CN110172078B - 19羟化可托多松衍生物及19-羟基雄烯二酮的制备方法 - Google Patents
19羟化可托多松衍生物及19-羟基雄烯二酮的制备方法 Download PDFInfo
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- CN110172078B CN110172078B CN201910517841.2A CN201910517841A CN110172078B CN 110172078 B CN110172078 B CN 110172078B CN 201910517841 A CN201910517841 A CN 201910517841A CN 110172078 B CN110172078 B CN 110172078B
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- hydroxyandrostenedione
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- XGUHPTGEXRHMQQ-BGJMDTOESA-N 19-hydroxyandrost-4-ene-3,17-dione Chemical compound O=C1CC[C@]2(CO)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 XGUHPTGEXRHMQQ-BGJMDTOESA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims abstract description 10
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 4
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 abstract description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 4
- 230000004048 modification Effects 0.000 abstract description 4
- 238000012986 modification Methods 0.000 abstract description 4
- KMZYFPGBXDCJKA-UHFFFAOYSA-N 1-iodo-7-oxabicyclo[4.1.0]hepta-2,4-diene Chemical compound IC12C(C=CC=C1)O2 KMZYFPGBXDCJKA-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 229940053934 norethindrone Drugs 0.000 abstract description 3
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 abstract description 3
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- 239000003433 contraceptive agent Substances 0.000 abstract description 2
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- 125000001424 substituent group Chemical group 0.000 abstract description 2
- LRPTXRCORNOMTB-UHFFFAOYSA-N [SiH4].I Chemical compound [SiH4].I LRPTXRCORNOMTB-UHFFFAOYSA-N 0.000 abstract 1
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
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- 240000004808 Saccharomyces cerevisiae Species 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 241001544321 Thanatephorus cucumeris Species 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- FSAJRXGMUISOIW-UHFFFAOYSA-N bismuth sodium Chemical compound [Na].[Bi] FSAJRXGMUISOIW-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 229940041514 candida albicans extract Drugs 0.000 description 3
