CN115583970A - 一种由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法 - Google Patents
一种由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法 Download PDFInfo
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- CN115583970A CN115583970A CN202211267152.9A CN202211267152A CN115583970A CN 115583970 A CN115583970 A CN 115583970A CN 202211267152 A CN202211267152 A CN 202211267152A CN 115583970 A CN115583970 A CN 115583970A
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- -1 diaryl phosphine oxide Chemical compound 0.000 title claims abstract description 191
- 238000000034 method Methods 0.000 title claims abstract description 57
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- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 title claims abstract description 28
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- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
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- 125000002947 alkylene group Chemical group 0.000 claims description 6
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- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
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- JYVHOGDBFNJNMR-UHFFFAOYSA-N hexane;hydrate Chemical compound O.CCCCCC JYVHOGDBFNJNMR-UHFFFAOYSA-N 0.000 claims description 3
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- 125000001624 naphthyl group Chemical class 0.000 claims description 2
- GJVFBWCTGUSGDD-UHFFFAOYSA-L pentamethonium bromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCC[N+](C)(C)C GJVFBWCTGUSGDD-UHFFFAOYSA-L 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 abstract description 5
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- 125000000524 functional group Chemical group 0.000 abstract description 2
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- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 39
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
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- Veterinary Medicine (AREA)
Abstract
本发明属于医药技术领域,涉及一种由硝酮制备α‑(羟基氨基)二芳基膦氧化物的方法。本发明在温和的条件下,以硝酮和二芳基氧化磷为原料,建立了一种简单、无催化剂的合成α‑(羟基氨基)膦氧化物的方法。本发明反应可在无溶剂下或低添加溶剂中反应,反应原子经济性高,可经简单的重结晶方法纯化,并表现出广泛的底物范围和良好的官能团耐受性,具有原料廉价易得,收率高,操作简便,安全性高,无污染,底物适用范围广,适合工业化生产的特点。药理活性实验表明,该类化合物具有较好的抑癌活性,并且无明显细胞毒性,具有潜在的药用价值,有望用于各种抗癌药物的制备。
Description
技术领域
本发明属于医药技术领域,具体涉及一种硝酮制备α-(羟基氨基)二芳基膦氧化物的方法。
背景技术
有机磷化合物作为有机合成的重要化合物在医药化学、农工业等领域具有相当重要的意义,例如:药品(抗病毒和抗癌剂)、农用化学品(农药和除草剂)、催化配体和工业添加剂(例如,聚合物和阻燃剂)。这些化合物的经典合成工艺受到化学计量添加剂的使用、保护基团的需要以及官能团耐受性差的影响。这促使研究将P(O)-H键直接添加到C=N不饱和键上,这有可能具有100%原子效率。
α-(羟基氨基)膦氧化物尚未有人大量合成,其可能具有独特的生物学活性和药用价值,并且其可作为合成α-胺基膦类化合物的中间体,α-胺基膦类化合物具有抗病毒、抗菌、抗癌和酶抑制活性。因此,有机磷氧化物作为一类重要的有机合成中间体,在天然产物合成、化工、医药等领域中具有重要的应用价值,开发绿色、高效、经济的有机膦氧化物的合成方法,受到相关领域研究人员的广泛关注。
在现有技术中,在不添加溶剂或催化剂的情况下在烯烃或炔烃上添加P(O)-H键的方法已被研究出来。现有技术还公开了一种用于异氰酸酯和异硫氰酸酯的氢膦酰化的无催化剂、低溶剂方法。但在硝酮的不饱和C=N双键上添加P(O)-H键的方法还无人研究。因此,开发经济、环保且高效的合成方法具有重要意义,并且有利于增加有机膦化合物结构的多样性。
恶性肿瘤是威胁人类健康与生命的严重疾病,在中国为主要致死原因之一。寻找和发现治疗和预防肿瘤的新药也是当前面临的重大课题。α-(羟基氨基)膦氧化物的抗肿瘤活性研究目前尚未见报道。
发明内容
基于以上技术问题,本发明的目的在于提供一种α-(羟基氨基)二芳基膦氧化物的绿色合成方法,以制备得到一种新的有机磷化合物,具有原料廉价易得,收率高,操作简便,安全性高,无污染,底物适用范围广,适合工业化生产的特点。
本发明制备的化合物在体外抗肿瘤活性测试中显现良好的结果,并且无明显细胞毒性。
根据本发明具体实施方式的由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法,以如式(2)所示的硝酮、式(3)所示的二芳基膦氧化合物为原料,在加热条件下进行反应,得到式(1)所示的α-(羟基氨基)二芳基膦氧化物,
其中,R1选自C1-C10的烷基、呋喃基、噻吩基、C5-C6亚烷基环、苯基或芳香基中的一种,
R2选自C1-C10的烷基、C5-C6亚烷基环、取代或未取代的苯基中的一种;
R3、R4各自独立的选自苯基、芳香基的一种。
术语“烷基”指饱和或不饱和的脂肪烃基,其可为直链或支链的且在链上具有1到10个原子。优选的烷基在链上具有1到6个碳原子。“支链的”指一个或多个低级烷基如甲基、乙基或丙基被连接到线性的烷基链上。“低级烷基”指在链上具有1到4个碳原子,其可为直链或支链的。所述烷基可被一个或多个相同或不同的包括例如卤素、环烷基、羟基、烷氧基、氨基、酰胺基、芳酰胺基、羧基的“烷基取代基”取代。
根据本发明具体实施方式的由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法,R1选自乙基、丙基、异丙基、丁基、异丁基、环己基、卤代苯基、烷基取代的苯基、甲氧基取代的苯基、甲氨基取代的苯基、乙酰氧基取代的苯基、萘基或联苯基。
术语“卤代”指由元素周期表中的卤族的原子所取代,且具体包括氟、氯、溴和碘原子。
根据本发明具体实施方式的由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法,R2选自乙基、丙基、异丙基、丁基、异丁基、环己基、苯基或苄基。
优选的,R1、R2各自独立地选自C5-C6亚烷基环。
根据本发明具体实施方式的由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法,只要能促使上述亲核加成反应发生的原料的用量都是可行的,为了提高反应收率和原料利用率,按物质的量比计,硝酮、二芳基膦氧化合物的比例为1:1-2,优选的,硝酮、二芳基膦氧化合物的比例为1:1.5。
根据本发明具体实施方式的由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法,只要能促使上述亲核加成反应发生的溶剂不会导致原料及产物变性,溶剂的用量对反应有积极作用,促进反应的进行都是可行的,某个实施例中,以硝酮、二芳基膦氧化合物为原料,以水或正己烷作为溶剂,优选的,水的物质的量可为硝酮物质的量的50-100倍,正己烷的物质的量可为硝酮物质的量的50-100倍。
根据本发明具体实施方式的由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法,反应时长为1-3小时。
根据本发明具体实施方式的由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法,以如式(2)所示的硝酮、式(3)所示的二芳基膦氧化合物为原料,在温度为60-90℃条件下进行反应。
根据本发明具体实施方式的由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法,得到式(1)所示的α-(羟基氨基)二芳基膦氧化物后,对其进行纯化,纯化步骤为:除去溶剂,使用重结晶或打浆的方法纯化,获得纯品。
优选的,重结晶的步骤为:先使用乙酸乙酯溶解产物,在用正己烷使产物析出,经抽滤,得到纯品;
打浆的步骤为:先在产物中加入正己烷,快速搅拌,使杂质溶解,经抽滤,得到纯品。
上述制备方法中,所述重结晶溶剂为1-5体积份的正己烷和1体积份的乙酸乙酯组成。正己烷也可换成石油醚,经重结晶反应可有效的将产物和其他杂质分离,且产率极高。
