound 1b in 5ml CH2C12Adding 0.20ml of 33% hydrogen bromide-acetic acid solution, reacting at room temperature for 1.5h, and completing the reaction to obtain saturated NaHCO3Quenching the solution, aqueous phase with CH2Cl2Extracting, washing the combined organic phase with saturated brine, anhydrous Na2SO4The crude product obtained by drying, filtration and concentration was isolated by column chromatography to give 0.314g of compound 2b (92.8% yield).
The second method comprises the following steps: synthesis of Compound 2b from Compound 1c
0.316g of Compound 1c are dissolved in 5ml of CH2Cl2Adding 0.30ml of 33% hydrogen bromide-acetic acid solution, reacting at room temperature for 3.0h, and completing the reaction, wherein the saturated NaHCO is3Quenching the solution, aqueous phase with CH2Cl2Extracting, washing the combined organic phase with saturated brine, anhydrous Na2SO4The crude product obtained by drying, filtration and concentration was isolated by column chromatography to give 0.295g of compound 2b (87.4% yield).
Compound 2 b: c29H43BrO4；FW 534；
1H-NMR(CDCl3，300 MHz)δ：5.38(1H，t，J＝4.4Hz，6-H)，4.62(1H，m，3-H)，3.45(2H，d，J＝5.2Hz，26-H)，2.17(3H，s，OAc)，1.04(6H，s，18，19-CH3)；
MS(ESI)：536(M++2)；
IR v：2960，1728，1456，1375，1247，1021cm-1；
Theoretical values of elemental analysis C65.04%, H8.09%,
measured C65.46%, H8.42%.
EXAMPLE 4 Synthesis of Compound 2d
0.3g of compound 1d is taken up in 10ml of CH2Cl2Dissolving, adding 0.22ml 33% hydrogen bromide-acetic acid solution (2.0eq.), reacting at room temperature, tracking by TLC until the reaction is completed, and taking 1.5h, and adding saturated NaHCO3Quenching the solution, aqueous phase with CH2Cl2Extracting, washing the combined organic phase with saturated brine, anhydrous Na2SO4Drying, filtering and concentrating the crude product obtained was isolated by column chromatography (PE: EA: 16: 1) to yield 0.306g of compound 2d (89% yield).
Compound 2 d: c29H45BrO4；FW 536；
1HNMR(CDCl3，300 MHz)δ：4.67(1H，m，3-H)，3.34(1H，m，26-H)，2.77(1H，m，20-H)，2.03(3H，s，OAc)，1.13(3H，d，J＝6.4 Hz，21-CH3)，0.91(3H，d，J＝6.8 Hz，27-CH3)，0.85(3H，s，19-CH3)，0.77(3H，s，18-CH3)；
MS(ESI)：538(M++2)；
IR v：2960，1728，1020cm-1；
Theoretical values of elemental analysis C64.79%, H8.44%,
measurement C64.76%, H8.49%.
EXAMPLE 5 Synthesis of Compound 2e
0.433g of Compound 1e in 5ml CH2Cl2Adding 0.15ml of 37% hydrogen bromide-acetic acid solution, reacting at room temperature, tracking by TLC until the reaction is finished, and saturating by NaHCO3Quenching the solution, aqueous phase with CH2Cl2Extracting, washing the combined organic phase with saturated brine, anhydrous Na2SO4Drying, filtering and concentrating the crude product, and separating by column chromatography to obtain 0.357g of compound 2e (75.6% yield).
Compound 2 e: c43H59BrO4Si；FW 746；
1HNMR(CDCl3，300 MHz)δ：7.69-7.65 and 7.40-7.36(10H，m，Ar)，3.49(1H，m，3-H)，3.31(m，2H，26-H)，1.06(9H，s，t-Bu)，1.10(d，3H，J＝6.9Hz，21-H)，0.96(d，3H，J＝5.4Hz，27-Me)，0.86(s，3H，18-Me)，0.85(s，3H，19-Me)；
MS(ESI)：748(M++2)；
Theoretical values of elemental analysis C69.05%, H7.95%,
measurement C68.83%, H8.07%.
EXAMPLE 6 Synthesis of Compound 2f
0.339g of compound 1f is taken and 5ml of CH is used2Cl2Dissolving, adding 0.35ml of 33% hydrogen bromide-acetic acid solution,reaction at room temperature, TLC tracing to completion of reaction, saturated NaHCO3Quenching the solution, aqueous phase with CH2Cl2Extracting, washing the combined organic phase with saturated brine, anhydrous Na2SO4Drying, filtering and concentrating the crude product, and separating by column chromatography to obtain compound 2f0.194g (51.3% yield).
