CN112047898A - 一种苯并[c][1,2]噁嗪骨架类新化合物及其制备方法 - Google Patents
一种苯并[c][1,2]噁嗪骨架类新化合物及其制备方法 Download PDFInfo
- Publication number
- CN112047898A CN112047898A CN202011095195.4A CN202011095195A CN112047898A CN 112047898 A CN112047898 A CN 112047898A CN 202011095195 A CN202011095195 A CN 202011095195A CN 112047898 A CN112047898 A CN 112047898A
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- Prior art keywords
- benzo
- oxazine
- novel
- compound
- oxazine skeleton
- Prior art date
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- BZIXPAXPMJNKFW-UHFFFAOYSA-N 1h-2,1-benzoxazine Chemical group C1=CC=C2NOC=CC2=C1 BZIXPAXPMJNKFW-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 150000001875 compounds Chemical class 0.000 title claims abstract description 28
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- 150000003431 steroids Chemical class 0.000 claims abstract description 10
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- 229920001184 polypeptide Polymers 0.000 claims abstract description 9
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 9
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 9
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 6
- -1 polytetrafluoroethylene Polymers 0.000 claims description 32
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- 239000003814 drug Substances 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 229940079593 drug Drugs 0.000 claims description 20
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 18
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 8
- 229910052697 platinum Inorganic materials 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims description 7
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- MHCFAGZWMAWTNR-UHFFFAOYSA-M lithium perchlorate Chemical compound [Li+].[O-]Cl(=O)(=O)=O MHCFAGZWMAWTNR-UHFFFAOYSA-M 0.000 claims description 2
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- KBLZDCFTQSIIOH-UHFFFAOYSA-M tetrabutylazanium;perchlorate Chemical compound [O-]Cl(=O)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC KBLZDCFTQSIIOH-UHFFFAOYSA-M 0.000 claims description 2
- WGHUNMFFLAMBJD-UHFFFAOYSA-M tetraethylazanium;perchlorate Chemical compound [O-]Cl(=O)(=O)=O.CC[N+](CC)(CC)CC WGHUNMFFLAMBJD-UHFFFAOYSA-M 0.000 claims description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/02—1,2-Oxazines; Hydrogenated 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/695—Silicon compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
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Abstract
本发明首次用羟基肟酸与烯烃通过电化学氧化[4+2]环化一步合成苯并[c][1,2]噁嗪骨架。该方案不仅具有反应底物羟基肟酸和烯烃来源易得、范围广泛的特点，还具有反应条件温和、操作简便、无氧化剂、无金属、区域选择性和立体选择性高、可与萜类、多肽和甾体兼容等优点。本发明不仅提供了一种羟基肟酸在苯并[c][1,2]噁嗪骨架合成中的新应用，同时也实现了工业成熟的电解法在该类化合物合成中的首次应用。
Description
技术领域
本发明属于化学化工领域，具体涉及一种新的苯并[c][1,2]噁嗪骨架类化合物及这种化合物的制备方法和在制备具有苯并[c][1,2]噁嗪结构单元的萜类药物以及多肽药物以及甾体类药物中的用途。
背景技术
