CN101223153A - 二苯并环庚烷化合物和含有这些化合物的药物 - Google Patents
二苯并环庚烷化合物和含有这些化合物的药物 Download PDFInfo
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- CN101223153A CN101223153A CNA2006800229705A CN200680022970A CN101223153A CN 101223153 A CN101223153 A CN 101223153A CN A2006800229705 A CNA2006800229705 A CN A2006800229705A CN 200680022970 A CN200680022970 A CN 200680022970A CN 101223153 A CN101223153 A CN 101223153A
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- dibenzo
- ketone
- dihydro
- amino
- oxa
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Abstract
本发明涉及式I的化合物,其中R1,R2,R3,R4,X和Z具有说明书中所指出的含义。所述化合物具有免疫调节作用以及抑制或调节IL-1β和/或TNF-α的释放的作用。所以可以利用它们来治疗与免疫系统损伤相关联的病症。
Description
本发明涉及式I的二苯并环庚烷化合物,
其中X,Y和R1至R4具有下面所指出的含义,并且涉及包含式I的化合物的药物组合物。所述化合物是白介素-1β(IL-1β)的抑制剂和肿瘤坏死因子α(TNF-α)的抑制剂,可以用于治疗炎性病症。
IL-1β和TNF-α保护机体免受传染性病原体、肿瘤或组织损伤。不过在自身免疫疾病中,存在IL-1β和TNF-α的增加的生产,可能导致骨和软骨破坏。所以可以使用调节IL-1β和TNF-α的释放的药物来治疗炎性病症。
在WO 98/32730中公开了一类抑制IL-1β和TNF-α的释放的化合物。它们对应于以下通式
并且可以用于治疗和预防哮喘、变态反应、类风湿性关节炎、脊椎关节炎、痛风、动脉粥样硬化、慢性炎性肠病,增殖性和炎性皮肤疾病如银屑病和特应性皮炎。
这一类的其它化合物描述在WO 01/05744,WO 01/05745,WO 01/05746,WO 01/05749,WO 01/05751,WO 01/42189,WO 02/45752,WO 02/076447和WO 03/018535中和J.Med.Chem(医药化学杂志),2003,46,5651-5662和Bioorganic & Medicinal Chemistry Letters(生物有机&药物化学通讯)14(2004)3601-3605中。不过,这些化合物的效果并不完全令人满意。
所以本发明是基于提供具有改进的抗炎效果的化合物的目的。
这一目的通过式I的化合物实现。因而本发明涉及式I的二苯并环庚烷化合物,
其中
环原子X和Y其中之一是CH2而另一个是O,S,SO,SO2或NR5;或-X-Y-是-CH2-CH2-或-CH=CH-;
R1是H或C1-C6-烷基;
R2是H,卤素或C1-C4-烷基-C≡C-,其任选地被氨基基团所取代;
R3选自:
a)-NH2;
e)-NH-C1-C6-亚烷基-NH2
f)卤素;
R4是H,卤素或C1-C6-烷基,或R3和R4连接于苯环的邻近C原子并与这些C原子在一起形成具有氮杂原子的5-或6-元芳族或非芳族杂环,其中杂环可以由一个或两个C1-C6-烷基基团所取代或可以稠合到环己基基团上;
R5是H或C1-C6-烷基;
R6是H或C1-C6-烷基;
R7选自:
H,
NH2,
单-C1-C6-烷基氨基,
二-C1-C6-烷基氨基
C1-C6-烷基-CONH-,
C1-C6-烷基-NHCONH-,
C1-C6-烷基-O-CO-NH-,
C1-C6-烷基,
C1-C6-烷氧基,
NO2或
卤素;
R8是H,NH2,单-C1-C6-烷基氨基,二-C1-C6-烷基氨基,C1-C6-烷氧基或卤素;
R9是H或NH2;
和生理上耐受的盐以及所述化合物和所述盐的溶剂合物。
术语“烷基”(还与其它基团联合,如卤代烷基等)包括直链和支链烷基基团,其优选具有1-6或1-4个碳原子,如甲基,乙基,正和异丙基,正、异和叔丁基,仲丁基,正戊基和正己基。
术语“卤素”代表氟,氯,溴或碘原子,特别是氟或氯原子。
本发明的一个实施方案是式Ia的化合物:
其中Y是O或S,且R1,R2,R3和R4具有上述含义。
另一个实施方案是式Iaa的化合物,
其中Y是O或S,且R7和R8具有上述含义。
本发明的另一个实施方案是式Ib的化合物,
其中X是O或S,且R1,R2,R3和R4具有上述含义。
另一个实施方案是式Ic的化合物
其中-X-Y-是-CH2-CH2-或-CH=CH-,且R1,R2,R3和R4具有上述含义。
另一个实施方案是式Ica的化合物:
其中-X-Y-是-CH2-CH2-或-CH=CH-,且R7和R8具有上述含义。
R1和R2优选H。
在一个实施方案中,R3选自上述式(b)到(e),特别是(b)和(c)。R3特别优选选自
其中R7和R8具有上述含义。
R4,R5和R6优选H。
R7优选NH2,C1-C6-烷基-CONH-,C1-C6-烷基-NHCONH-或C1-C6-烷基-O-CO-NH;
R8优选H,NH2或卤素。
本发明还包括式I的化合物的生理上耐受的盐。在本申请中,它们特别是酸加成盐。通过采用无机酸如盐酸,硫酸或磷酸或有机酸如酒石酸,柠檬酸,马来酸,反丁烯二酸,苹果酸,扁桃酸,抗坏血酸,葡糖酸,甲磺酸,苯磺酸或甲苯磺酸等来形成酸加成盐。
在本发明的化合物具有不对称中心的情况下,本发明同样涉及外消旋物和个别的旋光异构体(对映体,非对映体)。
本发明还涉及式I化合物的溶剂合物,或其盐的溶剂合物,特别是水合物。
通过下面阐述的方法之一来制备本发明的化合物:
方案I:
(Ac2O=乙酸酐)
方案I通过举例说明了式I化合物的制备,其中X是CH2,且Y是S。
起始自3-氨基苯硫酚,以常规的方式,通过例如与乙酸酐的酰基化作用,获得在巯基上和在氨基上酰化的化合物(1)。通过用碱,例如碱金属氢氧化物如氢氧化钠进行部分水解,将这种化合物转变成化合物(2)。将化合物(2)与2-苯并[c]呋喃酮反应,产生化合物(3a)。在极性非质子溶剂如二甲基甲酰胺中在强碱如氢化钠存在下发生硫羟基团与2-苯并[c]呋喃酮的苄基化作用。通过使用适当取代的2-苯并[c]呋喃酮可以引入原子团R1和R2。卤素-或烷基-取代的2-苯并[c]呋喃酮的制备是已知的。如果R2是C1-C4-烷基-C≡C-,可以通过WO 02/076447中所述的方法引入这一基团。
可以在极性有机溶剂如环丁砜中通过例如用多磷酸进行的环闭合来将化合物(3a)转变成化合物(4a)。酸性或碱性水解生成化合物(5a)。
起始自3-氨基苯酚,以类似的方式可以制备氧杂(oxepine)衍生物,即式I的化合物,其中X是CH2而Y是O。
式(5a)的化合物进一步反应,如方案II所示。
方案II
方案II举例说明了原子团R3的引入,用于化合物(7a)的制备的实例。为此目的,在极性溶剂中,使化合物(5a)以亲核芳族取代与2-硝基氟苯反应以给出化合物(6a)。以常规方式例如,用Sn/HCl将化合物(6a)中的硝基基团还原成氨基,形成化合物(7a)。
以类似的方式可以引入其它基团R3。以类似的方式也可以获得相应的氧杂化合物。
在方案III中举例说明用于引入原子团R3的备选方法。
方案III:
在此方法中的第一步也是通过将化合物(5c)与3-硝基苯胺反应以亲核芳族取代引入原子团R3。随后将得到的化合物(6e)转变成化合物(7e)。如上所述结合方案II来进行反应。可以类似的方式引入其它原子团R3,如同制备相应的硫杂(thiepine)化合物那样。
起始自氟化的化合物(5)如,例如,化合物(5c),还可以通过与未活化但具反应性的胺如2-氨基苄胺,乙二胺或1,2-二氨基环己烷反应而引入原子团R3。在方案IV中举例说明了这一反应。
方案IV:
化合物(5)与合适的胺在升高的温度下,无溶剂的情况下方便地发生反应。优选使用大约80到150℃范围内的温度。通常过量使用胺,特别是5-到25-倍过量。
通过修饰氨基(R7=NH2),其中R3是原子团(b)或(c)其中之一,R7是NH2的式I的化合物,可以转变成合适的衍生物。这种类型的反应总结于方案V中:
方案V:
这些包括氨基的常规衍生化作用,并且所需的试剂和反应条件是熟练技术人员所公知的。
其中R3和R4与它们所结合的碳原子一起形成具有氮杂原子的5-或6-元杂环的式I的化合物,可以通过与羟基酮类化合物反应来制备。在方案VI中举例说明了这一反应。
方案VI:
该反应于极性有机溶剂中发生,例如烷醇,如甲醇,乙醇或异丙醇,并且在升高的温度下进行。反应温度一般在反应混合物的沸点区内。
以常规方式,例如使用过化合物如间氯过苯甲酸,通过氧化其中Y是S的化合物来制备式I的化合物,其中Y是SO或SO2。
通过在方案VII到IX中所述的方法来制备式I的化合物,其中X-Y是CH2-CH2或CH=CH。
方案VII:
方案VII举例说明用于化合物(25)和(35)的实施例的起始化合物的制备。在自由基引发剂如偶氮异丁腈存在的情况下,在惰性溶剂如二氯甲烷或氯仿中,通过最初用例如N-溴琥珀酰亚胺(NBS)溴化(20),以常规方式由2-甲基-苯甲酸甲酯(20)起始来制备(25)或(35)。随后将得到的化合物(21)与三苯膦反应以给出化合物(22)。在Wittig反应中用3-硝基苯甲醛或3-氟苯甲醛将其转变成化合物(24)或(34)。酯水解产生化合物(25)或(35)。
方案VIII:
方案VIII举例说明了二苯并环庚酮化合物,例如化合物(30)或(32)的制备。起始自化合物(25),一开始用例如氢/贵金属催化剂或锡/盐酸还原硝基基团,得到化合物(26)。以常规方式,例如用乙酸酐来将(26)中的氨基进行酰化。接着在100到200℃温度下,使用在惰性极性溶剂如环丁砜中的多磷酸(PPA)进行环闭合给出(28)。随后乙酰氨基进行酸水解,得到化合物(29),其通过以亲核芳族取代的方式与硝基-取代的氟苯反应,随后进行硝基基团的还原,转变成化合物(30)或(32)。如对于方案I所述的那样来进行这些反应。
方案IX:
通过在惰性极性溶剂中用多磷酸进行环闭合来将方案VII中获得的化合物(35)转变成化合物(36)。将化合物(36)以亲核芳族取代的方式与2-硝基苯胺反应,随后还原硝基基团以给出化合物(38)。类似于方案II中所阐述的反应来进行这些反应。
起始自化合物(36),可以以类似于方案IV中所阐述的反应来制备式I的其它化合物。起始自化合物(38),通过方案V中所示的氨基修饰可以制备式I的其它化合物。
通过方案X中例如对于氧杂化合物所阐述的已知方法来制备式I的化合物,其中X是O,S,SO,SO2或NR5。可以类似于方案V的方式来制备其它化合物:
方案X
本发明的化合物显示体外和体内的免疫调节效果以及抑制TNF-α和IL-1β的释放的效果。所以本发明的化合物适于治疗与免疫系统损伤相关联的病症。它们适于例如治疗自身免疫疾病,癌症,类风湿性关节炎、痛风、脓毒性休克、骨质疏松症、神经病痛、HIV传播、HIV痴呆、病毒性心肌炎、胰岛素依赖型糖尿病、牙周病症、再狭窄、脱发、HIV感染或AIDS中的T细胞损耗、银屑病、急性胰腺炎、对同种异体移植物的排斥反应、变态反应相关肺炎、动脉硬化、多发性硬化、恶病质、阿尔茨海默病、中风、黄疸、溃疡性结肠炎、局限性回肠炎、炎性肠病(IBD),局部缺血、充血性心力衰竭、肺纤维化、肝炎、成胶质细胞瘤、吉-巴综合征、系统性红斑狼疮、成人呼吸窘迫综合征(ARDS)和呼吸窘迫综合征。
可以作为单一治疗活性成分或作为与其它治疗活性成分的混合物来施用本发明的化合物。可以单独施用所述化合物,但通常以药物组合物的形式来给药和施用,所述组合物即作为活性成分与合适药物载体或稀释剂的混合物。可以口服或胃肠外施用所述化合物或组合物,优选以口服剂型给予它们。
药物组合物或载体或稀释剂的性质取决于所希望给药的形式。口服组合物可以例如是片剂或胶囊的形式,并且可以包含常规赋形剂如粘合剂(例如糖浆、阿拉伯树胶、明胶、山梨糖醇、西黄蓍胶或聚乙烯吡咯烷酮),填充剂(例如乳糖、糖、玉米淀粉、磷酸钙、山梨糖醇或甘氨酸),滑润剂(例如硬脂酸镁、滑石、聚乙二醇或二氧化硅),崩解剂(例如淀粉)或润湿剂(例如月桂基硫酸钠)。液体口服产品可以是水性或油性混悬剂、溶液剂、乳剂、糖浆、酏剂或喷雾剂等等的形式。它们还可以是干粉的形式,其进行制备来用水或另一种合适的载体重构。这种类型的液体产品可以包含常规添加剂,例如悬浮剂、调味剂、稀释剂或乳化剂。可以采用具有常规药物载体的溶液或混悬液进行胃肠外给药。