本发明还提供α-(羟基氨基)二芳基膦氧化物在制备抗肿瘤药物中的应用。所述药物包括α-(羟基氨基)二芳基膦氧化物、α-(羟基氨基)二芳基膦氧化物的药学上可接受的盐。
术语“药学上可接受的盐”指保留了本发明的化合物的生物有效性和特性的盐,且不在生物方面或其他方面是不理想的。在许多实例中,本发明的化合物利用氨基和/或羧基或类似的基团的存在可形成酸式和/或碱盐。药学上可接受的酸式加成盐可由无机或有机酸制备,而药学上可接受的碱式加成盐可由无机或有机碱制备。例如,上述盐包括那些衍生自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等,以及由有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、枸橼酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、磺胺酸、富马酸、甲磺酸和甲苯磺酸等。
其中,所述的肿瘤指实体瘤,包括乳腺癌、***癌、肺癌、胃癌、肝癌等。
本发明的有益效果:
本发明提供的α-(羟基氨基)二芳基膦氧化物的制备方法,是将芳香或脂肪族硝酮衍生物与二芳基氧化磷在溶剂中混合后进行亲核加成反应,实现α-(羟基氨基)二芳基膦氧化物的合成。
该制备方法可在空气和无溶剂条件下进行,反应条件温和且易于控制;所得原料易得,底物适用范围广;该反应过程可在无催化剂的条件下进行;反应专一性强,在较短时间内可以得到较高的收率,且后处理简便、绿色环保,适合大规模工业化生产。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为本发明方法制备α-(羟基氨基)二芳基膦氧化物的机理示意图。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面将对本发明的技术方案进行详细的描述。显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动的前提下所得到的所有其它实施方式,都属于本发明所保护的范围。
本发明制备α-(羟基氨基)二芳基膦氧化物的反应式:
如式(5)所示:
其反应机理如图1所示,最初,二芳基氧化膦2上的质子进行转移,与硝酮1上的氧负离子结合,形成中间体I和亲核部分II,其中N以阳离子、P以阴离子的形式存在。其次,P负离子再去进攻II中碳氮双键的碳原子,使碳氮双键的整体电子向N上转移,生成所需的氢膦酰化产品3。另外,在酸性条件下,二芳基氧化膦难以发生质子转移,抑制中间体II的生成,从而抑制了反应的进行。在碱性条件下,硝酮2难以与质子的结合,抑制中间体II的形成,使得硝酮主要以1的形式存在。因此,中心N原子正电荷密度小,电子转移倾向不足,且OH-会围绕在N+周围,溶剂化作用强,削弱了N+的缺电子性,减少了P负离子对碳氮双键的进攻,抑制了产物3的形成。由此,本发明的反应为亲核加成反应机理。
实施例1(((羟基)苄氨基)(苯基)甲基)二苯基膦氧化合物(化合物1)的合成。
化合物1结构式为:
方法一合成过程为:在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-苯基硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应2小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率93%。
方法二合成过程为:在容积为25ml的圆底烧瓶中,依次加入N-苄基-α-苯基硝酮(0.001mol)、二苯氧磷(0.0015mol)、水(10ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(90℃)反应4小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液用50ml×3乙酸乙酯萃取反应液三次,分液合并有机层,有机相用无水硫酸钠干燥,过滤,滤液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率93%。
方法三合成过程为:在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-苯基硝酮(0.001mol)、二苯氧磷(0.002mol),温度(65℃)使反应物呈熔融状态,反应2小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率94%。
在实际合成过程中可根据反应量、成本、操作难易程度、反应是否绿色、反应收率等方面合理选择合成的方法。
核磁共振检测化合物1结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.86(t,J=9.2Hz,2H),7.50(ddt,J=25.1,19.5,8.5Hz,7H),7.38–6.98(m,11H),6.72(s,1H),4.64(d,J=7.2Hz,1H),4.10(d,J=13.1Hz,1H),3.64(d,J=13.2Hz,1H).13C NMR(101MHz,CDCl3)δ136.59,131.43,131.32,131.23,130.99,130.91,129.10,128.21,128.09,128.04,127.88,127.77,127.16,77.16,76.84,76.53,61.20.
实施例2(((羟基)苄氨基)(2-萘基)甲基)二苯基膦氧化合物(化合物2)的合成
化合物2结构式为:
合成过程为:在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(2-萘基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应4小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率92%。
核磁共振检测化合物2结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.93–7.85(m,3H),7.80–7.76(m,2H),7.74–7.67(m,2H),7.63(dd,J=8.5,1.6Hz,1H),7.60–7.54(m,2H),7.52–7.43(m,8H),7.25–7.23(m,2H),7.12(dt,J=7.3,2.4Hz,3H),4.80(d,J=7.4Hz,1H),4.09(d,J=13.2Hz,1H),3.63(d,J=13.2Hz,1H).13C NMR(101MHz,CDCl3)δ136.92,133.10,132.96,132.70,132.68,131.77,131.75,131.67,131.60,131.58,131.38,131.31,131.27,131.19,130.87,130.76,129.41,129.34,129.12,129.08,128.95,128.75,128.55,128.43,128.36,128.25,128.22,128.10,127.99,127.70,127.66,127.60,127.49,127.46,126.58,126.37,126.08,125.99,77.48,77.16,76.84,61.56,61.45.
实施例3(((羟基)苄氨基)(环己基)甲基)二苯基膦氧化合物(化合物3)的合成。
化合物3结构式为:
合成过程为:在容积为25ml的圆底烧瓶中,依次加入N-苄基-α-环己基硝酮(0.001mol)、二苯氧磷(0.0015mol)、水(10ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(90℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液用50ml×3乙酸乙酯萃取反应液三次,分液合并有机层,有机相用无水硫酸钠干燥,过滤,滤液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率95%。
核磁共振检测化合物3结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.68(tdd,J=8.4,4.6,1.5Hz,1H),7.62–7.56(m,3H),7.46(td,J=7.2,1.6Hz,2H),7.41–7.35(m,5H),7.06(dd,J=5.1,2.1Hz,1H),6.35(d,J=7.4Hz,1H),4.73(s,2H),2.86(tdt,J=11.1,7.4,3.7Hz,1H),1.77–1.69(m,2H),1.58–1.53(m,2H),1.27–1.16(m,2H),1.15–1.08(m,1H),1.01(qd,J=11.7,3.4Hz,3H).13C NMR(101MHz,CDCl3)δ143.37,137.66,133.26,132.67,132.64,131.97,131.73,131.31,131.21,131.13,131.04,130.96,130.83,130.72,129.10,129.04,128.95,128.92,128.83,128.64,128.57,128.52,128.46,128.43,128.21,127.24,77.48,77.16,76.84,69.38,35.09,28.83,26.76,26.13,25.99,25.28.
实施例4(((羟基)苄氨基)(2-呋喃)甲基)二苯基膦氧化合物(化合物4)的合成
化合物4结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(2-呋喃)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:石油醚/乙酸乙酯,70:30)纯化,获得纯品。收率91%。
核磁共振检测化合物4结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.67–7.60(m,2H),7.50–7.30(m,7H),7.27–7.14(m,6H),7.10–7.01(m,2H),6.61(t,J=2.6Hz,1H),6.25(dd,J=3.3,1.9Hz,1H),4.73(d,J=11.1Hz,1H),4.07(d,J=12.6Hz,1H),3.58(d,J=12.7Hz,1H).13C NMR(101MHz,CDCl3)δ144.85,144.80,142.48,142.46,136.15,131.67,131.64,131.63,131.60,131.33,131.24,130.83,130.78,130.69,129.84,129.41,128.27,128.15,128.09,127.97,127.31,113.52,113.48,110.76,77.16,76.84,76.52,61.45.