苯并噁嗪是一类具有氮和氧两种杂原子的特殊结构的含氮化合物(生物碱)。该类化合物被证明具有抗肿瘤、抗菌、镇静、助眠、消炎等广泛的生物活性(J.Med.Chem.1990,33,464)，可用于肿瘤和遗传性肥胖症等多种疾病的治疗(J.Med.Chem.1999,42,5437；J.Med.Chem.2002,45,5217；Bioorg.Med.Chem.Lett.2004,14,4751；J.Med.Chem.2016,110,326)。在农药方面，苯并噁嗪具有杀虫、杀菌和植物生长调节等作用，因此这类化合物在药学和农学上都具有极其重要的价值。
FR900482、FR66979、FK317、FK973和paeciloxazine等分子是以苯并[c][1,2]噁嗪为结构核心支架的有成药前景的分子，激起了众多药学家的研究兴趣。
FR66979和FR900482自1987年被Fujisawa制药公司发现并证明属于新型抗肿瘤抗生素以来，多年来的大量的研究和临床抗肿瘤实验证明：FR900482及其衍生物(如：FK973和FK317)可以用于治疗多种肿瘤(Angew.Chem.Int.Ed.2002,41,24；J.Am.Chem.Soc.2000,122,10781)，并且FK317不会引起血管泄漏综合征(VLS)等由药物产生的副作用，是有望替换抗癌药物mitomycin C(丝裂霉素C)的分子。结构新颖的天然产物paeciloxazine(CJ-12662)(J.UK Pat.Appl.2240 100,1991；J.Antibiot.2004,57,24)则属于独特的萜类吡咯苯并[c][1,2]噁嗪天然产物，具有良好的抗寄生虫——包括壁虱、模式线虫等体内和体外寄生虫活性。
苯并噁嗪类分子的合成是化学家研究的热点。截止目前，多个课题组陆续完成了(±)FR900482(J.Am.Chem.Soc.；1995,117,4722；J.Am.Chem.Soc.；1992,114,383)、(+)-FR66979、7-Epi(+)-FR900482(Org.Lett.,2008,10,1369)等具有苯并[c][1,2]噁嗪核心结构支架的明星分子并进一步证明了这些分子的相关活性。此外，刘瑞雄课题组也实现了利用金、银共催化的方法分别以邻硝基苯乙烯和富电子烯烃以及乙烯基联烯和亚硝基苯为底物的热反应构建苯并[c][1,2]噁嗪骨架(J.Am.Chem.Soc.；2011,133,1769；Angew.Chem.Int.Ed.；2019,58,9831)。
发明内容
与上述贵金属催化合成方法不同，本发明首次用羟基肟酸与烯烃通过电化学氧化[4+2]环化一步合成苯并[c][1,2]噁嗪骨架。该方案不仅具有反应底物羟基肟酸和烯烃来源易得、范围广泛的特点，还具有反应条件温和、操作简便、无氧化剂、无金属、区域选择性和立体选择性高、可与萜类、多肽和甾体兼容等优点。本发明不仅提供了一种羟基肟酸在苯并[c][1,2]噁嗪骨架合成中的新应用，同时也实现了工业成熟的电解法在该类化合物合成中的首次应用。
所述的苯并[c][1,2]噁嗪骨架类新化合物的制备方法，其特征在于：合成路线如下式所示：
以上描述的反应是在一个带有支口的Schlenk管中装入磁子，加入羟肟酸(0.075M～0.15M)和电解质，安装带有电极的聚四氟乙烯密封塞，置换保护气体后加入相对应的烯烃、溶剂等。然后在一定室温(0～80℃)下搅拌，并且连接电化学仪器在恒定电流3-10mA(或者在恒定电压(0.6～1.5V)下电解4～6个小时，通过后处理提纯产物。
①电极材料：阳极有(网状玻碳(RVC)、石墨棒、玻碳、碳片、铂片或者铂丝)阴极有(铂片或铂丝、镍、铜、铁、锌片)
②电解质：四正丁基氟硼酸铵、四正丁基六氟膦酸铵、四正丁基高氯酸铵、四正丁基对甲苯磺酸铵、四乙基氟硼酸铵、四乙基高氯酸铵、四乙基六氟膦酸铵、高氯酸锂。
③溶剂:二氯甲烷+六氟异丙醇+乙腈、二氯甲烷、二氯甲烷+六氟异丙醇、乙腈、1,2-二氯乙烷、二氯甲烷+乙腈、乙腈+六氟异丙醇、
④温度(T)：室温
⑤保护气：氮气或者氩气
所述苯并[c][1,2]噁嗪骨架类新化合物均以上述方法制备获得。
本发明的特点是化合物制备方法是：首次使用羟基肟酸与烯烃通过电化学氧化[4+2]环化合成苯并[c][1,2]噁嗪骨架。该方案条件温和、无氧化剂、区域选择性和立体选择性高、烯类和羟肟酸的底物范围广，化合物制备方法简便可行，化合物结构新颖，可与萜类药物以及多肽药物和甾体类药物兼容。
本发明提供了含有所述的具有式一—式六所示的结构，预期这些化合物可为开发抗肿瘤等药物提供更多的候选分子或其药学上可接受的盐的药物，所述药物包括药学上可接受的辅助剂；所属药物为注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂等。
所述的苯并[c][1,2]噁嗪骨架类化合物或其药学上可接受的盐单独或以组合物形式在制备抗肿瘤等的药物的应用。
本发明提供一种药物，包括有效量的所述的苯并[c][1,2]噁嗪骨架类化合物，或其药学上可接受的盐，和药学上可接受的载体。
本发明的式一—式六示化合物可与各种药物上可接受的载体、赋形剂或辅料配伍制成药物，用于抗肿瘤等疾病的治疗。
本发明的目的是提供一种新的苯并[c][1,2]噁嗪骨架类化合物的合成方法，预期这类化合物可为开发抗肿瘤等药物提供更多的候选分子，本发明提供的这类化合物，及其在制备具有苯并[c][1,2]噁嗪结构单元的萜类药物以及具有苯并[c][1,2]噁嗪结构单元的多肽类药物以及具有苯并[c][1,2]噁嗪结构单元的甾体类药物中的用途。
一种苯并[c][1,2]噁嗪骨架类新化合物，其特征在于：所述的苯并[c][1,2]噁嗪骨架类化合物具有如下所示的结构，
具体实施方式
下面结合具体实施例进一步详细说明本发明。除非特别说明，本发明实施例述及的实际均为本技术领域常规使用的试剂。
化合物的制备：
实施例1：ethyl 4-phenyl-3,4-dihydro-1H-benzo[c][1,2]oxazine-1-carboxylate的制备
如式一所示，在一个带有支口的Schlenk管中装入磁子，加入N-苯基羟肟酸乙酯(0.075M)和电解质四丁基氟硼酸铵(0.1M)，安装带有网状玻碳电极为阳极(RVC)和铂片为阴极的聚四氟乙烯密封塞，通过三次置换气体使反应瓶内为氩气或者氮气氛围，分别加入苯乙烯(0.15M)、二氯甲烷:六氟异丙醇:乙腈(35:4:1)，然后在室温下搅拌，并且连接电化学仪器在恒定电流6mA下电解4小时，反应结束后减压旋转蒸发浓缩，粗品通过柱层析分离提纯得到65mg，产率为76％。
1H NMR(400MHz,CDCl3):δ7.64(d,J＝8.4Hz,1H),7.33-7.18(m,6H),7.05-7.01(m,1H),6.97(d,J＝11.6Hz,1H),4.51(dd,J＝11.6,6.0Hz,1H),4.38-4.30(m,3H),4.25-4.20(m,1H),1.38(t,J＝7.2Hz,3H)；13C NMR(100.6MHz,CDCl3):δ153.9,142.1,137.2,129.6,129.0,128.7,127.2,127.2,126.6,124.8,121.3,76.4,62.8,43.2,14.5；ESI-HRMS:Calcdfor C17H17NO3+H+[M]:284.1281,found 284.1281.