本发明的化合物或组合物能够以大约0.5mg-100mg/kg体重/天的剂量施用给哺乳动物(人或动物)。可以单一剂量或多次剂量来给予它们。通过如Donat C.和Laufer S.在Arch.Pharm.Pharm.Med.Chem.(药物医药化学文献)333,增刊1,1-40,2000中所述的下列测试系统研究了所述化合物作为TNF-α和IL-1β释放的抑制剂的效果范围。
用人全血进行的体外测试方法
将人EDTA钾全血(400μl每份)的样品与测试物质混合并在CO2保温箱(5%CO2;95%湿度-饱和空气)中于37℃预温育15min。随后在CO2保温箱(5%CO2;95%湿度-饱和空气)中于37℃用1μg/ml LPS(大肠杆菌(E.coli)026:B6)刺激样品4小时。通过将样品放置于冰上,添加DPBS缓冲液,随后于1000·g离心15min来终止反应。随后通过ELISA测量血浆上清液中IL-1β和TNFα的量。
用PBMC进行的体外测试方法
1)通过密度梯度离心的方式(Histopaque-1,077)从1∶3-稀释的人EDTA钾全血中分离出单核细胞(PBMCs)。用DPBS缓冲液将这些细胞洗涤两次,重悬于巨噬细胞SFM培养基中并调节至1*106细胞/ml的细胞量。
2)将得到的PBMCs混悬液(每份样品390μl)在CO2保温箱(5%CO2;95%湿度-饱和空气)中于37℃与测试物质一起温育15min。随后在每种情况中在CO2保温箱(5%CO2;95%湿度-饱和空气)中于37℃用1μg/ml LPS(大肠杆菌026:B6)刺激样品4小时。通过将样品放置于冰上,添加DPBS缓冲液,随后于15 880*g离心12min来终止反应。随后通过ELISA测量血浆上清液中IL-1β和TNFα的量。
激酶测定(p38MAP激酶测定)
用50μl ATF2溶液(20μg/ml)于37℃将微量滴定板包被一小时。在用水洗涤三次后,将50μl激酶混合物(50mM tris-HCl 10mM MgCl2,10mMβ-磷酸甘油,10μg/ml BSA,1mM DTT,100μM ATP,100μM Na3VO4,10ng活化的p38α)伴有或没有抑制剂放入孔中并于37℃温育1小时。在洗涤三次后,将板与磷-ATF-2抗体于37℃一起温育1小时。在再次洗涤三次后,于37℃添加标记了碱性磷酸酶的山羊抗兔IgG持续一小时(为了保留抗体磷酸化的蛋白质-底物复合体)。在洗涤三次后,于37℃添加碱性磷酸酶底物溶液(3mM 4-NPP,50mM NaHCO3,50mM MgCl2,100μl/孔)持续1.5小时。利用微量滴定板读数器于405nm测量4-硝基苯酚盐的形成。计算IC50值。
测试的结果显示于下表1中。
表1
实施例化合物编号 | p38 MAP激酶测定IC50(μM) | 抑制作用 | |
TNF-α(全血)IC50(μM) | IL-1β(全血)IC50(μM) | ||
4 | 1.1 | - | - |
5 | 0.3 | - | - |
24 | 0.038 | - | - |
25 | 0.09 | 2.3 | 1.8 |
28 | 0.159 | - | - |
下列实施例举例说明本发明,而非限制它。
实施例
使用下列材料和方法确定物理化学数据:
1.熔点:
Büchi熔点B-545(热力学校正)
2.NMR光谱学:
Bruker Advance 200(200MHz)
内标:四甲基硅烷(TMS),δ[ppm]=0
3.IR光谱学:
Perkin Elmer Spectrum One(ATR Technique)
4.GC/MS:
Hewlett Packard HP 6890系列GC系统
Hewlett Packard HP 5973质量选择性检测器
方法1:
入口温度:250℃
斜坡坡度[K/min] | 最终温度[℃] | 持续时间[min] |
100 | 1 | |
10 | 160 | 10 |
15 | 200 | 15 |
方法2:
入口温度:250℃
斜坡坡度[K/min] | 最终温度[℃] | 持续时间[min] |
100 | 1 | |
10 | 160 | 10 |
15 | 200 | 15 |
10 | 270 | 20 |
方法3:
入口温度:250℃
斜坡坡度[K/min] | 最终温度[℃] | 持续时间[min] |
160 | 1 | |
10 | 240 | 5 |
10 | 270 | 15 |
方法4:
入口温度:250℃
斜坡坡度[K/min] | 最终温度[℃] | 持续时间[min] |
160 | 1 | |
10 | 240 | 5 |
10 | 270 | 30 |
方法5:
温度[℃] | 运行时间[min] |
100 | 0-1 |
100→160 | 1-7 |
160 | 7-17 |
160→200 | 17-19.67 |
200 | 34.67 |
方法6:
温度[℃] | 运行时间[min] |
150 | 0-1 |
150→230 | 1-9 |
230 | 9-14 |
230→270 | 14-22 |
270 | 22-40 |
1.通用方法A1(在这里和下文中的脚注与实施例结尾处的参考文献列表有关)
苯硫酚化合物的苄基化作用(方案I):
向二甲基甲酰胺中的氢化钠的混悬液中以小份加入待去质子化的反应物。在气体逸出停止后,加入第二种前体并于大约160℃进行回流。将反应混合物冷却,并在加入冰水后,用盐酸(20%)进行酸化。滤去得到的沉淀物,用盐酸(10%)洗涤并通过氯化钙干燥。
2.通用方法B1
环闭合以给出二苯并硫杂,二苯并氧杂或二苯并氮杂(参照,例如,方案I)。
在保护性气体(氩气)下,通过加热到大约100℃将待进行环闭合的羧酸化合物溶于环丁砜中。当酸完全溶解后,加入多磷酸,并将混合物于100℃搅拌2h。随后加入冰水,并将混合物于室温搅拌过夜。滤去沉淀产物并通过氯化钙干燥。
3.通用方法C2
还原硝基苯化合物以给出相应的苯胺化合物(参照,例如,方案II)。
通过加热至回流将待还原的化合物溶于异丙醇中。当所有的前体溶解后,缓慢加入浓盐酸。随后逐份加入锡。在锡添加结束后,将混合物回流大约1.5-2h。冷却后,用氢氧化钠溶液(20%)进行碱化,并用乙酸乙酯(EtOAc)抽提。将合并的乙酸乙酯抽提物进行蒸发并通过柱色谱法进行纯化。
4.通用方法D7
制备均二苯代乙烯化合物(参照方案VII)
通过在室温(RT)下于干燥500ml三颈烧瓶中搅拌一定量的在甲醇中的甲醇钠(sodium methanolate)溶液(30%于MeOH中)15min,随后向混合物中加入磷鎓盐,再搅拌30min,并在将混合物加热到50℃后,加入合适的醛,通过Wittig反应合成均二苯代乙烯(24)和(34)。于80℃回流一定的时期,随后真空脱去过量的乙醇。将残余物与150ml水混合并用二乙醚抽提几次。在干燥(Na2SO4)后浓缩合并的有机相得到粗制产物,使用CH2Cl2或SiO2通过柱色谱法对其进行纯化。
5.通用方法E8
酯水解(参照方案VII)
通过加热将一定量的酯溶于MeOH,小心加入20%浓度的氢氧化钠溶液,于大约80℃回流,对获自Wittig反应的产物进行分解。真空除去乙醇并用CH2Cl2抽提残余物几次。用浓HCl酸化水相得到沉淀形式的粗制产物,将其滤去。通过用二乙醚消化来纯化这种沉淀物,并在真空中将滤液浓缩干燥。
6.通用方法F8
环闭合以得到二苯并环庚酮化合物(见方案VIII)
通过加热在干燥500ml三颈烧瓶中在氩气下将一定量的羧酸溶于环丁砜中,随后加入多磷酸并于110℃回流来合成酮(28)和(36)。用冰水水解后在室温下搅拌,滤去在此过程中沉淀的粗制产物,随后通过用H2O洗涤纯化。
7.通用方法G12
通过用3-氟硝基苯取代二苯并环庚酮化合物,还原获得的硝基化合物(参照方案VIII)
通过用异丙醇将过滤残余物洗入100ml圆底烧瓶中并在室温搅拌的同时缓慢加入浓HCl来还原获自化合物(29)和(36)的取代反应的硝基化合物。在加热到100℃后,加入锡粉,随后回流2h。冷却后,用20%浓度的NaOH进行碱化,并用EtOAc反复抽提;将合并的有机相干燥(Na2SO4),随后在真空中浓缩。
8.通用方法H4
硝基化合物的还原
例如,通过将待还原的化合物溶于乙醇,添加二水合氯化锡(II)并于70℃搅拌大约2h来还原实施例11(7f)的硝基化合物。在冷却至室温后,向混合物中加入冰水,用氢氧化钠溶液对其进行碱化。用乙酸乙酯抽提水相,使用饱和盐水进行洗涤,并除去溶剂。
A.制备式I的化合物,其中Y=O或S
实施例1
3-氨基-6,11-二氢二苯并[b,e]硫杂(thiepin)-11-酮·HCl(5a)
a)2-(3-乙酰氨基苯硫基甲基)苯甲酸(3a)
(1)3-乙酰基硫烷基乙酰苯胺(1)3
如参考文献(3)中所述制备这种化合物。
(2)3-乙酰氨基苯硫酚(2)1
在回流下于50℃将20.0g(95.6mmol)的1,140ml氢氧化钠溶液(10%)和60ml乙醇搅拌大约20min。随后用盐酸(20%)来酸化冷却的混合物。产物沉淀为粘性块并用二乙醚抽提三次。去除乙醚,得到产物。
GC(方法1) 12.0min
MS m/z(%):167(52.5),125(100.0),97(19.9),93(13.2),81(30.2),63(10.5)
(3)2-(3-乙酰氨基苯硫基甲基)苯甲酸(3a)1
通过通用方法A,将4.05g(92.8mmol)氢化钠(55%),15.0g(89.7mmol)的2和12.15g(90.6mmol)的2-苯并[c]呋喃酮与90ml的二甲基甲酰胺一起使用。反应时间为大约5h。用大约180ml的冰水来进行后处理。
产率:23.7g(87.6%);熔点:161-163℃
1H-NMR(DMSO-d6)δ(ppm):13.05(s,1H,-COOH),9.95(s,1H,>NH),7.85(d,1H,J=3.48Hz,芳基H),7.62(s,1H,芳基H),7.48-7.30(m,4H,芳基H),7.20(t,1H,J=7.87Hz,芳基H),6.97(d,1H,J=3.72Hz,芳基H),4.56(s,2H,-CH2-S-),2.03(s,3H,-CO-CH3)
IR(ATR)(cm-1):1699,1580,1542,1420,1397,1292,1247,1230,778,720.
b)3-氨基-6,11-二氢二苯并[b,e]硫杂-11-酮·HCl(5a)
(1)3-乙酰氨基-6,11-二氢二苯并[b,e]硫杂-11-酮(4a)1
通过通用方法B,使用10.0g(33.2mmol)的3a,50ml环丁砜和100ml(206g)多磷酸(PPA)。获得3-乙酰氨基-6,11-二氢二苯并[b,e]硫杂-11-酮和3-氨基-6,11-二氢二苯并[b,e]硫杂-11-酮的混合物,但不进行分离或纯化。
1H-NMR(DMSO-d6)δ(ppm):10.31(s,1H,>NH),8.10(d,1H,J=4.40Hz,芳基H),7.80(d,1H,J=0.90Hz,芳基H),7.53-7.37(m,5H,芳基H),4.22(s,2H,-CH2-S-),2.07(s,3H,-COCH3)
IR(ATR)(cm-1):1690,1618,1584,1568,1507,1371,1267,1244,1065,930
GC(方法2)55.1min
MS m/z(%):283(100.0),250(26.2),241(31.2),213(20.6),208(89.6),197(10.7),184(34.0),180(48.5),152(40.2),139(11.3),89(23.3),63(17.7).
(2)3-氨基-6,11-二氢二苯并[b,e]硫杂-11-酮·HCl(5a)1
通过加热将来自在前阶段的物质混合物(4a)溶于大约120ml甲醇中。随后加入30ml浓盐酸,并将混合物回流大约2h。随后将其在真空中浓缩。向残余物中加入10%盐酸,搅拌混合物并让产物结晶。将过滤的产物通过氯化钙干燥。
产率:8.0g(86.7%,基于4a);熔点:204-206℃
1H-NMR(DMSO-d6)δ(ppm):7.99(d,1H,J=4.26Hz,芳基H),7.51-7.42(m,2H,芳基H),7.36-7.28(m,2H,芳基H),6.56-6.51(m,2H,芳基H),4.89(s,3H,-NH3 +),4.11(s,2H,-CH2-S-)
IR(ATR)(cm-1):1650,1597,1583,1558,1537,1276,1240,931,735,685
GC(方法2)40.2min
m/z(%):241(94.7),212(62.4),208(100.0),197(10.5),195(10.3),184(15.3),180(72.0),152(32.4),121(10.3),106(15.5),89(25.5),77(10.4),63(21.1).
