CN117164418A - 一种α-卤代酮、其高效合成方法及应用 - Google Patents
一种α-卤代酮、其高效合成方法及应用 Download PDFInfo
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- CN117164418A CN117164418A CN202311050829.8A CN202311050829A CN117164418A CN 117164418 A CN117164418 A CN 117164418A CN 202311050829 A CN202311050829 A CN 202311050829A CN 117164418 A CN117164418 A CN 117164418A
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 43
- 150000002576 ketones Chemical class 0.000 title claims abstract description 24
- -1 alkenyloxy pyridinium salt Chemical class 0.000 claims abstract description 103
- 238000006243 chemical reaction Methods 0.000 claims abstract description 50
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 claims abstract description 9
- 229960003250 telithromycin Drugs 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
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- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
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Abstract
本发明公开一种α‑卤代酮、其高效合成方法及应用。所述合成方法包括:使包含烯氧基吡啶鎓盐和卤化季铵盐的均匀混合反应体系于室温下进行反应,获得α‑卤代酮。所述合成方法采用高活性的烯氧基吡啶鎓盐为反应物,使卤化季铵盐中的卤负离子进攻烯氧基吡啶鎓盐中的双键进行反应,以实现α‑卤代酮的便捷、高效制备。所述α‑卤代酮可被用于制备药物或药物中间体,例如适合用于制备替洛利生。
Description
技术领域
本发明属于有机化学技术领域,具体涉及一种α-卤代酮、其高效合成方法及其在制备药物或药物中间体中的应用,例如在制备替洛利生中的应用。
背景技术
α-卤代酮类化合物是一类重要的功能有机分子,在生物、医药等多个领域均有深入而广泛的应用。传统的α-卤代酮类化合物的合成方法主要有芳基酮的直接α-卤化法、烃或仲醇的氧卤化法、以及相应芳烃与卤代乙酰卤化物的Friedel-Crafts酰化法。在这些合成方法中,使用的卤化剂一般是卤素、HX(X=Cl、Br、I)和卤化酰胺等,但是上述的卤化剂通常都具有一定的腐蚀性和毒性,安全性低。
季铵盐是一种性质稳定且低成本的化合物,通常被应用在杀菌剂、絮凝剂以及水处理等领域,季铵盐与上述传统的卤化剂相比,毒性和成本低,且反应废水易于处理。虽然目前在采用卤化季铵盐制备α-卤代酮方面已经取得了一些方面的研究进展,但是仍存在一些挑战,例如非区域特异性卤化、反应时间较长、合成过程较为繁琐、副产物较多等,这些问题均限制着卤化季铵盐作为卤化剂的实际应用前景。
因而,设计一种以卤化季铵盐为卤素源的简便、条件温和、低成本、低毒性的α-卤代酮合成方法,是目前亟待解决的问题之一。
发明内容
为解决上述全部或部分技术问题,本发明提供以下技术方案:
本发明的目的之一在于提供一种α-卤代酮的合成方法,所述合成方法包括:使包含烯氧基吡啶鎓盐和卤化季铵盐的均匀混合反应体系于室温下进行反应,获得α-卤代酮;
所述烯氧基吡啶鎓盐具有式I所示结构:
其中,R包括H、卤素、取代或未取代的烷基、取代或未取代的芳基、取代或未取代的杂环基、取代或未取代的烯基、炔基、酯基、氨基或氰基;R1包括H、甲基,Xa-包括负电性基团;Xa-包括负电性基团;
在部分实施例中,所述卤化季铵盐包括四丁基卤化铵,所述四丁基卤化铵具有式II所示结构:
其中,Xb包括Cl、Br或I。
所述合成方法采用高活性的烯氧基吡啶鎓盐为反应物,使卤化季铵盐中的卤负离子进攻烯氧基吡啶鎓盐中的双键进行反应,以实现α-卤代酮的便捷、高效制备,产率较高。
在部分实施例中,所述卤化季铵盐与烯氧基吡啶鎓盐的摩尔比为1.1~2∶1。
在部分实施例中,所述合成方法的反应时间为5-15min。本发明提供的合成方法在5-15min中内即可完成反应,合成效率较高。
在部分实施例中,Xa-包括-NTf2。
在部分实施例中,所述均匀混合反应体系还包括有机溶剂。
在部分实施例中,所述有机溶剂包括四氢呋喃、二氯甲烷、二氯乙烷、乙腈、甲醇和六氟异丙醇中的一种或多种。
在部分优选实施例中,所述卤化季铵盐为Bu4NXb;当Xb为Cl时,所述有机溶剂选自四氢呋喃、二氯甲烷和甲醇中的至少一种;当Xb为Br或I时,所述有机溶剂包括六氟异丙醇。
本发明的目的之二在于提供一种α-卤代酮,所述α-卤代酮具有式III所示结构:
其中,R包括H、卤素、取代或未取代的烷基、取代或未取代的芳基、取代或未取代的杂环基、取代或未取代的烯基、炔基、酯基、氨基或氰基;X包括Cl、Br或I。
在部分实施例中,所述α-卤代酮包括下列任一种化合物:
本发明的目的之三在于提供上述任一项所述的α-卤代酮在制备药物或药物中间体中的应用。特别是在制备替洛利生中的用途。本发明提供的合成方法简便、高效且低毒性,适用于工业化生产α-卤代酮,作为制备替洛利生的原料试剂易于获得。
与现有技术相比,本发明提供的α-卤代酮的制备方法至少具有以下技术效果:
(1)本发明提供的合成方法采用烯氧基吡啶鎓盐,烯氧基吡啶鎓盐的结构中具有强亲电性的双键不饱和基团,使烯氧基吡啶鎓盐具有高亲电活性,而四丁基卤化铵易生成卤负离子,卤负离子的亲核性促使其进攻烯氧基吡啶鎓盐进行反应,在5-15min中内即可完成反应,以实现α-卤代酮的高效制备;
(2)本发明进一步提供适用于该合成方法的优选有机试剂,通过选择合适的有机试剂以提高产率;
(3)该合成方法无需使用有毒和有腐蚀性的卤素单质,具备良好的绿色可持续性;
(4)该合成方法在室温下反应即可,无需进行严格控温,操作简便,具备可实际生产性;
(5)本发明提供的合成方法具有通用性,至少适用于84种以上的不同结构的α-卤代酮的合成,且产率普遍较高;
(6)该合成方法无需另外添加催化剂等,成本较为可控,具备可商业性。
具体实施方式
下面结合若干优选实施例对本发明的技术方案做进一步详细说明,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获得的所有其他实施例,都属于本发明保护的范围。
鉴于现有技术中的不足,本案发明人经长期研究和大量实践,得以提出本发明的技术方案:在烯氧基吡啶鎓盐的结构中具有强亲电性的双键不饱和基团,即烯氧基吡啶鎓盐本身是高活性的亲电试剂,并利用四丁基卤化铵易的生成卤负离子的特点,通过使卤负离子进攻烯氧基吡啶鎓盐进行反应,可以实现α-卤代酮的高效制备,从而改善了已有合成α-卤代酮技术的产率低,反应慢的特点。
在如下实施例中,所有试剂和溶剂均从商业来源购买,使用时未经进一步净化,除非另有说明。所有反应均采用薄层色谱法(TLC)进行监测。除非另有说明,所有反应均在空气中进行。在硅胶(200-300目)上进行柱层析,用紫外线观察。用乙酸乙酯和石油醚作为洗脱剂。在室温下,以MDB为内标,CDCl3为溶剂,在JEOL ECZ400上记录1H、13C和19F光谱。多重性缩写为:s,单峰;d,双峰;t,三重峰;q,四重峰;se-Pt七重奏;m,多重峰;傅立叶变换红外光谱(FT-IR)在Agilent Technologies Cary 630仪器上记录。HRMS分析采用ESI-TOF方法。熔点在微熔点仪上测定。
1、烯氧基吡啶鎓盐的合成及其表征
烯氧基吡啶鎓盐合成路线可参阅下式:
其中,R包括H、卤素、取代或未取代的烷基、取代或未取代的芳基、取代或未取代的杂环基、取代或未取代的烯基、炔基、酯基、氨基或氰基;R1包括氢或甲基。
合成步骤:将吡啶氧化物和Tf2NH以1.2∶1.1的摩尔比预混,然后储存在反应瓶中直接用于反应。将PPh3AuNTf2(39mg,0.025equiv.)加入炔(2mmol)、上述预混盐(826mg,1.1equiv.)和HFIP(2mL)的混合物中,室温下装入反应瓶。然后将反应混合物在室温下搅拌,用薄层色谱(CH2Cl2/MeOH=10/1)监测反应过程。反应结束后,用硅胶柱层析法(CH2Cl2/MeOH=100/1)纯化n-烯氧基吡啶盐。
通过上述方法合成的部分产物及表征数据如下:
(1)1-((3-((4-fluorobenzyl)oxy)prop-1-en-2-yl)oxy)pyridin-1-iumbis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);843.0mg,78%产率.1HNMR(400MHz,Chloroform-d)δ8.93(d,J=5.9Hz,2H),8.57(t,J=7.8Hz,1H),8.23-8.14(m,2H),7.29-7.23(m,2H),7.02(t,J=8.7Hz,2H),5.03(d,J=4.8Hz,1H),4.57(d,J=4.8Hz,1H),4.49(s,2H),4.19(s,2H).13C NMR(101MHz,Chloroform-d)δ162.71(d,JC-F=246.6Hz),159.97,146.67,141.51,132.69(d,JC-F=3.3Hz),130.21,130.09(d,JC-F=8.2Hz),119.85(q,JC-F=321.2Hz),115.62(d,JC-F=21.5Hz),99.07,72.24,66.92.19FNMR(376MHz,Chloroform-d)δ-78.77,-113.47.IR(cm-1):3118,3074,1510,1352,1195,1136,1056,615,570,513;HRMS(ESI+)m/z calcd.For C17H15F7N2O6S2[M+]:260.1081;found:260.1080.
(2)1-((3-((4-chlorobenzyl)oxy)prop-1-en-2-yl)oxy)pyridin-1-iumbis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);913.3mg,82%产率.1HNMR(400MHz,Chloroform-d)δ8.93(d,J=6.0Hz,2H),8.57(t,J=7.7Hz,1H),8.19(t,J=6.7Hz,2H),7.31(d,J=7.6Hz,2H),7.24(t,J=7.9Hz,2H),5.10-4.93(m,1H),4.56(d,J=4.1Hz,1H),4.50(s,2H),4.20(s,2H).13C NMR(101MHz,Chloroform-d)δ159.93,146.69,141.55,135.40,134.16,130.26,129.56,128.91,119.85(q,JC-F=321.2Hz),99.12,72.19,67.06.19F NMR(376MHz,Chloroform-d)δ-78.84.IR(cm-1):3091,2910,1732,1492,1352,1195,1136,1056,615,570,513;HRMS(ESI+)m/z calcd.For C17H15ClF6N2O6S2[M+]:276.0786;found:276.0786.
(3)1-((3-((3-chlorobenzyl)oxy)prop-1-en-2-yl)oxy)pyridin-1-iumbis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);935.6mg,84%产率.1HNMR(400MHz,Chloroform-d)δ8.93(d,J=6.2Hz,2H),8.56(t,J=7.8Hz,1H),8.17(t,J=7.1Hz,2H),7.26(d,J=6.4Hz,2H),7.22(s,1H),7.16(d,J=6.3Hz,1H),5.02(d,J=4.8Hz,1H),4.53(d,J=4.6Hz,1H),4.49(s,2H),4.21(s,2H).13C NMR(101MHz,Chloroform-d)δ159.83,146.68,141.48,139.06,134.40,130.19,130.12,128.36,127.89,126.16,119.85(q,JC-F=321.2Hz),98.83,72.04,67.21.19F NMR(376MHz,Chloroform-d)δ-78.81.IR(cm-1):3118,3072,1481,1352,1195,1136,1056,788,615,570,513;HRMS(ESI+)m/z calcd.ForC17H15ClF6N2O6S2[M+]:276.0786;found:276.0784.