实施例5(((羟基)苄氨基)(4-氟苯基)甲基)二苯基膦氧化合物(化合物5)的合成
化合物5结构式为:
合成过程为:在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(4-氟苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:石油醚/乙酸乙酯,80:20)纯化,获得纯品。收率82%。
核磁共振检测化合物5结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.86–7.78(m,2H),7.56(td,J=7.3,1.5Hz,1H),7.52–7.28(m,8H),7.27–7.19(m,5H),7.12–7.05(m,2H),6.93(t,J=8.6Hz,2H),6.72(s,1H),4.59(d,J=7.6Hz,1H),4.06(d,J=13.1Hz,1H),3.58(d,J=13.1Hz,1H).13C NMR(101MHz,CDCl3)δ136.35,133.25,133.18,131.51,131.34,131.29,131.21,130.89,130.80,129.07,128.25,128.13,128.09,128.01,127.89,127.26,114.96,114.75,77.16,76.84,76.52,61.17,61.05.
实施例6(((羟基)苄氨基)(4-氯苯基)甲基)二苯基膦氧化合物(化合物6)的合成
化合物6结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(4-氯苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:石油醚/乙酸乙酯,80:20)纯化,获得纯品。收率84%。
核磁共振检测化合物6结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.87–7.81(m,2H),7.59(td,J=7.3,1.5Hz,1H),7.53–7.41(m,6H),7.36(td,J=7.3,1.4Hz,1H),7.30–7.22(m,7H),7.13–7.04(m,2H),6.69(s,1H),4.61(d,J=7.6Hz,1H),4.08(d,J=13.1Hz,1H),3.60(d,J=13.1Hz,1H).13C NMR(101MHz,CDCl3)δ132.82,132.75,131.58,131.50,131.31,131.22,130.90,130.82,129.10,128.30,128.18,128.14,128.10,127.98,127.34,77.16,76.84,76.53,61.21,61.10.
实施例7(((羟基)苄氨基)(4-溴苯基)甲基)二苯基膦氧化合物(化合物7)的合成
化合物7结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(4-溴苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:石油醚/乙酸乙酯,80:20)纯化,获得纯品。收率84%。
核磁共振检测化合物7结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.85–7.78(m,2H),7.56(td,J=7.3,1.5Hz,1H),7.51–7.45(m,2H),7.44–7.31(m,7H),7.27–7.20(m,5H),7.11–7.03(m,2H),6.72(s,1H),4.58(d,J=7.6Hz,1H),4.05(d,J=13.1Hz,1H),3.58(d,J=13.1Hz,1H).13C NMR(101MHz,CDCl3)δ136.19,133.11,133.05,131.58,131.48,131.30,131.21,131.03,130.89,130.80,130.06,129.09,128.28,128.16,128.12,128.10,127.98,127.32,122.48,77.16,76.84,76.53,61.21,61.10.
实施例8(((羟基)苄氨基)(4-(三氟甲基)苯基)甲基)二苯基膦氧化合物(化合物8)的合成
化合物8结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(4-(三氟甲基)苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:石油醚/乙酸乙酯,80:20)纯化,获得纯品。收率85%。
核磁共振检测化合物8结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.76(ddd,J=11.4,8.3,1.4Hz,2H),7.50(td,J=8.0,7.4,1.4Hz,3H),7.41(ddt,J=6.6,5.2,2.1Hz,4H),7.36–7.28(m,2H),7.24(td,J=7.4,1.5Hz,1H),7.19–7.10(m,5H),7.01(dd,J=7.4,2.2Hz,2H),6.71(s,1H),4.58(d,J=7.3Hz,1H),3.99(d,J=13.1Hz,1H),3.50(d,J=13.2Hz,1H).13C NMR(101MHz,CDCl3)δ136.50,135.78,132.72,132.10,132.04,131.96,131.93,131.86,131.83,131.72,131.64,131.56,131.27,131.16,131.08,130.54,130.29,130.22,129.40,128.63,128.51,128.46,128.41,128.30,127.68,125.46,125.00,124.96,124.92,122.75,77.48,77.36,77.16,76.84,69.11,68.23,61.76,61.65.
实施例9(((羟基)苄氨基)(3-氯苯基)甲基)二苯基膦氧化合物(化合物9)的合成
化合物9结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(3-氯苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:石油醚/乙酸乙酯,80:20)纯化,获得纯品。收率84%。
核磁共振检测化合物9结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.90–7.83(m,2H),7.60(td,J=7.4,1.7Hz,1H),7.54–7.42(m,6H),7.36(td,J=7.4,1.6Hz,1H),7.31–7.23(m,6H),7.22–7.13(m,3H),7.12–6.74(m,1H),4.62(d,J=7.1Hz,1H),4.13(d,J=13.2Hz,1H),3.64(d,J=13.2Hz,1H).13C NMR(101MHz,CDCl3)δ136.31,133.62,133.37,132.51,131.49,131.47,131.40,131.37,131.27,131.21,131.18,131.03,130.88,130.80,130.05,129.61,129.55,129.09,129.01,128.23,128.18,128.17,128.11,128.05,127.98,127.86,127.22,77.16,76.84,76.52,61.39,61.28.
实施例10(((羟基)苄氨基)(3-氟苯基)甲基)二苯基膦氧化合物(化合物10)的合成
化合物10结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(3-氟苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由打浆的方法(溶剂:石油醚或正己烷)纯化,获得纯品。收率87%。
核磁共振检测化合物10结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.90–7.82(m,2H),7.62–7.58(m,1H),7.57–7.43(m,5H),7.36(td,J=7.3,1.5Hz,1H),7.27(tq,J=10.8,3.7Hz,8H),7.13(dd,J=7.2,2.4Hz,2H),7.01–6.94(m,1H),4.63(d,J=7.4Hz,1H),4.12(d,J=13.1Hz,1H),3.65(d,J=13.1Hz,1H).13C NMR(101MHz,CDCl3)δ136.63,133.93,132.88,132.72,131.88,131.85,131.74,131.72,131.62,131.53,131.38,131.23,131.15,130.89,130.78,130.40,129.56,129.48,129.42,129.09,128.97,128.59,128.47,128.42,128.33,128.22,127.60,118.84,118.77,118.56,115.53,115.31,77.48,77.16,76.84,61.66.
实施例11(((羟基)苄氨基)(2-溴苯基)甲基)二苯基膦氧化合物(化合物11)的合成化合物11结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(2-溴苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由打浆的方法(溶剂:石油醚或正己烷)纯化,获得纯品。收率85%。
核磁共振检测化合物11结构,结果如下:
1H NMR(400MHz,CDCl3)δ8.33(d,J=7.9Hz,1H),8.05(ddd,J=11.3,8.1,1.6Hz,2H),7.66–7.51(m,6H),7.45–7.42(m,1H),7.36–7.31(m,2H),7.26(td,J=5.1,4.7,2.2Hz,6H),7.11(t,J=7.7Hz,1H),6.71(s,1H),5.57(d,J=6.0Hz,1H),3.97–3.87(m,2H).13C NMR(101MHz,CDCl3)δ137.43,133.68,133.64,133.41,132.38,132.30,131.72,131.69,131.53,131.50,131.40,131.38,131.29,131.14,131.05,129.81,129.79,129.02,128.60,128.48,128.05,127.98,127.86,127.50,127.48,127.15,126.25,126.16,77.43,77.11,76.79,62.20,62.08.