实施例2
3-氨基-6,11-二氢二苯并[b,e]氧杂-11-酮·HCl(5b)a)2-(3-乙酰氨基苯氧基甲基)苯甲酸(3b)1
通过通用方法A,将4.56g(105mmol)氢化钠(55%),15.0g(99.2mmol)的3-乙酰氨基苯酚和2和13.5g(101mmol)2-苯并[c]呋喃酮与90ml的二甲基甲酰胺一起使用。反应时间为大约5h。用大约180ml的冰水来进行后处理。
产率:14.2g(50%);熔点:200-202℃
1H-NMR(DMSO-d6)δ(ppm):13.05(s,1H,-COOH),9.93(s,1H,>NH),7.94(d,1H,J=3.49Hz,芳基H),7.72-7.10(m,6H,芳基H),6.66(s,1H,芳基H),5.42(s,2H,-CH2-O-),2.02(s,3H,-CO-CH3)
IR(ATR)(cm-1):1680,1667,1605,1493,1416,1315,1270,1255,1156,1054,1044,732,681.
b)3-氨基-6,11-二氢二苯并[b,e]氧杂-11-酮·HCl(5b)
(1)3-乙酰氨基-6,11-二氢二苯并[b,e]氧杂-11-酮(4b)
通过通用方法B,使用10.0g(35.1mmol)3b,50ml的环丁砜和100ml(206g)多磷酸。获得3-乙酰氨基-6,11-二氢二苯并[b,e]氧杂-11-酮和3-氨基-6,11-二氢二苯并[b,e]氧杂-11-酮的混合物,但不进行分离或纯化。
GC(方法2)37.0min
MS m/z(%):267(59.9),225(100.0),196(65.4),180(13.5),168(23.5),152(14.2),139(10.0),115(13.2),89(17.2),77(10.7),63(10.3).
(2)3-氨基-6,11-二氢二苯并[b,e]氧杂-11-酮·HCl(5b)1
通过对于5a所述的方法将保护基从物质混合物4b上除去。产率:5.0g(54.5%,基于4b);熔点:210℃
1H-NMR(DMSO-d6)δ(ppm):7.89(d,1H,J=4.42Hz,芳基H),7.82-7.77(m,1H,芳基H),7.63-7.44(m,3H,芳基H),6.40(dd,1H,J1=3.4Hz,J2=5.6Hz,芳基H),6.13(d,1H,J=1.07Hz,芳基H),5.15(s,2H,-CH2-O-),4.85(s,3H,-NH3 +)
IR(ATR)(cm-1):2922,2852,1642,1622,1598,1542,1459,1301,1252,1151,1124,755,698
GC(方法2)35.0min
MSm/z(%):225(100.0),196(61.9),180(15.0),168(18.3),152(9.8),141(9.0),128(4.4),115(10.5),89(15.5),77(6.1),63(10.4),51(8.4).
实施例3
3-氟-6,11-二氢二苯并[b,e]氧杂-11-酮(5c)
a)2-(3-氟苯氧基甲基)苯甲酸(3c)
通过通用方法A,将2.30g(52.7mmol)氢化钠(55%),5.61g(50.0mmol)3-氟苯酚和6.80g(50.7mmol)2-苯并[c]呋喃酮与50ml二甲基甲酰胺一起使用。反应时间为大约5h。用大约90ml的冰水来进行后处理。
产率:4.37g(48.5%);熔点:90-92℃
1H-NMR(CDCl3)δ(ppm):8.19-7.25(m,7H,芳基H),6.80-6.67(m,1H,芳基H),5.34(s,2H,-CH2-O-)
IR(ATR)(cm-1):1690,1613,1595,1581,1490,1311,1287,1273,1165,1139,1042,999,957,755,735,679,671.
b)3-氟-6,11-二氢二苯并[b,e]氧杂-11-酮(5c)
通过通用方法B,使用5.00g(20.3mmol)3c,25ml环丁砜和48.5ml(100g)的多磷酸。用大约150ml的冰水进行后处理。
产率:2.30g(49.7%);熔点:79-81℃
1H-NMR(CDCl3)δ(ppm):8.28(dd,1H,J1=1.10Hz,J2=7.90Hz,芳基H),7.90(dd,1H,J1=3.00Hz,J2=4.60Hz,芳基H),7.62-7.44(m,2H,芳基H),7.37(dd,1H,J1=2.95Hz,J2=4.15Hz,芳基H),6.90-6.71(m,2H,芳基H),5.21(s,2H,-CH2-O-)
13C-NMR(CDCl3)δ(ppm):189.52(C11),165.96(d,J=166.45Hz,C3),163.54(d,J=32.68Hz,C4a),140.24(C6a),135.00(C10a),134.38(C8),133.66(d,J=47.00Hz,C1),129.44(C10),129.31(C9),127.74(C7),122.17(d,J=1.32Hz,C11a),110.33(d,J=10.90Hz,C2),106.86(d,J=11.85Hz,C4),73.76(C6)
IR(ATR)(cm-1):1643,1611,1596,1576,1296,1242,1208,1138,1115,1104,1023,851,753,693
GC(方法1)18.8min
MS m/z(%):228(100.0),199(73.6),170(24.9),89(13.6).
实施例4
3-(2-氨基苯胺基)-6,11-二氢二苯并[b,e]硫杂-11-酮(7a)
(1)3-(2-硝基苯胺基)-6,11-二氢二苯并[b,e]硫杂-11-酮(6a)
通过通用方法A,将0.45g(10.3mmol)氢化钠(55%),1.00g(3.60mmol)5a和0.51g(3.60mmol)2-氟硝基苯与7.5ml二甲基甲酰胺一起使用。将混合物回流过夜(大约15h)。用大约50ml的冰水进行后处理。以此方式获得的红褐色粉末可以通过柱色谱法来纯化以给出橙色粉末。
产率:570mg(43.7%);熔点:186-188℃
1H-NMR(DMSO-d6)δ(ppm):9.28(s,1H,>NH),8.17-8.07(m,2H,芳基H),7.70-7.58(m,1H,芳基H),7.58-7.48(m,3H,芳基H),7.43-7.32(m,2H,芳基H),7.72-7.07(m,3H,芳基H),4.22(s,2H,-CH2-S-)
IR(ATR)(cm-1):1590,1578,1498,1441,1347,1251,1233,1167,1146,732.
(2)3-(2-氨基苯胺基)-6,11-二氢二苯并[b,e]硫杂-11-酮(7a)
通过通用方法C,将0.50g(1.38mmol)6a与5ml异丙醇,5ml浓盐酸和1.2g锡一起使用。
产率:320mg(43.4%);熔点:195℃
(cm-1):2922,2853,1615,1583,1564,1497,1479,1457,1275,1238,1136,735
实施例5
3-(2-氨基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮(7b)
(1)3-(2-硝基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮(6b)
通过通用方法A,将0.52g(12.0mmol)氢化钠(55%),1.00g(3.82mmol)5b和0.54g(3.82mmol)2-氟硝基苯与8ml二甲基甲酰胺一起使用。将混合物回流过夜(大约15h)。用大约50ml的冰水进行后处理。以此方式获得的红褐色粉末可以通过柱色谱法来纯化以给出橙色粉末。
或者,通过通用方法A,将0.20g(4.60mmol)氢化钠(55%),1.00g(4.38mmol)5c和0.61g(4.43mmol)2-硝基苯胺与5ml二甲基甲酰胺一起使用。将混合物回流过夜(大约15h)。用大约50ml的冰水进行后处理。
产率:1.32g(100%)
IR (ATR)(cm-1):1588,1577,1504,1330,1296,1257,1214,1150,1124,735,713.
(2)3-(2-氨基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮(7b)
通过通用方法C,将1.00g(2.89mmol)7b与15ml异丙醇,15ml浓盐酸和2.5g锡一起使用。
或者,通过通用方法H,将0.75g(2.17mmol)6b溶于4ml乙醇中,加入2.45g(10.9mmol)二水合氯化锡(II),将混合物于70℃搅拌大约2h。冷却至室温后,向混合物中加入冰水,所述混合物用氢氧化钠溶液进行过碱化。用乙酸乙酯抽提水相,使用饱和盐水进行洗涤,并将溶液浓缩4。
产率:135mg(15%);熔点:122-124℃
1H-NMR(DMSO-d6)δ(ppm):8.16(s,1H,>NH),7.96(d,1H,J=4.46Hz,芳基H),7.79(d,1H,J=3.65Hz,芳基H),7.60-7.46(m,3H,arylH),7.01-6.93(m,2H,芳基H),6.78(d,1H,J=3.94Hz,芳基H),6.62-6.49(m,2H,芳基H),6.08(s,1H,芳基H),5.15(s,2H,-CH2-O-),4.86(s,2H,-NH2)
13C-NMR(CDCl3)δ(ppm):188.70(C11),163.45(C4a),152.31(C3),142.26(C2’),140.72(C6a),135.54(C10a),134.20(C8),132.10(C1),129.57(C10),129.08(C9),127.56(C7),127.51(C5′),127.01(C4′),125.65(C1′),119.45(C6′),117.52(C11a),116.67(C3′),109.86(C2),102.25(C4),73.64(C6)
IR(ATR)(cm-1):1587,1559,1498,1459,1297,1276,1253,1229,1154,1118,746
GC(方法3)29.4min
MS m/z(%):316(100.0),301(15.5),287(14.2),273(12.5),269(13.7),181(24.1),169(22.7),152(24.2),145(17.7),141(10.2),132(14.3),128(13.6),115(18.3),107(11.2),89(29.6),80(22.7),77(16.7),65(29.3),63(16.9),51(11.6).
实施例6
3-(4-氨基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮(7c)
(1)3-(4-硝基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮(6c)
通过通用方法A,将0.52g(12.0mmol)氢化钠(55%),1.00g(3.82mmol)5b和0.54g(3.82mmol)4-氟硝基苯与8ml二甲基甲酰胺一起使用。将混合物回流过夜(大约15h)。用大约50ml的冰水进行后处理。
产率:1.32g(100%)
IR(ATR)(cm-1):2854,2923,1585,1572,1500,1322,1293,1250,1109,712
(2)3-(4-氨基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮(7c)
通过通用方法C,将1.00g(2.89mmol)6c与15ml异丙醇,15ml浓盐酸和2.5g锡一起使用。
产率:186mg(20.3%);熔点:131-133℃(分解作用)
1H-NMR(CDCl3)δ(ppm):8.15(d,1H,J=4.46Hz,芳基H),7.97-7.92(m,1H,芳基H),7.51-7.43(m,2H,芳基H),7.33-7.25(m,1H,芳基H),7.03-7.97(m,2H,芳基H),6.70-6.65(m,2H,芳基H),6.52(dd,1H,J1=3.32Hz,J2=5.60Hz,芳基H),6.33(d,1H,J=1.15Hz,芳基H),5.92(s,1H,>NH),5.12(s,2H,-CH2-O-),3.56(s,2H,-NH2)
13C-NMR(CDCl3)δ(ppm):188.29(C11),163.37(C4a),152.78(C3),143.85(C4’),140.65(C6a),135.52(C10a),134.04(C8),131.86(C1),130.56(C1′),129.51(C10),128.92(C9),127.39(C7),125.41(2C,C2′和C6′),116.98(C11a),115.80(2C,C3′和C5′),109.62(C2),101.50(C4),73.52(C6)
IR(ATR)(cm-1):1626,1589,1564,1510,1329,1301,1277,1256,1156,1120,826
GC(方法4)32.5min
MSm/z(%):316(100.0),287(10.9),281(10.5),253(6.1),207(51.3),181(7.0),107(8.2).
实施例7
3-(2-氟-4-氨基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮(7d)
(1)3-(2-氟-4-硝基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮(6d)
通过通用方法A,将0.52g(12.0mmol)氢化钠(55%),1.00g(3.82mmol)5b和0.54g(3.82mmol)3-氟硝基苯与8ml二甲基甲酰胺一起使用。将混合物回流过夜(大约15h)。用大约50ml的冰水进行后处理。
产率:0.80g(57.5%);
IR(ATR)(cm-1):1588,1575,1528,1505,1489,1320,1290,1271,1251,1188,1154,1122,710,678
(2)3-(2-氟-4-氨基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮(7d)
通过通用方法C,将0.80g(2.20mmol)6d与10ml异丙醇,10ml浓盐酸,和2.0g锡一起使用。
产率:150mg(20.4%);熔点:123-125℃
1H-NMR(CDCl3)δ(ppm):8.16(d,1H,J=4.46Hz,芳基H),7.94(d,1H,J=3.57Hz,芳基H),7.51-7.43(m,2H,芳基H),7.33-7.25(m,1H,芳基H),7.10(t,2H,J=8.71Hz,芳基H),6.55-6.42(m,2H,芳基H),6.30(d,1H,J=1.09Hz,芳基H),5.74(s,1H,>NH),5.13(s,2H,-CH2-O-),3.77(s,2H,-NH2)
13C-NMR(CDCl3)δ(ppm):188.51(C11),163.29(C4a),57.46(d,J=121.73Hz,C2′),152.39(C3),145.44(d,J=5.10Hz,C4′),140.60(C6a),135.49(C10a),133.99(C8),132.05(C1),129.49(C10),128.95(C9),127.43(C7),127.07(d,J=12.08Hz,C6′),117.79(d,J=7.35Hz,C1′),117.37(C11a),110.69(d,J=5.95Hz,C5′),109.66(C2),102.87(d,J=11.60Hz,C3′),101.85(C4),73.54(C6)
IR(ATR)(cm-1):1624,1589,1564,1517,1494,1299,1277,1229,1155,1120
GC(方法4)30.5min
MS m/z(%):334(100),305(10.5),181(7.8),152(8.7),125(11.2).
实施例8
2,11,12,13,14-五氢-10H-(苯并[e]氧杂)[2,3-c]咔唑-7-酮(8a)
将1.00g(3.82mmol)5b和0.44g(3.82mmol)2-羟基环己酮溶于乙醇中并回流大约16h。反应结束后,加入冰水。滤去得到的沉淀物并进行纯化。获得浅黄色粉末。
产率:1.12g(96.6%);熔点:226-228℃
1H-NMR(DMSO-d6)δ(ppm):11.17(s,1H,>NH),7.91-7.72(m,2H,芳基H),7.68-7.44(m,2H,芳基H),7.01(d,1H,J=4.38Hz,芳基H),5.77(s,1H,C9H),5.31(s,2H,-CH2-O-),2.85(s,2H,>C11H2),2.66(s,2H,>C14H2),1.78(s,4H,-C12H2-C13H2)
13C-NMR(CDCl3)δ(ppm):190.75(C7),157.81(C14c),141.29(C2a),140.16(C9a),135.46(C6a),133.33(C10a),131.79(C4),129.39(C6),128.91(C5),127.30(C3),124.89(C8),118.19(C14b),117.24(C7a),112.42(C14a),106.00(C9),74.04(C2),23.29(C13),23.13(C12),23.06(C11),22.62(C14)
IR(ATR)(cm-1):1607,1586,1568,1349,1314,1282,1236,1164,1098,751,736,707
GC(方法2)50.1min
MS m/z(%):303(100),286(10.7),274(50.2),258(14.1),246(21.2),207(18.5).