(4)1-((3-((3-bromobenzyl)oxy)prop-1-en-2-yl)oxy)pyridin-1-iumbis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);962.1mg,80%产率.1HNMR(400MHz,Chloroform-d)δ8.91(d,J=5.7Hz,2H),8.55(t,J=7.8Hz,1H),8.20-8.11(m,2H),7.39(t,J=4.5Hz,1H),7.37(s,1H),7.20(d,J=5.0Hz,2H),5.02(d,J=4.8Hz,1H),4.52(d,J=4.8Hz,1H),4.48(s,2H),4.21(s,2H).13C NMR(101MHz,Chloroform-d)δ159.78,146.65,141.43,139.37,131.24,130.76,130.39,130.13,126.62,122.53,119.85(q,JC-F=321.2Hz),115.05,98.78,71.93,67.22.19F NMR(376MHz,Chloroform-d)δ-78.79.IR(cm-1):3118,2920,1670,1481,1352,1197,1138,1056,788,615,570;HRMS(ESI+)m/zcalcd.For C18H17BrF6N2O6S2[M+]:320.0281;found:320.0280.
(5)1-((3-((3-methylbenzyl)oxy)prop-1-en-2-yl)oxy)pyridin-1-iumbis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);847.6mg,79%产率.1HNMR(400MHz,Chloroform-d)δ8.84(d,J=5.8Hz,2H),8.52(t,J=7.8Hz,1H),8.16-8.08(m,2H),7.22(t,J=7.5Hz,1H),7.13-7.03(m,3H),5.00(d,J=4.8Hz,1H),4.50(d,J=4.8Hz,1H),4.47(s,2H),4.19(s,2H),2.32(s,3H).13C NMR(101MHz,Chloroform-d)δ160.02,146.55,141.37,138.39,136.79,130.03,129.02,128.94,128.57,125.27,119.85(q,JC-F=321.2Hz),98.46,72.87,66.87,21.25.19F NMR(376MHz,Chloroform-d)δ-78.83.IR(cm-1):3118,3070,2924,2868,1672,1608,1481,1352,1195,1056,788,617,570,513;HRMS(ESI+)m/z calcd.For C18H18F6N2O6S2[M+]:256.1332;found:256.1331.
(6)1-((3-((2-chlorobenzyl)oxy)prop-1-en-2-yl)oxy)pyridin-1-iumbis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);969.0mg,87%产率.1HNMR(400MHz,Chloroform-d)δ8.89(d,J=5.8Hz,2H),8.54(t,J=7.8Hz,1H),8.20-8.08(m,2H),7.38-7.34(m,1H),7.34-7.29(m,1H),7.26-7.21(m,2H),5.03(d,J=4.8Hz,1H),4.59(s,2H),4.51(d,J=4.8Hz,1H),4.24(s,2H).13C NMR(101MHz,Chloroform-d)δ159.79,146.61,141.33,134.46,133.40,130.10,130.07,129.67,129.53,127.15,119.85(q,JC-F=321.2Hz),98.54,70.04,67.33.19F NMR(376MHz,Chloroform-d)δ-78.84.IR(cm-1):3118,3072,1672,1608,1479,1352,1195,1056,761,615,570,514;HRMS(ESI+)m/zcalcd.For C17H15ClF6N2O6S2[M+]:276.0786;found:276.0786.
(7)1-((3-((2-methylbenzyl)oxy)prop-1-en-2-yl)oxy)pyridin-1-iumbis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);847.6mg,79%产率.1HNMR(400MHz,Chloroform-d)δ8.82(d,J=5.8Hz,2H),8.51(t,J=7.8Hz,1H),8.16-8.09(m,2H),7.21(d,J=6.5Hz,2H),7.16(d,J=6.7Hz,2H),5.00(d,J=4.8Hz,1H),4.53(s,2H),4.48(d,J=4.8Hz,1H),4.21(s,2H),2.30(s,3H).13C NMR(101MHz,Chloroform-d)δ160.18,146.63,141.43,137.22,134.93,130.64,130.16,129.19,128.64,126.08,119.85(q,JC-F=321.2Hz),98.67,71.51,67.12,18.84.19F NMR(376MHz,Chloroform-d)δ-78.82.IR(cm-1):3118,3070,2926,2872,1670,1608,1481,1352,1195,1056,763,617,570,513;HRMS(ESI+)m/z calcd.For C18H18F6N2O6S2[M+]:256.1332;found:256.1331.
(8)1-((3-(benzyloxy)prop-1-en-2-yl)oxy)-4-methylpyridin-1-iumbis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);879.8mg,82%产率.1HNMR(400MHz,Methanol-d4)δ9.10(d,J=7.0Hz,2H),8.11(d,J=6.8Hz,2H),7.50-7.41(m,5H),5.15(d,J=4.6Hz,1H),4.69(s,2H),4.62(d,J=4.6Hz,1H),4.41(s,2H),2.81(s,3H).13C NMR(101MHz,Methanol-d4)δ162.92,161.78,141.81,138.65,131.12,129.52,129.21,129.07,121,18(q,JC-F=320.6Hz),97.06,73.74,68.13,22.23.19F NMR(376MHz,Methanol-d4)δ-80.34.IR(cm-1):3242,2875,1732,1643,1506,1456,1352,1193,1136,1056,788,615,570,513;HRMS(ESI+)m/z calcd.For C18H18F6N2O6S2[M+]:256.1332;found:256.1339.
(9)1-((3-((4-fluorobenzyl)oxy)prop-1-en-2-yl)oxy)-4-methylpyridin-1-ium bis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);876.0mg,79%产率.1HNMR(400MHz,Methanol-d4)δ9.20-8.94(m,2H),8.05(d,J=6.8Hz,2H),7.41-7.31(m,2H),7.09(t,J=8.8Hz,2H),5.04(d,J=4.5Hz,1H),4.57(s,2H),4.50(d,J=4.6Hz,1H),4.30(s,2H),2.72(s,3H).13C NMR(101MHz,Methanol-d4)δ163.9(d,JC-F=182.7Hz),163.02,161.86,142.0(d,JC-F=1.8Hz),134.78(d,JC-F=2.1Hz),131.27,131.19,121,18(q,JC-F=320.6Hz),116.18(d,JC-F=16.2Hz),96.73,72.93,68.08,22.23.19F NMR(376MHz,Methanol-d4)δ-80.50,-1116.32.IR(cm-1):3115,2872,1732,1624,1510,1463,1352,1195,1136,1056,788,617,570,513;HRMS(ESI+)m/z calcd.For C18H17F7N2O6S2[M+]:274,1238;found:274,1238.
(10)1-((3-((4-chlorobenzyl)oxy)prop-1-en-2-yl)oxy)-4-methylpyridin-1-ium bis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);924.9mg,81%产率.1HNMR(400MHz,Methanol-d4)δ9.07(d,J=6.9Hz,2H),8.06(d,J=6.8Hz,2H),7.37(d,J=2.2Hz,4H),5.07(d,J=4.6Hz,1H),4.60(s,2H),4.52(d,J=4.6Hz,1H),4.33(s,2H),2.74(s,3H).13C NMR(101MHz,Methanol-d4)δ162.97,161.73,141.92,137.55,134.72,131.17,130.70,129.57,121,18(q,JC-F=320.6Hz),96.83,72.76,68.20,22.23.19F NMR(376MHz,Methanol-d4)δ-80.01.IR(cm-1):3115,2870,1670,1624,1494,1350,1195,1136,1056,788,617,570,513;HRMS(ESI+)m/z calcd.For C18H17ClF6N2O6S2[M+]:290.0942;found:290.0942.
(11)1-((3-((4-bromobenzyl)oxy)prop-l-en-2-yl)oxy)-4-methylpyridin-1-ium bis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);923.0mg,75%产率.1HNMR(400MHz,Methanol-d4)δ9.10(d,J=6.9Hz,2H),8.10(d,J=6.9Hz,2H),7.58(d,J=8.3Hz,2H),7.36(d,J=8.3Hz,2H),5.12(d,J=4.7Hz,1H),4.63(s,2H),4.58(d,J=4.6Hz,1H),4.39(s,2H),2.79(s,3H).13C NMR(101MHz,METHANOL-D4)δ162.92,161.62,141.82,137.99,132.55,131.14,130.96,122.67,121,18(q,JC-F=320.6Hz),96.88,72.75,68.20,22.25.19F NMR(376MHz,Methanol-d4)δ-80.28.IR(cm-1):3113,2870,1641,1624,1489,1350,1193,1136,1056,790,617,570,513;HRMS(ESI+)m/z calcd.For C18H17BrF6N2O6S2[M+]:334.0437;found:334.0431.
(12)4-methyl-1-((3-((4-methylbenzyl)oxy)prop-1-en-2-yl)oxy)pyridin-1-ium bis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色固体(CH2Cl2/MeOH=100/1);792.7mg,72%产率.m.p 29.4-33.6℃.1H NMR(400MHz,Methanol-d4)δ9.04(d,J=6.9Hz,2H),8.03(d,J=6.8Hz,2H),7.22(d,J=8.1Hz,2H),7.18(d,J=8.2Hz,2H),5.04(d,J=4.5Hz,1H),4.53(s,2H),4.52(d,J=4.4Hz,1H),4.27(s,2H),2.71(s,3H),2.34(s,3H).13C NMR(101MHz,Methanol-d4)δ162.91,161.87,141.90,139.03,135.66,135.57,131.11,130.13,129.40,121,18(q,JC-F=320.6Hz),97.04,73.63,67.95,22.22,21.19,20.86.19F NMR(376MHz,Methanol-d4)δ-80.53.IR(cm-1):3113,2868,1624,1494,1352,1193,1138,1056,615,570,513;HRMS(ESI+)m/z calcd.For C19H20F6N2O6S2[M+]:270.1489;found:270.1489.
(13)1-((3-((3-chlorobenzyl)oxy)prop-1-en-2-yl)oxy)-4-methylpyridin-1-ium bis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);890.6mg,78%产率.1HNMR(400MHz,Methanol-d4)δ9.10(d,J=6.8Hz,2H),8.09(d,J=6.8Hz,2H),7.45-7.32(m,4H),5.11(d,J=4.7Hz,1H),4.64(s,2H),4.56(d,J=4.6Hz,1H),4.39(s,2H),2.78(s,3H).13C NMR(101MHz,Methanol-d4)δ162.95,161.58,141.83,141.10,135.23,131.15,131.08,128.96,128.78,127.26,121,18(q,JC-F=320.6Hz),96.97,72.71,68.35,22.25.19F NMR(376MHz,Methanol-d4)δ-80.33.IR(cm-1):3115,2870,1624,1496,1350,1193,1138,1056,788,615,570,514;HRMS(ESI+)m/z calcd.For C18H17ClF6N2O6S2[M+]:290.0942;found:290.0942.