实施例2：ethyl(3R*,4S*)-3-methyl-4-phenyl-3,4-dihydro-1H-benzo[c][1,2]oxazine-1-carboxylate
其具体制备过程同实施例1，只需将式一中原料b1替换为β-甲基苯乙烯，得到目标产物54mg，产率为60％。
1H NMR(400MHz,CDCl3):δ7.61(d,J＝8.0Hz,1H),7.32-7.24(m,3H),7.27-7.21(m,1H),7.12(d,J＝6.8,3H),7.00-6.94(m,1H),6.82(d,J＝7.6Hz,1H),4.42-4.29(m,2H),4.24-4.16(m,1H),3.99(d,J＝9.6Hz,1H),1.38(t,J＝7.2Hz,3H),1.33(d,J＝6.0Hz,3H)；13C NMR(100.6MHz,CDCl3):δ154.1,141.1,137.1,129.5,129.3,128.9,128.7,127.2,126.3,124.78,121.2,82.3,62.7,51.5,17.9,14.51；ESI-HRMS:Calcd for C18H19NO3+H+[M]:298.1438,found 298.1445.
实施例3：
ethyl(6aS*,11bS*)-7,11b-dihydrobenzo[c]indeno[1,2-e][1,2]oxazine-5(6aH)-carboxylate
其具体制备过程同实施例1，只需将原料b1替换为茚，得到白色固体产物38mg，产率为43％
1H NMR(400MHz,CDCl3):δ7.62-7.55(m,2H),7.40-7.38(m,2H),7.28-7.23(m,3H),7.22-7.16(m,2H),4.97(t,J＝4.8Hz,1H),4.38-4.24(m,2H),3.40(dd,J＝17.6,5.2Hz,1H),3.28(d,J＝17.6Hz,1H),1.35(t,J＝7.2Hz,3H)；13C NMR(100.6MHz,CDCl3):δ153.9,142.1,139.8,136.7,129.1,127.3,126.8,126.6,126.2,124.9,124.8,124.2,121.8,82.8,62.7,46.0,37.6,14.5；ESI-HRMS:Calcd for C18H17NO3+H+[M]:296.1281,found 296.1288.