实施例9
2-氢-11,12-二甲基-10H-(苯并[e]氧杂)[2,3-e]吲哚-7-酮(8b)
将1.00g(3.82mmol)5b和0.34g(3.82mmol)的3-羟基丁-2-酮溶于15ml乙醇中并回流过夜(大约16h)。向混合物中加入冰水,并将得到的沉淀物滤去。通过由甲醇中再结晶获得黄绿色粉末。
产率:0.11g(10.4%);熔点:160℃
1H-NMR(DMSO-d6)δ(ppm):11.18(s,1H,>NH),7.95-7.75(m,2H,芳基H),7.63-7.47(m,3H,芳基H),6.99(d,1H,J=4.40Hz,芳基H),5.33(s,2H,-CH2-O-),2.32(s,3H,>C11CH3),2.26(s,3H,>C12-CH3)
13C-NMR(CDCl3)δ(ppm):190.74(C7),158.09(C12b),141.21(C2a),139.84(C9a),135.56(C6a),131.81(C4),130.14(C11),129.43(C6),128.90(C5),127.24(C3),124.78(C8),119.16(C12a),117.25(C7a),109.70(C12),105.83(C9),74.05(C2),11.17(11-甲基),10.90(12-甲基)
IR(ATR)(cm-1):2922,1592,1568,1341,1307,1268,1249,1164,752,708
GC(方法2)43.1min
MS m/z(%):277(100),262(22),248(58.2),234(18.5),232(15.1),124(8.5).
实施例10
3-(3-氨基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮(7e)
(1)3-(3-硝基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮(6e)
通过通用方法A,将0.20g(4.58mmol)氢化钠(55%),0.61g(4.44mmol)3-硝基苯胺和1.00g(4.38mmol)5c与5ml二甲基甲酰胺一起使用。将混合物回流过夜(大约15h)。用大约50ml的冰水进行后处理。
产率:1.40g(92.3%);
IR(ATR)(cm-1):2923,2854,1587,1528,1479,1458,1350,1325,1292,1250,1119,1100,712.
(2)3-(3-氨基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮(7e)
通过通用方法C,将1.00g(2.89mmol)6e与15ml异丙醇,15ml浓盐酸和2.5g锡一起使用。
产率:71mg(7.8%);熔点:~150℃(分解作用)
1H-NMR(CDCl3)δ(ppm):8.19(d,1H,J=4.43Hz,芳基H),7.95(dd,1H,J1=4.43Hz,J2=2.80Hz,芳基H),7.80-7.71(m,1H,芳基H),7.53-7.46(m,2H,芳基H),7.36-7.32(m,1H,芳基H),7.18-7.06(m,1H,芳基H),6.73-6.36(m,4H,芳基H),6.09(s,2H,-NH2),5.16(s,2H,-CH2-O-),4.68(s,1H,>NH)
13C-NMR(CDCl3)δ(ppm):188.47(C11),163.16(C4a),150.51(C3),147.47(C3′),141.05(C1′),140.58(C6a),135.48(C10a),133.94(C8),132.01(C1),130.23(C10),129.50(C9),128.99(C5′),127.46(C7),117.84(C11a),111.28(C2),110.86(C6′),110.55(C4′),107.31(C2′),103.38(C4),73.54(C6)
IR(ATR)(cm-1):1585,1569,1490,1459,1297,1276,1254,1230,1156,1121,759,701
GC(方法4)32.8min
MS m/z(%):316(100.0),287(13.8),281(9.6),223(21.3),207(39.2),181(9.0),106(10.0).
实施例11
3-(2,4-二氨基苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮(7f)
(1)3-(2,4-二硝基苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮(6f)
通过通用方法A,将0.10g(2.30mmol)氢化钠(55%),0.40g(2.21mmol)2,4-二硝基苯胺和0.50g(2.19mmol)5c与5ml二甲基甲酰胺一起使用。将混合物回流过夜(大约15h)。用大约50ml冰水和用HCl酸化来进行后处理。通过用二氯甲烷作为流动相在硅胶柱上进行柱色谱法来纯化已经滤去的沉淀物。以此方式获得黄色产物。
产率:720mg(84.0%);
1H-NMR(CDCl3)δ(ppm):10.01(s,1H,芳基H),9.20(d,1H,J=0.99Hz,芳基H),8.46-8.27(m,2H,芳基H),7.99-7.91(m,1H,芳基H),7.64-7.28(m,3H,芳基H),7.13-6.97(m,2H,芳基H),5.26(s,2H,-CH2-O-),>NH未检测
13C-NMR(CDCl3)δ(ppm):189.36(C11),162.33(C4a),144.77(C3),143.12(C1′),140.18(C6a),138.48(C4′),134.96(C10a),134.32(C8),132.95(C1),129.92(C10),129.50(C9+C2′),127.91(C7),123.83(C5′),123.41(C2),116.96(C11a+C6′),116.80(C3′),114.14(C4),73.73(C6)
IR(ATR)(cm-1):1594,1521,1503,1337,1310,1296,1281,1266,1246,1140,1125.
(2)3-(2,4-二氨基苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮(7f)
通过通用方法H,将0.72g(1.84mmol)6f与4ml乙醇和4.00g(18.4mmol)二水合氯化锡(II)一起使用。通过在RP18硅胶柱上用乙腈/水6+4流动相进行MPLC来纯化得到的粗制产物。
产率:30mg(4.9%);
1H-NMR(CDCl3)δ(ppm):8.15(d,1H,J=4.40Hz,芳基H),7.94(d,1H,J=3.34Hz,芳基H),7.57-7.40(m,2H,芳基H),7.36-7.23(m,1H,芳基H),6.87(d,1H,J=3.85Hz,芳基H),6.44(d,1H,J=4.33Hz,芳基H),6.20-6.05(m,3H,芳基H),5.50(s,1H,>NH),5.12(s,2H,-CH2-O-),3.68(s,4H,-NH2)]
13C-NMR(CDCl3)δ(ppm):188.50(C11),163.46(C4a),153.73(C3),146.51(C4′),144.53(C2′),140.66(C6a),135.46(C10a),134.10(C8),131.88(C1),129.50(C10),129.45(C6′),128.93(C9),127.41(C7),116.94(C11a),116.14(C1′),109.21(C2),106.12(C5′),101.93(C4),101.32(C3′),73.51(C6)
IR(ATR)(cm-1):1622,1590,1563,1514,1468,1384,1300,1276,1255,1235,1155,1119,922,758,700.
实施例12
3-(2-氨基苄基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮(9)
通过加热熔化2.27g(18.6mmol)的2-氨基苄基胺。向熔化物中按份加入0.25g(1.10mmol)5c。完成添加后,将混合物搅拌4h。向混合物中加入冰水,所述混合物用二氯乙醇进行了抽提。通过柱色谱法纯化以此方式获得的产物以给出黄橙色粉末5。
产率:160mg(44.0%);熔点:72℃
1H-NMR(CDCl3)δ(ppm):8.17(d,1H,J=4.46Hz,芳基H),7.98-7.94(m,1H,芳基H),7.53-7.46(m,2H,芳基H),7.37-7.27(m,1H,芳基H),7.16-7.14(m,2H,芳基H),6.77-6.72(m,2H,芳基H),6.45(dd,1H,J1=3.24Hz,J2=5.64Hz,芳基H),6.25(d,1H,J=1.16Hz,芳基H),5.17(s,2H,-CH2-O-),4.27(s,3H,-NH-CH2-),3.90(s,2H,-NH2)
13C-NMR(CDCl3)δ(ppm):188.46(C11),163.49(C4a),154.13(C3),145.12(C2’),140.64(C6a),135.46(C10a),133.93(C8),131.94(C1),129.97(C6′),129.51(C10),129.25(C9),128.97(C4′),127.44(C7),121.36(C1′),118.64(C5′),116.67(C11a),116.05(C3′),109.24(C2),100.49(C4),73.64(C6),45.60(-NH-CH2-)
IR(ATR)(cm-1):1626,1591,1564,1495,1458,1302,1262,1233,1156,1121,750,703
GC(方法4)34.0min
MS m/z(%):330(57.6),225(40.2),196(9.8),152(5.4),106(100.0),77(8.2).
实施例13
3-(2-氨基乙基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮(10)向加热到大约120℃的4.50g(74.9mmol)乙二胺中按份加入1.00g(4.38mmol)5c。在完成添加后,将混合物回流4h。向混合物中加入冰水,滤去得到的沉淀物并由甲醇/水中再结晶。获得淡褐色粉末。5
产率:660mg(56.2%);熔点:113-115℃
1H-NMR(CDCl3)δ(ppm):8.13(d,1H,J=4.42Hz,芳基H),7.95(d,1H,J=3.10Hz,芳基H),7.50-7.26(m,3H,芳基H),6.38(d,1H,J=4.12Hz,芳基H),6.12(s,1H,芳基H),5.14(s,2H,-CH2-O-),4.81(s,1H,>NH),3.22(d,2H,J=2.39Hz,-(NH)-CH2-),2.96(s,2H,-CH2-(NH2)),1.64(s,2H,-NH2)
13C-NMR(CDCl3)δ(ppm):188.18(C11),163.57(C4a),154.38(C3),140.68(C6a),135.55(C10a),133.91(C8),131.77(C1),129.51(C10),128.88(C9),127.35(C7),116.06(C11a),109.02(C2),99.73(C4),73.59(C6),45.38(C1′),29.56(C2)
IR(ATR)(cm-1):1591,1561,1527,1391,1310,1277,1233,1124,823,764
GC(方法2)36.6min
MS m/z(%):268(36.3),238(100.0),225(13.0),210(25.0),207(14.9),196(8.0),181(13.6),152(28.7).
实施例14
3-(顺式-2-氨基环己基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮(11a)
通过对于10所述的方法,采用1.94g(17.0mmol)顺式-1,2-二氨基环己烷和0.23g(1.00mmol)5c,获得暗褐色粉末。
产率:140mg(43.4%);熔点:116-118℃
1H-NMR(CDCl3)δ(ppm):8.12(d,1H,J=4.46Hz,芳基H),7.95(d,1H,J=3.42Hz,芳基H),7.57-7.44(m,2H,芳基H),7.33-7.27(m,1H,芳基H),6.37(d,1H,J=4.35Hz,芳基H),6.11(s,1H,芳基H),5.13(s,2H,-CH2-O-),4.98(s,1H,>NH),3.43(s,1H,C1′H),3.15(s,1H,C2′H),1.72(s,4H,C3′H2和C6′H2),1.43(s,4H,C4′H2和C5′H2)
13C-NMR(CDCl3)δ(ppm):188.01(C11),163.63(C4a),153.63(C3),140.71(C6a),135.55(C10a),133.97(C8),131.71(C1),129.42(C10),128.85(C9),127.33(C7),115.60(C11a),109.37(C2),99.72(C4),73.56(C6),53.30(C1′),49.11(C2′),32.49(C3′),29.57(C6′),23.21(C5′),20.18(C4′)
IR(ATR)(cm-1):2924,1628,1591,1564,1520,1450,1300,1277,1252,1233,1156,1117,756,702
GC(方法2)50.5min
MS m/z(%):322(69.7),304(21.1),292(17.6),278(10.5),264(26.9),252(17.8),238(41.4),226(100.0),210(13.4),181(12.9),152(22.8),97(42.9).
实施例15
3-((1R)-反式-2-氨基环己基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮(11b)
通过对于9所述的方法,将1.94g(17.0mmol)的(1R)-反式-1,2-二氨基环己烷和0.23g(1.00mmol)5c进行反应,获得红棕色粉末。
产率:210mg(65.1%);熔点:114-116℃
1H-NMR(CDCl3)δ(ppm):8.11(d,1H,J=4.42Hz,芳基H),7.95-7.88(m,1H,芳基H),7.60-7.25(m,3H,芳基H),6.42(d,1H,J=3.93Hz,芳基H),6.18(s,1H,芳基H),5.13(s,2H,-CH2-O-),4.49(s,1H,>NH),2.94(s,3H,-NH2和>NH),2.56(s,1H,C2′H),2.05(t,2H,J=12.58Hz,环己基-CH2),1.70(d,2H,J=2.91Hz,环己基-CH2),1.06(t,2H,J=11.12Hz,环己基-CH2),0.87(d,2H,J=2.93Hz,环己基-CH2)
13C-NMR(CDCl3)δ(ppm):188.12(C11),163.45(C4a),154.14(C3),140.63(C6a),135.47(C10a),133.99(C8),131.85(C1),129.46(C10),128.92(C9),127.42(C7),115.98(C11a),109.34(C2),100.15(C4),73.55(C6),58.45(C1′),55.35(C2′),34.23(C3′),31.97(C6′),29.59(C5′),24.73(C4′)
IR(ATR)(cm-1):2924,1628,1591,1564,1524,1452,1299,1274,1250,1157,1115,756,702
GC(方法2)49.7min
MS m/z(%):322(59.6),304(20.6),292(16.6),278(10.1),264(26.9),262(11.8),252(17.3),238(40.7),226(100.0),210(13.1),181(13.4),152(24.1),97(48.2),69(11.0),56(10.3).