(14)1-((3-((3-bromobenzyl)oxy)prop-1-en-2-yl)oxy)-4-methylpyridin-1-ium bis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);923.0mg,75%产率.1HNMR(400MHz,Methanol-d4)δ9.10(d,J=6.4Hz,2H),8.08(d,J=6.7Hz,2H),7.57-7.47(m,2H),7.39-7.28(m,2H),5.09(d,J=4.6Hz,1H),4.61(s,2H),4.55(d,J=5.1Hz,1H),4.36(s,2H),2.76(s,3H).13C NMR(101MHz,Methanol-d4)δ162.99,161.64,141.92,141.40,132.00,131.80,131.37,131.16,127.72,123.34,121,18(q,JC-F=320.6Hz),97.10,72.72,68.40,22.26.19F NMR(376MHz,Methanol-d4)δ-80.44.IR(cm-1):3115,2870,1624,1496,1471,1350,1192,1136,1056,788,615,570,513;HRMS(ESI+)m/z calcd.ForC18H17BrF6N2O6S2[M+]:334.0437;found:334.0429.
(15)4-methyl-1-((3-((3-methylbenzyl)oxy)prop-1-en-2-yl)oxy)pyridin-1-ium bis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);825.7mg,75%产率.1HNMR(400MHz,Methanol-d4)δ9.04(d,J=5.8Hz,2H),8.04(d,J=6.1Hz,2H),7.25(d,J=7.7Hz,1H),7.16(d,J=9.9Hz,3H),5.05(d,J=4.0Hz,1H),4.56(s,2H),4.51(d,J=3.8Hz,1H),4.30(s,2H),2.72(s,3H),2.36(s,3H).13C NMR(101MHz,Methanol-d4)δ162.94,161.89,141.93,139.32,138.55,131.12,129.90,129.77,129.45,126.34,121,18(q,JC-F=320.6Hz),96.90,73.81,22.22.19F NMR(376MHz,Methanol-d4)δ-80.56.IR(cm-1):3109,2870,1732,1643,1352,1193,1136,1056,788,617,570,513;HRMS(ESI+)m/z calcd.ForC19H20F6N2O6S2[M+]:270.1489;found:270.1485.
(16)1-((3-((2-chlorobenzyl)oxy)prop-1-en-2-yl)oxy)-4-methylpyridin-1-ium bis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);982.0mg,86%产率.1HNMR(400MHz,Methanol-d4)δ9.08(d,J=7.0Hz,2H),8.06(d,J=6.9Hz,2H),7.52-7.48(m,1H),7.45-7.42(m,1H),7.37-7.33(m,2H),5.10(d,J=4.6Hz,1H),4.72(s,2H),4.54(d,J=4.6Hz,1H),4.40(s,2H),2.74(s,3H).13C NMR(101MHz,Methanol-d4)δ163.00,161.71,141.92,136.58,136.24,134.47,134.15,131.18,131.12,130.63,130.48,128.19,121.18(q,JC-F=320.6Hz),96.98,70.91,68.59,22.24.19F NMR(376MHz,Methanol-d4)δ-80.44.IR(cm-1):3099,2924,1732,1643,1475,1350,1195,1136,1056,761,615,570,513;HRMS(ESI+)m/z calcd.For C18H17ClF6N2O6S2[M+]:290.0942;found:290.0941.
(17)1-((3-((2-bromobenzyl)oxy)prop-1-en-2-yl)oxy)-4-methylpyridin-1-ium bis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色液体(CH2Cl2/MeOH=100/1);1009.2mg,82%产率.1H NMR(400MHz,Methanol-d4)δ9.09(d,J=6.9Hz,2H),8.06(d,J=6.7Hz,2H),7.61(d,J=8.0Hz,1H),7.49(d,J=7.6Hz,1H),7.39(t,J=7.5Hz,1H),7.26(t,J=7.7Hz,1H),5.11(d,J=4.6Hz,1H),4.69(s,2H),4.55(d,J=4.6Hz,1H),4.40(s,2H),2.73(s,3H).13C NMR(101MHz,Methanol-d4)δ163.00,161.69,141.90,137.89,133.80,131.20,131.16,130.82,128.77,121,18(q,JC-F=320.6Hz),97.06,73.19,68.61,61.54,22.25.19F NMR(376MHz,Methanol-d4)δ-80.55.IR(cm-1):3115,2926,1672,1624,1496,1350,1193,1136,1058,761,615,570,513;HRMS(ESI+)m/z calcd.For C18H17BrF6N2O6S2[M+]:334.0437;found:334.0433.
(18)4-methyl-1-((3-((2-methylbenzyl)oxy)prop-1-en-2-yl)oxy)pyridin-l-ium bis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠固体(CH2Cl2/MeOH=100/1);858.8mg,78%产率.m.p32.2-35.7℃.1H NMR(400MHz,Methanol-d4)δ9.03(d,J=6.9Hz,2H),8.04(d,J=6.9Hz,2H),7.30(d,J=7.4Hz,1H),7.28-7.16(m,3H),5.06(d,J=4.6Hz,1H),4.63(s,2H),4.50(d,J=4.6Hz,1H),4.34(s,2H),2.72(s,3H),2.37(s,3H).13C NMR(101MHz,METHANOL-D4)δ162.98,162.01,141.93,138.37,136.52,131.36,131-15,130.26,129.41,126.87,121,18(q,JC-F=320.6Hz),96.66,72.32,68.24,22.23,18.90.19F NMR(376MHz,Methanol-d4)δ-80.51.IR(cm-1):3113,2924,1730,1641,1494,1352,1193,1138,1056,788,740,617,570,513;HRMS(ESI+)m/z calcd.For C19H20F6N2O6S2[M+]:270.1489;found:270.1489.m.p 32.2-35.7℃.
(19)1-((6-(benzyloxy)-6-oxohex-1-en-2-yl)oxy)pyridin-1-iumbis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);971.9mg,84%产率.1HNMR(400MHz,Chloroform-d)δ8.86(d,J=5.8Hz,2H),8.60(t,J=7.8Hz,1H),8.23-8.16(m,2H),7.34-7.30(m,4H),7.30-7.26(m,1H),5.10(s,2H),4.47(d,J=5.5Hz,1H),3.61(d,J=5.5Hz,1H),2.46(dt,J=7.1,15.2Hz,4H),1.98(p,J=7.1Hz,2H).13C NMR(101MHz,CHLOROFORM-D)δ173.02,164.76,146.84,142.10,135.92,130.30,128.66,128.37,128.18,124.61,121.41,118.22,115.02,89.62,66.45,32.90,30.59,21.38.19F NMR(376MHz,Chloroform-d)δ-78.81.IR(cm-1):3118,2945,1732,1666,1481,1352,1056,910,788,740,700,570,514;HRMS(ESI+)m/z calcd.For C20H20F6N2O7S2[M+]:298.1438;found:298.1438.
(20)1-((6-methoxy-6-oxohex-1-en-2-yl)oxy)pyridin-1-ium bis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);823.9mg,82%产率.1HNMR(400MHz,Chloroform-d)δ8.92(d,J=5.7Hz,2H),8.64(t,J=7.8Hz,1H),8.27-8.19(m,2H),4.50(d,J=5.5Hz,1H),3.68(d,J=5.5Hz,1H),3.60(s,3H),2.40(dt,J=7.3,13.8Hz,4H),1.93(p,J=7.1Hz,2H).13C NMR(101MHz,Chloroform-d)δ173.59,164.87,146.92,142.14,130.30,124.51,121.32,118.12,114.92,89.51,51.67,32.63,30.44,21.39.19FNMR(376MHz,Chloroform-d)δ-78.93.IR(cm-1):2956,1737,1666,1479,1348,1053,788,740,570,514;HRMS(ESI+)m/z calcd.For C14H16F6N2O7S2[M+]:222.1125;found:222.1126.
(21)1-((5-ethoxy-4-(ethoxycarbonyl)-5-oxopent-1-en-2-yl)oxy)pyridin-1-ium bis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);827.2mg,72%产率.1HNMR(400MHz,Chloroform-d)δ8.96(d,J=5.7Hz,2H),8.71(t,J=7.8Hz,1H),8.35-8.25(m,2H),4.65(d,J=5.8Hz,1H),4.23(qd,J=2.6,7.1Hz,4H),3.85(d,J=5.8Hz,1H),3.80(t,J=7.7Hz,1H),3.01(d,J=7.7Hz,2H),1.27(t,J=7.1Hz,6H).13C NMR(101MHz,CHLOROFORM-D)δ168.05,161.96,147.33,142.17,130.60,124.64,121.44,118.24,115.05,91.92,62.36,49.67,30.41,14.09.19F NMR(376MHz,Chloroform-d)δ-78.84.IR(cm-1):3118,2987,1732,1479,1352,1195,1138,1058,617,570,513;HRMS(ESI+)m/z calcd.ForC17H20F6N2O9S2[M+]:294.1336;found:294.1332.
(22)1-((1-phenylvinyl)oxy)pyridin-1-ium bis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);641.0mg,67%产率.1HNMR(400MHz,Methanol-d4)δ9.46(d,J=7.0Hz,2H),8.77-8.72(m,1H),8.31(t,J=7.2Hz,2H),7.77(dd,J=2.1,7.5Hz,2H),7.51-7.46(m,3H),5.37(d,J=5.4Hz,1H),4.40(d,J=5.4Hz,1H).13C NMR(101MHz,Methanol-d4)δ163.65,147.97,143.41,131.88,131.10,130.03,128.57,127.33,121,18(q,JC-F=320.6Hz).19F NMR(376MHz,Methanol-d4)δ-80.48.IR(cm-1):3182,3120,1637,1539,1489,1350,1193,1136,1056,742,615,570,513;HRMS(ESI+)m/z calcd.For C15H12F6N2O5S2[M+]:198.0913;found:198.0915.
(23)1-((1-(4-chlorophenyl)vinyl)oxy)pyridin-1-ium bis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);584.6mg,57%产率.1HNMR(400MHz,Methanol-d4)δ9.45(d,J=6.5Hz,2H),8.78(t,J=7.8Hz,1H),8.34(t,J=6.6Hz,2H),7.80(d,J=7.1Hz,2H),7.5l(d,J=7.1Hz,2H),5.41(d,J=7.2Hz,1H),4.41(d,J=4.4Hz,1H).13C NMR(101MHz,Methanol-d4)δ162.62,148.15,143.54,137.78,131.18,130.33,130.17,128.86,121,18(q,JC-F=320.6Hz),93.23.19F NMR(376MHz,Methanol-d4)δ-80.50.IR(cm-1):3091,1635,1489,1350,1193,1136,1056,615,570,513;HRMS(ESI+)m/zcalcd.For C15H11ClF6N2O5S2[M+]:232.0524;found:232.0522.
(24)1-((6-(((3S,8S,9S,10R,13R,14S,17R)-17-((2S,5S)-5-ethyl-6-methylheptan-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-6-oxohex-1-en-2-yl)oxy)pyridin-1-ium bis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);1486.9mg,84%产率.1HNMR(400MHz,Chloroform-d)δ8.96(d,J=5.8Hz,2H),8.69(t,J=7.8Hz,1H),8.37-8.25(m,2H),5.35(d,J=5.0Hz,1H),4.60(dd,J=5.7,11.3Hz,1H),4.56(d,J=5.5Hz,1H),3.74(d,J=5.5Hz,1H),2.47(t,J=7.4Hz,2H),2.41(t,J=6.9Hz,2H),2.33-2.23(m,2H),1.98(dt,J=7.2,14.2Hz,4H),1.82(d,J=13.0Hz,3H),1.68-1.62(m,1H),1.56(d,J=8.5Hz,2H),1.51-1.44(m,3H),1.38-1.29(m,3H),1.28-1.09(m,10H),1.01(s,4H),0.91(d,J=6.5Hz,4H),0.82(dd,J=7.0,9.0Hz,10H),0.67(s,3H).13C NMR(101MHz,Chloroform-d)δ172.65,165.08,147.04,142.28,139.66,130.49,122.90,119.85(q,JC-F=321.2Hz),89.91,74.48,56.79,56.13,50.11,45.91,42.41,39.81,38.21,37.04,36.70,36.27,35.56,34.02,33.36,32.01,31.94,30.75,29.21,28.36,27.85,26.13,24.40,23.15,21.59,21.12,19.95,19.40,19.13,18.89,12.09,11.97.19F NMR(376MHz,Chloroform-d)δ-78.78.IR(cm-1):3118,3072,2937,1728,1668,1481,1350,1136,1056,854,788,740,615,570,513;HRMS(ESI+)m/z calcd.For C42H62F6N2O7S2[M+]:604.4724;found:604.4728.