实施例4：
ethyl(S*)-4-((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)-3,4-dihydro-1H-benzo[c][1,2]oxazine-1-carboxylate
其具体制备过程同实施例1，只需将原料b1替换为(8R,9S,13S,14S)-13-methyl-3-vinyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one，得到白色固体产物89mg，产率为65％。
1H NMR(400MHz,CDCl3):δ7.63(d,J＝8.4Hz,1H),7.26-7.19(m,2H),7.05-7.00(m,2H),6.99-6.95(m,1H),6.93-6.92(m,1H),4,49(dd,J＝10.4,4.8Hz,1H),4.35(q,J＝7.2Hz,2H),4.27-4.19(m,2H),2.88-2.84(m,2H),2.50(dd,J＝19.2,8.8Hz,1H),2.43-2.38(m,1H),2.30-2.25(m,1H),2.18-2.11(m,1H),2.09-2.08(m,1H),2.07-2.02(m,1H),1.97-1.94(m,1H),1.65-1.62(m,1H),1.59-1.54(m,1H),1.53-1.50(m,2H),1.50-1.47(m,1H),1.38(t,J＝7.2Hz,3H),0.90(s,3H)；13C NMR(100.6MHz,CDCl3):δ220.7,153.8,139.4,139.3,138.6,137.11,137.08,136.9,136.8,129.6,129.2,129.1,127.4,126.4,126.14,126.07,125.7,125.6,124.7,121.2,76.4,62.8,50.4,47.9,44.2,42.71,42.67,38.0,35.8,31.5,29.3,26.4,25.6,21.5,14.5,13.8；ESI-HRMS:Calcd for C29H33NO4+H+[M]:460.2482,found 460.2490
实施例5：
ethyl(4S*)-4-(4-(((4R)-4-((3R,8R,9S,10S,13R,14S,17R)-3-acetoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoyl)oxy)phenyl)-3,4-dihydro-1H-benzo[c][1,2]oxazine-1-carboxylate
其具体制备过程同实施例1，只需将原料b1替换为4-vinylphenyl(4R)-4-((3R,8R,9S,10S,13R,14S,17R)-3-acetoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate，得到白色固体产物89mg，产率为56％。
1NMR(400MHz,CDCl3):δ7.64(d,J＝8.0Hz,1H),7.27-7.18(m,3H),7.05-7.00(m,3H),6.98-6.96(m,1H),4.73-4.71(m,1H),4.49(dd,J＝11.6,6.0Hz,1H),4.37-4.29(m,3H),4.20(dd,J＝12.0,6.4Hz,1H),2.59-2.55(m,1H),2.50-2.46(m,1H),2.02(s,3H),2.00-1.97(m,1H),1.93-1.79(m,5H),1.70-1.67(m,1H),1.59-1.51(m,3H),1.49-1.36(m,10H),1.34-1.30(m,1H),1.26-1.23(m,2H),1.20-1.17(m,1H),1.15-1.12(m,1H),1.08-1.02(m,4H),0.97(d,J＝6.4Hz,3H),0.93(s,3H),0.66(s,3H)；13C NMR(100.6MHz,CDCl3):δ172.6,170.5,153.8,149.8,139.5,137.1,129.64,129.59,126.8,126.7,124.7,121.8,121.3,76.2,74.3,62.8,56.4,55.9,42.7,42.5,41.8,40.3,40.1,35.7,35.3,35.0,34.5,32.2,31.3,30.8,28.1,26.9,26.5,26.2,24.1,23.2,21.4,20.8,18.2,14.5,12.0；ESI-HRMS:Calcd for C43H57NO7+H+[M]:700.4208,found 700.4212.
实施例6：
ethyl(S*)-4-(4-(((2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carbonyl)oxy)phenyl)-3,4-dihydro-1H-benzo[c][1,2]oxazine-1-carboxylate
其具体制备过程同实施例1，只需将原料b1替换为4-vinylphenyl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate，得到白色固体产物100mg，产率为45％。
1H NMR(400MHz,CDCl3):δ7.64(d,J＝5.2Hz,1H),7.24-7.20(m,3H),7.06-7.04(m,1H),7.03-6.97(m,3H),5.66-5.60(d,J＝2.0Hz,1H),4.52-4.49(dd,J＝7.6,4Hz,1H),4.37-4.33(m,3H),4.23-4.19(m,1H),3.23(s,1H),2.79-2.77(d,J＝8Hz,1H),2.34(s,1H),2.12-2.10(m,1H),2.07-2.03(m,3H),1.76-1.74(m,1H),1.66-1.64(m,1H),1.59-1.46(m,5H),1.43-1.4,1(m,2H),1.40(s,3H),1.39(s,6H),1.39(s,3H),1.37-1.33(m,1H),1.23(s,6H),1.22-1.13(m,1H),1.00(s,3H),0.97-0.85(m,1H),0.85(s,3H),0.81(s,3H),0.71-0.69(d,J＝7.2Hz,1H)；13C NMR(100.6MHz,CDCl3):δ200.1,175.1,168.8,153.9,149.9,139.7,139.6,137.6,129.8,129.71,129.69,128.6,126.92,126.86,126.8,124.9,121.7,121.34,121.33,78.7,76.28,76.26,62.9,61.8,54.9,48.43,48.42,45.4,44.3,43.2,42.6,41.1,39.10,39.07,37.7,37.1,32.7,31.9,31.1,28.6,28.1,27.3,26.44,26.39,23.4,18.6,17.4,16.3,15.5,14.5；ESI-HRMS:Calcd for C47H61NO7+H+[M]:752.4521,found752.4525.
实施例7：
ethyl(6aS*,11aS*)-6a-methyl-11-pivaloyl-11,11a-dihydrobenzo[3,4][1,2]oxazino[5,6-b]indole-5(6aH)-carboxylate
其具体制备过程同实施例1，只需将原料b1替换为2,2-dimethyl-1-(3-methyl-1H-indol-1-yl)propan-1-one，得到白色固体产物89mg，产率为83％。
1H NMR(400MHz,CDCl3):δ7.67(d,J＝8.4Hz,1H),7.59-7.56(m,2H),7.41-7.39(m,1H),7.26-7.21(m,2H),7.16-7.12(m,1H),7.08-7.04(m,1H),5.50(s,1H),4.38-4.28(m,2H),1.82(s,3H),1.39-1.36(m,12H)；13C NMR(100.6MHz,CDCl3):δ178.0,152.7,142.8,139.1,133.4,129.1,128.6,127.7,127.4,125.3,124.5,123.8,119.5,119.1,90.3,66.0,62.5,40.9,28.4,24.5,14.5；ESI-HRMS:Calcd for C23H26N2O4+H+[M]:395.1965,found395.1967.