实施例16
3-((1S)-反式-2-氨基环己基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮(11c)
通过对于9所述的方法,将1.94g(17.0mmol)的(1S)-反式-1,2-二氨基环己烷和0.23g(1.00mmol)5c进行反应,获得红棕色粉末。
产率:150mg(46.5%);熔点:115-117℃
1H-NMR(CDCl3)δ(ppm):8.12(d,1H,J=4.46Hz,芳基H),7.96-7.91(m,1H,芳基H),7.55-7.28(m,3H,芳基H),6.41(dd,1H,J1=3.52Hz,J2=5.52Hz,芳基H),6.18(d,1H,J=0.93Hz,芳基H),5.13(s,2H,-CH2-O-),4.41(d,1H,J=4.14Hz,>NH),3.11(d,1H,J=3.66Hz,C1′H),2.69-2.57(m,3H,-NH2和C2′H),2.06(t,2H,J=11.44Hz,环己基-CH2),1.72(d,2H,J=2.87Hz,环己基-CH2),1.06(t,2H,J=14.18Hz,环己基-CH2),0.84(d,2H,J=2.44Hz,环己基-CH2)
13C-NMR(CDCl3)δ(ppm):188.13(C11),163.46(C4a),154.14(C3),140.65(C6a),135.48(C10a),134.00(C8),131.84(C1),129.48(C10),128.92(C9),127.41(C7),116.02(C11a),109.33(C2),100.18(C4),73.57(C6),58.63(C1′),55.44(C2′),34.41(C3′),32.03(C6′),29.60(C5′),24.77(C4′)
IR(ATR)(cm-1):2924,1628,1592,1569,1525,1452,1299,1275,1248,1157,1137,1116,755,701
GC(方法2)49.5min
MS m/z(%):322(60.2),304(20.1),292(16.8),278(10.0),264(26.7),262(12.0),252(17.2),238(40.7),226(100.0),210(12.8),181(12.3),152(22.7),97(45.2).
实施例17
3-(2-乙酰氨基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮(12)
将0.50g(1.58mmol)7b,1ml乙酸酐和1ml吡啶于100℃回流大约8h。随后向混合物中加入冰水,滤去得到的沉淀物。通过由乙醇/水再结晶获得浅褐色粉末。
产率:280mg(49.4%);熔点:168℃
1H-NMR(DMSO-d6)δ(ppm):9.44(s,1H,-Ph-NH-CO-),8.28(s,1H,Ph-NH-Ph),8.07-7,97(m,1H,芳基H),7.89-7.80(m,1H,芳基H),7.70-7.45(m,4H,芳基H),7.37-7.29(m,1H,芳基H),7.23-7.10(m,2H,芳基H),6.64(dd,1H,J1=3.45Hz,J2=5.42Hz,芳基H),6.30(d,1H,J=0.94Hz,芳基H),5.19(s,2H,-CH2-O-),2.01(s,3H,-CO-CH3)
IR(ATR)(cm-1):1589,1573,1515,1453,1296,1277,1254,1228,1120,754.
实施例18
1-乙基-3-[2-(11-氧代-6,11-二氢二苯并[b,e]氧杂-3-基氨基)苯基]脲(13)
将0.50g(1.58mmol)7b和0.12g(1.74mmol)异氰酸乙酯溶于6ml二氯甲烷中并于室温搅拌大约5h。将混合物蒸发,在通过柱色谱法纯化后,从甲醇中再结晶。以此方式获得红棕色的产物。6
产率:100mg(16.3%);熔点:135℃
1H-NMR(DMSO-d6)δ(ppm):9.26(s,1H,-Ph-NH-CO-),8.41(s,1H,CO-NH-Et),8.07-7.78(m,3H,芳基H),7.65-7.44(m,3H,芳基H),7.21-7.09(m,2H,芳基H),7.01-6.91(m,1H,芳基H),6.54(dd,1H,J1=3.36Hz,J2=5.62Hz,芳基H),6.12(d,1H,J=1.10Hz,芳基H),5.17(s,2H,-CH2-O-),4.04(s,1H,Ph-NH-Ph),3.08(quint,2H,J=7.2Hz,>N-CH2-),1.00(t,3H,J=7.22Hz,-CH3)
IR(ATR)(cm-1):1590,1550,1509,1447,1297,1276,1250,1226,1154,1119,752.
实施例19
[2-(11-氧代-6,11-二氢-二苯并[b,e]氧杂-3-基氨基)苯基]氨基甲酸乙酯(14)
将0.50g(1.58mmol)的7b和0.17g(1.58mmol)氯甲酸乙酯与0.15g吡啶一起于室温搅拌大约8h。向混合物中加入冰水,并滤去得到的沉淀物。通过柱色谱法纯化获得橙红色产物。
产率:150mg(24.4%);熔点:125℃
1H-NMR(DMSO-d6)δ(ppm):8.74(s,1H,-Ph-NH-CO-),8.29(s,1H,Ph-NH-Ph),8.07-7.96(m,1H,芳基H),7.82-7.78(m,1H,芳基H),7.65-7.49(m,4H,芳基H),7.29-7.26(m,1H,芳基H),7.18-7.13(m,2H,芳基H),6.62(dd,1H,J1=3.35Hz,5.57Hz,芳基H),6.24(d,1H,J=1.10Hz,芳基H),5.182H,-CH2-O-),4.07(q,2H,J1=3.54Hz,J2=10.59Hz,-CH2-),1.16(t,3H,J=7.14Hz,-CH3)
IR(ATR)(cm-1):1589,1572,1522,1454,1297,1277,1221,1121,61,757.
实施例20
3-(2-甲基氨基苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮(15)
将0.15g(0.47mmol)7b溶于20ml DMSO中。向溶液中加入0.14g(0.98mmol)甲基碘和3.78g(27.4mmol)碳酸钾。将混合物于100℃搅拌3h。在冷却到室温后,向其中加入冰水,并滤去得到的沉淀物。通过用乙腈/水6+4在RP18硅胶上的HPLC纯化以此方式获得的粗制产物,获得微黄色产物。
1H-NMR(CDCl3)δ(ppm):8.23-8.12(m,1H,芳基H),7.99-7.92(m,1H,芳基H),7.54-7.41(m,3H,芳基H),7.36-7.26(m,2H,芳基H),7.17-6.98(m,1H,芳基H),6.85-6.79(m,1H,芳基H),6.53-6.47(m,1H,芳基H),6.18-6.16(m,1H,芳基H),5.15(s,2H,-CH2-O-),3.28(s,1H,>NH),3.05(s,4H,-NH-CH3)
13C-NMR(CDCl3)δ(ppm):188.42(C11),163.04(C4a),155.40(C3),143.22(C2′),140.71(C6a),135.66(C10a),133.81(C8),131.74(C1),129.54(C10),128.88(C9),128.39(C7),128.25(C5′),127.42(C4′),127.38(C1′),119.38(C6′),116.36(C3′),115.03(C11a),107.30(C2),99.80(C4),73.63(C6),39.86(-Me)
IR(ATR)(cm-1):1627,1591,1564,1537,1384,1300,1283,1255,1235,1203,1159,1116,1102,755,701
GC(方法4)37.7min
MS m/z(%):330(100.0),315(15.7),301(10.5),287(8.0),285(7.1),197(6.0),181(6.1),159(13.4),152(6.2).
实施例21
3-(2,4-二氟苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮(16a)
通过通用方法A,将0.10g(2.30mmol)氢化钠(55%),0.29g(2.21mmol)2,4-二氟苯胺和0.50g(2.19mmol)5c与5ml二甲基甲酰胺一起使用。将混合物回流大约8h。用大约50ml冰水而不用酸化来进行后处理。滤去沉淀物并将其通过用乙腈/水6+4作为流动相在RP18硅胶柱上的MPLC进行纯化。
产率:50mg(6.8%)
1H-NMR(CDCl3)δ(ppm):8.30-8.17(m,2H,芳基H),7.95(d,1H,J=3.72Hz,芳基H),7.78-7.70(m,1H,芳基H),7.59-7.29(m,2H,芳基H),6.98-6.81(m,2H,芳基H),6.67-6.62(m,1H,芳基H),6.48(s,1H,芳基H),5.93(s,1H,>NH),5.16(s,2H,-CH2-O-)
13C-NMR(CDCl3)δ(ppm):188.65(C11),184.28,181.52,163.12(C4a),153.70,150.22(C3),140.50(C6a),135.35(C10a),134.82,134.29,134.12(C8),133.83,133.64,132.86,132.16(C1),129.65,129.49(C10),129.06(C9),127.52(C7),126.79,124.20,124.06,118.38(C11a),115,68,111.57,111.50,111.13,111.06,110.36(C2),108.32,105.19,104.66,104.19,103.17(C4),73.59(C6)
IR(ATR)(cm-1):1667,1629,1588,1575,1552,1523,1500,1479,1457,1436,1376,1360,1348,1329,1307,1288,1261,1231,1219,1181,1157,1142,1121,1097,1062,1028,965,926,849,827,761,720,711,704
GC(方法3)24.5min
MS m/z(%):337(100),308(22.8),288(3.8),280(2.7),209(4.3),181(12.4),152(11.6),139(2.9),128(3.1),115(3.2),89(5.5),63(4.3).
实施例22
3-(2,4-二氯苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮(16b)
通过通用方法A,将0.05g(1.15mmol)氢化钠(55%),0.18g(1.11mmol)2,4-二氯苯胺和0.25g(1.10mmol)5c与2.5ml二甲基甲酰胺一起使用。将混合物回流过夜。用大约30ml的冰水而不用酸化来进行后处理。滤去沉淀物并通过用乙腈作为流动相在RP18硅胶柱上的MPLC来进行纯化。
1H-NMR(CDCl3)δ(ppm):8.37-8.19(m,1H,芳基H),8.00-7.89(m,1H,芳基H),7.61-7.32(m,5H,芳基H),7.29-7.17(m,1H,芳基H),6.81-6.74(m,1H,芳基H),6.70-6.64(m,1H,芳基H),6.27(s,1H,>NH),5.19(s,2H,-CH2-O-)
13C-NMR(CDCl3)δ(ppm):188.73(C11),162.95(C4a),148.45(C3),140.45(C6a),136.06(C1′),135.31(C10a),134.12(C8),132.29(C1),129.65(C3′),129.51(C10),129.14(C9),127.59(C7和C4′),127.16(C2′),125.01(C5′),120.54(C6′),119.24(C11a),111.68(C2),105.20(C4),73.60(C6)
IR(ATR)(cm-1):1589,1573,1514,1468,1326,1298,1278,1253,1121,1100,758,703
GC(方法3)41.9min
MS m/z(%):373(12.0),371(66.1),369(100.0),344(1.9),342(9.4),340(13.8),299(14.3),270(7.9),243(7.1),241(7.6),209(5.7),181(17.6),152(18.2),135(9.7),120(10.6),89(11.4),63(6.5).
实施例23
3-(2,4-二溴苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮(16c)
通过通用方法A,将0.10g(2.29mmol)氢化钠(55%),0.55g(2.21mmol)2,4-二溴苯胺和0.50g(2.19mmol)5c与5ml二甲基甲酰胺一起使用。将混合物回流大约8h。用大约30ml的冰水而不用酸化来进行后处理。滤去沉淀物并通过用乙腈作为流动相在RP18硅胶柱上的MPLC来进行纯化以得到微黄色产物。
产率:80mg(8.0%);熔点:157.2-159.2℃
1H-NMR(CDCl3)δ(ppm):8.31-8.20(m,1H,芳基H),7.98-7.89(m,1H,芳基H),7.86-7.69(m,1H,芳基H),7.60-7.29(m,5H,芳基H),6.88-6.75(m,1H,芳基H),6.70-6.62(m,1H,芳基H),6.26(s,1H,>NH),5.19(s,2H,-CH2-O-)
13C-NMR(CDCl3)δ(ppm):188.74(C11),162.95(C4a),148.36(C3),140.44(C6a),137.74(C1′),135.31(C10a和C3′),134.13(C8),132.30(C1),131.15(C5′),129.50(C10),129.14(C9),127.59(C7),120.89(C6′),119.32(C11a),115.47(C4′),114.86(C2′),111.75(C2),105.34(C4),73.60(C6)
IR(ATR)(cm-1):1634,1602,1586,1561,1463,1329,1301,1276,1252,1121,1049,818,759,702,686
GC(方法3)62.0min
MS m/z(%):461(51.3),459(100.0),457(51.1),432(4.6),430(8.6),428(4.3),299(24.8),270(21.9),254(7.0),241(15.0),181(16.0),152(16.3),150(17.5),135(11.8),121(16.1),90(14.5),89(14.3),63(8.4).