实施例12(((羟基)苄氨基)(4-硝基苯基)甲基)二苯基膦氧化合物(化合物12)的合成
化合物12结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(4-硝基苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应4小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由打浆的方法(溶剂:石油醚或正己烷)纯化,获得纯品。收率83%。
核磁共振检测化合物12结构,结果如下:
1H NMR(400MHz,CDCl3)δ8.07(d,J=8.4Hz,2H),7.87–7.81(m,2H),7.64(d,J=8.3Hz,2H),7.58(dd,J=7.5,1.6Hz,1H),7.49(td,J=7.6,3.1Hz,2H),7.44–7.36(m,3H),7.33(dd,J=7.5,1.6Hz,1H),7.28–7.22(m,5H),7.12–7.07(m,2H),4.72(d,J=7.0Hz,1H),4.07(d,J=13.1Hz,1H),3.59(d,J=13.1Hz,1H).13C NMR(101MHz,CDCl3)δ147.60,139.45,136.12,132.52,132.46,131.99,131.97,131.94,131.91,131.50,131.41,131.00,130.92,129.33,128.59,128.47,128.44,128.41,128.32,127.71,122.96,77.40,77.08,76.76,68.82,67.95,61.97,61.86.
实施例13(((羟基)苄氨基)(2-氯苯基)甲基)二苯基膦氧化合物(化合物13)的合成
化合物13结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(2-氯苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由打浆的方法(溶剂:石油醚或正己烷)纯化,获得纯品。收率84%。
核磁共振检测化合物13结构,结果如下:
1H NMR(400MHz,CDCl3)δ8.27(d,J=7.8Hz,1H),7.97(ddd,J=11.3,8.2,1.5Hz,2H),7.59(dd,J=7.2,1.6Hz,1H),7.57–7.51(m,3H),7.50–7.48(m,1H),7.35–7.30(m,1H),7.29–7.20(m,7H),7.17(dt,J=8.6,5.1Hz,3H),6.59(s,1H),5.49(d,J=6.5Hz,1H),3.96–3.76(m,2H).13C NMR(101MHz,CDCl3)δ137.32,133.71,133.68,133.40,132.68,132.40,131.84,131.81,131.65,131.63,131.48,131.39,131.10,131.01,130.89,130.77,130.48,130.38,129.63,129.61,129.38,129.13,129.07,128.96,128.67,128.55,128.14,128.12,128.00,127.28,126.95,126.93,77.48,77.16,76.84,62.28,62.16.
实施例14(((羟基)苄氨基)(2,6-二氯苯基)甲基)二苯基膦氧化合物(化合物14)的合成
化合物14结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(2,6-二氯苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由打浆的方法(溶剂:石油醚或正己烷)纯化,获得纯品。收率81%。
核磁共振检测化合物14结构,结果如下:
1H NMR(400MHz,CDCl3)δ8.17–8.07(m,2H),7.72–7.64(m,2H),7.57(dt,J=6.1,2.6Hz,3H),7.46–7.40(m,2H),7.36–7.22(m,7H),7.13(dd,J=8.0,1.3Hz,1H),7.03(td,J=8.0,1.5Hz,1H),6.70(s,1H),6.09(d,J=4.2Hz,1H),3.92–3.76(m,2H).13C NMR(101MHz,CDCl3)δ137.34,136.82,136.78,136.19,136.12,135.60,134.59,131.51,131.28,131.26,131.14,131.11,130.99,130.97,130.90,130.88,130.14,130.12,129.43,129.40,128.86,128.41,128.30,127.83,127.77,127.30,127.18,126.89,77.16,76.84,76.53,71.22,70.38,62.43,62.32.
实施例15(((羟基)苄氨基)(4-甲基苯基)甲基)二苯基膦氧化合物(化合物15)的合成
化合物15结构式为:
在容积为10ml的圆底烧瓶中,依次加入依次加入N-苄基-α-(4-甲基苯基)硝酮(0.001mol)、二苯氧磷(0.002mol),温度(65℃)使反应物呈熔融状态,反应2小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率91%。
核磁共振检测化合物15结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.73(ddd,J=11.2,8.3,1.4Hz,2H),7.47(td,J=6.5,5.8,1.5Hz,1H),7.37(dddd,J=12.6,11.0,7.4,2.3Hz,4H),7.24(ddd,J=11.9,7.6,1.4Hz,3H),7.17–7.10(m,5H),7.01(dd,J=7.3,2.3Hz,2H),6.96(d,J=7.8Hz,2H),6.58(s,1H),4.48(d,J=7.4Hz,1H),3.97(d,J=13.2Hz,1H),3.50(d,J=13.1Hz,1H),2.20(s,3H).13C NMR(101MHz,CDCl3)δ138.16,137.00,133.28,131.73,131.67,131.63,131.54,131.50,131.32,131.24,129.41,128.93,128.49,128.37,128.33,128.21,128.10,127.41,77.48,77.16,76.84,61.37,61.26,21.32.
实施例16(((羟基)苄氨基)(3-甲基苯基)甲基)二苯基膦氧化合物(化合物16)的合成
化合物16结构式为:
合成过程为:在容积为10ml的圆底烧瓶中,依次加入依次加入N-苄基-α-(3-甲基苯基)硝酮(0.001mol)、二苯氧磷(0.002mol),温度(65℃)使反应物呈熔融状态,反应2小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率90%。
核磁共振检测化合物16结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.85(ddd,J=11.2,8.3,1.4Hz,2H),7.78–7.70(m,1H),7.62–7.57(m,1H),7.57–7.53(m,1H),7.53–7.49(m,2H),7.47(d,J=1.3Hz,1H),7.46–7.42(m,2H),7.36–7.31(m,1H),7.28–7.23(m,6H),7.16–7.14(m,2H),7.07(d,J=7.6Hz,1H),4.61(d,J=6.9Hz,1H),4.10(d,J=13.2Hz,1H),3.65(d,J=13.2Hz,1H),2.28(s,3H).13CNMR(101MHz,CDCl3)δ137.76,137.01,132.72,132.69,132.41,132.35,132.29,131.69,131.66,131.64,131.55,131.51,131.49,131.36,131.33,131.28,130.89,130.78,129.42,129.36,129.15,129.13,129.09,128.97,128.81,128.75,128.50,128.44,128.38,128.32,128.12,128.03,128.01,127.43,77.48,77.16,76.84,61.55,61.44,21.50.
实施例17(((羟基)苄氨基)(3,4-二甲基苯基)甲基)二苯基膦氧化合物(化合物17)的合成
化合物17结构式为:
在容积为10ml的圆底烧瓶中,依次加入依次加入N-苄基-α-(3,4-二甲基苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,60:40)纯化,获得纯品。收率89%。
核磁共振检测化合物17结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.88–7.82(m,2H),7.75(ddd,J=13.8,8.1,1.4Hz,1H),7.61–7.58(m,1H),7.58–7.55(m,1H),7.51(dq,J=6.9,4.0,3.0Hz,4H),7.44(d,J=6.9Hz,1H),7.38–7.33(m,1H),7.26(dd,J=5.1,2.0Hz,4H),7.20(d,J=8.0Hz,1H),7.15–7.13(m,1H),7.04(d,J=7.7Hz,1H),6.66(s,1H),4.60(d,J=7.5Hz,1H),4.11(d,J=13.2Hz,1H),3.64(d,J=13.2Hz,1H),2.22(d,J=6.8Hz,6H).13C NMR(101MHz,CDCl3)δ137.02,136.71,136.69,136.22,132.85,132.79,132.62,132.59,131.57,131.54,131.51,131.49,131.39,131.36,131.29,131.20,130.79,130.68,129.72,129.67,129.32,129.29,129.23,129.19,129.13,128.99,128.95,128.90,128.87,128.37,128.33,128.25,128.20,128.05,127.94,127.27,126.49,71.00,61.26,61.15,19.77,19.54.