实施例8：
ethyl(6aS*,11aS*)-6a-(2-((tert-butyldimethylsilyl)oxy)ethyl)-11-pivaloyl-11,11a-dihydrobenzo[3,4][1,2]oxazino[5,6-b]indole-5(6aH)-carboxylate
其具体制备过程同实施例1，只需将原料b1替换为1-(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-1-yl)-2,2-dimethylpropan-1-one，得到无色油状产物53mg，产率为33％。
1H NMR(400MHz,CDCl3):δ7.62(d,J＝7.6Hz,1H),7.56(t,J＝7.2Hz,2H),7.33(dd,J＝7.6,0.8Hz,1H),7.23-7.18(m,2H),7.10(td,J＝7.6,1.2Hz,1H),7.02(td,J＝7.6,0.8Hz,1H),5.76(s,1H),4.28(q,J＝6.8Hz,2H),4.04-3.98(m,1H),3.86-3.80(m,1H),1.37-1.33(m,12H),0.83(s,9H),-0.01(d,J＝2.4Hz,6H)；13C NMR(100.6MHz,CDCl3):δ177.9,152.7,142.1,139.0,132.0,129.2,129.1,127.7,127.2,125.2,124.8,124.0,119.2,119.0,90.8,65.0,62.4,58.2,40.8,39.9,28.4,25.9,18.2,14.5,-5.4,-5.4；ESI-HRMS:Calcd for C30H42N2O5Si+H+[M]:539.2936,found539.2937.
实施例9：
ethyl(6aS8*,11aS8*)-11-pivaloyl-5H,11H-6a,11a-propanobenzo[3,4][1,2]oxazino[5,6-b]indole-5-carboxylate
其具体制备过程同实施例1，只需将原料b1替换为1-(2,3-dihydrocyclopenta[b]indol-4(1H)-yl)-2,2-dimethylpropan-1-one，得到无色油状产物96mg，产率为76％。
1H NMR(400MHz,CDCl3):δ7.83(dd,J＝7.6,1.6Hz,1H),7.57(dd,J＝7.6,0.8Hz,1H),7.51(d,J＝7.6Hz,1H),7.26-7.16(m,3H),7.03(td,J＝7.6,0.8Hz,1H),6.84(d,J＝8.4Hz,1H),4.12-3.99(m,2H),2.98-2.90(m,1H),2.66-2.58(m,1H),2.36-2.29(m,1H),2.25-2.18(m,1H),1.82-1.72(m,1H),1.64-1.54(m,1H)；13C NMR(100.6MHz,CDCl3):δ181.3,152.0,144.8,138.8,129.9,129.4,129.3,129.0,127.6,126.4,124.6,122.4,120.4,114.5,100.4,75.4,61.9,42.4,37.9,37.5,28.1,23.5,14.2；ESI-HRMS:Calcd forC25H28N2O4+H+[M]:421.2122,found 421.2120.
实施例10：
ethyl(1S*,4R*,4aS*,10bS*)-1,2,3,4,4a,10b-hexahydro-6H-1,4-methanodibenzo[c,e][1,2]oxazine-6-carboxylate
其具体制备过程同实施例1，只需将原料b1替换为降冰片烯且用量为(1.5Equiv.)，得到白色固体产物66mg，产率为71％。
1H NMR(400MHz,CDCl3):δ7.69(d,J＝8.0Hz,1H),7.28-7.24(m,1H),7.23-7.19(m,1H),7.18-7.16(m,3H),7.15-7.10(m,2H),4.81-4.77(m,1H),4.37-4.25(m,2H),4.07(d,J＝5.6Hz,1H),2.88-2.81(m,1H),2.75-2.67(m,1H),2.32-2.24(m,1H),2.13-1.84(m,1H),1.37(t,J＝7.2Hz,3H)；13C NMR(100.6MHz,CDCl3):δ154.1,140.5,137.3,137.0,129.5,129.3,129.1,128.8,128.5,128.3,127.6,127.1,126.4,124.8,121.4,88.0,62.7,50.2,14.4；ESI-HRMS:Calcd for C16H19NO3+H+[M]:274.1438,found 274.1440.