实施例24
3-(4-氟-2-硝基苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮a)2-(3-氟苯氧基)甲基苯甲酸
将2.30g(52.7mmol)氢化钠(55%)混悬于50ml二甲基甲酰胺中。随后加入5.61g(50.0mmol)3-氟苯酚。在气体逸出停止后,加入6.80g(50.7mmol)的2-苯并[c]呋喃酮,并将混合物于大约160℃回流大约5h。在反应混合物冷却后,加入90ml冰水,并使用20%浓度盐酸进行酸化。滤去得到的沉淀物并用10%浓度的盐酸洗涤并通过氯化钙干燥。
产率:4.37g(48.5%);熔点:90-92℃
1HNMR(CDCl3)δ(ppm):8.19-7.25(m,7H,芳基H),6.80-6.67(m,1H,芳基H),5.34(s,2H,-CH2-O-)
13C-NMR(CDCl3)δ(ppm):171.16(d,J=1040Hz,-COOH),163.54(d,J=243.60Hz,C1’),159.86(d,J=10.86Hz,C3’),143.19(d,J=323.10Hz,C2),132.61(d,J=92.76Hz,C4),131.43(d,J=248.16Hz,C5’),130.16(d,J=9.96Hz,C6),127.31(d,J=9.46Hz,C5),125.95(d,J=29.06Hz,C1),123.84(d,J=187.00Hz,C3),110.56(d,J=2.96Hz,C5),107.76(d,J=21.16Hz,C4’),102.65(d,J=24.70Hz,C2’),68.92(d,J=64.56Hz,-CH2-O-)
IR(ATR(cm-1):1690,1613,1595,1581,1490,1311,1287,1273,1165,1139,1042,999,957,755,735,679,671.
b)3-氟-6,11-二氢二苯并[b,e]氧杂-11-酮
在氩气下通过加热到大约100℃将5.00g(20.3mmol)的2-(3-氟苯氧基)甲基苯甲酸溶于25ml环丁砜中。随后加入48.5ml(100g)多磷酸,并将混合物于100℃搅拌2h。在反应结束后,加入大约150ml冰水,并于室温将混合物搅拌过夜。滤去沉淀产物并通过氯化钙干燥。
产率:2.30g(49.7%);熔点:79-81℃
1H NMR(CDCl3)δ(ppm):8.28(dd,1H,J1=9.00Hz,J2=6.80Hz,芳基H),7.90(dd,1H,J1=7.60Hz,J2=1.40Hz,芳基H),7.62-7.44(m,2H,芳基H),7.37(dd,1H,J1=7.10Hz,J2=1.30Hz,芳基H),6.90-6.71(m,2H,芳基H),5.21(s,2H,-CH2-O-)
13C-NMR(CDCl3)δ(ppm):189.52(C11),165.96(d,J=332.90Hz,C3),163.54(d,J=65.36Hz,C4a),140.24(C6a),135.00(C10a),134.38(C8),133.66(d,J=94.00Hz,C1),129.44(C10),129.31(C9),127.74(C7),122.17(d,J=2.64Hz,C11a),110.33(d,J=21.80Hz,C2),106.86(d,J=23.70Hz,C4),73.76(C6)
IR(ATR)(cm-1):1643,1611,1596,1576,1296,1242,1208,1138,1115,1104,1023,851,753,695
GC(方法1)18.8min
MS m/z(%):228(100.0),199(73.6),170(24.9),89(13.6).
c)3-(4-氟-2-硝基苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮
通过在a)下所述的方法,利用4ml二甲基甲酰胺和应用0.10g(2.30mmol)氢化钠(55%),0.34g(2.21mmol)2-氟-4-硝基苯胺和0.50g(2.19mmol)3-氟-6,11-二氢二苯并[b,e]氧杂-11-酮。将混合物于大约80℃回流大约8h。用大约50ml冰水而不用酸化来进行后处理。用乙酸乙酯来抽提粗制产物,在旋转式蒸发仪中除去溶剂,并由乙醇中将残余物再结晶。
产率:320mg(40.1%)
1H NMR(CDCl3)δ(ppm):8.37-8.24(m,2H,芳基H),7.97-7.90(m,2H,芳基H),7.61-7.49(m,3H,芳基H),7.40-7.36(m,1H,芳基H),6.97-6.87(m,2H,芳基H),5.22(s,2H,-CH2-O-),>NH未检测
13C-NMR(CDCl3)δ(ppm):189.02(C11),162.58(C4a),152.56(C4’),145.96(C2’),152.64(C3),140.31(C6a),135.19(C10a),134.09(C8),132.57(C1),129.51(C10),129.27(C9),127.72(C7),127.16(C1’),123.46(C5’),121.25(C11a),119.82(C6’),114.61(C2),112.23(C3’),109.92(C4),73.65(C6)
IR(ATR)(cm-1):1607,1588,1509,1461,1421,1310,1298,1261,1244,1229,1212,1187,1154,1122,1060,1025,933,924,821,758,697.
d)3-(2-氨基-4-氟苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮
将0.25g(0.69mmol)3-(4-氟-2-硝基苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮溶于5ml乙醇中,并加入0.78g(3.44mmol)二水合氯化锡(II),将混合物于70℃搅拌大约2h。在混合物冷却到室温后,加入冰水并使用氢氧化钠溶液来呈碱性。用乙酸乙酯抽提水相,用饱和氯化钠溶液洗涤乙酸乙酯相,并除去溶剂。通过在RP18硅胶柱上的MPLC来纯化得到的粗制产物,所述硅胶柱开始以乙腈/水6+4随后以纯乙腈作为流动相。
产率:60mg(26.0%);熔点:182.6℃
1H NMR(CDCl3)δ(ppm):8.16(d,1H,J=8.96Hz,芳基H),7.93(d,1H,J=7.04Hz,芳基H),7.52-7.39(m,2H,芳基H),7.31(d,1H,J=7.00Hz,芳基H),7.09-7.01(m,1H,芳基H),6.54-6.39(m,3H,芳基H),6.11(s,1H,芳基H),5.59(s,1H,>NH),5.12(s,2H,-CH2-O-),3.20(ws,2H,-NH2)
13C-NMR(CDCl3)δ(ppm):188.63(C11),163.36(C4a),162.16(d,J=2.42.50Hz,C4’),152.64(C3),144.90(d,J=11.30Hz,C2’),140.57(C6a),135.37(C10a),134.16(C8),132.02(C1),129.44(C10),129.32(d,J=12.10Hz,C6’),128.99(C9),127.47(C7),120.72(C1’),117.43(C11a),109.43(C2),105.35(d,J=22.60Hz,C5’),102.55(d,J=25.54Hz,C3’),101.83(C4),73.54(C6)
IR(ATR)(cm-1):1625,1591,1565,1508,1470,1303,1275,1255,1232,1157,1120,975,923,842,758,701
GC(方法4)35.21min
MS m/z(%):334(100.0),319(12.3),317(8.1),315(5.3),305(10.6),303(2.5),291(6.4),287(6.0),277(2.4),275(3.1),263(2.3),199(3.8),187(4.3),181(5.3),163(3.9),158(4.7),152(6.3),150(3.3),144(3.1),137(3.3),128(2.2),125(3.5),115(2.7),98(3.7),89(4.5),83(2.7),63(2.4).
B.式I的化合物的制备,其中X-Y是CH2-CH2或CH=CH
实施例25
2-(2-氨基苯基氨基)-10,11-二氢二苯并[a,d]环庚烷-5-酮(30)
a)2-溴甲基苯甲酸甲酯(21)
通过在干燥500ml三颈烧瓶中搅拌将60.0g(0.4mol)邻-甲苯甲酸甲酯20溶于375ml CHCl3中,加入75.0g(0.42mol)N-溴琥珀酰亚胺和0.75g氮杂异丁腈。用回流冷凝器将混合物小心加热至大约65℃直到反应开始,随后移去加热源,并在反应平息后将混合物于70℃回流5h。冷却至RT后(室温),琥珀酰亚胺沉淀并将其滤去。过滤物的浓缩得到粗制产物,对其进一步利用而无需加工。
GC(方法5)7.3min
MS m/z(%):230/228(21,M+),199/197(22),149(100,M+-Br),118(41),91(54,鎓+).
b)(2-甲氧基羰基苄基)三苯基溴化磷(22)
在干燥500ml圆底烧瓶中,将40.0g(0.175mol)2-溴甲基苯甲酸甲酯21溶于300ml丙酮中并于室温搅拌15min。加入52.0g(0.2mol)三苯膦,随后于大约60℃回流5h。标题化合物在冷却后沉淀并被滤去,在用丙酮洗涤后,在真空中干燥。7
产率:51.9g(60.5%);熔点:在234℃以上的分解作用
IR(ATR)1711(COOR),1696,1585,1438,1273,1109,753,716,706,689cm-1.
c)(E/Z)-3’-硝基均二苯代乙烯-2-羧酸甲酯(24)
通过通用方法D,使用280ml甲醇中的16.8g甲醇钠溶液(30%在MeOH中),40.0g(81.4mmol)磷鎓盐22和12.8g(84.7mmol)的3-硝基苯甲醛23来合成均二苯代乙烯24。回流6h,在水中吸收后用3×100ml Et2O抽提淡黑红色油状残余物。
产率:18.0g(78.1%);熔点:66.5℃
GC(方法B)(E-)9.7min,(Z-)12.8min
MS(E-)m/z(%):283(100,M+),266(22),251(31),236(24),205(21),194(14),176(43),165(26),151(15),76(13,C6H4).
(Z-)m/z(%):283(100,M+),266(20),251(28),236(22),205(18),194(13),176(36),165(21),151(12),76(11,C6H4).
IR(ATR)1714(COOR),1525,1435,1348,1295,1267,1252,1188,1130,1079,956,747,719,704,672cm-1.
d)(E/Z)-3’-硝基均二苯代乙烯-2-羧酸(25)
通过通用方法E,使用16.0g(56.5mmol)酯24,150ml MeOH和75ml 20%浓度的氢氧化钠溶液来分解所述酯。回流时间5.5h,用3×100ml CH2Cl2抽提。用浓HCl将粗制产物沉淀为微黄色沉淀物形式,将其滤去。通过用二乙醚消化来进行纯化并将滤液浓缩到干燥。
产率:12.2g(80.0%);熔点:164-166℃
IR(ATR)1682(COOH),1519,1349,1304,1268,1249,1077,907,754,733,716cm-1.
e)2-[2-(3-氨基苯基)乙基]苯甲酸8(26)
将10.0g(37.1mmol)硝基化合物25缓慢溶于氢化器皿中的150mlEtOAc(乙酸乙酯)中,随后搅拌加入1.0g Pd/C(10%),封闭装置,在用H2冲洗几次后,应用4巴的恒压。10h后,通过过滤钯-碳并蒸馏除去溶剂来分离标题化合物26。
熔点:114℃
GC 10.5min(方法6)
MS m/z(%):241(77,M+),223(14,M+-H2O),208(8),194(7),106(100,NH2-Ph-CH2 +),77(17,C6H4).
f)2-[2-(3-乙酰氨基苯基)乙基]苯甲酸8(27)
将阶段(e)中获得的残余物与25ml乙酸酐混合并于室温搅拌15h。向混合物中加入200ml冰水,并用200ml EtOAc对它进行反复抽提。将合并的有机相浓缩至大约50ml并用2×50ml水再次抽提,随后于真空中去除溶剂。余下微黄色油状残余物,通过在少量MeOH中吸收而从其中分离出产物,用冰水沉淀并过滤。
产率:通过2阶段的8.3g(78.9%);熔点:145-148℃
1H-NMR(DMSO-d6)δ(ppm):2.02(s,3H,CH3),2.73-3.20(m,4H,CH2-CH2),6.9(d,1H,7.6Hz),7.18(t,1H,8.2Hz),7.29-7.33(m,2H),7.40-7.48(m,3H),7.81(dd,1H,3.5Hz),9.86(s,1H,NH),12.81(s,1H,COOH).
IR(ATR)1690(C=O),1664(酰胺),1593(酰胺II),1558,1489,1305,1278,782,747,699cm-1.
g)2-(乙酰氨基)-10,11-二氢二苯并[a,d]环庚烷-5-酮8(28)
通过通用方法F,将3.6g(12.7mmol)羧酸27溶于40ml环丁砜中,加入100g PPA,并将反应混合物于110℃回流5h。在室温搅拌17h期间用250ml冰水水解导致粗制产物的沉淀,滤去产物并通过用H2O洗涤来纯化。
产率:2.35g(69.7%);熔点:152℃
1H-NMR(DMSO-d6)δ(ppm):2.01(s,1H,CH3),3.11(s,4H,CH2-CH2),7.34(t,2H,7.4Hz),7.47(d,1H),7.55(d,2H,8.5Hz),7.84(d,1H,7.7Hz),7.94(d,1H,8.3Hz),10.23(s,1H,NH).
GC(方法6)18.7min
MS m/z(%):265(99,M+),223(100,氨基二苯并软木酮+),208(9,二苯并软木酮+),194(70),178(13),165(22),152(12).
IR(ATR)3351(C-N),1689(C=O),1627(酰胺),1587(酰胺II),1524,1290,1271,1240,938,764,698cm-1.
h)2-氨基-10,11-二氢二苯并[a,d]环庚烷-5-酮*HCl8,9(29)
将2.0g(7.54mmol)乙酰胺28悬浮于60ml 20%浓度HCl中并于大约100℃回流4h。冷却后滤去得到的沉淀物,并将产物作为沙色(sandy-color)粉末保留。
产率:1.8g(91.9%);熔点:219℃
1H-NMR(DMSO-d6)δ(ppm):2.96-3.10(m,4H,CH2-CH2),5.37(s,2H,NH2),6.86(d,1H,2.0Hz),6.95(d,1H,3.12Hz),7.35(t,2H,7.8Hz),7.49(t,1H,8.2Hz),7.86(d,1H,6.5Hz),7.95(d,1H,8.5Hz).
13C-NMR(DMSO-d6)δ(ppm):34.3(CH2),35.3(CH2),117.0(C3),118.7(C1),126.9(C7),129.4(C9),130.5(C6),131.2(C4a),132.5(C4),133.2(C8),138.8(C5a),142.1(C9a),145.0(C11a),145.1,(C2),192.2(C5).
GC(方法6)12.1min
MS m/z(%):223(100,M+),208(8,二苯并软木酮+),194(74),180(13),165(15),152(9),97(13).