实施例18(((羟基)苄氨基)(4-甲氧基苯基)甲基)二苯基膦氧化合物(化合物18)的合成
化合物18结构式为:
在容积为25ml的圆底烧瓶中,依次加入N-苄基-α-(4-甲氧基苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、水(10ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(90℃)反应4小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液用50ml×3乙酸乙酯萃取反应液三次,分液合并有机层,有机相用无水硫酸钠干燥,过滤,滤液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率93%。
核磁共振检测化合物18结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.79(ddd,J=11.2,6.9,1.9Hz,2H),7.53–7.49(m,1H),7.47–7.34(m,6H),7.28(d,J=1.7Hz,1H),7.24–7.16(m,5H),7.10–7.01(m,2H),6.79–6.50(m,3H),4.53(t,J=7.5Hz,1H),4.03(dd,J=13.1,3.9Hz,1H),3.73(d,J=4.3Hz,3H),3.56(dd,J=13.1,2.6Hz,1H).13C NMR(101MHz,CDCl3)δ159.62,137.05,133.11,131.67,131.56,131.31,131.23,129.40,128.51,128.40,128.36,128.27,128.15,127.44,113.63,77.48,77.16,76.84,61.33,61.21,55.29,29.84.
实施例19(((羟基)苄氨基)(3-甲氧基苯基)甲基)二苯基膦氧化合物(化合物19)的合成
化合物19结构式为:
合成过程为:在容积为25ml的圆底烧瓶中,依次加入N-苄基-α-(3-甲氧基苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、水(10ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(90℃)反应4小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液用50ml×3乙酸乙酯萃取反应液三次,分液合并有机层,有机相用无水硫酸钠干燥,过滤,滤液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率92%。
核磁共振检测化合物19结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.84–7.77(m,2H),7.69(ddd,J=13.7,8.2,1.4Hz,2H),7.54(dt,J=3.8,1.7Hz,1H),7.51(dd,J=4.1,2.2Hz,1H),7.48–7.45(m,3H),7.41(dt,J=3.7,1.2Hz,1H),7.39(d,J=1.6Hz,1H),7.31–7.28(m,1H),7.21(dd,J=5.2,2.1Hz,3H),7.12–7.09(m,2H),7.05–7.00(m,1H),6.98–6.94(m,1H),6.79–6.74(m,1H),4.59(d,J=6.8Hz,1H),4.07(d,J=13.2Hz,1H),3.81(s,1H),3.70(s,3H).13C NMR(101MHz,CDCl3)δ159.32,132.72,132.69,131.76,131.62,131.53,131.35,131.26,130.89,130.78,129.51,129.38,129.36,129.12,129.09,128.97,128.54,128.42,128.34,128.20,128.09,127.52,121.83,114.60,112.34,55.35.
实施例20(((羟基)苄氨基)(2-甲氧基苯基)甲基)二苯基膦氧化合物(化合物20)的合成
化合物20结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(2-甲氧基苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率92%。
核磁共振检测化合物20结构,结果如下:
1H NMR(400MHz,CDCl3)δ8.10(d,J=7.7Hz,1H),7.93–7.86(m,2H),7.57–7.39(m,5H),7.30–7.10(m,9H),6.92(td,J=7.5,1.1Hz,1H),6.65(dt,J=8.3,1.1Hz,1H),6.57(s,1H),5.42(d,J=6.8Hz,1H),3.95(d,J=13.5Hz,1H),3.69(d,J=13.4Hz,1H),3.60(s,3H).13C NMR(101MHz,CDCl3)δ156.80,156.74,137.20,133.51,132.52,131.62,131.22,131.20,131.17,131.13,130.97,130.94,130.72,130.63,129.12,129.10,128.89,128.12,128.00,127.66,127.45,127.34,126.81,120.36,120.34,120.18,109.37,77.16,76.84,76.52,61.78,61.66,54.78.
实施例21(((羟基)苄氨基)(3,5-二甲氧基苯基)甲基)二苯基膦氧化合物(化合物21)的合成
化合物21结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(3,5-二甲氧基苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率90%。
核磁共振检测化合物21结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.86–7.77(m,2H),7.60–7.39(m,7H),7.37–7.31(m,1H),7.23(dt,J=4.9,2.4Hz,4H),7.13(dd,J=6.6,2.9Hz,2H),6.63–6.56(m,2H),6.33(d,J=1.2Hz,1H),4.55(d,J=6.7Hz,1H),4.09(d,J=13.2Hz,1H),3.79(s,1H),3.68(s,6H).13CNMR(101MHz,CDCl3)δ160.36,133.63,133.11,132.68,132.12,131.77,131.74,131.64,131.60,131.55,131.38,131.29,130.89,130.78,130.73,129.47,129.38,129.13,129.09,128.96,128.54,128.42,128.34,128.21,128.09,127.50,109.62,109.56,100.94,77.48,77.16,76.84,55.59,55.47.
实施例22(((羟基)苄氨基)(4-(乙酰氧基)苯基)甲基)二苯基膦氧化合物(化合物22)的合成
化合物22结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(4-(乙酰氧基)苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由打浆的方法(溶剂:石油醚或正己烷)纯化,获得纯品。收率84%。
核磁共振检测化合物22结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.85–7.78(m,2H),7.73–7.66(m,1H),7.54(dd,J=7.6,1.6Hz,1H),7.48–7.43(m,4H),7.42–7.35(m,3H),7.30(dd,J=7.5,1.6Hz,1H),7.24–7.20(m,4H),7.10(dt,J=7.4,3.5Hz,2H),6.97(d,J=8.3Hz,2H),4.62(d,J=7.2Hz,1H),4.07(d,J=13.2Hz,1H),3.61(d,J=13.2Hz,1H),2.26(s,3H).13C NMR(101MHz,CDCl3)δ169.11,150.76,136.79,132.71,132.68,132.65,131.78,131.75,131.65,131.62,131.53,131.25,131.16,130.87,130.75,130.03,129.40,129.31,129.10,129.07,128.95,128.53,128.42,128.36,128.30,128.19,127.50,121.74,121.25,77.48,77.16,76.84,21.29.
实施例23(((羟基)苄氨基)(4-(二甲氨基)苯基)甲基)二苯基膦氧化合物(化合物23)的合成
化合物23结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(4-(二甲氨基)苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率88%。
核磁共振检测化合物23结构,结果如下:
1H NMR(400MHz,CDCl3)δ9.44(s,3H),7.57–7.51(m,5H),7.30(td,J=7.4,1.4Hz,3H),7.26(s,2H),7.19(dp,J=7.3,2.9Hz,7H),7.12(d,J=6.0Hz,5H),3.43(s,2H),1.30–1.22(m,2H).13C NMR(101MHz,CDCl3)δ134.00,131.30,131.21,130.26,128.66,128.18,128.11,127.98,77.48,77.16,76.84,42.74.
实施例24(((羟基)苄氨基)(4-异丙基苯基)甲基)二苯基膦氧化合物(化合物24)的合成
化合物24结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(4-异丙基苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率95%。
核磁共振检测化合物24结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.82(ddd,J=11.2,8.3,1.4Hz,2H),7.57–7.51(m,1H),7.46(ddd,J=8.5,6.6,3.1Hz,2H),7.42–7.34(m,4H),7.31–7.26(m,1H),7.24–7.15(m,5H),7.14–7.05(m,4H),6.66(s,1H),4.59(d,J=7.0Hz,1H),4.08(d,J=13.1Hz,1H),3.62(d,J=13.2Hz,1H),2.83(p,J=6.9Hz,1H),1.22–1.14(m,6H).13C NMR(101MHz,CDCl3)δ149.00,148.98,137.08,133.33,132.34,131.86,131.65,131.61,131.58,131.56,131.37,131.34,131.32,131.24,130.88,129.38,128.62,128.44,128.33,128.28,128.07,127.96,127.36,126.23,77.48,77.16,76.84,61.47,61.35,33.85,23.99,23.95.