实施例11：
ethyl(1S*,4R*,4aS*,10bS*)-7-methoxy-1,2,3,4,4a,10b-hexahydro-6H-1,4-methano-dibenzo[c,e][1,2]oxazine-6-carboxylate
其具体制备过程同实施例1，只需将原料a1替换为N-(2-甲氧基)苯基羟肟酸乙酯b1为降冰片烯且用量为(1.5Equiv.)，得到白色固体产物46mg，产率为50％。
1H NMR(400MHz,CDCl3):δ7.19(t,J＝8.0Hz,1H),6.94(d,J＝7.2Hz,1H),6.78(d,J＝8.4Hz,1H),4.57(d,J＝6.4Hz,1H),4.39-4.31(m,1H),4.22-4.15(m,1H),3.83(s,3H),2.62-2.58(m,2H),2.50(s,1H),1.68-1.60(m,2H),1.53(d,J＝10.0Hz,1H),1.34-1.26(m,5H),1.10(d,J＝10.4Hz,1H)；13C NMR(100.6MHz,CDCl3):δ154.2,152.2,132.0,128.5,127.1,119.4,109.3,86.1,62.4,55.8,44.2,42.3,40.8,33.4,29.0,24.2,14.6；ESI-HRMS:Calcd for C17H21NO4+H+[M]:304.1543,found304.1542.
实施例12：
ethyl(1S*,4R*,4aS*,10bS*)-9-fluoro-1,2,3,4,4a,10b-hexahydro-6H-1,4-methanodibenzo[c,e][1,2]oxazine-6-carboxylate
其具体制备过程同实施例1，只需将原料a1替换N-(4-氟)苯基羟肟酸乙酯原料b1为将冰片烯且用量为(1.5Equiv.)，得到无色油状产物49mg，产率为57％。
White solid,mp 108-110℃；Rf＝0.38(8:1petroleum ether/ethyl acetate)；49mg,57％yield；1H NMR(400MHz,CDCl3):δ7.35(dd,J＝8.8,4.8Hz,1H),7.04(dd,J＝8.8,2.8Hz,1H),6.88(td,J＝8.8,2.8Hz,1H),4.52(d,J＝6.0Hz,1H),4.37-4.22(m,2H),2.58-2.54(m,3H),1.70-1.61(m,3H),1.38-1.26(m,5H),1.15(d,J＝10.4Hz,1H)；13C NMR(100.6MHz,CDCl3):δ160.2(d,1JC-F＝244.5Hz),153.5,134.5(d,4JC-F＝3.0Hz),131.8(d,3JC-F＝8.0Hz),123.7(d,3JC-F＝8.0Hz),114.5(d,2JC-F＝23.1Hz),112.8(d,2JC-F＝23.1Hz),86.2,62.6,44.5,42.4,40.9,33.4,29.1,23.9,14.6；19F NMR(376MHz,CDCl3):δ-116.2；ESI-HRMS:Calcd for C16H18FNO3+H+[M]:292.1343,found 292.1342.
实施例13：
ethyl(1S*,4R*,4aS*,10bS*)-9-chloro-10-methoxy-1,2,3,4,4a,10b-hexahydro-6H-1,4-methanodibenzo[c,e][1,2]oxazine-6-carboxylate
其具体制备过程同实施例1，只需将原料a1替换N-(3-甲氧基-4-氯)苯基羟肟酸乙酯原料b1为降冰片烯且用量为(1.5Equiv.)，得到白色固体产物39mg，产率为38％。
1H NMR(400MHz,CDCl3):δ7.19(dd,J＝20.0,8.8Hz,2H),4.40(d,J＝6.4Hz,1H),4.36-4.25(m,2H),3.89(s,3H),2.81-2.73(m,2H),2.58(d,J＝3.6Hz,1H),1.70-1.59(m,3H),1.42-1.34(m,4H),1.28-1.24(m,1H),1.09(d,J＝10.8Hz,1H)；13C NMR(100.6MHz,CDCl3):δ154.5,153.4,137.2,127.4,124.8,124.2,118.6,86.2,62.7,60.0,42.0,41.9,40.8,33.5,29.8,24.1,14.6；ESI-HRMS:Calcd for C17H20ClNO4+H+[M]:338.1154,found338.1153.
实施例14：
ethyl(1S*,4R*,4aS*,10bS*)-9-(((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)carbamoyl)-1,2,3,4,4a,10b-hexahydro-6H-1,4-methanodibenzo[c,e][1,2]oxazine-6-carboxylate
其具体制备过程同实施例1，只需将原料a1替换为ethyl(4-(((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)carbamoyl)phenyl)(hydroxy)carbamate，b1为降冰片烯且用量为(1.5Equiv.)，得到白色固体产物73mg，产率为51％。
1H NMR(400MHz,CDCl3):δ7.79(s,1H),7.44(s,2H),5.85(s,1H),4.54(d,J＝6.4Hz,1H),4.36-4.26(m,2H),2.68(s,1H),2.60-2.54(m,2H),2.19(s,1H),1.97(s,2H),1.81-1.73(m,4H),1.68-1.61(m,3H),1.45-1.32(m,9H),1.27-1.13(m,3H),0.88(s,6H)；13CNMR(100.6MHz,CDCl3):δ166.2,153.1,140.7,132.7,129.7,127.4,123.6,121.3,86.8,62.7,54.0,50.6,47.6,44.4,42.7,42.4,40.9,40.2,33.4,32.5,30.2,30.1,29.1,23.8,14.6；ESI-HRMS:Calcd for C29H38N2O4+H+[M]:479.2904,found 479.2907.