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- 239000011780 sodium chloride Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 3
- 239000012138 yeast extract Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
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- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
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- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 229910001447 ferric ion Inorganic materials 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- 235000009518 sodium iodide Nutrition 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 description 1
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- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 1
- FRXSZNDVFUDTIR-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydroquinoline Chemical class N1CCCC2=CC(OC)=CC=C21 FRXSZNDVFUDTIR-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 1
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- 238000006392 deoxygenation reaction Methods 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
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- IMBKASBLAKCLEM-UHFFFAOYSA-L ferrous ammonium sulfate (anhydrous) Chemical compound [NH4+].[NH4+].[Fe+2].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O IMBKASBLAKCLEM-UHFFFAOYSA-L 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
本发明公开了一种19羟化可托多松衍生物及19‑羟基雄烯二酮的制备方法，属于有机合成及药学领域。本发明以19‑羟基可托多松为原料，在双氧水、三甲基碘硅烷、钯碳、二氯二氰基苯醌、氧化碘苯、硼氢化钠和高碘酸钠等试剂的分别作用下，使19‑羟基可托多松进行如下反应中的至少一种：对19‑羟基可托多松A环、B环进行结构修饰；使19‑羟基可托多松的17、21和/或19位羟基被取代基取代；切除19‑羟基可托多松的侧链。本发明极大程度地提高了炔诺酮类避孕药合成的必需中间体19‑羟基雄烯二酮的制备效率，降低了药物生产成本。
Description
技术领域
本发明涉及有机合成及药学领域，更具体的涉及19羟化可托多松衍生物及19-羟基雄烯二酮的制备方法。
背景技术
甾体化合物又称类固醇，此类化合物种类繁多，在临床上占有重要的地位([1]Fernandes P.,Cruz A.,Angelova B.,Pinheiro H.M.,Cabral J.M.S.Enzyme MicrobTechnol.2003,32,688-705.[2]Tong W.Y.,Dong X.Recent Pat.Biotechnol.,2009,3,141-153.[3]Donova M.V.,Egorova O.V.Appl.Microbiol.Biotechnol.,2012,94,1423-1447.[4]Bhatti H.N.,Khera R.A.Steroids,2012,77,1267-1290)，根据其功能大致可以分为性激素、皮质激素和蛋白同化激素。目前，临床上使用的甾体药物多达300余种，占全部临床使用药物总数的15％左右。