实施例25(((羟基)苄氨基)(1,1'-联苯基)甲基)二苯基膦氧化合物(化合物25)的合成
化合物25结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-(1,1'-联苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率88%。
核磁共振检测化合物25结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.84(dd,J=11.2,7.6Hz,2H),7.71(dd,J=13.8,7.4Hz,2H),7.63(dd,J=10.7,8.0Hz,2H),7.55(d,J=7.5Hz,3H),7.51–7.47(m,6H),7.43(d,J=7.2Hz,4H),7.36–7.33(m,1H),7.29(d,J=7.4Hz,1H),7.25–7.22(m,3H),7.13(dd,J=6.8,2.6Hz,2H),5.08(s,1H),4.12(d,J=13.0Hz,1H),3.67(d,J=13.2Hz,1H).13C NMR(101MHz,CDCl3)δ141.02,140.56,140.25,136.74,132.72,132.70,132.18,132.12,131.79,131.66,131.58,131.34,131.25,130.89,130.78,129.51,129.38,129.24,129.12,129.09,128.99,128.97,128.88,128.56,128.44,128.38,128.27,128.16,127.95,127.55,127.18,127.14,127.11,126.83,77.48,77.16,76.84,71.31,61.60.
实施例26(1-((羟基)苄氨基)丙基)二苯基膦氧化合物(化合物26)的合成。
化合物26结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-乙基硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率82%。
核磁共振检测化合物26结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.75(ddd,J=11.1,8.3,1.5Hz,4H),7.52–7.40(m,7H),7.21(dd,J=5.0,1.9Hz,3H),7.09–7.03(m,2H),4.25(d,J=13.2Hz,1H),3.99(d,J=13.2Hz,1H),3.64(td,J=7.0,5.2Hz,1H),2.23(ddt,J=14.9,11.4,7.4Hz,1H),1.76(dddd,J=19.3,9.6,7.5,5.2Hz,1H),0.92(t,J=7.5Hz,3H).13C NMR(101MHz,CDCl3)δ137.48,133.07,132.70,132.67,132.56,132.11,131.92,131.89,131.72,131.69,131.65,131.39,131.30,131.20,130.85,130.74,129.43,129.29,129.06,129.01,128.93,128.73,128.62,128.51,128.31,127.36,66.02,65.21,61.67,61.57,17.29,17.25,13.92,13.84.
实施例27(1-((羟基)苄氨基)丁基)二苯基膦氧化合物(化合物27)的合成
化合物27结构式为:
合成过程为:在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-丙基硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率85%。
核磁共振检测化合物27结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.80–7.72(m,4H),7.51–7.47(m,2H),7.44(dt,J=8.1,3.3Hz,4H),7.38(s,1H),7.20(dd,J=5.0,2.0Hz,2H),7.05(dd,J=6.7,2.8Hz,2H),6.40(s,1H),4.24(d,J=13.2Hz,1H),3.97(d,J=13.2Hz,1H),3.73(td,J=7.1,5.1Hz,1H),2.26–2.10(m,1H),1.73–1.60(m,1H),1.51–1.41(m,1H),1.22–1.11(m,1H),0.79(t,J=7.3Hz,3H).13C NMR(101MHz,CDCl3)δ137.46,133.04,132.69,132.66,132.50,132.08,131.93,131.90,131.71,131.68,131.59,131.43,131.34,131.28,131.19,130.85,130.74,129.38,129.28,129.06,129.00,128.98,128.93,128.70,128.61,128.59,128.50,128.29,127.35,77.48,77.16,76.84,64.24,63.43,61.66,61.57,25.91,25.87,22.26,22.18,14.20,14.07.
实施例28(1-((羟基)苄氨基)异丁基)二苯基膦氧化合物(化合物28)的合成
化合物28结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-异丙基硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率83%。
核磁共振检测化合物28结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.80(dddd,J=11.1,8.4,3.1,1.5Hz,4H),7.62–7.34(m,7H),7.19(dd,J=5.1,2.0Hz,3H),7.04–6.93(m,2H),6.73(s,1H),4.24(d,J=13.2Hz,1H),4.09(d,J=13.2Hz,1H),3.63(dd,J=7.9,4.6Hz,1H),2.45(dpd,J=11.4,6.9,4.6Hz,1H),1.06(dd,J=24.9,6.9Hz,6H).13C NMR(101MHz,CDCl3)δ137.54,134.71,133.78,132.89,131.70,131.67,131.48,131.45,131.30,131.20,131.05,130.96,130.79,130.67,129.14,129.05,128.99,128.93,128.86,128.62,128.58,128.51,128.46,128.19,127.25,77.38,77.06,76.74,69.12,68.40,62.61,62.54,28.12,28.06,22.23,22.16,21.82,21.78.
实施例29(1-((羟基)苄氨基)戊基)二苯基膦氧化合物(化合物29)的合成
化合物29结构式为:
合成过程为:在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-丁基硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由打浆的方法(溶剂:石油醚或正己烷)纯化,获得纯品。收率88%。
核磁共振检测化合物29结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.75(tt,J=8.5,2.2Hz,4H),7.51–7.47(m,2H),7.43(dq,J=7.7,3.7Hz,4H),7.37(s,1H),7.20(dd,J=4.9,2.0Hz,3H),7.07–7.04(m,1H),6.46(s,1H),4.24(d,J=13.1Hz,1H),3.96(d,J=13.2Hz,1H),3.70(q,J=6.5Hz,1H),2.20(dtt,J=16.6,11.4,5.7Hz,1H),1.78–1.61(m,1H),1.43(ddt,J=13.9,8.7,5.3Hz,1H),1.24–1.05(m,3H),0.75(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ137.47,132.99,132.66,132.63,132.49,132.03,131.88,131.85,131.66,131.63,131.57,131.41,131.33,131.27,131.18,130.81,130.70,129.35,129.27,129.02,128.96,128.93,128.90,128.65,128.61,128.57,128.54,128.49,128.45,128.25,127.30,77.48,77.16,76.84,64.39,63.58,61.58,61.48,31.20,31.12,27.65,26.55,23.28,23.24,22.70,13.80.
实施例30(1-((羟基)苄氨基)-3-甲基丁基)二苯基膦氧化合物(化合物30)的合成
化合物30结构式为:
合成过程为:在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-异丁基硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由打浆的方法(溶剂:石油醚或正己烷)纯化,获得纯品。收率93%。
核磁共振检测化合物30结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.82–7.75(m,3H),7.69(ddd,J=13.7,8.2,1.4Hz,1H),7.57–7.43(m,7H),7.38(s,1H),7.19(dd,J=5.0,1.9Hz,2H),7.10–7.01(m,2H),4.25(d,J=13.3Hz,1H),3.99(d,J=13.3Hz,1H),3.85(td,J=7.6,4.9Hz,1H),2.13(dddd,J=14.1,10.8,7.8,5.8Hz,1H),1.65–1.39(m,2H),0.84(d,J=6.5Hz,3H),0.71(d,J=6.5Hz,3H).13CNMR(101MHz,CDCl3)δ137.61,133.14,133.06,132.68,132.65,132.48,132.18,131.94,131.91,131.76,131.74,131.57,131.46,131.38,131.29,130.85,130.74,129.35,129.19,129.05,129.01,128.97,128.92,128.69,128.66,128.58,128.54,128.26,127.30,77.48,77.16,76.84,62.62,61.83,61.61,61.52,32.99,32.95,26.25,26.17,26.07,23.02,22.68,21.93.