Compound 2 f: c31H51BrO6；FW 598；
1HNMR(CDCl3，300 MHz)δ：4.75-4.71(m，2H，12-OCH 2 OCH3)，4.68(s，2H，3-OCH 2 OCH3)，3.75(m，2H，3-H，12-H)，3.37(s，3H，12-OCH2OCH 3 )，3.35(s，3H，3-OCH2OCH 3 )，3.30(m，2H，26-H)，1.04(d，J＝6.6Hz，3H，21-CH3)，0.96(d，3H，J＝5.4Hz，27-Me)，0.87(s，3H，18-CH3)，0.85(s，3H，19-CH3)；
MS(ESI)：600(M++2)；
Theoretical values of elemental analysis C62.09%, H8.57%,
measurement C62.40%, H8.49%.
EXAMPLE 7 Synthesis of Compound 2g
0.424g of compound 1g is taken, 5ml of CH2Cl2Dissolving, adding 0.20ml 30% hydrogen bromide-acetic acid solution, reacting at room temperature, tracking by TLC until the reaction is completed, and collecting saturated NaHCO3Quenching the solution, aqueous phase with CH2Cl2Extracting, washing the combined organic phase with saturated brine, anhydrous Na2SO4Drying, filtering, and concentratingThe crude product was isolated by column chromatography to give 2g of compound 0.187g (40.4% yield).
Compound 2 g: c41H49BrO7；FW 732；
1HNMR(CDCl3，300MHz)δ：8.03-7.46(10H，m，Ar)，3.99(m，2H，1-H and 3-H)，3.44(1H，m，26-H)，3.04(m，1H，6-H)，1.18(d，3H，J＝6.9Hz，21-H)，1.00(3H，s，19-Me)，0.95(3H，s，18-Me)，0.89(3H，d，J＝6.3Hz，27-Me)；
MS(ESI)：734(M++2)；
Theoretical values of elemental analysis C67.11%, H6.73%,
measurement C67.02%, H6.54%.
EXAMPLE 8 Synthesis of Compound 3a
200mg of Compound 2a was dissolved in 5ml of ethanol, and 180mg (10.0eq.) of zinc powder and 38mg of NH were added4Cl (2.5eq.), reflux heating for 10h, complete reaction, filtration to remove solids, spin-drying ethanol, dissolving the residue with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, concentration to obtain crude reaction product, and flash column chromatography to obtain compound 3a 90mg (68.3% yield).
Compound 3 a: c29H44O4；FW 456；
1H-NMR(CDCl3，300 MHz)δ：5.37(1H，d，J＝5.1Hz，6-H)，4.62(1H，m，3-H)，2.04(3H，s，OAc)，1.06(3H，d，J＝6.0Hz，21-Me)，1.05(3H，s，19-Me)，0.91(6H，d，J＝6.0Hz，26，27-Me)，0.81(3H，s，18-Me)；
MS(EI)：441(M+-15，5.4％)，397(11.5％)，340(100％)；
IR v：1732，1712cm-1.
EXAMPLE 9 Synthesis of Compound 3d
1.072g of Compound 2d are dissolved in 50mL of ethanol, 0.65g (5.0eq) of zinc dust and 0.268g of NH are added4Cl (2.5eq), reflux-heating for 4h to complete the reaction, filtering to remove solids, spin-drying ethanol, dissolving the residue with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating to obtain crude reaction product, and flash column chromatography to obtain compound 3d 0.805mg (87.9% yield).
Compound 3 d: c29H46O4；FW 458；
1H-NMR(CDCl3，300 MHz)δ：4.61(1H，m，3-H)，2.04(3H，s，OAc)，1.06(3H，d，J＝6.0Hz，21-Me)，0.91(6H，d，J＝6.0Hz，26，27-Me)，0.85(3H，s，19-Me))，0.79(3H，s，18-Me)；
Theoretical values of elemental analysis C75.94%, H10.11%,
measured C75.82%, H9.87%.
EXAMPLE 10 Synthesis of Compound 4
2.290g of Compound 3a are dissolved in 35ml of HOAc, and 1.06ml of HSCH are added2CH2SH (2.5eq.), then 1.3ml BF was added dropwise3·Et2O (2.0eq.) and reacting at room temperature for 2.5h, the raw material disappears. Further 20ml of Ac were added2O, the mixture immediately turns from white turbidity to orange-red transparent, and the reaction is finished after 20 min. Adding saturated NaHCO3Solution, then solid NaHCO3Until no bubble emerges, extracting with ethyl acetate, and separating the organic phase with NaHCO3The solution was washed with saturated NaCl solution, MgSO4Drying, filtering, evaporating the solvent under reduced pressure and flash column chromatography (PE: EA: 40: 1) gave compound 4 as a pale yellow viscous oil, 1.830g (63.5%).