甾体的基本骨架由四个稠合的碳环(A-D环)和两个角甲基(C18，C19)组成。C19-甲基由于处于甾体平面上方，对甾体和靶蛋白的结合具有关键的作用，因此其变化往往会产生强烈的生理活性，具有重要的药学价值([5]McRobb L.,Handelsman,D.J.,Kazlauskas,R.,Wilkinson,S.,McLeod,M.D.,Heather,A.K.J.Steroid Biochem.Mol.Biol.2008,110,39-47.)，其中19位羟基修饰药物和19-去甲基类药物以炔诺酮、双醋炔诺醇、醋炔醚、炔雌醇、雌二醇、雌三醇、戊酸雌二醇和苯丙酸诺龙等药物为典型代表；然而，由于周围化学环境形成较大的位阻及自身的反应惰性，C19-甲基载体骨架在化学和生物学上都难以被修饰。迄今为止，通过化学的手段实现甾体19位C-H键的羟化都只能通过间接的方法。常用的策略有Suárez反应、Norrish-Type II光反应和Barton亚硝酸酯光反应。然而，这些方法大多需要预先合成特殊的官能团、反应条件苛刻、收率低等原因，极大地限制了这些方法的使用范围。因此甾体C19羟基可托多松类似物的合成是一个非常关键，也极具意义的工作，亟需发展直接的、高效的转化方法。
发明内容
本发明的目的在于解决现有技术中存在的缺点与不足，提供一种19羟化可托多松衍生物及19-羟基雄烯二酮的制备方法。
本发明的目的通过下述技术方案实现：
一种19羟化可托多松衍生物及19-羟基雄烯二酮的制备方法，其反应通式如下：
所述的制备方法包括如下步骤：以19-羟基可托多松为原料，使其进行如下反应中的至少一种：对19-羟基可托多松A环、B环进行结构修饰；使19-羟基可托多松的17、21和/或19位羟基被取代基取代；切除19-羟基可托多松的侧链。
所述的19羟化可托多松衍生物具有通式I所表示的结构式：
通式I中，R1、R2、R3、R4可以为氢、羟基及羟基保护基乙酰基、苯甲酰基、苄基、甲基、硅基等基团中的一种；碳1、2位和/或碳4、5位为双键、单键、环氧等结构；除上述规定基团和修饰以外，甾体骨架A环羰基还原、双键加成及氧化等，B环C7引入羟基及羟基保护基酰基、烷基醚、硅基等，C环C11、C12氧化和侧链羰基还原、脱氧等修饰也包含。
所述的19-羟基雄烯二酮的结构为：
进一步地，所述的19羟化可托多松衍生物及19-羟基雄烯二酮的制备方法，包括如下步骤：将19-羟基可托多松溶于溶剂中，加入下述试剂或试剂组合中的一种进行一步或多步反应得到19羟化可托多松衍生物或19-羟基雄烯二酮：
双氧水、氢氧化钠；
钯碳；
钯碳、乙酸酐、4-二甲氨基吡啶；
乙酸酐、4-二甲氨基吡啶、二甲基叔丁基氯硅烷、二氯二氰基苯醌；
乙酸酐、三甲基氯硅烷、碘化钠、氧化碘苯；
三甲基碘硅烷；
硼氢化钠、高碘酸钠/高碘酸；
甲醇钠；
铋酸钠。
所述的溶剂包括甲醇、乙醇、乙酸、二氯甲烷、1,4-二氧六环、乙酸酐、乙腈、丙酮、水和乙酸等。
进一步地，所述的制备方法用于制备19-羟基雄烯二酮时，包括如下步骤：
将19-羟基可托多松溶解于由二氯甲烷和乙醇按体积比1:10～10:1组成的溶剂中，加入硼氢化钠在-78～70℃进行反应，反应结束后，加入丙酮淬灭反应，再加入水和高碘酸钠或者高碘酸于-78～70℃进行反应，得到19-羟基雄烯二酮；
或：将19-羟基可托多松溶解于二氧六环中，加入甲醇钠，回流进行反应，得到19-羟基雄烯二酮；
或：将19-羟基可托多松溶解于由乙酸中，加入铋酸钠进行反应，得到19-羟基雄烯二酮。
本发明的方法可以高效地制备19羟化可托多松衍生物及19-羟基雄烯二酮，和现有技术相比，本发明具有下列优势：
本发明方法所制备的19羟化可托多松衍生物，结构多式多样，是Stereonsteroid类、Sclerosteriod类和Ceratosteriod类等诸多天然活性产物的重要前体，具有潜在的成药价值；19-羟基雄烯二酮，是炔诺酮类避孕药合成的必需中间体，本发明方法优化了原有工业上的合成步骤，极大程度地提高了其制备效率，使原料药的成本急剧降低，为工业化生产奠定了良好的基础。
具体实施方式
下面通过实施例对本发明给予进一步说明，值得注意的是，本发明的实施方式不仅限于下述的实施例。
实施例1：19-羟基-可托多松的制备
(1)将菌株Thanatephorus cucumeris NBRC 6298接种于PDA培养基(土豆200g/L，葡萄糖20g/L和琼脂15g/L)上于30℃恒温培养箱进行活化培养。6-10天后平板上生长良好的菌株接种于含有100mL酵母液体培养基(葡萄糖25g/L，酵母膏20g/L)的250mL锥形瓶中，在30℃和200rpm条件下大约生长2-3天，取5mL生长良好的菌液转接于含有100mL新鲜酵母液体培养基的250mL锥形瓶中，继续在相同条件下培养2-3天，将25mg可托多松和硫酸亚铁铵投入到该菌体培养基中(铁离子终浓度1.5mmol/L)，继续培养转化约3-4天直至转化率达到最高，得到化合物19-羟基-可托多松(转化率45％)。