实施例31(1-((羟基)苄氨基)苯丙基)二苯基膦氧化合物(化合物31)的合成
化合物31结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-苯乙基硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由打浆的方法(溶剂:石油醚或正己烷)纯化,获得纯品。收率82%。
核磁共振检测化合物31结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.76–7.64(m,5H),7.55–7.52(m,2H),7.50–7.42(m,4H),7.29(s,1H),7.26–7.19(m,5H),7.07–7.01(m,2H),6.97(d,J=1.8Hz,1H),6.68–6.36(m,1H),4.27(d,J=13.1Hz,1H),4.00(d,J=13.1Hz,1H),3.81–3.72(m,1H),2.85(t,J=4.2Hz,1H),2.65–2.54(m,2H),2.09–1.96(m,1H).13C NMR(101MHz,CDCl3)δ132.95,132.70,132.04,131.80,131.42,131.35,131.32,131.26,130.90,130.79,129.44,129.10,129.03,128.97,128.84,128.75,128.72,128.66,128.59,128.42,127.48,126.41,126.19,62.76,61.87,61.78,34.22,34.14,26.09,26.04.
实施例32((羟基(甲基)氨基)(苯基)甲基)二苯基膦氧化合物(化合物32)的合成
化合物32结构式为:
合成过程为:在容积为10ml的圆底烧瓶中,依次加入N-甲基-α-苯基硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率88%。
核磁共振检测化合物32结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.97–7.86(m,2H),7.54–7.41(m,5H),7.31(ddd,J=8.8,7.0,1.6Hz,3H),7.25–7.05(m,6H),4.61(d,J=5.3Hz,1H),2.59(s,3H).13C NMR(101MHz,CDCl3)δ133.39,132.41,132.12,131.84,131.81,131.68,131.62,131.56,131.53,131.49,131.48,131.26,131.20,130.70,128.63,128.52,128.34,128.33,128.18,128.14,128.02,46.75,46.64.
实施例33((羟基(甲基)氨基)(4-甲基苯基)甲基)二苯基膦氧化合物(化合物33)的合成
化合物33结构式为:
在容积为10ml的圆底烧瓶中,依次加入N-甲基-α-(4-甲基苯基)硝酮(0.001mol)、二苯氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率92%。
核磁共振检测化合物33结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.88(ddd,J=11.1,8.2,1.5Hz,2H),7.55–7.45(m,5H),7.37–7.32(m,1H),7.25(d,J=5.7Hz,2H),7.21–7.16(m,2H),6.98(d,J=7.8Hz,2H),6.76(s,1H),4.53(d,J=5.9Hz,1H),2.55(s,3H),2.25(s,3H).13C NMR(101MHz,CDCl3)δ131.66,131.64,131.57,131.24,128.92,128.65,128.53,128.18,128.07,77.48,77.16,76.84,46.55,46.43,21.29.
实施例34(((羟基)苄氨基)(苯基)甲基)(3,5-二甲苯基)膦氧化物(化合物34)的合成
化合物34结构式为:
合成过程为:在容积为10ml的圆底烧瓶中,依次加入N-苄基-α-苯基硝酮(0.001mol)、3,5-二甲苯基氧磷(0.0015mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应3小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率75%。
核磁共振检测化合物34结构,结果如下:
1H NMR(400MHz,CDCl3)δ7.30(dddd,J=17.2,7.0,3.4,2.0Hz,5H),7.15–7.10(m,6H),7.07–6.98(m,3H),6.86(dd,J=11.4,1.6Hz,2H),6.78(s,1H),4.41(d,J=8.0Hz,1H),3.94(d,J=13.1Hz,1H),3.49(d,J=13.2Hz,1H),2.24(s,6H),2.01(s,6H).13C NMR(101MHz,CDCl3)δ138.15,138.03,137.76,137.64,136.95,133.54,133.51,133.27,131.99,131.93,129.45,129.38,129.17,129.12,129.09,128.98,128.89,128.75,128.59,128.35,128.28,128.24,128.03,127.45,77.48,77.16,76.84,21.53,21.24.
实施例35(2-羟基-1,2,3,4-四氢异喹啉-1-基)二苯基膦氧化物(化合物35)的合成
化合物35结构式为:
合成过程为:在容积为10ml的圆底烧瓶中,依次加入3,4-二氢异喹啉-2-氧化物(0.001mol)、二苯氧磷(0.0012mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应5小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率85%。
核磁共振检测化合物35结构,结果如下:
1H NMR(500MHz,CDCl3)δ7.87–7.78(m,4H),7.57–7.45(m,6H),7.24–7.14(m,2H),7.12(dd,J=4.8,1.2Hz,2H),4.60(p,J=6.0Hz,1H),4.40(ddd,J=11.5,6.0,1.0Hz,1H),3.99(d,J=6.4Hz,1H),2.99(dddd,J=14.8,8.0,5.7,1.1Hz,1H),2.77(dddd,J=14.8,7.9,5.7,0.9Hz,1H),2.05(ddt,J=13.7,7.9,5.7Hz,1H),1.87(ddt,J=13.6,8.1,5.7Hz,1H).13C NMR(125MHz,CDCl3)δ134.88,133.46,132.56,131.76,131.30,129.35,128.59,127.21,126.92,126.68,70.81,48.93,28.60,27.28.
实施例36((2R,3S,4R)-2,3-双(苄氧基)-4-((苄氧基)甲基)-5-羟基环戊基)二苯基氧化物(化合物36)的合成
化合物36结构式为:
合成过程为:在容积为10ml的圆底烧瓶中,依次加入(2S,3S,4S)-3,4-双(苄氧基)-2-((苄氧基)甲基)-3,4-二氢-2H-吡咯1-氧化物(0.001mol)、二苯氧磷(0.0012mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应5小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率88%。
核磁共振检测化合物36结构,结果如下:
1H NMR(500MHz,CDCl3)δ7.87(ddt,J=13.3,6.8,1.4Hz,4H),7.56–7.48(m,2H),7.46(tdd,J=8.0,4.0,1.0Hz,4H),7.34(tddd,J=5.0,3.3,2.3,1.2Hz,4H),7.34–7.24(m,11H),4.73(dd,J=6.6,5.9Hz,1H),4.62(ddt,J=12.1,6.0,0.9Hz,2H),4.56–4.49(m,2H),4.49–4.38(m,3H),4.29(dd,J=5.9,4.2Hz,1H),4.07(dd,J=11.4,6.6Hz,1H),3.83(dd,J=10.6,4.6Hz,1H),3.69(dd,J=10.5,4.7Hz,1H),3.31(q,J=4.5Hz,1H).13C NMR(125MHz,CDCl3)δ137.82,137.59,137.42,131.79,130.98,130.72,128.62,128.43,128.41,128.40,128.22,128.13,128.10,128.08,128.07,127.99,127.95,81.64,81.29,73.30,72.87,72.39,67.00,61.80,58.93.
实施例37((3R,4S,5S)-3,4-双(苄氧基)-5-((S)-1,2-双(苄氧基)乙基)-1-羟基吡咯烷-2-基)二苯基膦氧化物
化合物37结构式为:
合成过程为:在容积为10ml的圆底烧瓶中,依次加入(2S,3S,4S)-3,4-双(苄氧基)-2-((S)-1,2-双(苄氧基)乙基)-3,4-二氢-2H-吡咯-1-氧化物(0.001mol)、二苯氧磷(0.0012mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应8小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率82%。
核磁共振检测化合物37结构,结果如下:
1H NMR(500MHz,CDCl3)δ7.90–7.81(m,4H),7.55–7.48(m,2H),7.46(tdd,J=7.9,3.9,1.0Hz,4H),7.38–7.24(m,20H),4.93(dd,J=6.6,5.9Hz,1H),4.77(s,1H),4.72(dt,J=12.1,1.1Hz,1H),4.62(dt,J=12.1,1.1Hz,1H),4.58–4.50(m,2H),4.52–4.45(m,2H),4.42(ddt,J=15.9,12.1,1.0Hz,2H),4.25(t,J=5.9Hz,1H),4.07(dd,J=11.5,6.6Hz,1H),3.80–3.70(m,2H),3.56(dd,J=11.0,5.9Hz,1H),3.23(dd,J=6.2,5.3Hz,1H).13C NMR(125MHz,CDCl3)δ137.79,137.76,137.50,137.43,131.74,130.94,130.67,128.63,128.46,128.45,128.43,128.41,128.39,128.27,128.24,128.21,128.18,128.15,128.14,128.07,128.01,128.00,81.98,80.73,74.53,73.60,72.94,72.50,71.18,70.95,62.88,61.85.