实施例15：
6-ethyl9-((1R*,2S*,5R*)-2-isopropyl-5-methylcyclohexyl)(1S*,4R*,4aS*,10bS*)-1,2,3,4,4a,10b-hexahydro-6H-1,4-methanodibenzo[c,e][1,2]oxazine-6,9-dicarboxylate
其具体制备过程同实施例1，只需将原料a1替换(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl4-((ethoxycarbonyl)(hydroxy)amino)benzoateb1替换为降冰片烯且用量为(1.5Equiv.)，得到白色固体产物62mg，产率为45％。
1H NMR(400MHz,CDCl3):δ8.04(d,J＝7.2Hz,1H),7.86(dd,J＝8.4,0.8Hz,1H),7.49(d,J＝8.4Hz,1H),4.96-4.92(m,1H),4.54(d,J＝6.0Hz,1H),4.55-4.27(m,2H),2.70(d,J＝10.8Hz,1H),2.62(t,J＝6.4Hz,1H),2.56(d,J＝2.4Hz,1H),2.11(dd,J＝12.0,2.8Hz,1H),1.97-1.92(m,1H),1.75-1.64(m,5H),1.59-1.53(m,2H),1.42-1.28(m,5H),1.28-1.10(m,3H),0.93(dd,J＝6.4,4.8Hz,7H),0.80(dd,J＝6.8,2.4Hz,3H)；13C NMR(100.6MHz,CDCl3):δ165.7,165.6,153.0,142.2,129.8,129.7,129.4,127.5,127.5,127.1,127.1,121.4,121.3,86.9,74.9,74.8,62.8,47.3,47.3,44.3,42.4,41.0,41.0,34.3,33.4,31.5,29.2,29.2,26.6,26.5,23.9,23.8,23.7,23.6,22.1,20.8,20.7,16.6,16.5,14.6,14.6；ESI-HRMS:Calcd for C27H37NO5+H+[M]:456.2744,found 456.2742.
实施例16：
ethyl(1S*,4R*,4aS*,10bS*)-9-(((8S,9R,13R,14R)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-2-yl)oxy)-1,2,3,4,4a,10b-hexahydro-6H-1,4-methanodibenzo[c,e][1,2]oxazine-6-carboxylate
其具体制备过程同实施例1，只需将原料a1替换为ethylhydroxy(4-(((8S,9R,13R,14R)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-2-yl)oxy)phenyl)carbamate，b1替换为降冰片烯且用量为(1.5Equiv.)，得到白色固体产物140mg，产率为86％。
1H NMR(400MHz,CDCl3):δ7.33(d,J＝8.8Hz,1H),7.25(d,J＝8.8Hz,1H),7.01(d,J＝2.4Hz,1H),6.83-6.79(m,2H),6.74(d,J＝2.8Hz,1H),4.51(d,J＝6.0Hz,1H),4.36-4.24(m,2H),2.89-2.86(m,2H),2.58-2.48(m,4H),2.43-2.40(m,1H),2.31-2.26(m,1H),2.18-1.95(m,4H),1.67-1.49(m,9H),1.46-1.26(m,5H),1.14(d,J＝10.4Hz,1H),0.93(s,3H)；13CNMR(100.6MHz,CDCl3):δ220.8,155.2,154.7,153.6,138.3,134.7,133.7,131.3,126.6,123.3,118.6,118.3,116.4,116.0,86.3,62.5,50.4,48.0,44.6,44.1,42.4,40.9,36.2,35.9,33.5,31.6,29.5,29.1,26.5,25.9,24.0,21.6,14.6,13.9；ESI-HRMS:Calcd forC34H39NO5+H+[M]:542.2901,found542.2904.