IR(ATR)2563(NH3 +),1652(C=O),1595,1510,1290,910,846,763,693cm-1.
i)2-(2-氨基苯基氨基)-10,11-二氢二苯[a,d]环庚烷-5-酮(30)
在具有回流冷凝器、干燥试管和中隔的干燥100ml三颈烧瓶中将0.52g NaH(55-60%)悬浮于12ml THF(四氢呋喃)中,并加入1.0g(3.85mmol)软木酮29。在气体逸出停止后,逐滴加入0.54g(3.85mmol)2-氟硝基苯,并将混合物于大约150℃回流17.5h。此后用75ml冰水水解并过滤得到的沉淀物,其包含中间产物2-(2-硝基苯基氨基)-10,11-二氢-二苯并[a,d]环庚烷-5-酮。
通过通用方法G,使用30ml i-PrOH,15ml浓HCl和500mg锡粉进行这种硝基化合物(过滤残余物大约0.5g)的还原。进行碱化,随后用2×75ml EtOAc进行抽提。通过用CH2Cl2/EtOH(95+5)在SiO2上的柱色谱法进行纯化,随后由MeOH/H2O再结晶。
产率:0.13g(10.7%);熔点:153℃
1H-NMR(DMSO-d6)δ(ppm):2.96-3.07(m,4H,CH2-CH2),4.86(s,2H,NH2),6.46(d,1H,2.1Hz),6.58-6.64(m,2H),6.77(d,1H,8.3Hz),6.90-7.04(m,2H),7.32(t,2H,8.3Hz),7.41-7.46(m,1H),7.84(d,1H,6.4Hz),7.94-7.98(2H,NH+ar).
13C-NMR(DMSO-d6)δ(ppm):34.4(CH2),36.3(CH2),112.2(C3),113.2(C1),116.2(C3’),117.2(C6’),125.5(C1’),126.1(C4’),126.4(2C,C4a+C5’),126.7(C7),128.9(C9),130.6(C6),132.1(C4),133.8(C8),139.5(C5a),142.0(C9a),143.4(C2’),145.7(C11a),151.0(C2),190.7(C5).
GC(方法6)29.6min
MS m/z(%):314(100,M+),299(10,M+-NH),285(10),271(7),178(7),165(7),143(5),107(6).
IR(ATR)1599(C=O),1581,1566,1499,1290,1279,1258,1111,750,694cm-1.
实施例26
2-(4-氨基苯基氨基)-10,11-二氢二苯并[a,d]环庚烷-5-酮(32)
在具有回流冷凝器、干燥试管和中隔的干燥100ml三颈烧瓶中将0.39g NaH(55-60%)悬浮于18ml THF中,并加入0.75g(2.85mmol)软木酮29。在气体逸出停止后,逐滴加入0.40g(2.85mmol)4-氟硝基苯,并将混合物于大约150℃回流17h。此后用75ml冰水水解并过滤得到的沉淀物,其包含中间产物2-(4-硝基苯基氨基)-10,11-二氢二苯并[a,d]环庚烷-5-酮。
通过通用方法G使用10ml i-PrOH,5ml浓HCl和200mg锡粉进行这种硝基化合物(过滤残余物大约0.2g)的还原。进行碱化,随后用2×50ml EtOAc进行抽提。通过用CH2Cl2/EtOH(95+5)在SiO2上,随后用Et2O在SiO2上的柱色谱法进行纯化。
产率:0.05g(5.5%);熔点:217℃
1H-NMR(CDCl3)δ(ppm):3.06-3.16(m,4H,CH2-CH2),3.66(d,2H,NH2),5.81(s,1H,NH),6.55(d,1H,2.3Hz),6.69-6.75(m,3H),7.04(d,2H,6.5Hz),7.19(d,1H),7.31-7.41(m,2H),8.02(d,1H,9.3Hz),8.15(d,1H,8.7Hz).
13C-NMR(CDCl3)δ(ppm):34.7(CH2),36.3(CH2),112.1(C3),113.0(C1),115.9(2C,C3’+C5’),125.2(2C,C2’+C6’)126.4(C7),127.8(C4a),128.3(C9),130.7(C6),131.1(C1’),131.6(C4),134.1(C8),139.5(C5a),141.6(C9a),143.6(C4’),145.6(C11a),150.0(C2),192.9(C5).
GC(方法6)36.3min
MS m/z(%):314(100,M+),286(5,M+-CO),178(5),165(5),143(5),107(10).
IR(ATR)1582(C=O),1562,1506,1295,1281,1211,1109,825,758cm-1.
实施例27
2-(2-氨基苯基氨基)二苯并[a,d]环庚烯-5-酮(38)
a)(E/Z)-3’-氟均二苯代乙烯-2-羧酸甲酯(34)
通过通用方法D,使用225ml甲醇中的13.0g甲醇钠溶液(30%于MeOH中),40.0g(81.4mmol)鏻盐22和11.2g(90.2mmol)3-氟苯甲醛来合成化合物34。回流时间7h,在水中用3×150ml Et2O吸收后抽提微黄白色油状残余物。
产率:16.5g(79.1%)
GC(方法6)(E-)5.9min,(Z-)7.7min
MS(E-)m/z(%):256(100,M+),241(5,M+-CH3),225(41,M+-OCH3),197(83,M+-COOCH3),177(29),170(16),161(11),98(15).
(Z-)m/z(%):256(100,M+),241(4,M+-CH3),225(40,M+-OCH3),197(77,M+-COOCH3),177(23),170(13),161(10),98(18).
b)3’-氟均二苯代乙烯-2-羧酸11(35)
通过通用方法E,使用13.0g(50.7mmol)酯34,70ml MeOH和60ml20%浓度的氢氧化钠溶液来分解所述酯。回流时间6h,用2×75ml的CH2Cl2抽提。用浓HCl沉淀微黄色油形式的粗制产物,其随着搅拌逐渐固化成沉淀物,将其滤去。通过用Et2O消化进行纯化并将滤液浓缩至干燥。
产率:6.5g(52.9%);熔点:113℃
GC(方法6)(E-)7.0min,(Z-),9.0min
MS(E-)m/z(%):242(100,M+),224(15,M+-H2O),196(68,224-CO),177(22),133(42),98(11).
(Z-)m/z(%):242(100,M+),224(16,M+-H2O),196(68,224-CO),177(21),133(48),106(53).
IR(ATR)1675(C=O),1582,1303,1266,1219,929,890,777,768,758,738,706cm-1.
c)2-氟二苯并[a,d]环庚烯-5-酮10(36)
通过通用方法F,将6.5g(26.8mmol)羧酸35溶于65ml环丁砜中,加入130g PPA,将混合物于110℃回流6h。用250ml冰水水解导致粗制产物在室温搅拌16h时沉淀,将产物滤去,并用H2O洗涤。通过用CH2Cl2在SiO2上进行柱色谱法来进行纯化。
产率:2.45g(40.7%);熔点:120℃
1H-NMR(DMSO-d6)δ(ppm):7.17-7.34(m,2H,CH=CH),7.48(t,1H,8.8Hz),7.60-7.71(m,2H),7.75-7.80(m,2H),8.10-8.21(m,2H).
GC(方法6)7.7min
MS m/z(%):224(55,m+),196(100,M+-Co),170(10,196-CH=CH).
IR(ATR)1644(C=O),1606,1570,1300,1251,955,797,730,686cm-1.
d)2-(2-氨基苯基氨基)二苯并[a,d]环庚烯-5-酮(38)
在具有回流冷凝器、干燥试管和中隔的干燥100ml三颈烧瓶中将150mg NaH(55-60%)和450mg(3.25mmol)2-硝基苯胺37悬浮于6ml二甲基甲酰胺中。在气体逸出停止后,逐滴加入700mg(3.12mmol)环庚烯酮(suberenone)36,将混合物于大约150℃回流24h。此后用75ml冰水水解,并过滤得到的沉淀物,其包含中间产物2-(2-硝基苯基氨基)二苯并[a,d]环庚烷-5-酮。
通过通用方法G,使用20ml i-PrOH,10ml浓HCl和400mg锡粉进行这种硝基化合物(过滤残余物大约0.4g)的还原。进行碱化,随后用2×75ml EtOAc进行抽提。通过用CH2Cl2/EtOH(95+5)在SiO2上的柱色谱法,和随后由MeOH/H2O中再结晶进行纯化。
产率:0.07g(7.2%);熔点:232℃
1H-NMR(DMSO-d6)δ(ppm):4.88(s,2H,NH2),6.61(t,1H,6.4Hz),6.75-6.82(m,2H),6.88-6.94(m,2H),7.02(d,2H,CH=CH,14.5Hz),7.10(d,1H,6.3Hz),7.57-7.61(m,1H,),7.67-7.70(2H),8.03-8.09(m,2H,NH+ar),8.19(d,1H,7.7Hz).
13C-NMR(DMSO-d6)δ(ppm):113.7(C1),115.6(C3),115.9(C3’),116.8(C6’),125.2(C1’),126.0(C4’),126.5(C5’),128.3(C4a),129.1(C9),130.4(C7),131.7(2C,C10+C11),132.2(C6),132.7(C4),132.8(C8),134.8(C5a),137.2(C9a),138.4(C2’),144.1(C11a),150.7(C2),188.7(C5).
GC(方法6)34.8min
MS m/z(%):312(100,M+),295(18),176(7),165(16),141(10),134(10),119(10).
IR(ATR)1596(C=O),1571,1558,1497,1370,1304,1257,1226,806,751,735cm-1.
实施例28
2-(2-甲氧基苯基氨基)-10,11-二氢二苯并[a,d]环庚烯-5-酮
将1.5g(5.65mmol)2-乙酰氨基二苯并[a,d]软木酮,17.0g(90.9mmol)2-溴苯甲醚,0.90g(6.5mmol)K2CO3,2勺尖KI和2勺尖铜粉于210℃(油浴温度)熔化并回流15h。冷却,随后通过Fluorisil过滤并用CH2Cl2洗涤。通过用CH2Cl2→CH2Cl2/EtOH 95+5在SiO2上的柱色谱法进行纯化。
产率:0.3g(16.3%);熔点:52.5℃
1H NMR(DMSO-δ6)δ(ppm):3.03(m,4H,CH2-CH2),3.79(s,3H,CH3),6.71(d,1H),6.83(d,1H),6.90-7.00(m,1H),7.09(d,2H),7.26-7.35(m,3H),7.43(d 1H),7.83(d,1H),7.95(d,1H),8.18(s,1H,NH).
13C-NMR(DMSO-δ6)δ(ppm):34.39(C10),36.19(C11),55.8(O-CH3),112.43(C3),112.85(C1),114.16(C3’),120.99(C4’),122.69(C6’),124.61(C5’),126.74(C7),127.09(C4a),128.98(C9),129.58(C1’),130.51(C6),132.14(C4),133.55(C8),139.50(C5a),142.02(C9a),145.50(C11a),149.70(C2),152.26(C2’),191.02(C5).
MS m/z(%):329(100,M+),314(6,M+-CH3),296(5),196(23),183(24),165(6),151(6).
IR(ATR):3399,3335,3061,2937,2835,1627,1579,1565,1519,1494,1460,1290,1268,1244,1214,1110,1024,910,831,744,693cm-1.
C.其中X=O且Y=CH2的式I的化合物的制备
实施例29
8-(2-氨基苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮(45)
a)2-溴甲基-4-硝基苄腈(39)
于大约70℃将3.00g(18.52mmol)2-甲基-4-硝基苄腈溶于20ml无水四氯甲烷中。随后加入3.30g(18.97mmol)N-溴化琥珀酰亚胺和少许偶氮二异丁腈和元素溴。将混合物回流,同时用500W聚光灯照射大约5h。反应结束后,将沉积在表面上的琥珀酰亚胺,在冷却至室温后,通过过滤去除。蒸发滤液,得到产物为黄橙色油。
产率:3.23g(50%)
1H NMR(CDCl3)δ(ppm):8.44-8.43(m,1H,芳基H),8.31-8.25(m,2H,芳基H),4.71(s,2H,-CH2Br)
IR(ATR)(cm-1):1712,1525,1348,1299,904,845,808,746.
b)4-硝基-2-苯氧基甲基苄腈(40)
将2.85g(30.32mmol)苯酚溶于10ml丙酮中,加入4.20g(30.43mmol)碳酸钾和7.31g(30.35mmol)2-溴甲基-4-硝基苄腈。将反应混合物于大约70℃回流5h,并随后除去溶剂。将残余物在乙酸乙酯中吸收,并用20%浓度的盐酸抽提,除去有机相的溶剂。通过用乙腈/水6+4进行RP-18MPLC柱色谱法来纯化得到的暗褐色产物,得到黄色产物。
产率:3.23g(41.9%);熔点:112℃
1H NMR(CDCl3)δ(ppm):8.88(s,1H,芳基H),8.33-8.28(m,2H,芳基H),7.92(d,1H,J=8.52Hz,芳基H),7.41-7.33(m,2H,芳基H),7.11-6.74(m,3H,芳基H),5.36(s,2H,-CH2-O-)
IR(ATR)(cm-1):1527,1350,1244,1232,809,757,744,693.
c)4-硝基-2-苯氧基甲基苯甲酸(41)
将0.5g(1.97mmol)4-硝基-2-苯氧基甲基苄腈于大约80℃溶于25ml乙醇中并加热至回流。随后加入7.00g KOH,将反应混合物再次回流大约4h。冷却后用20%浓度的盐酸酸化,滤去得到的沉淀物并进行干燥,得到产物。
产率:0.41g(76.2%);熔点:154℃
IR(ATR)(cm-1):1691,1600,1586,1497,1344,1242,1274,1046,811,750
d)8-硝基-6H-二苯并[b,e]氧杂-11-酮(42)
在氩气下通过加热到大约100℃将0.60g(2.19mmol)4-硝基-2-苯氧基甲基苯甲酸溶于10ml环丁砜中。在酸完全溶解后,加入15ml(30.0g)多磷酸,于100℃将混合物搅拌大约2h。随后加入冰水,并滤去沉淀的产物,由乙醇中再结晶。
产率:0.54g(96.6%)
IR(ATR)(cm-1):1640,1596,1524,1472,1445,1299,1245,1204,1138,1014,908,766,738,728,691
e)8-氨基-6,11-二氢二苯并[b,e]氧杂-11-酮(43)
将1.00g(3.92mmol)8-硝基-6H-二苯并[b,e]氧杂-11-酮溶于10ml乙醇中,加入2.00g(8.85mmol)二水合氯化锡(II),将混合物于70℃搅拌大约2h。在混合物冷却至室温后,加入冰水,并使用氢氧化钠溶液来呈碱性。用乙酸乙酯抽提水相,蒸发乙酸乙酯相,得到产物。
产率:0.70g(79.3%);熔点:177℃
1H NMR(CDCl3)δ(ppm):8.35(d,1H,J=1.76Hz,芳基H),7.92(d,1H,J=4.44Hz,芳基H),7.44(t,1H,J=4.24Hz,芳基H),7.14-7.04(m,2H,芳基H),6.68(d,1H,J=2.14Hz,芳基H),6.53(s,1H,芳基H),5.13(s,2H,-CH2-O-),4.21(s,2H,-NH2)
IR(ATR)(cm-1):1602,1579,1550,1303,1276,1023,757,692.
f)8-(2-硝基苯基氨基)-6H-二苯并[b,e]氧杂-11-酮(44)
将0.30g来自阶段e)的产物按小份逐渐加至在10ml二甲基甲酰胺中的0.10g(4.17mmol)氢化钠的混悬液中。在气体逸出停止后,加入0.20g(1.42mmol)2-氟硝基苯,将混合物在冰浴中搅拌大约1h。随后向反应混合物中加入冰水,滤去得到的沉淀物,并由甲醇再结晶粗制产物。
产率:0.30g(65.1%)
IR(ATR)(cm-1):1644,1602,1571,1315,1254,1145,739.
g)8-(2-氨基苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮(45)
通过阶段e)中所述的方法使用10ml乙醇将0.35g(3.92mmol)8-硝基-6H-二苯并[n.e]氧杂-11-酮,2.00g(8.85mmol)二水合氯化锡(II)反应,得到产物。
产率:0.16g(50.0%)
IR(ATR)(cm-1):1591,1577,1546,1301,1245,1208,767,736.