HRMS(ESI-TOF):calcd for C21H25NaNSO4[M+Na+]410.1397,found 410.1410.1HNMR(400MHz,CDCl3):δ7.58–7.55(m,2H),7.11–7.08(m,2H),7.02–6.95(m,2H),6.75(d,J＝8.0Hz,1H),5.59(dd,J＝10.1,3.9Hz,1H),4.14(qd,J＝7.1,2.7Hz,2H),3.80–3.73(m,1H),3.69–3.62(m,1H),2.78–2.66(m,3H),2.60(dd,J＝14.6,3.9Hz,1H),2.35(s,3H),2.31(s,3H),1.28(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3):δ170.25,143.25,137.25,134.07,133.93,133.11,129.39,128.73,127.18,127.15,126.95,61.14,51.52,41.03,39.10,26.54,21.56,18.81,14.29.
(2)将菌株Thanatephorus cucumeris NBRC 6298接种于PDA培养基上于30℃恒温培养箱进行活化培养。6-10天后平板上生长良好的菌株接种于含有100mL酵母液体培养基(葡萄糖25g/L，酵母膏20g/L)的250mL锥形瓶中，在30℃和200rpm条件下大约生长2-3天，取5mL生长良好的菌液转接于含有100mL新鲜酵母液体培养基的250mL锥形瓶中，继续在相同条件下培养2-3天，将25mg 17-乙酰基-可托多松和硫酸亚铁铵投入到该菌体培养基中(铁离子终浓度1.5mmol/L)，继续培养转化约3-4天直至转化率达到最高，得到化合物19-羟基-可托多松(转化率81％)。
(3)将菌株Thanatephorus cucumeris NBRC 6298接种于PDA培养基上于30℃恒温培养箱进行活化培养。6-10天后平板上生长良好的菌株接种于含有100mL酵母液体培养基(葡萄糖25g/L，酵母膏20g/L)的250mL锥形瓶中，在30℃和200rpm条件下大约生长2-3天，取5mL生长良好的菌液转接于含有100mL新鲜酵母液体培养基的250mL锥形瓶中，继续在相同条件下培养2-3天，将25mg 21-乙酰基-可托多松和硫酸亚铁铵投入到该菌体培养基中(铁离子终浓度1.5mmol/L)，继续培养转化约3-4天直至转化率达到最高，得到化合物19-羟基-可托多松(转化率30％)。
实施例2：化合物I-1的制备
将10mg 19-羟基-可托多松溶于1mL的甲醇中，然后在0℃条件下依次加入10μL3M的氢氧化钠水溶液和20μL 30％双氧水。搅拌4小时后，反应液用5mL二氯甲烷稀释，有机相依次用水和饱和食盐水萃取。合并的有机相经过无水硫酸钠干燥，减压过滤，低压浓缩，得到的粗产物进一步用硅胶柱层析分离纯化(洗脱剂为二氯甲烷:乙酸乙酯＝1:2，V/V)，得到6.6mg I-1(58％)。
(c 0.46,CH3OH)；HRMS(m/z):calcd for C21H30O6Na,[M+Na]+401.1935；found,401.1941；1H NMR(400MHz,Methanol-d4)δ4.72–4.52(m,2H),4.28(d,J＝19.2Hz,1H),4.02(d,J＝11.3Hz,1H),3.76(d,J＝11.4Hz,1H),2.68(ddd,J＝14.3,11.4,2.7Hz,1H),2.36–2.21(m,2H),2.20–2.10(m,1H),1.96–1.90(m,1H),1.86–1.73(m,3H),1.68–1.60(m,2H),1.56–1.47(m,2H),1.44–1.37m,1H),1.37–1.30(m,4H),1.23–1.09(m,3H),0.66(s,3H).13C NMR(101MHz,MeOD)δ211.9,207.1,89.0,68.8,66.4,63.5,59.7,50.8,46.1,41.4,35.0,33.5,31.6,30.5,30.5,29.7,23.2,21.7,20.7,14.1.
实施例3：化合物I-3的制备
将10mg 19-羟基-可托多松溶于1.5mL的甲醇中，在氢气氛围下，加入5.0mg 10％钯碳。室温反应1小时，反应液使用硅藻土过滤，除去不溶的钯碳，滤液减压浓缩，干燥，得到粗产物I-2。将上述得到的I-2溶于2mL二氯甲烷中，然后加入10mg乙酸酐和3mg 4-二甲氨基吡啶(DMAP)。在氩气和室温条件下，反应搅拌12小时，反应液用二氯甲烷稀释，并依次用饱和碳酸氢钠和氯化钠溶液萃取。所得有机相经过无水硫酸钠干燥，减压过滤，浓缩，得到的粗产物进一步用硅胶柱层析分离纯化(洗脱剂为石油醚:乙酸乙酯＝1:1，V/V)，得到7.7mgI-3(63％)。
(c 0.48,CHCl3)；HRMS(m/z):calcd for C25H36O7Na,[M+Na]+471.2353；found,471.2359；1H NMR(400MHz,CDCl3)δ5.08(dd,J＝17.5,12.9Hz,1H),4.83(d,J＝17.4Hz,0.19Hα),4.80(d,J＝17.4Hz,0.64Hβ),4.46–4.37(m,1H),4.08(d,J＝11.3Hz,1H).13C NMR(101MHz,CDCl3)δ212.2,205.1,171.2,170.7,90.0,67.8,66.3,51.4,48.5,42.0,40.4,37.9,36.9,36.6,35.5,34.9,31.0,30.7,29.7,29.3,25.9,25.5,23.5,21.0,20.9,20.6,14.8.