(25)1-((6-oxo-6-(((4S,5′R,6aS,8aS,8bR,9S,10R,11aS,12aS,12bR)-5′,6a,8a,9-tetramethyl-2a,3,3′,4,4′,5,5′,6,6a,6b,6′,7,8,8a,8b,9,11a,12,12a,12b-icosahydrospiro[naphtho[2′,1′:4,5]indeno[2,1-b]furan-10,2′-pyran]-4-yl)oxy)hex-1-en-2-yl)oxy)pyridin-1-ium bis((trifluoromethyl)sulfonyl)amide
柱层析纯化后的黄色粘稠液体(CH2Cl2/MeOH=100/1);1451.4mg,82%产率.1HNMR(400MHz,Chloroform-d)δ8.95(d,J=6.2Hz,2H),8.69(t,J=7.7Hz,1H),8.30(t,J=7.1Hz,2H),5.35(d,J=4.8Hz,1H),4.61(dd,J=4.6,11.3Hz,1H),4.56(d,J=5.5Hz,1H),4.40(q,J=7.4Hz,1H),3.74(d,J=5.5Hz,1H),3.46(dd,J=4.2,9.6Hz,1H),3.36(t,J=10.9Hz,1H),2.47(t,J=7.4Hz,2H),2.41(t,J=6.9Hz,2H),2.30(d,J=7.5Hz,2H),2.00-1.95(m,3H),1.91-1.82(m,3H),1.81-1.69(m,4H),1.62(q,J=11.1Hz,7H),1.51-1.37(m,3H),1.26(dd,J=6.4,12.0Hz,1H),1.11(dt,J=11.0,18.9Hz,3H),1.03(s,3H),0.96(d,J=6.9Hz,4H),0.78(t,J=3.1Hz,6H).13C NMR(101MHz,CHLOROFORM-D)δ172.62,165.07,147.04,142.27,139.70,130.49,122.60,119.85(q,JC-F=321.2Hz),109.42,89.93,80.91,74.39,66.96,62.16,56.53,50.02,41.70,40.36,39.81,38.18,37.00,36.84,33.34,32.14,31.94,31.48,30.75,30.40,28.90,27.82,21.58,20.90,19.42,17.26,16.40,14.65.19F NMR(376MHz,Chloroform-d)δ-78.79.IR(em-1):3118,2943,2902,1730,1481,1450,1352,1193,1136,1056,738,617,570,513;HRMS(ESI+)m/z calcd.ForC40H54F6N2O9S2[M+]:604.3994;found:604.3993.
2、α-卤代酮的合成及其表征
本发明提供的α-卤代酮合成方法的合成路线如下:
其中,TBAC为四丁基氯化铵,TBAB为四丁基溴化铵,TBAI为四丁基碘化铵;R包括H、卤素、取代或未取代的烷基、取代或未取代的芳基、取代或未取代的杂环基、取代或未取代的烯基、炔基、酯基、氨基或氰基。
合成步骤:将对应的烯氧基吡啶鎓盐溶于有机溶剂(0.5ml THF/HFIP)中,搅拌均匀后加入TBAC/TBAB/TBAI(1.1equiv),室温搅拌,反应5~15min,TLC监测反应进展(石油醚/乙酸乙酯=5/1)。反应结束后,采用硅胶柱层析对反应体系进行纯化。
(1)α-卤代酮1a、1b、1c的合成:
实施例1
化合物1a的合成:将上式中的烯氧基吡啶鎓盐0.2mol溶于1.0ml THF中,搅拌均匀后加入0.24mol的TBAC,于室温下进行反应,TLC监测反应进展(石油醚/乙酸乙酯=5/1),反应时间为15min。反应结束后,采用硅胶柱层析对反应体系进行纯化,得到化合物1a的表征如下:
化合物1a:1-(benzyloxy)-3-chloropropan-2-one
液体,产率86%(通过1H NMR与内标比较测定产率).1H NMR(400MHz,Chloroform-d)δ7.37(qd,J=5.2,8.1Hz,5H),4.61(s,2H),4.32(s,2H),4.25(s,2H).13CNMR(101MHz,Chloroform-d)δ200.47,136.70,128.80,128.46,128.13,73.81,73.75,46.97.
实施例2
化合物1b的合成:将上式中对应的烯氧基吡啶鎓盐0.2mol溶于1.0ml HFIP中,搅拌均匀后加入0.24mol的TBAB,于室温下进行反应,TLC监测反应进展(石油醚/乙酸乙酯=5/1),反应时间为5min。反应结束后,采用硅胶柱层析对反应体系进行纯化,得到化合物1b的表征如下:
化合物1b:1-(benzyloxy)-3-bromopropan-2-one
液体,产率93%(通过1H NMR与内标比较测定产率).1H NMR(400MHz,Chloroform-d)δ7.41-7.31(m,5H),4.62(s,2H),4.28(s,2H),4.06(s,2H).13C NMR(101MHz,Chloroform-d)δ200.24,136.78,128.76,128.40,128.13,73.77,73.19,31.89.
实施例3
化合物1c的合成:将上式对应的烯氧基吡啶鎓盐0.2mol溶于1.0ml HFIP中,搅拌均匀后加入0.24mol的TBAI,于室温下进行反应,TLC监测反应进展(石油醚/乙酸乙酯=5/1),反应时间为5min。反应结束后,采用硅胶柱层析对反应体系进行纯化,得到化合物1c的表征如下:
化合物1c:1-(benzyloxy)-3-iodopropan-2-one
液体,产率85%(通过1H NMR与内标比较测定产率).1H NMR(400MHz,Chloroform-d)δ7.47-7.29(m,5H),4.62(s,2H),4.30(s,2H),3.93(s,2H).13C NMR(101MHz,Chloroform-d)δ201.87,136.92,128.73,128.35,128.13,73.75,72.08,1.80.IR(cm-1):1722,1494,1454,1247,1205,1120,1026,740,698;HRMS(ESI+)m/z calcd.ForC10H11NaIO2[M+Na]+:312.9696;found:312.9694.
实施例4
实施例4与实施例1的区别仅在于,将实施例1中的THF替换为CH3OH,其他与实施例1相同的实施,得到α-卤代酮的产率为84%。
实施例5
实施例4与实施例1的区别仅在于,将实施例1中的THF替换为HFIP,其他与实施例1相同的实施,得到α-卤代酮的产率为20%。
实施例6
实施例6与实施例1的区别仅在于,将实施例1中的THF替换为DCM,其他与实施例1相同的实施,得到α-卤代酮的产率为83%。
对比实施例1和实施例4~6可知,在采用TBAC合成α-卤代酮的反应体系中,THF、CH3OH和DCM为较为优选的有机试剂,采用上述有机试剂进行α-氯代酮合成能够得到较高的产率。
实施例7
实施例7与实施例2的区别仅在于,将实施例2中HFIP替换为THF,其他与实施例2相同的实施,得到α-卤代酮的产率为46%。
对比实施例2和实施例7可知,在采用TBAB合成α-卤代酮的反应体系中,HFIP为较为优选的有机试剂,采用HFIP作为有机试剂进行α-溴代酮合成能够得到较高的产率。
实施例8
实施例8与实施例3的区别仅在于,将实施例3中HFIP替换为THF,其他与实施例3相同的实施,得到α-卤代酮的产率为25%。
对比实施例3和实施例8可知,在采用TBAI合成α-卤代酮的反应体系中,HFIP为较为优选的有机试剂,采用HFIP作为有机试剂进行α-碘代酮合成能够得到较高的产率。
对比例1
对比例1与实施例1的区别仅在于,将实施例1中的CTAB替换为1-丁基-2,3-二甲基咪唑氯盐(CAS:98892-75-2),其他与实施例1相同实施,得到α-卤代酮的产率为60%。
对比例2
对比例2与实施例1的区别仅在于,将实施例1中的CTAB替换为1-丁基-4-甲基氯化吡啶鎓(112400-86-9),其他与实施例1相同实施,得到α-卤代酮的产率为66%。
对比例3
对比例3与实施例1的区别仅在于,将实施例1中的CTAB替换为四甲基氯化铵,其他与实施例1相同实施,得到α-卤代酮的产率为31%。
对比实施例1和对比例1~3可知,相比于其他卤化剂,本发明采用四丁基卤化铵作为卤化剂能够得到较高的产率。
为证明本发明提供的合成方法具有普适性,另外提供下述(2)~(26)组α-卤代酮的合成及相应表征如下:
(2)
合成步骤:将对应的烯氧基吡啶鎓盐溶于有机溶剂(0.5ml THF/HFIP)中,搅拌均匀后加入TBAC/TBAB/TBAI(1.1equiv),室温搅拌,TLC监测反应进展(石油醚/乙酸乙酯=5/1)。反应结束后,采用硅胶柱层析对反应体系进行纯化,得到化合物2a、2b、2c的表征如下。
化合物2a:1-chloro-4-phenylbutan-2-one
柱层析纯化后的白色固体(石油醚/乙酸乙酯=30/1);32,1mg产率88%.1H NMR(400MHz,Chloroform-d)δ7.30(t,J=7.3Hz,2H),7.24-7.17(m,3H),4.04(s,2H),2.94(t,J=4.1Hz,4H).13C NMR(101MHz,Chloroform-d)δ202.02,140.43,128.76,128.46,126.52,48.44,41.47,29.72.
化合物2b:1-bromo-4-phenylbutan-2-one
柱层析纯化后的白色固体(石油醚/乙酸乙酯=1/1);38.2mg产率84%.1H NMR(400MHz,Chloroform-d)δ7.30(t,J=7.3Hz,2H),7.21(t,J=8.9Hz,3H),3.85(s,2H),2.97(dq,J=11.4,6.1Hz,4H).13C NMR(101MHz,Chloroform-d)δ201.41,140.45,128.75,128.46,126.51,41.57,34.47,30.02.
化合物2c:1-iodo-4-phenylbutan-2-one
柱层析纯化后的白色固体(CH2Cl2);47.7mg产率87%.1H NMR(400MHz,Chloroform-d)δ7.29(t,J=7.2Hz,2H),7.24-7.17(m,3H),3.77(s,2H),3.07-3.01(m,2H),2.98-2.91(m,2H).13C NMR(101MHz,Chloroform-d)δ202.38,140.53,128.73,128.47,126.47,41.02,30.39,6.30.
(3)
合成步骤:将对应的烯氧基吡啶鎓盐溶于有机溶剂(0.5ml THF/HFIP)中,搅拌均匀后加入TBAC/TBAB/TBAI(1.1equiv),室温搅拌,TLC监测反应进展(石油醚/乙酸乙酯=5/1)。反应结束后,采用硅胶柱层析对反应体系进行纯化,得到化合物3a、3b、3c的表征如下。
化合物3a:methyl 6-chloro-5-oxohexanoate
柱层析纯化后的液体(石油醚/乙酸乙酯=30/1);30.4mg产率85%.1H NMR(400MHz,Chloroform-d)δ4.07(s,2H),3.67(s,3H),2.69(t,J=7.1Hz,2H),2.37(t,J=7.1Hz,2H),1.95(p,J=7.1Hz,2H).13C NMR(101MHz,Chloroform-d)δ202.15,173.53,51.78,48.21,38.64,32.87,18.80.