参考文献
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Claims (17)
1.式I的二苯并环庚烷化合物,
其中
环原子X和Y其中之一是CH2并且另一个是CH2,O,S,SO,SO2或NR5;
或-X-Y-是-CH2-CH2-或-CH=CH-;
R1是H或C1-C6-烷基;
R2是H,卤素或C1-C4-烷基-C≡C-,其任选地被氨基取代;
R3选自:
a)-NH2;
e)-NH-C1-C6-亚烷基-NH2
f)卤素;
R4是H,卤素或C1-C6-烷基,或R3和R4连接苯环的邻近C原子并与这些C原子在一起形成具有氮杂原子的5-或6-元芳族或非芳族杂环,其中杂环可以由一个或两个C1-C6-烷基基团所取代或可以与环己基基团稠合;
R5是H或C1-C6-烷基;
R6是H或C1-C6-烷基;
R7选自:
H,
NH2,
单-C1-C6-烷基氨基,
二-C1-C6-烷基氨基,
C1-C6-烷基-CONH-,
C1-C6-烷基-NHCONH-,
C1-C6-烷基-O-CO-NH-,
C1-C6-烷基,
C1-C6-烷氧基,
NO2或
卤素;
R8是H,NH2,单-C1-C6-烷基氨基,二-C1-C6-烷基氨基,C1-C6-烷氧基,或卤素;
R9是H或NH2;
及其生理耐受盐,和所述化合物和所述盐的溶剂合物。
5.前述权利要求任一项所述的化合物,其中R1和R2是H。
8.前述权利要求任一项所述的化合物,其中R4是H。
9.前述权利要求任一项所述的化合物,其中R5和R6是H。
10.前述权利要求任一项所述的化合物,其中R7是NH,C1-C6-烷基-CONH-,C1-C6-烷基-NHCONH-或C1-C6-烷基-O-CO-NH-。
13.权利要求1所述的化合物:
(1)3-氨基-6,11-二氢二苯并[b,e]硫杂-11-酮
(2)3-氨基-6,11-二氢二苯并[b,e]氧杂-11-酮
(3)3-氟-6,11-二氢二苯并[b,e]氧杂-11-酮
(4)3-(2-氨基苯胺基)-6,11-二氢二苯并[b,e]硫杂-11-酮
(5)3-(2-氨基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(6)3-(4-氨基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(7)3-(2-氟-4-氨基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(8)2,11,12,13,14-五氢-10H-(苯并[e]氧杂)[2,3-c]咔唑-7-酮
(9)2-氢-11,12-二甲基-10H-(苯并[e]氧杂)[2,3-e]吲哚-7-酮
(10)3-(3-氨基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(11)3-(2,4-二氨基苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(12)3-(2-氨基苄基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(13)3-(2-氨基乙基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(14)3-(顺-2-氨基-环己基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(15)3-((1R)-反-2-氨基环己基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(16)3-((1S)-反-2-氨基环己基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(17)3-(2-乙酰氨基苯胺基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(18)1-乙基-3-[2-(11-氧代-6,11-二氢二苯并[b,e]氧杂-3-基氨基)苯基]脲
(19)乙基[2-(11-氧代-6,11-二氢二苯并[b,e]氧杂-3-基氨基)苯基]carbamalate
(20)3-(2-甲基氨基苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(21)3-(2,4-二氟苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(22)3-(2,4-二氯苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(23)3-(2,4-二溴苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(24)2-(2-氨基苯基氨基)-10,11-二氢二苯并[a,d]环庚烷-5-酮
(25)2-(4-氨基苯基氨基)-10,11-二氢二苯并[a,d]环庚烷-5-酮
(26)2-(4-氨基苯基氨基)二苯并[a,d]环庚烯-5-酮
(27)3-乙酰氨基-6,11-二氢二苯并[b,e]硫杂-11-酮
(28)3-(4-氟-2-硝基苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(29)8-(2-氨基苯基氨基)-6,11-二氢二苯并[b,e]氧杂-11-酮
(30)2-(2-甲氧基苯基氨基)-10,11-二氢二苯并[a,d]环庚烯-5-酮。
14.一种药物组合物,其包含至少一种权利要求1至13任一项所述的式I的化合物,如果适合还包含生理耐受的赋形剂。
15.至少一种权利要求1至13任一项所述的式I的化合物用于制备药物组合物的应用,所述药物组合物用于免疫调节和/或用于抑制IL-1β和/或TNF-α的释放。
16.至少一种权利要求1至13任一项所述的式I的化合物用于治疗下述各项疾病的应用:自身免疫疾病、癌症、类风湿性关节炎、痛风、脓毒性休克、骨质疏松症、神经病痛、HIV传播、HIV痴呆、病毒性心肌炎、胰岛素依赖型糖尿病、牙周病症、再狭窄、脱发、HIV感染或AIDS中的T细胞损耗、银屑病、急性胰腺炎、对同种异体移植物的排斥反应、变态反应相关肺炎、动脉硬化、多发性硬化、恶病质、阿尔茨海默病、中风、黄疸、溃疡性结肠炎、局限性回肠炎、炎性肠病(IBD)、局部缺血、充血性心力衰竭、肺纤维化、肝炎、成胶质细胞瘤、吉-巴综合征、系统性红斑狼疮、成人呼吸窘迫综合征(ARDS)和呼吸窘迫综合征。
17.一种用于在需要这样治疗的人中免疫调节和/或调节IL-1β和/或TNF-α释放的方法,其中将一定量的权利要求1至13任一项所述的式I的化合物施用于所述人,所述量具有免疫调节作用和/或调节或抑制IL-1β和/或TNF-α的释放。
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US60/679,967 | 2005-05-12 | ||
DE102005022020.7 | 2005-05-12 | ||
DE102005022020A DE102005022020A1 (de) | 2005-05-12 | 2005-05-12 | Dibenzocycloheptanverbindungen und pharmazeutische Mittel, welche diese Verbindungen enthalten |
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CN101223153A true CN101223153A (zh) | 2008-07-16 |
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US (1) | US20090105327A1 (zh) |
EP (1) | EP1881968A2 (zh) |
JP (1) | JP2008544952A (zh) |
CN (1) | CN101223153A (zh) |
CA (1) | CA2608889A1 (zh) |
DE (1) | DE102005022020A1 (zh) |
WO (1) | WO2006120010A2 (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102427726A (zh) * | 2009-03-27 | 2012-04-25 | 普雷西迪奥制药公司 | 丙型肝炎的稠环抑制剂 |
CN106631793A (zh) * | 2016-10-19 | 2017-05-10 | 浙江师范大学 | 一种二苯并环庚烷衍生物的制备方法 |
WO2023221981A1 (en) * | 2022-05-16 | 2023-11-23 | Bp Apollo Limited | Taxamairin analogs and methods of use thereof |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
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EP2206534A1 (de) | 2008-10-09 | 2010-07-14 | c-a-i-r biosciences GmbH | Dibenzocycloheptanonderivate und pharmazeutische Mittel, welche diese Verbindungen enthalten |
WO2012040389A2 (en) | 2010-09-22 | 2012-03-29 | Presidio Pharmaceuticals, Inc. | Substituted bicyclic hcv inhibitors |
US8999967B2 (en) | 2010-09-29 | 2015-04-07 | Presidio Pharmaceuticals, Inc. | Tricyclic fused ring inhibitors of hepatitis C |
WO2021038292A1 (en) * | 2019-08-27 | 2021-03-04 | Synovo Gmbh | Centrally active p38alpha inhibiting compounds |
WO2023186881A1 (en) | 2022-03-29 | 2023-10-05 | Baden-Württemberg Stiftung Ggmbh | P38 map kinase inhibitors for use in the treatment of colorectal cancer |
CN115385887B (zh) * | 2022-06-08 | 2024-01-23 | 北京联本医药化学技术有限公司 | 一种铵盐离子液体催化环合反应制备伊索克酸的方法 |
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FR2138257B1 (zh) * | 1971-05-21 | 1974-08-23 | Roussel Uclaf | |
IL57077A0 (en) * | 1978-04-21 | 1979-07-25 | Syntex Inc | 6,11-dihydrodibenzo-thiepin-11-one s-oxides their preparation and pharmaceutical compositions containing them |
JPS55108868A (en) * | 1979-02-14 | 1980-08-21 | Dai Ichi Seiyaku Co Ltd | Dibenzoxepin derivative |
JPS55124777A (en) * | 1979-03-20 | 1980-09-26 | Toa Eiyou Kagaku Kogyo Kk | Novel dibenzoxepin derivative and its preparation |
AU2258683A (en) * | 1983-01-03 | 1984-07-05 | American Home Products Corporation | Dibenzocycloheptenylidenes and derivatives theof |
JPH03181443A (ja) * | 1989-12-08 | 1991-08-07 | Hisamitsu Pharmaceut Co Inc | 新規なジベンゾ〔a,d〕シクロヘプテン誘導体 |
JPH0478774A (ja) * | 1990-07-19 | 1992-03-12 | Mazda Motor Corp | 自動車の前部車体構造 |
DE69612835T2 (de) * | 1995-10-16 | 2001-10-04 | Kyowa Hakko Kogyo Kk | Tricyclische verbindungen |
ZA978792B (en) * | 1996-10-04 | 1998-04-06 | Novo Nordisk As | N-substituted azaheterocyclic compounds. |
GB9701453D0 (en) * | 1997-01-24 | 1997-03-12 | Leo Pharm Prod Ltd | Aminobenzophenones |
CN1240684C (zh) * | 2001-06-27 | 2006-02-08 | 宇部兴产株式会社 | 二苯并环庚烯化合物 |
WO2003018535A2 (en) * | 2001-08-28 | 2003-03-06 | Leo Pharma A/S | Novel aminobenzoephenones |
TW200400816A (en) * | 2002-06-26 | 2004-01-16 | Lilly Co Eli | Tricyclic steroid hormone nuclear receptor modulators |
PT1697350E (pt) * | 2003-12-19 | 2008-09-18 | Lilly Co Eli | Moduladores do receptor nuclear da hormona esteróide tricíclica |
-
2005
- 2005-05-12 DE DE102005022020A patent/DE102005022020A1/de not_active Withdrawn
-
2006
- 2006-05-12 CA CA002608889A patent/CA2608889A1/en not_active Abandoned
- 2006-05-12 EP EP06742900A patent/EP1881968A2/de not_active Withdrawn
- 2006-05-12 WO PCT/EP2006/004488 patent/WO2006120010A2/de active Application Filing
- 2006-05-12 CN CNA2006800229705A patent/CN101223153A/zh active Pending
- 2006-05-12 JP JP2008510505A patent/JP2008544952A/ja active Pending
- 2006-05-12 US US11/914,078 patent/US20090105327A1/en not_active Abandoned
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102427726A (zh) * | 2009-03-27 | 2012-04-25 | 普雷西迪奥制药公司 | 丙型肝炎的稠环抑制剂 |
CN102427726B (zh) * | 2009-03-27 | 2014-10-08 | 普雷西迪奥制药公司 | 丙型肝炎的稠环抑制剂 |
CN106631793A (zh) * | 2016-10-19 | 2017-05-10 | 浙江师范大学 | 一种二苯并环庚烷衍生物的制备方法 |
CN106631793B (zh) * | 2016-10-19 | 2019-03-08 | 浙江师范大学 | 一种二苯并环庚烷衍生物的制备方法 |
WO2023221981A1 (en) * | 2022-05-16 | 2023-11-23 | Bp Apollo Limited | Taxamairin analogs and methods of use thereof |
Also Published As
Publication number | Publication date |
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CA2608889A1 (en) | 2006-11-16 |
DE102005022020A1 (de) | 2006-11-23 |
US20090105327A1 (en) | 2009-04-23 |
WO2006120010A3 (de) | 2007-01-18 |
JP2008544952A (ja) | 2008-12-11 |
WO2006120010A2 (de) | 2006-11-16 |
EP1881968A2 (de) | 2008-01-30 |
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