实施例4：化合物I-4的制备
将6mg 19-羟基-可托多松溶于1mL二氯甲烷中，然后加入7.8μL乙酸酐和2mg 4-二甲氨基吡啶(DMAP)。在氩气和室温条件下，反应搅拌4小时，反应液用二氯甲烷稀释，并依次用饱和碳酸氢钠和氯化钠溶液萃取。所得有机相经过无水硫酸钠干燥，减压过滤，浓缩得到C19、21乙酰基保护的可托多松。将上述得到的产物溶解于1mL 1,4-二氧六环中，0℃依次加入0.6mg二甲基叔丁基氯硅烷(TBSCl)和12mg二氯二氰基苯醌(DDQ)，然后反应液回流反应5小时，反应液用二氯甲烷稀释，并依次用饱和碳酸氢钠和氯化钠溶液萃取。所得有机相经过无水硫酸钠干燥，减压过滤，浓缩，得到的粗产物进一步用硅胶柱层析分离纯化(洗脱剂为石油醚:乙酸乙酯＝1:1，V/V)，得到6.5mg I-4(81％)。
(c 0.18,CHCl3)；HRMS(m/z):calcd for C25H34O8Na,[M+Na]+485.2146；found,485.2153；1H NMR(400MHz,CDCl3)δ7.08(d,J＝10.2Hz,1H),6.35(dd,J＝10.2,1.9Hz,1H),6.18(d,J＝1.6Hz,1H),5.06(d,J＝17.5Hz,1H),4.81(d,J＝17.5Hz,1H),4.62(d,J＝11.0Hz,1H),4.39(d,J＝10.9Hz,1H),2.77–2.68(m,1H),2.56–2.48(m,1H),2.45–2.38(m,1H),2.16(s,3H),2.07–1.98(m,1H),1.97–1.92(m,1H),1.91(s,3H),1.83–1.62(m,4H),1.55–1.46(m,1H),1.44–1.34(m,1H),1.30–1.09(m,4H),0.73(s,3H).13C NMR(101MHz,CDCl3)δ205.2,186.4,170.9,170.8,164.5,151.9,130.4,126.6,89.8,68.0,63.7,52.6,50.6,48.5,47.9,36.2,34.9,33.9,32.8,30.4,23.8,23.1,20.8,20.7,14.8.
实施例5：化合物I-5的制备
将5mg 19-羟基可托多松和8.7mg碘化钠溶解于1mL乙酸酐中，向溶液中鼓20分钟氩气，除去溶剂中的氧气，然后在0℃加入7.6μL三甲基氯硅烷(TMSCl)。在室温反应4小时后，将反应液倒入饱和碳酸氢钠水溶液中，并用乙酸乙酯萃取三次，合并的有机相再用饱和硫代硫酸钠和食盐水洗涤，有机相经过无水硫酸钠干燥，减压过滤，浓缩，得到乙酰酯中间体。将上述得到的乙酰酯中间体溶解于1mL 1,4-二氧六环中，加入5.1mg氧化碘苯(PhIO)。室温搅拌反应7小时，反应液用乙酸乙酯稀释，并依次用饱和碳酸氢钠和食盐水萃取，合并的有机相经过无水硫酸钠干燥，减压过滤，浓缩，得到的粗产物进一步用硅胶柱层析分离纯化(洗脱剂为石油醚:乙酸乙酯＝1:1，V/V)，得到6.5mg I-5(52％)。
(c 0.51,CHCl3)；HRMS(m/z):calcd for,C25H30O7Na,[M+Na]+467.2040；found,467.2045；1H NMR(400MHz,CDCl3)δ6.00(s,1H),5.08(d,J＝17.5Hz,1H),4.81(d,J＝17.4Hz,1H),4.75(dd,J＝11.1,1.4Hz,1H),4.41–4.35(m,2H),2.79–2.70(m,1H),2.68–2.57(m,1H),2.45–2.32(m,3H),2.17(s,3H),2.14–2.04(m,2H),2.02(s,3H),1.87–1.71(m,5H),1.58–1.37(m,4H),1.15–1.07(m,1H),0.75(s,3H).13C NMR(101MHz,CDCl3)δ205.0,199.9,170.9,170.7,162.0,128.9,89.8,72.7,68.4,67.8,53.6,50.7,48.3,41.1,38.7,34.79,34.76,34.5,30.4,30.3,29.7,23.5,21.2,21.1,20.6,14.7
实施例6：化合物I-6的制备
将100mg 19-羟基可托多松溶解于70mL无水乙腈中，然后在零下20℃缓慢滴加221mg三甲基碘硅烷(TMSI)。搅拌反应2.5小时后，加入饱和硫代硫酸钠溶液淬灭反应，减压除去大部分乙腈溶剂，二氯甲烷稀释反应液，然后依次用饱和碳酸氢钠和食盐水萃取，合并的有机相经过无水硫酸钠干燥，减压过滤，浓缩，得到的粗产物进一步用硅胶柱层析分离纯化(洗脱剂为二氯甲烷:甲醇＝15:1，V/V)，得到80mg I-6(84％)。
(c 0.33,CHCl3)；HRMS(m/z):calcd for C21H30O4Na,[M+Na]+369.2036；found,369.2038；1H NMR(600MHz,CDCl3):δ5.99(s,1H),4.24(d,J＝19.2Hz,1H),4.20(d,J＝19.0Hz,1H),4.09(d,J＝10.7Hz,1H),3.94(d,J＝10.8Hz,1H),2.83–2.69(m,1H),2.52–2.35(m,5H),2.29–2.24(m,1H),2.01–1.93(m,2H),1.85–1.76(m,4H),1.73–1.68(m,2H),1.56–1.49(m,1H),1.45–1.28(m,2H),1.22–1.11(m,2H),0.99(s,α-0.14H),0.73(s,β-3H).13C NMR(101MHz,CDCl3):δ210.2,200.4,167.0,126.9,69.5,65.9,59.0,56.5,53.8,44.8,43.9,38.8,36.3,35.1,33.6,33.5,32.1,24.5,23.0,21.5,13.7.