化合物3b:methyl 6-bromo-5-oxohexanoate
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);36.6mg产率82%.1H NMR(400MHz,Chloroform-d)δ3.88(s,2H),3.67(s,3H),2.75(t,J=7.1Hz,2H),2.41-2.33(m,2H),1.94(p,J=7.2Hz,2H).13C NMR(101MHz,Chloroform-d)δ201.56,173.57,51.81,38.74,34.24,32.82,19.02.
化合物3c:methyl 6-iodo-5-oxohexanoate
柱层析纯化后的液体(CH2Cl2);46.5mg产率86%.1H NMR(400MHz,Chloroform-d)δ3.80(s,2H),3.67(s,3H),2.80(t,J=7.1Hz,2H),2.36(t,J=7.2Hz,2H),1.94(p,J=7.2Hz,2H).13C NMR(101MHz,Chloroform-d)δ202.52,173.56,51.78,38.14,32.80,19.29,6.08.
(4)
合成步骤:将对应的烯氧基吡啶鎓盐溶于有机溶剂(0.5ml THF/HFIP)中,搅拌均匀后加入TBAC/TBAB/TBAI(1.1equiv),室温搅拌,TLC监测反应进展(石油醚/乙酸乙酯=5/1)。反应结束后,采用硅胶柱层析对反应体系进行纯化,得到化合物4a、4b、4c的表征如下。
化合物4a:2-chloro-1-phenylethan-1-one
柱层析纯化后的白色固体(石油醚/乙酸乙酯=30/1);25.4mg产率82%.1H NMR(400MHz,Chloroform-d)δ8.05-7.89(m,2H),7.63(t,J=7.2Hz,1H),7.50(t,J=7.9Hz,2H),4.73(s,2H).13C NMR(101MHz,Chloroform-d)δ191.23,134.37,134.18,129.06,128.67.46.19.
化合物4b:2-bromo-1-phenylethan-1-one
柱层析纯化后的白色固体(石油醚/乙酸乙酯=1/1);33.0mg产率83%.1H NMR(400MHz,Chloroform-d)δ8.06-7.93(m,2H),7.66-7.57(m,1H),7.50(t,J=7.6Hz,2H),4.46(s,2H).13C NMR(101MHz,Chloroform-d)δ191.45,134.13,129.09,129.03,31.07.化合物4c:2-iodo-1-phenylethan-1-one
柱层析纯化后的白色固体(CH2Cl2);41.8mg产率85%.1H NMR(400MHz,Chloroform-d)δ8.06-7.94(m,2H),7.60(t,J=7.4Hz,1H),7.49(t,J=7.7Hz,2H),4.37(s,2H).13C NMR(10lMHz,Chloroform-d)δ192.98,133.97,133.59,129.18,128.98,29.83,1.80.
(5)
合成步骤:将对应的烯氧基吡啶鎓盐溶于有机溶剂(0.5ml THF/HFIP)中,搅拌均匀后加入TBAC/TBAB/TBAI(1.1equiv),室温搅拌,TLC监测反应进展(石油醚/乙酸乙酯=5/1)。反应结束后,采用硅胶柱层析对反应体系进行纯化,得到化合物5a、5b、5c的表征如下。
化合物5a:1-chloroheptan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=30/1);24.7mg产率83%.1H NMR(400MHz,Chloroform-d)δ4.08(s,2H),2.58(t,J=7.4Hz,2H),1.63(p,J=7.5Hz,2H),1.31(td,J=8.9,7.7,5.4Hz,4H),0.90(t,J=6.9Hz,3H).13C NMR(101MHz,Chloroform-d)δ202.99,48.36,39.83,31.35,23.43,22.51,14.01.
化合物5b:1-bromoheptan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);31.7mg产率82%.1H NMR(400MHz,Chloroform-d)δ3.89(s,2H),2.64(t,J=7.4Hz,2H),1.62(p,J=7.4Hz,2H),1.30(td,J=8.7,7.7,5.6Hz,4H),0.89(t,J=7.0Hz,3H).13C NMR(101MHz,Chloroform-d)δ39.97,34.49,31.32,23.68,22.52,14.04.
化合物5c:1-iodoheptan-2-one
柱层析纯化后的液体(CH2Cl2);39.9mg产率83%.1H NMR(400MHz,Chloroform-d)δ3.80(s,2H),2.71(t,J=7.4Hz,2H),1.62(p,J=7.4Hz,2H),1.36-1.26(m,4H),0.89(t,J=7.0Hz,3H).13C NMR(101MHz,Chloroform-d)δ203.52,39.43,31.29,24.01,22.51,14.03,6.36.
(6)
合成步骤:将对应的烯氧基吡啶鎓盐溶于有机溶剂(0.5ml THF/HFIP)中,搅拌均匀后加入TBAC/TBAB/TBAI(1.1equiv),室温搅拌,TLC监测反应进展(石油醚/乙酸乙酯=5/1)。反应结束后,采用硅胶柱层析对反应体系进行纯化,得到化合物6a、6b、6c的表征如下。
化合物6a:2-(5-chloro-4-oxopentyl)isoindoline-1,3-dione
柱层析纯化后的白色固体(石油醚/乙酸乙酯=30/1);46.8mg产率88%.1H NMR(400MHz,Chloroform-d)δ7.84(dd,J=5.5,3.0Hz,2H),7.73(dd,J=5.5,3.0Hz,2H),4.11(s,2H),3.77-3.68(m,2H),2.66(t,J=7.0Hz,2H),2.02(p,J=6.9Hz,2H).13C NMR(101MHz,Chloroform-d)δ201.79,168.68,134.23,132.08,123.47,48.38,36.98,36.79,22.69.
化合物6b:2-(5-bromo-4-oxopentyl)isoindoline-1,3-dione
柱层析纯化后的白色固体(石油醚/乙酸乙酯=1/1);52,1mg产率84%.1H NMR(400MHz,Chloroform-d)δ7.84(dd,J=5.5,3.0Hz,2H),7.72(dd,J=5.5,3.1Hz,2H),3.91(s,2H),3.71(t,J=6.6Hz,2H),2.71(t,J=7.0Hz,2H),2.01(p,J=6.9Hz,2H).13C NMR(101MHz,Chloroform-d)δ201.14,168.63,134.20,132.09,123.44,37.00,36.92,34.45,22.98.
化合物6c:2-(5-iodo-4-oxopentyl)isoindoline-1,3-dione
柱层析纯化后的白色固体(CH2Cl2);63.6mg产率89%.1H NMR(400MHz,Chloroform-d)δ7.84(dd,J=5.4,3.1Hz,2H),7.72(dd,J=5.4,3.1Hz,2H),3.83(s,2H),3.71(t,J=6.7Hz,2H),2.79(t,J=7.1Hz,2H),2.00(p,J=6.9Hz,2H).13C NMR(101MHz,Chloroform-d)δ202.16,168.61,134.19,132.09,123.44,37.08,36.36,23.30,6.25.(7)(7)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物7a:1-chloro-3-((4-fluorobenzyl)oxy)propan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=30/1);38.6mg产率89%.1H NMR(400MHz,Chloroform-d)δ7.32(dd,J=8.5,5.4Hz,2H),7.06(t,J=8.7Hz,2H),4.57(s,2H),4.28(s,2H),4.26(s,2H).13C NMR(101MHz,Chloroform-d)δ200.22,162.82(d,J=184.10Hz),132.61(d,J=2.35Hz),129.94(d,J=6.12Hz),115.71(d,J=16.05Hz),73.64,73.12,46.65.19F NMR(376MHz,Chloroform-d)δ-113.55.IR(cm-1):2935,2873,1743,1602,1510,1417,1222,1097,825,418;HRMS(ESI+)m/z calcd.For C10H10NaClFO2[M+Na]+:239.0246;found:239.0238.
化合物7b:1-bromo-3-((4-fluorobenzyl)oxy)propan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);45.4mg产率87%.1H NMR(400MHz,Chloroform-d)δ7.34(dd,J=5.6,8.0Hz,2H),7.06(t,J=8.5Hz,2H),4.57(s,2H),4.28(s,2H),4.03(s,2H).13C NMR(101MHz,Chloroform-d)δ200.01,161.60,129.96(d,J=6.06Hz),115.70(d,J=16.10Hz),73.11,31.43.19F NMR(376MHz,Chloroform-d)δ-113.62.IR(cm-1):2926,1732,1604,1510,1386,1224,1157,1093,825,418;HRMS(ESI+)m/zcalcd.For C10H10NaBrFO2[M+Na]+:282.974;found:282.9735.
化合物7c:1-((4-fluorobenzyl)oxy)-3-iodopropan-2-one
柱层析纯化后的液体(CH2Cl2);44.4mg产率72%.1H NMR(400MHz,Chloroform-d)δ7.41-7.30(m,1H),7.06(t,J=8.2Hz,1H),4.58(s,1H),4.31(s,1H),3.92(s,1H).13C NMR(101MHz,Chloroform-d)δ201.64,162.77(d,J=184.07Hz),132.74(d,J=2.24Hz),129.96(d,J=6.16Hz),115.64(d,J=16.04Hz),73.00,71.97,1.58.19F NMR(376MHz,Chloroform-d)δ-113.72.IR(cm-1):2922,2860,1716,1506,1456,1249,1114,1020,806,418;HRMS(ESI+)m/z calcd.For C10H10NaIFO2[M+Na]+:330.9602;found:330.9592.
(8)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物8a:1-chloro-3-((4-chlorobenzyl)oxy)propan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=30/1);40.6mg产率87%.1H NMR(400MHz,Chloroform-d)δ7.35(d,J=8.4Hz,2H),7.28(d,J=8.4Hz,2H),4.57(s,2H),4.28(s,2H),4.27(s,2H).13C NMR(101MHz,Chloroform-d)δ200.14,135.29,134.25,129.38,128.96,73.72,73.01,46.66.IR(cm-1):2935,2868,1745,1598,1490,1394,1089,1014,808;HRMS(ESI+)m/z calcd.For C10H10NaCl2O2[M+Na]+:254.995;found:254.9945.
化合物8b:1-bromo-3-((4-chlorobenzyl)oxy)propan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);47.7mg产率86%.1H NMR(400MHz,Chloroform-d)δ7.35(d,J=8.3Hz,2H),7.30(d,J=8.4Hz,2H),4.58(s,2H),4.29(s,2H),4.03(s,2H).13C NMR(101MHz,Chloroform-d)δ199.91,135.40,134.24,129.40,128.96,73.20,73.02,31.39.IR(cm-1):2924,1732,1490,1352,1195,1058,802,617;HRMS(ESI+)m/z calcd.For C10H10NaClBrO2[M+Na]+:298.9445;found:298.9441.
化合物8c:1-((4-chlorobenzyl)oxy)-3-iodopropan-2-one
柱层析纯化后的液体(CH2Cl2);53.2mg产率82%.1H NMR(400MHz,Chloroform-d)δ7.35(d,J=8.4Hz,2H),7.31(d,J=8.0Hz,2H),4.58(s,2H),4.31(s,2H),3.92(s,2H).13CNMR(101MHz,Chloroform-d)δ201.53,135.46,134.15,129.41,128.92,72.92,72.06,1.52.IR(cm-1):2924,2866,1722,1598,1490,1408,1249,1089,1014,810;HRMS(ESI+)m/zcalcd.For C10H10NaClIO2[M+Na]+:346.9306;found:346.9302.