本发明化合物可单独或以药物组合物的形式给药。给药途径可以是口服、非肠道或局部给药。药物组合物可根据给药途径配成各种适宜的剂型。
本发明化合物的药物组合物可以下面的任意方式施用：口服，喷雾吸入，直肠用药，鼻腔用药，颊部用药，局部用药，非肠道用药，如：皮下，静脉，肌内，腹膜内，鞘内，心室内，胸骨内和颅内注射或输入，或借助一种外植储器用药。其中优选口服、腹膜内或静脉内给药方式。
当口服给药时，本发明化合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊、水溶液或水悬浮液。其中，片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如：硬脂酸镁。胶囊剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂混合使用。任选地，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
但皮肤局部施用时，本发明可制成适当的软膏、洗剂或霜剂制剂形式，其中将活性成分悬浮或溶解于一种或几种载体中。软膏剂使用的载体包括但不限于：矿物油、液体凡士林、白凡士林、丙二醇、聚氧化丙烯、乳化蜡和水；洗剂或霜剂可使用的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳2-辛基十二烷醇、卞醇和水。
本发明化合物还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液。其中，可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质。如：单甘油酯或二甘油酯。
另外，需要指出，本发明化合物使用剂量和使用方法取决于诸多因素。包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的严重程度以及诊治医师的主观判断。
本发明所述制备方法兼容性强，可以应用于具有烯键的萜类药物先导分子或萜类药物的修饰和改造，因此本发明所述制备方法可以应用于制备具有苯并[c][1,2]噁嗪结构单元的萜类药物。
本发明所述制备方法兼容性强，可以应用于具有色氨酸的多肽类药物的修饰和改造，因此本发明所述制备方法可以应用于制备具有苯并[c][1,2]噁嗪结构单元的多肽药物。
本发明所述制备方法兼容性强，可以应用于具有烯键的甾体类药物先导分子或甾体药物的修饰和改造，因此本发明所述制备方法可以应用于制备具有苯并[c][1,2]噁嗪结构单元的甾体类药物。
最后应说明的是：以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的内容和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种苯并[c][1,2]噁嗪骨架类新化合物的制备方法，其特征在于：合成路线如下式所示，
其中，R1R2R3R4R5可为：卤素、多氟代烷、烷氧基、羰基、酯基、酰胺基、磺酰基、芳基及其被甾体，萜类，多肽修饰的芳基和杂芳基其中之一。
2.根据权利要求1所述的一种苯并[c][1,2]噁嗪骨架类新化合物的制备方法，其特征在于：制备步骤为：
所述的反应是在一个反应管中装入磁子，加入羟肟酸或者衍生物(0.075M～0.15M)和电解质，安装带有电极的聚四氟乙烯密封塞，置换保护气体后加入相对应的烯烃、溶剂等。然后在一定室温(0～80℃)下搅拌，并且连接电化学仪器在恒定电流3-10mA或者在恒定电压0.6～1.5V下电解4～6个小时，通过后处理提纯产物。
3.根据权利要求2所述的一种苯并[c][1,2]噁嗪骨架类新化合物的制备方法，其特征在于：
所述反应管使用带有支口的Schlenk管或玻璃管或者聚四氟乙烯的瓶子；
电极材料：阳极有为网状玻碳(RVC)、石墨棒、玻碳、碳片、铂片或者铂丝其中之一；阴极有为铂片或铂丝、镍、铜、铁、锌片其中之一；电解质为四正丁基氟硼酸铵、四正丁基六氟膦酸铵、四正丁基高氯酸铵、四正丁基对甲苯磺酸铵、四乙基氟硼酸铵、四乙基高氯酸铵、四乙基六氟膦酸铵、高氯酸锂其中之一或组合；溶剂使用二氯甲烷+六氟异丙醇+乙腈、二氯甲烷、二氯甲烷+六氟异丙醇、乙腈、1,2-二氯乙烷、二氯甲烷+乙腈、乙腈+六氟异丙醇其中任一。
4.根据权利要求2所述的一种苯并[c][1,2]噁嗪骨架类新化合物的制备方法，其特征在于：电极材料：阳极为网状玻碳(RVC)阴极为铂片或铂丝；
电解质：四正丁基氟硼酸铵
溶剂:二氯甲烷+六氟异丙醇+乙腈。
5.一种苯并[c][1,2]噁嗪骨架类新化合物，其特征在于：通过权利要求1或2所述方法制备所得，所述的苯并[c][1,2]噁嗪骨架类化合物具有如下所示的结构，
6.根据权利要求5所述的一种苯并[c][1,2]噁嗪骨架类新化合物，其特征在于：所述的苯并[c][1,2]噁嗪骨架类新化合物或其药学上可接受的盐单独或以混合物形式在制备药物的应用。
7.根据权利要求5所述的一种苯并[c][1,2]噁嗪骨架类新化合物，其特征在于：包括有效量的苯并[c][1,2]噁嗪骨架类新化合物，或其药学上可接受的盐，和药学上可接受的载体。
8.根据权利要求5所述的一种苯并[c][1,2]噁嗪骨架类新化合物，其特征在于：在制备具有苯并[c][1,2]噁嗪结构单元的萜类药物的应用。
9.根据权利要求5所述的一种苯并[c][1,2]噁嗪骨架类新化合物，其特征在于：在制备具有苯并[c][1,2]噁嗪结构单元的多肽类药物的应用。
10.根据权利要求5所述的一种苯并[c][1,2]噁嗪骨架类新化合物，其特征在于：在制备具有苯并[c][1,2]噁嗪结构单元的甾体类药物的应用。
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| WO2023176822A1 (ja) * | 2022-03-15 | 2023-09-21 | 富士フイルム株式会社 | 化合物および脂質組成物 |
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