实施例7：化合物19-羟基-雄烯二酮的制备
(1)将10mg 19-羟基可托多松溶解于2mL 1:1(V:V)的二氯甲烷和乙醇溶剂中，然后在0℃缓慢加入0.7mg硼氢化钠。搅拌反应1.5小时后，加入1mL丙酮淬灭反应，随后将反应液回复至室温，再加入32mg高碘酸钠和1mL水，反应体系在25℃搅拌过夜，利用硅藻土过滤，滤液减压浓缩，得到的粗产物进一步用硅胶柱层析分离纯化(洗脱剂为石油醚:乙酸乙酯＝2:1，V/V)，得到7mg 19-羟基-雄烯二酮(84％)。1H NMR(400MHz,CDCl3):δ5.96(s,1H),4.07(dd,J＝10.7,1.3Hz,1H),3.94(d,J＝10.7Hz,1H),2.72(ddd,J＝16.9,14.1,5.9Hz,1H),2.52–2.32(m,5H),2.16–1.94(m,3H),1.91–1.74(m,4H),1.64–1.44(m,3H),1.23–1.05(m,3H),0.91(s,3H).13C NMR(101MHz,CDCl3):δ220.4,199.9,166.2,127.3,66.1,54.1,51.3,47.7,43.9,36.0,35.8,35.1,33.6,33.5,31.8,31.0,21.8,21.0,14.0.
(2)将10mg 19-羟基可托多松溶解于1mL二氧六环中，加入7.5mg甲醇钠。回流反应2小时后，加入二氯甲烷稀释反应液，并用1M的盐酸水溶液萃取，有机相经过无水硫酸钠干燥，减压过滤，浓缩，得到的粗产物进一步用硅胶柱层析分离纯化(洗脱剂为石油醚:乙酸乙酯＝2:1，V/V)，得到4.2mg 19-羟基-雄烯二酮(52％)。
(3)将10mg 19-羟基可托多松溶解于1mL乙酸中，加入23mg铋酸钠。室温反应8小时后，加入二氯甲烷稀释反应液，并用饱和碳酸氢钠水溶液萃取，有机相经过无水硫酸钠干燥，减压过滤，浓缩，得到的粗产物进一步用硅胶柱层析分离纯化(洗脱剂为石油醚:乙酸乙酯＝2:1，V/V)，得到2.5mg 19-羟基-雄烯二酮(30％)。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (1)
1.一种19-羟基雄烯二酮的制备方法，其特征在于：包括如下步骤：
将19-羟基可托多松溶解于由二氯甲烷和乙醇按体积比1:10～10:1组成的溶剂中，加入硼氢化钠在-78～70℃进行反应，反应结束后，加入丙酮淬灭反应，再加入水和高碘酸钠或者高碘酸于-78～70℃进行反应，得到19-羟基雄烯二酮；
或将19-羟基可托多松溶解于二氧六环中，加入甲醇钠，回流进行反应，得到19-羟基雄烯二酮。
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