(9)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物9a:1-((4-bromobenzyl)oxy)-3-chloropropan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=30/1);48.3mg产率87%.1H NMR(400MHz,Chloroform-d)δ7.50(d,J=8.3Hz,2H),7.23(d,J=8.3Hz,2H),4.56(s,2H),4.28(s,2H),4.27(s,2H).13C NMR(101MHz,Chloroform-d)δ200.12,135.81,131.93,129.67,122.39,73.74,73.05,46.64.IR(cm-1):2916,2868,1734,1487,1101,1070,1012,802;HRMS(ESI+)m/z calcd.For C10H10NaClBrO2[M+Na]+:298.9445;found:298.9439.
化合物9b:1-bromo-3-((4-bromobenzyl)oxy)propan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);56.0mg产率87%.1H NMR(400MHz,Chloroform-d)δ7.50(d,J=7.7Hz,2H),7.24(d,J=7.7Hz,2H),4.56(s,2H),4.29(s,2H),4.03(s,2H).13C NMR(101MHz,Chloroform-d)δ199.87,135.89,131.88,129.67,122.31,73.19,72.99,31.45.IR(cm-1):2939,1732,159l,1487,1384,1182,1093,1070,1010,802,478;HRMS(ESI+)m/z calcd.For C10H10NaBr2O2[M+Na]+:342.894;found:342.8937.
化合物9c:1-((4-bromobenzyl)oxy)-3-iodopropan-2-one
柱层析纯化后的液体(CH2Cl2);59.0mg产率80%.1H NMR(400MHz,Chloroform-d)δ7.50(d,J=7.5Hz,2H),7.25(d,J=6.8Hz,3H),4.56(s,2H),4.31(s,2H),3.91(s,2H).13CNMR(101MHz,Chloroform-d)δ201.50,135.98,131.87,129.70,122.28,72.94,72.08,1.51.IR(cm-1):2866,,1722,1593,1487,1247,1122,1010,804,518;HRMS(ESI+)m/zcalcd.For C10H10NaBrIO2[M+Na]+:390.8801;found:390.8797.
(10)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物10a:1-iodo-3-((4-methylbenzyl)oxy)propan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=30/1);35.3mg产率83%.1H NMR(400MHz,Chloroform-d)δ7.23(d,J=8.0Hz,2H),7.18(d,J=7.9Hz,2H),4.56(s,2H),4.30(s,2H),4.22(s,2H),2.36(s,3H).13C NMR(101MHz,Chloroform-d)δ200.52,138.29,133.66,129.45,128.27,73.70,73.60,46.93,21.32.IR(cm-1):2926,1743,1456,1352,1197,1101,806,482;HRMS(ESI+)m/z calcd.For C11H13NaClO2[M+Na]+:235.0496;found:235.0492.
化合物10b:1-bromo-3-((4-methylbenzyl)oxy)propan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);43.7mg产率85%.1H NMR(400MHz,Chloroform-d)δ7.24(d,J=7.9Hz,2H),7.18(d,J=7.7Hz,2H),4.57(s,2H),4.25(s,2H),4.05(s,2H),2.36(s,3H).13C NMR(101MHz,Chloroform-d)δ200.36,138.27,133.74,129.45,128.31,73.70,73.08,31.91,21.34.IR(cm-1):2922,1732,1516,1386,1093,804;HRMS(ESI+)m/z calcd.For C11H13NaBrO2[M+Na]+:278.999l;found:278.9988.
化合物10c:1-iodo-3-((4-methylbenzyl)oxy)propan-2-one
柱层析纯化后的液体(CH2Cl2);48.7mg产率80%.1H NMR(400MHz,Chloroform-d)δ7.26-7.21(m,2H),7.17(d,J=7.5Hz,2H),4.56(s,2H),4.26(s,2H),3.92(s,2H),2.35(s,3H).13C NMR(101MHz,Chloroform-d)δ202.04,138.19,133.84,129.41,128.30,73.63,71.94,21.35,1.91.IR(cm-1):2920,2860,1716,1506,1456,1249,1114,1020,806,418;HRMS(ESI+)m/z calcd.For C11H13NaIO2[M+Na]+:326.9852;found:326.9852.(11)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物11a:1-chloro-3-((3-chlorobenzyl)oxy)propan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=30/1);42.4mg产率91%.1H NMR(400MHz,Chloroform-d)δ7.35(s,1H),7.32-7.28(m,2H),7.25-7.20(m,1H),4.58(s,2H),4.30(s,2H),4.28(s,2H).13C NMR(101MHz,Chloroform-d)δ200.06,138.86,134.71,130.07,128.53,127.99,125.96,73.83,72.98,46.68.IR(cm-1):2935,2870,1745,1575,1429,1394,1207,1105,781,682;HRMS(ESI+)m/z calcd.For C10H10NaCl2O2[M+Na]+:254.995;found:254.9945.
化合物11b:1-bromo-3-((3-chlorobenzyl)oxy)propan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);48.3mg产率87%.1H NMR(400MHz,Chloroform-d)δ7.36(s,1H),7.30(s,2H),7.24(s,1H),4.59(s,2H),4.30(s,2H),4.05(s,2H).13C NMR(101MHz,Chloroform-d)δ199.84,138.93,134.68,130.05,128.50,128.01,125.98,73.27,72.94,31.51.IR(cm-1):2916,1728,1433,1095,1032,781,682;HRMS(ESI+)m/z calcd.For C10H10NaClBrO2[M+Na]+:298.9445;found:298.9441.
化合物11c:1-((3-chlorobenzyl)oxy)-3-iodopropan-2-one
柱层析纯化后的液体(CH2Cl2);53.2mg产率82%.1H NMR(400MHz,Chloroform-d)δ7.38(s,1H),7.30(d,J=5.4Hz,2H),7.25(s,1H),4.59(s,2H),4.32(s,2H),3.93(s,2H).13C NMR(101MHz,Chloroform-d)δ201.43,139.04,134.66,130.02,128.45,128.04,125.99,72.88,72.14,1.52.IR(cm-1):2926,2870,1722,1429,1205,1122,783,682;HRMS(ESI+)m/z calcd.For C10H10NaCUO2[M+Na]+:346.9306;found:346.9304.
(12)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物12a:1-((3-bromobenzyl)oxy)-3-chloropropan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=30/1);48.8mg产率88%.1H NMR(400MHz,Chloroform-d)δ7.25(d,J=8.2Hz,1H),4.57(s,1H),4.29(s,1H),4.28(s,1H).13CNMR(101MHz,Chloroform-d)δ200.04,139.14,131.47,130.92,130.36,126.44,122.88,73.83,72.92,46.67.IR(cm-1):2935,2870,1747,1571,1474,1203,1105,779,671;HRMS(ESI+)m/z calcd.For C10H10NaClBrO2[M+Na]+:298.9445;found:298.9444.
化合物12b 1-bromo-3-((3-bromobenzyl)oxy)propan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);,54,1mg产率84%.1H NMR(400MHz,Chloroform-d)δ7.52(s,1H),7.46(d,J=7.6Hz,1H),7.31-7.21(m,3H),4.58(s,2H),4.30(s,2H),4.04(s,2H).13C NMR(101MHz,Chloroform-d)δ199.83,139.21,131.44,130.95,130.35,126.47,122.87,73.28,72.90,31.48.IR(cm-1):2868,1734,1570,1473,1201,1103,1068,779,669;HRMS(ESI+)m/z calcd.For C10H10NaBr2O2[M+Na]+:342.894;found:342.893.
化合物12c:1-((3-bromobenzyl)oxy)-3-iodopropan-2-one
柱层析纯化后的液体(CH2Cl2);59.0mg产率80%.1H NMR(400MHz,Chloroform-d)δ7.54(s,1H),7.46(d,J=7.8Hz,1H),7.33-7.22(m,3H),4.59(s,2H),4.32(s,2H),3.93(s,2H).13C NMR(101MHz,Chloroform-d)δ201.44,139.29,131.39,130.97,130.32,126.48,122.84,72.81,72.12,1.52.IR(cm-1):2926,2868,1716,1570,1473,1199,1068,779,669,418;HRMS(ESI+)m/z calcd.For C10H10NaBrIO2[M+Na]+:390.8801;found:390.8798.
(13)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物13a:1-chloro-3-((3-methylbenzyl)oxy)propan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=30/1);36.2mg产率85%.1H NMR(400MHz,Chloroform-d)δ7.26(t,J=7.5Hz,1H),7.20-7.09(m,3H),4.57(s,2H),4.31(s,2H),4.24(s,2H),2.37(s,3H).13C NMR(101MHz,Chloroform-d)δ200.50,138.52,136.63,129.19,128.90,128.68,125.23,73.88,73.74,46.93,21.51.IR(cm-1):2922,2866,1732,1610,1489,1161,1103,777,698;HRMS(ESI+)m/z calcd.For C11H13NaClO2[M+Na]+:235.0496;found:235.0498.
化合物13b:1-bromo-3-((3-methylbenzyl)oxy)propan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);41.7mg产率81%.1H NMR(400MHz,Chloroform-d)δ7.31-7.22(m,2H),7.21-7.07(m,3H),4.58(s,2H),4.27(s,2H),4.06(s,2H),2.37(s,3H).13C NMR(101MHz,Chloroform-d)δ200.32,138.51,136.70,129.17,128.93,128.68,125.25,73.86,73.20,31.91,21.53.IR(cm-1):2924,2868,1734,1506,1456,1259,1188,1093,788,696;HRMS(ESI+)m/z calcd.For C11H13NaBrO2[M+Na]+:278.9991;found:278.9982.
化合物13c:1-iodo-3-((3-methylbenzyl)oxy)propan-2-one
柱层析纯化后的液体(CH2Cl2);48.0mg产率79%.1H NMR(400MHz,Chloroform-d)δ7.25(d,J=6.5Hz,1H),7.16(dd,J=7.1,16.1Hz,3H),4.58(s,2H),4.29(s,2H),3.93(s,2H),2.37(s,3H).13C NMR(101MHz,Chloroform-d)δ201.94,138.45,136.81,129.10,128.92,128.64,125.24,73.80,72.04,21.53,1.86.IR(cm-1):2918,2862,1714,1456,1251,1159,1118,1022,785,698;HRMS(ESI+)m/z calcd.For C11H13NaIO2[M+Na]+:326.9852;found:326.9850.
(14)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物14a:1-chloro-3-((2-chlorobenzyl)oxy)propan-2-one
柱层析纯化后的白色固体(石油醚/乙酸乙酯=30/1);43.8mg产率94%.m.p54.7-57.8℃.1H NMR(400MHz,Chloroform-d)δ7.50-7.42(m,1H),7.39(dd,J=2.1,7.1Hz,1H),7.33-7.27(m,2H),4.71(s,2H),4.35(s,2H),4.34(s,2H).13C NMR(101MHz,Chloroform-d)δ200.26,134.58,133.46,129.72,129.61,129.58,127.16,74.35,70.95,46.93.IR(cm-1):2939,2833,1745,1473,1442,1201,1111,1051,754;HRMS(ESI+)m/zcalcd.For C10H10NaCl2O2[M+Na]+:254.995;found:254.9945.
化合物14b:1-bromo-3-((2-chlorobenzyl)oxy)propan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);49.4mg产率89%.1H NMR(400MHz,Chloroform-d)δ7.48(dd,J=2.2,7.1Hz,1H),7.38(dd,J=2.0,7.3Hz,1H),7.33-7.26(m,2H),4.72(s,2H),4.36(s,2H),4.10(s,2H).13C NMR(101MHz,Chloroform-d)δ200.04,134.66,133.39,129.67,129.58,129.51,127.15,73.80,70.89,31.86.IR(cm-1):2926,2873,1737,1475,1442,1207,1105,1053,754;HRMS(ESI+)m/z calcd.ForC10H10NaClBrO2[M+Na]+:298.9445;found:298.9443.