Compound 4: c33H50O4S2；FW 574；[α]D28＝2 1.4°(C＝0.433，CHCl3)；
1H-NMR(CDCl3，300 MHz)δ：5.40(1H，d，J＝3.9Hz，6-H)，4.61(1H，m，3-H)，3.68(1H，q，J＝6.9Hz，20-H)，2.98 and 2.81(4H，m，SCH2CH2S)，2.35(3H，s，SAc)，2.04(3H，s，OAc)，1.22(3H，d，J＝7.2Hz，21-Me)，1.05(3H，s，19-Me)，0.98(3H，s，18-Me)，0.87(6H，d，J＝5.7Hz，26，27-Me)；
13C-NMR(CDCl3，75MHz)δ：210.98，195.10，170.51，153.39，139.92，131.03，122.11，73.79，56.49，50.09，48.87，46.84，38.58，38.04，36.74，36.71，35.07，34.39，32.98，31.25，30.59，30.07，29.75，27.62，22.43，22.35，21.39，20.42，19.15，17.14，14.34；
MS(EI)：574(M+，1.2％)，475(M+-99，100％)；
Hrms (maldi): calculated value C33H50O4S2Na: 597.3040, respectively; measurement values: 597.3043, respectively;
IR v：1734，1713，1696cm-1.
EXAMPLE 11 Synthesis of Compound 5
930mg of compound 4 is dissolved in 30ml of absolute ethanol, about 3.5g of W-2 type Raney nickel is added, reaction is carried out at room temperature for 0.5h, the raw material disappears, filtration is carried out, the residue is fully washed by the absolute ethanol, the filtrate is dried by spinning, and flash column chromatography separation is carried out (PE: EA is 20: 1), thus obtaining 641mg (90%) of compound 5 white solid.
Compound 5: c29H44O3；FW 440；
1H-NMR(CDCl3，300 MHz)δ：5.37(2H，br s，6-H and 16-H)，4.61(1H，m，3-H)，3.20(1H，q，J＝6.9Hz，20-H)，2.04(3H，s，OAc)，1.16(3H，d，J＝6.6Hz，21-Me)，1.06(3H，s，19-Me)，0.87(6H，d，J＝6.0Hz，26，27-Me)，0.85(3H，s，18-Me)；
MS(ESI)：441(M++1，100％)；
IR v：1735，1714，1244 cm-1.
Claims (2)
1. A synthetic method of 26-bromo-16, 22-dioxo-cholesterol compounds is characterized by comprising the following steps:
in an aprotic solvent, acetic acid or a mixed solvent of the aprotic solvent and the acetic acid, stirring a steroid sapogenin 16-site oxidation product 1 and a hydrogen bromide-acetic acid solution at a temperature of-20 ℃ to reflux temperature for 0.5 to 24 hours to obtain a 26-bromo-16, 22-dioxo-cholesterol compound 2, wherein the molar ratio of the compound 1 to the hydrogen bromide is 1: 1-10; the hydrogen bromide-acetic acid solution is an acetic acid solution containing 1-50% by weight of hydrogen bromide;
the structural formulas of the compound 1 and the compound 2 are shown as follows:
wherein,
represents upward or downward; r1Is H, OH, OMOM, OTHP, OTr, OAc, OBz, OPiv, OTES, OTBS, OTBDPS or with R2To form a carbonyl group; r2Is H, OH, OMOM, OTHP, OTr, OAc, OBz, OPiv, OTES, OTBS, OTBDPS or with R1To form a carbonyl group; r3Is H or C1-4A hydrocarbon group of (a); r4OH, OMOM, OBn, OPMB, OTHP, OTr, OAc, OBz, OPiv, OTMS, OTES, OTBS or OTBDPS; r5H, OH, OMOM, OBn, OPMB, OTHP, OTr, OAc, OBz, OPiv, OTMS, OTES, OTBS or OTBDPS; r6Is H, OH, OAc, OTMS, X or with R7To form a 5, 6-double bond or a 5, 6-epoxy; r7Is H, OH, OAc, OTMS, X or with R6To form a 5, 6-double bond or a 5, 6-epoxy;
MOM is methoxymethylene, Bn is benzyl, PMB is p-methoxybenzyl, THP is tetrahydropyranyl, Tr is trityl, Ac is acetyl, Bz is benzoyl, Piv is pivaloyl, TMS is trimethylsilyl, TES is triethylsilyl, TBS is tert-butyldimethylsilyl, TBDPS is tert-butyldiphenylsilyl, and X is halogen.
2. A method according to claim 1, characterised in that the aprotic solvent is dichloromethane, chloroform, carbon tetrachloride, dichloroethane, diethyl ether, tetrahydrofuran, 1, 4-dioxane, benzene, toluene, acetonitrile or mixtures thereof.
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| US20060004087A1 (en) * | 2004-07-01 | 2006-01-05 | Wyeth | Tetracyclic compounds as estrogen ligands |
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| GB2133406A (en) * | 1982-12-15 | 1984-07-25 | Armstrong World Ind Inc | Cholesteric liquid crystal compounds useful for preparing polymeric films |
| US5427828A (en) * | 1992-09-24 | 1995-06-27 | Samsung Electron Devices Co., Ltd. | Cholesteric liquid crystal and polymer dispersed liquid crystal display device utilizing the same |
| CN1100729A (en) * | 1993-09-20 | 1995-03-29 | 中国科学院上海有机化学研究所 | Trifluoromethyl steroids and the prepn. method |
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