实施例38((3R,4S,5R)-3,4-双(苄氧基)-5-((S)-1,2-双(苄氧基)乙基)-1-羟基吡咯烷-2-基)二苯基膦氧化物
化合物38结构式为:
合成过程为:在容积为10ml的圆底烧瓶中,依次加入(2R,3S,4S)-3,4-双(苄氧基)-2-((S)-1,2-双(苄氧基)乙基)-3,4-二氢-2H-吡咯-1-氧化物(0.001mol)、二苯氧磷(0.0012mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应8小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率80%。
核磁共振检测化合物38结构,结果如下:
1H NMR(500MHz,CDCl3)δ7.89(ddt,J=13.2,6.8,1.4Hz,4H),7.55–7.48(m,2H),7.46(tdd,J=7.9,3.9,1.1Hz,4H),7.38–7.24(m,20H),4.98(dd,J=6.6,5.9Hz,1H),4.62(dt,J=12.0,1.1Hz,1H),4.58–4.47(m,4H),4.51–4.37(m,3H),4.35(dt,J=12.1,1.0Hz,1H),4.16(dd,J=5.8,5.1Hz,1H),4.07(dd,J=11.6,6.6Hz,1H),3.80–3.69(m,2H),3.49(dd,J=11.3,5.4Hz,1H),3.27(t,J=5.2Hz,1H).13C NMR(125MHz,CDCl3)δ137.79,137.76,137.50,137.43,131.74,130.94,130.67,128.63,128.46,128.45,128.43,128.41,128.39,128.27,128.24,128.21,128.18,128.15,128.14,128.07,128.01,128.00,81.98,80.73,74.53,73.60,72.94,72.50,71.18,70.95,62.88,61.85.
实施例38((3R,4S,5S,6R)-3,4,5-三(苄氧基)-6-((苄氧基)甲基)-1-羟基哌啶-2-基)二苯基膦氧化物
化合物39结构式为:
合成过程为:在容积为10ml的圆底烧瓶中,依次加入(2R,3S,4S,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-2,3,4,5-四氢吡啶-1-氧化物(0.001mol)、二苯氧磷(0.0012mol)、正己烷(5ml),放入磁力搅拌子,置于磁力搅拌器上500转每分钟搅拌,温度(60℃)反应5小时,TLC监测反应,无硝酮类化合物剩余时,将混合溶液减压蒸馏除溶剂得初产物。然后初产物由重结晶的方法(溶剂:正己烷/乙酸乙酯,80:20)纯化,获得纯品。收率85%。
核磁共振检测化合物39结构,结果如下:
1H NMR(500MHz,CDCl3))δ7.86–7.77(m,5H),7.55–7.48(m,2H),7.45(tdd,J=7.8,3.9,1.0Hz,4H),7.40–7.32(m,6H),7.35–7.24(m,15H),4.80(ddt,J=11.9,3.5,1.0Hz,2H),4.63(dt,J=12.1,1.0Hz,2H),4.51(dt,J=12.1,0.9Hz,1H),4.48–4.36(m,4H),4.04(dd,J=11.5,6.6Hz,1H),3.99(dd,J=7.6,5.2Hz,1H),3.86(dd,J=5.2,3.6Hz,1H),3.80(dd,J=10.5,6.3Hz,1H),3.74(dd,J=10.5,6.3Hz,1H),3.16(td,J=6.3,3.7Hz,1H).13CNMR(125MHz,CDCl3))δ138.39,137.73,137.51,137.43,131.74,130.69,130.67,128.63,128.46,128.45,128.43,128.41,128.39,128.27,128.24,128.21,128.18,128.17,128.15,128.07,128.01,128.00,76.61,75.83,75.42,73.24,72.40,71.92,71.80,71.75,64.30,57.25.
实施例40
本发明合成化合物的体外抗肿瘤活性测试和对正常细胞的细胞毒性实验。
实验原理:四氮唑盐(micoculture tetrozolium,MTT)还原法进行体外测试。选用喜树碱(Camptothecin)作为阳性对照。
细胞株:人体的肺腺癌细胞(A549)、人乳腺癌细胞(MCF-7)、小鼠肺上皮细胞(TC-1)。
实验方法:
制备浓度为1×105μg/mL细胞悬液,加入96孔板中,每孔100μL,置37℃,5%CO2培养箱中孵育24h。
将不同浓度的受试物加到培养的肿瘤细胞和正常细胞的96孔板中,继续培养24h,倒置显微镜下观察。
弃去培养液,每孔加入0.05% MTT应用液100μL,培养4h。
弃去培养液,每孔加入100μL DMSO,振荡5min使甲瓒结晶溶解,在490nm处测定细胞吸光度(OD值)。
实验数据处理方法如下:
以未加药孔细胞的吸光度作为空白对照组吸光度(OD值),计算公式如下:
抑制率(%)=(空白对照组OD平均值-样品组OD平均值度)/空白对照OD平均值×100%,
根据不同时间、不同剂量下生长抑制率作图得到浓度及时间-生长抑制率曲线,采用GraphPad Prism 9.0软件作图,利用软件计算出目标化合物对两种肿瘤细胞的半数抑制浓度IC50。见下表。
从上表的结果可以看出,本发明化合物对A549/MCF-7肿瘤细胞有一定的抑制作用,并且它们对正常细胞TC-1无明显毒性,说明本发明化合物具有潜在药用价值,有望用于各种抗癌药物的制备。
以上所述,仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应以所述权利要求的保护范围为准。
Claims (10)
2.根据权利要求1所述的由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法,其特征在于,R1选自乙基、丙基、异丙基、丁基、异丁基、环己基、卤代苯基、烷基取代的苯基、甲氧基取代的苯基、甲氨基取代的苯基、乙酰氧基取代的苯基、萘基或联苯基。
3.根据权利要求1所述的由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法,其特征在于,R2选自乙基、丙基、异丙基、丁基、异丁基、环己基、苯基或苄基,优选的,R1、R2各自独立地选自C5-C6亚烷基环。
4.根据权利要求1所述的由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法,其特征在于,按物质的量比计,硝酮、二芳基膦氧化合物的比例为1:1-2。
5.根据权利要求1所述的由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法,其特征在于,以硝酮、二芳基膦氧化合物为原料,以水或正己烷作为溶剂,优选的,水、正己烷的物质的量为硝酮物质的量的50-100倍。
6.根据权利要求1所述的由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法,其特征在于,反应时长为1-3小时。
7.根据权利要求1所述的由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法,其特征在于,以如式(2)所示的硝酮、式(3)所示的二芳基膦氧化合物为原料,在温度为60-90℃条件下进行反应。
8.根据权利要求1所述的由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法,其特征在于,得到式(1)所示的α-(羟基氨基)二芳基膦氧化物后,对其进行纯化,纯化步骤为:除去溶剂,使用重结晶或打浆的方法纯化,获得纯品。
9.根据权利要求8所述的由硝酮制备α-(羟基氨基)二芳基膦氧化物的方法,其特征在于,重结晶的步骤为:先使用乙酸乙酯溶解产物,在用正己烷使产物析出,经抽滤,得到纯品;或
打浆的步骤为:先在产物中加入正己烷,快速搅拌,使杂质溶解,经抽滤,得到纯品。
10.权利要求1所述的方法制备得到的α-(羟基氨基)二芳基膦氧化物在制备抗肿瘤药物中的应用。
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