化合物14c:1-((2-chlorobenzyl)oxy)-3-iodopropan-2-one
柱层析纯化后的液体(CH2Cl2);54.5mg产率84%.1H NMR(400MHz,Chloroform-d)δ7.51(d,J=7.2Hz,1H),7.38(d,J=7.4Hz,1H),7.29(d,J=6.8Hz,2H),4.72(s,2H),4.39(s,2H),3.97(s,2H).13C NMR(101MHz,Chloroform-d)δ201.68,134.77,133.31,129.63,129.53,129.43,127.13,72.65,70.82,1.76.IR(cm-1):2872,1714,1573,1475,1442,1249,1053,754,682,518;HRMS(ESI+)m/z calcd.For C10H10NaClIO2[M+Na]+:346.9306;found:346.9305.
(15)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物1 5a:1-((2-bromobenzyl)oxy)-3-chloropropan-2-one
柱层析纯化后的白色固体(CH2Cl2);49.4mg产率89%.m.p 55.2-58.7℃.1HNMR(400MHz,Chloroform-d)δ7.57(d,J=6.9Hz,1H),7.45(d,J=7.8Hz,1H),7.35(t,J=7.5Hz,1H),7.23-7.17(m,1H),4.68(s,2H),4.36(s,2H),4.35(s,2H).13C NMR(101MHz,Chloroform-d)δ200.26,136.19,132.98,129.81,129.66,127.77,123.28,74.36,73.16,47.03.IR(cm-1):1743,1471,1332,1209,1024,837,613,559;HRMS(ESI+)m/z calcd.ForFor C10H10NaClBrO2[M+Na]+:298.9445;found:298.9445.
化合物15b:1-bromo-3-((2-bromobenzyl)oxy)propan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);55.4mg产率86%.1H NMR(400MHz,Chloroform-d)δ7.57(d,J=8.0Hz,1H),7.51(d,J=7.6Hz,1H),7.35(t,J=7.5Hz,1H),7.19(t,J=7.6Hz,1H),4.69(s,2H),4.39(s,2H),3.98(s,2H).13C NMR(101MHz,Chloroform-d)δ201.64,136.40,132.88,129.66,129.57,127.73,123.11,73.06,72.66,1.82.IR(cm-1):1732,1653,1558,1506,1456,1101,1026,750;HRMS(ESI+)m/zcalcd.For C10H10NaBr2O2[M+Na]+:342.894;found:342.8937.
化合物1 5c:1-((2-bromobenzyl)oxy)-3-iodopropan-2-one
柱层析纯化后的液体(CH2Cl2);60.5mg产率82%.1H NMR(400MHz,Chloroform-d)δ7.57(d,J=8.0Hz,1H),7.51(d,J=7.6Hz,1H),7.35(t,J=7.5Hz,1H),7.19(t,J=7.6Hz,1H),4.69(s,2H),4.39(s,2H),3.98(s,2H).13C NMR(101MHz,Chloroform-d)δ201.64,136.40,132.88,129.66,129.57,127.73,123.11,73.06,72.66,1.82.IR(cm-1):2922,1726,1440,134,1197,1128,1026,752;HRMS(ESI+)m/z calcd.For C10H10NaBrIO2[M+Na]+:390.8801;found:390.8796.
(16)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物1 6a:1-chloro-3-((2-methylbenzyl)oxy)propan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=30/1);37.0mg产率87%.1H NMR(400MHz,Chloroform-d)δ7.29(d,J=6.9Hz,1H),7.22(p,J=6.6Hz,3H),4.61(s,2H),4.31(s,2H),4.26(s,2H),2.37(s,3H).13C NMR(101MHz,Chloroform-d)δ200.49,137.11,134.67,130.68,129.10,128.66,126.11,73.86,72.26,46.91,18.98.IR(cm-1):2941,1745,1462,1242,1103,1076,1045,744;HRMS(ESI+)m/z calcd.For C11H13NaClO2[M+Na]+:235.0496;found:235.0492.
化合物16b:1-bromo-3-((2-methylbenzyl)oxy)propan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);43.2mg产率84%.1H NMR(400MHz,Chloroform-d)δ7.30(d,J=6.8Hz,1H),7.26-7.17(m,3H),4.62(s,2H),4.28(s,2H),4.06(s,2H),2.37(s,3H).13C NMR(101MHz,Chloroform-d)δ200.30,137.13,134.74,130.65,129.11,128.62,126.08,73.29,72.21,31.87,19.00.IR(cm-1):1732,1506,1456,1093,1029,744;HRMS(ESI+)m/z calcd.For C11H13NaBrO2[M+Na]+:278.9991;found:278.9991.
化合物16c:1-iodo-3-((2-methylbenzyl)oxy)propan-2-one
柱层析纯化后的液体(CH2Cl2);49.9mg产率82%.1H NMR(400MHz,Chloroform-d)δ7.33(d,J=7.5Hz,1H),7.28-7.17(m,3H),4.62(s,2H),4.31(s,2H),3.93(s,2H),2.38(s,3H).13C NMR(101MHz,Chloroform-d)δ201.97,137.11,134.85,130.61,129.10,128.55,126.06,72.15,72.13,19.06,1.84.IR(cm-1):2916,2870,1714,1462,1249,1126,1103,744HRMS(ESI+)m/z calcd.For C11H13NaIO2[M+Na]+:326.9852;found:326.9845.
(17)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物17a:1,5-dichloropentan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=30/1);26.0mg产率84%.1H NMR(400MHz,Chloroform-d)δ4.10(s,2H),3.60(t,J=6.2Hz,2H),2.82(t,J=6.9Hz,2H),2.11(p,J=6.7Hz,2H).13C NMR(101MHz,Chloroform-d)δ201.91,48.26,44.18,36.58,26.24.化合物17b:1-bromo-5-chloropentan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);33.1mg产率83%.1H NMR(400MHz,Chloroform-d)δ3.91(s,2H),3.61-3.57(m,2H),2.88(t,J=6.9Hz,2H),2.14-2.06(m,2H).13C NMR(101MHz,Chloroform-d)δ201.28,44.17,36.68,34.20,26.51.
化合物17c:5-chloro-1-iodopentan-2-one
柱层析纯化后的液体(CH2Cl2);41.4mg产率84%.1H NMR(400MHz,Chloroform-d)δ3.83(s,2H),3.59(t,J=6.2Hz,2H),2.94(t,J=6.9Hz,2H),2.10(p,J=6.5Hz,2H).13CNMR(101MHz,Chloroform-d)δ202.30,44.17,36.06,26.79,5.93.
(18)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物18a:6-chloro-5-oxohexanenitrile
柱层析纯化后的液体(石油醚/乙酸乙酯=5/1);24.5mg产率84%.1H NMR(400MHz,Chloroform-d)δ4.10(s,2H),2.83(t,J=6.9Hz,2H),2.46(t,J=7.0Hz,2H),1.99(p,J=6.9Hz,2H).13C NMR(101MHz,Chloroform-d)δ201.47,119.11,48.10,37.60,19.28,16.49.
化合物18b:6-bromo-5-oxohexanenitrile
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);30.4mg产率80%.1H NMR(400MHz,Chloroform-d)δ3.90(s,2H),2.89(t,J=6.8Hz,2H),2.45(t,J=7.0Hz,2H),1.99(p,J=6.9Hz,2H).13C NMR(101MHz,Chloroform-d)δ200.73,119.12,37.67,33.87,19.57,16.45.
化合物18c 6-iodo-5-oxohexanenitrile
柱层析纯化后的液体(CH2Cl2);39.3mg产率83%.1H NMR(400MHz,Chloroform-d)δ3.83(s,2H),2.95(t,J=6.7Hz,2H),2.44(t,J=6.9Hz,2H),1.99(p,J=6.9Hz,2H).13CNMR(101MHz,Chloroform-d)δ201.67,119.17,37.01,19.81,16.41,5.53.IR(cm-1):2926,2249,1701,1375,1184,1078,1024;HRMS(ESI+)m/z calcd.ForC6H8NaINO[M+Na]+:259.9543;found:259.9537.
(19)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物19a:benzyl 6-chloro-5-oxohexanoate
柱层析纯化后的液体(石油醚/乙酸乙酯=30/1);44.8mg产率88%.1H NMR(400MHz,Chloroform-d)δ7.42-7.29(m,5H),5.12(s,2H),4.04(s,2H),2.67(t,J=7.1Hz,2H),2.42(t,J=7.1Hz,2H),1.96(p,J=7.1Hz,2H).13C NMR(101MHz,Chloroform-d)δ202.10,172.89,135.95,128.74,128.46,128.41,66.48,48.22,38.55,33.06,18.78.IR(cm-1):2941,1732,1496,1454,1384,1168,738,698;HRMS(ESI+)m/z calcd.ForC13H15NaClO3[M+Na]+:277.0602;found:277.0609.
化合物19b:benzyl 6-bromo-5-oxohexanoate
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);51.5mg产率86%.1H NMR(400MHz,Chloroform-d)δ7.35(q,J=7.2,6.3Hz,5H),5.12(s,2H),3.84(s,2H),2.73(t,J=7.1Hz,2H),2.42(t,J=7.1Hz,2H),1.96(p,J=7.3Hz,2H).13C NMR(101MHz,Chloroform-d)δ201.51,172.92,135.97,128.75,128.47,128.43,66.49,38.67,34.22,33.06,19.05.
化合物19c:benzyl 6-iodo-5-oxohexanoate
柱层析纯化后的液体(CH2Cl2);58.2mg产率84%.1H NMR(400MHz,Chloroform-d)δ7.35(d,J=4.4Hz,5H),5.12(s,2H),3.77(s,2H),2.79(t,J=7.0Hz,2H),2.41(t,J=7.1Hz,2H),1.96(p,J=7.0Hz,2H).13C NMR(101MHz,Chloroform-d)δ202.50,172.93,135.98,128.74,128.44,66.46,38.07,33.01,19.29,6.09.IR(cm-1):2945,1732,1558,1456,1311,1159,698,418;HRMS(ESI+)m/z calcd.For C13H15NaIO3[M+Na]+:368.9958;found:368.9694.
(20)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物20a:1-chloro-3-phenethoxypropan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=30/1);34.9mg产率82%.1H NMR(400MHz,Chloroform-d)δ7.31(t,J=7.3Hz,2H),7.24(t,J=6.9Hz,3H),4.21(s,2H),4.21(s,2H),3.74(t,J=6.8Hz,2H),2.94(t,J=6.8Hz,2H).13C NMR(101MHz,Chloroform-d)δ200.75,138.43,129.01,128.62,126.65,74.96,73.01,46.92,36.26.IR(cm-1):2937,2868,1743,1496,1454,1116,1083,750,700;HRMS(ESI+)m/z calcd.For C11H13NaClO2[M+Na]+:235.0496;found:235.0491.
化合物20b:1-bromo-3-phenethoxypropan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);37.0mg产率72%.1H NMR(400MHz,Chloroform-d)δ7.35-7.28(m,2H),7.26-7.19(m,3H),4.23(s,2H),3.97(s,2H),3.75(t,J=6.8Hz,2H),2.94(t,J=6.8Hz,2H).13C NMR(101MHz,Chloroform-d)δ200.58,138.46,129.02,128.60,126.62,74.37,72.99,36.27,31.88.IR(cm-1):2941,1728,1496,1454,1103,1029,750,700;HRMS(ESI+)m/z calcd.For C11H13NaBrO2[M+Na]+:278.9991;found:278.9983.
化合物20c:1-iodo-3-phenethoxypropan-2-one
柱层析纯化后的液体(CH2Cl2);40.1mg产率66%.1H NMR(400MHz,Chloroform-d)δ7.35-7.28(m,2H),7.24(d,J=7.6Hz,3H),4.26(s,2H),3.84(s,2H),3.75(d,J=13.7Hz,2H),2.95(t,J=6.8Hz,2H).13C NMR(101MHz,Chloroform-d)δ202.36,138.56,129.08,128.62,126.61,73.20,72.97,36.33,1.75.IR(cm-1):2922,2866,1726,1454,1124,750,700;HRMS(ESI+)m/z calcd.For C11H13NaIO2[M+Na]+:326.9852;found:326.9842.
(21)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物21a:l-chlorohexadecan-2-one
柱层析纯化后的液体(石油醚/乙酸乙酯=30/1);50.6mg产率92%.1H NMR(400MHz,Chloroform-d)δ4.07(s,2H),2.58(t,J=7.4Hz,2H),1.61(p,J=7.4Hz,2H),1.27(d,J=9.7Hz,22H),0.91-0.87(m,3H).13C NMR(101MHz,Chloroform-d)δ203.01,48.35,39.89,32.07,29.83,29.80,29.72,29.57,29.50,29.46,29.22,23.77,22.84,14.26.
化合物21b:1-bromohexadecan-2-one
柱层析纯化后的白色固体(石油醚/乙酸乙酯=1/1);54.9mg产率86%.1H NMR(400MHz,Chloroform-d)δ3.88(s,2H),2.64(t,J=7.4Hz,2H),1.6l(p,J=7.1Hz,2H),1.26(d,J=9.8Hz,22H),0.90-0.84(m,4H).13C NMR(101MHz,Chloroform-d)δ202.48,40.01,34.48,32.07,29.82,29.79,29.72,29.57,29.50,29.46,29.17,24.00,22.84,14.28.
化合物21c:1-iodohexadecan-2-one
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柱层析纯化后的白色固体(CH2Cl2);68.1mg产率93%.m.p 57.2-58.5℃.1H NMR(400MHz,Chloroform-d)δ3.80(s,2H),2.70(t,J=7.2Hz,2H),1.66-1.58(m,2H),1.25(s,24H),0.88(t,J=6.4Hz,3H).13C NMR(101MHz,Chloroform-d)δ203.57,39.49,32.07,29.84,29.79,29.73,29.58,29.50,29.45,29.14,24.33,22.84,14.28,6.38.IR(cm-1):3851,2918,2846,1714,1558,1469,1409,1381,1211,1130,1068,1029,800,748,418;HRMS(ESI+)m/z calcd.For C16H31NaIO[M+Na]+:389.1312;found:389.1307.
(22)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物22a:2-chloro-1-(4-chlorophenyl)ethan-1-one
柱层析纯化后的白色固体(石油醚/乙酸乙酯=30/1);32.5mg产率86%.1H NMR(400MHz,Chloroform-d)δ8.00-7.83(m,2H),7.53-7.43(m,2H),4.66(s,2H).13C NMR(101MHz,Chloroform-d)δ190.19,140.75,132.62,130.13,129.42,45.78.
化合物22b:2-bromo-1-(4-chlorophenyl)ethan-1-one
柱层析纯化后的白色固体(石油醚/乙酸乙酯=1/1);39.2mg产率84%.1H NMR(400MHz,Chloroform-d)δ7.98-7.88(m,2H),7.52-7.41(m,2H),4.41(s,2H).13C NMR(101MHz,Chloroform-d)δ190.37,140.69,132.36,130.52,129.38,30.53.
化合物22c:1-(4-chlorophenyl)-2-iodoethan-l-one
柱层析纯化后的白色固体(CH2Cl2);48.24mg产率86%.1H NMR(400MHz,Chloroform-d)δ7.93(d,J=8.8Hz,2H),7.46(d,J=8.8Hz,2H),4.33(s,2H).13C NMR(101MHz,Chloroform-d)δ191.85,140.50,131.89,130.60,129.35,1.27.
(23)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物23a:3-chloro-2-oxopropyl acetate
柱层析纯化后的液体(石油醚/乙酸乙酯=8/1);25.6mg产率85%.1H NMR(400MHz,Chloroform-d)δ4.90(s,2H),4.16(s,2H),2.18(s,3H).13C NMR(101MHz,Chloroform-d)δ196.56,170.28,66.54,45.79,20.52.
化合物23b:3-bromo-2-oxopropyl acetate
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);33.9mg产率87%.1H NMR(400MHz,Chloroform-d)δ4.91(s,2H),3.94(s,2H),2.18(s,3H).13C NMR(101MHz,Chloroform-d)δ195.95,170.29,66.19,30.55,20.55.
化合物23c:3-iodo-2-oxopropyl acetate
柱层析纯化后的液体(CH2Cl2);43.6mg产率90%.1H NMR(400MHz,Chloroform-d)δ4.93(s,2H),3.86(s,2H),2.19(s,3H).13C NMR(101MHz,Chloroform-d)δ197.06,170.26,65.09,20.62,0.57.
(24)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物24a:diethyl 2-(3-chloro-2-oxopropyl)malonate
柱层析纯化后的液体(石油醚/乙酸乙酯=30/1);43.6mg产率87%.1H NMR(400MHz,Chloroform-d)δ4.20(qd,J=7.1,2.8Hz,4H),4.15(s,2H),3.89(t,J=7.2Hz,1H),3.17(d,J=7.2Hz,2H),1.26(t,J=7.1Hz,7H).13C NMR(101MHz,Chloroform-d)δ199.93,168.54,62.08,48.10,47.15,38.57,14.10.
化合物24b:diethyl 2-(3-bromo-2-oxopropyl)malonate
柱层析纯化后的液体(石油醚/乙酸乙酯=1/1);49.0mg产率83%.1H NMR(400MHz,Chloroform-d)δ4.21(qd,J=7.1,3.1Hz,4H),3.97(s,2H),3.89(t,J=7.2Hz,1H),3.25(d,J=7.2Hz,2H),1.28(t,J=7.1Hz,6H).13C NMR(101MHz,Chloroform-d)δ199.29,168.59,62.11,47.42,38.67,33.93,14.14.
化合物24c:diethyl 2-(3-iodo-2-oxopropyl)malonate
柱层析纯化后的液体(CH2Cl2);60.2mg产率88%.1H NMR(400MHz,Chloroform-d)δ4.20(qq,J=6.9,3.7Hz,4H),3.90-3.83(m,3H),3.31(d,J=7.2Hz,2H),1.27(t,J=7.1Hz,6H).13C NMR(101MHz,Chloroform-d)δ200.12,168.62,62.04,47.49,37.99,14.12,5.19.IR(cm-1):2935,2870,1745,1575,1394,1429,1207,1105,781,682;HRMS(ESI+)m/zcalcd.For C10H15NaIO5[M+Na]+:364.9856;found:364.9857.
(25)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物25a:
(3S,8S,9S,10R,13R,14S,17R)-17-((2S,5S)-5-ethyl-6-methylheptan-2-y1)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl6-chloro-5-oxohexanoate
柱层析纯化后的白色固体(石油醚/乙酸乙酯=30/1);92,1mg产率82%.m.p139.2-142.5℃.1H NMR(400MHz,Chloroform-d)δ5.38(d,J=4.9Hz,1H),4.68-4.55(m,1H),4.07(s,2H),2.69(t,J=7-2Hz,2H),2.33(q,J=7.7,8.3Hz,4H),2.06-1.90(m,4H),1.90-1.78(m,3H),1.66(dd,J=5.8,12.7Hz,lH),1.54(s,5H),1.46(dd,J=9.5,15.7Hz,3H),1.38-1.31(m,2H),1.27-1.07(m,8H),1.02(s,4H),0.92(d,J=6.5Hz,4H),0.87-0.74(m,10H),0.68(s,3H).13C NMR(101MHz,Chloroform-d)δ202.23,172.50,139.70,122.89,74.26,56.82,56.16,50.14,48.27,45.96,42.44,39.84,38.67,38.26,37.10,36.73,36.29,34.06,33.45,32.04,31.98,29.27,28.38,27.93,26.18,24.43,23.19,21.16,19.97,19.46,19.17,18.91,12.12,11.99.IR(cm-1):3853,3649,2958,2868,1734,1558,1506,1261,1188,1097,958,923,796,418;HRMS(ESI+)m/z calcd.For C35H57NaClO3[M+Na]+:583.3888;found:583.3889.
化合物25b:
(3S,8S,9S,10R,13R,14S,17R)-17-((2S,5S)-5-ethyl-6-methylheptan-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl6-bromo-5-oxohexanoate
柱层析纯化后的白色固体(石油醚/乙酸乙酯=1/1);100.6mg产率83%.m.p128.9-131.7℃.1H NMR(400MHz,Chloroform-d)δ5.44-5.31(m,1H),4.74-4.54(m,1H),3.88(s,2H),2.74(t,J=7.0Hz,2H),2.32(q,J=7.3Hz,4H),2.05-1.90(m,4H),1.84(t,J=9.0Hz,3H),1.69-1.61(m,1H),1.57(s,5H),1.52-1.42(m,3H),1.38-1.20(m,6H),1.18-1.10(m,4H),1.01(s,4H),0.92(d,J=6.2Hz,4H),0.83(q,J=7.8Hz,10H),0.67(s,3H).13CNMR(101MHz,Chloroform-d)δ201.63,172.52,139.70,122.88,74.26,56.81,56.15,50.13,45.95,42.44,39.84,38.77,38.26,37.10,36.72,36.29,35.59,34.26,34.05,33.42,32.03,31.98,29.25,28.38,27.93,26.16,24.42,23.18,21.15,19.96,19.45,19.16,18.91,12.12,11.99.IR(cm-1):2943,1734,1558,1465,1398,1282,1249,1197,1101,958,923,792;HRMS(ESI+)m/z calcd.For C35H57NaBrO3[M+Na]+:627.3383;found:627.3378.化合物25c:
(3S,8S,9S,10R,13R,14S,17R)-17-((2S,5S)-5-ethyl-6-methylheptan-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl6-iodo-5-oxohexanoate
柱层析纯化后的白色固体(CH2C12);108.4mg产率83%.m.p 121.7-123.8℃.1HNMR(400MHz,Chloroform-d)δ5.37(d,J=3.4Hz,1H),4.61(q,J=11.8Hz,1H),3.80(s,2H),2.81(t,J=7.0Hz,2H),2.32(q,J=3.7,5.6Hz,4H),2.04-1.90(m,4H),1.89-1.77(m,3H),1.69-1.63(m,1H),1.59(d,J=14.1Hz,5H),1.52-1.42(m,3H),1.37-1.19(m,6H),1.18-1.11(m,4H),1.01(s,4H),0.92(d,J=6.2Hz,4H),0.83(q,J=7.9Hz,10H),0.67(s,3H).13CNMR(101MHz,Chloroform-d)δ202.63,172.53,139.71,122.86,74.22,56.80,56.14,50.12,45.93,42.43,39.83,38.27,38.18,37.09,36.71,36.28,34.04,33.40,32.03,31.97,29.23,28.38,27.93,26.14,24.42,23.17,21.15,19.96,19.46,19.42,19.15,18.90,12.11,11.98,6.14.IR(cm-1):3851,3647,2960,1728,1699,1651,1558,1456,1384,1286,1190,1085,958,932,794;HRMS(ESI+)m/z calcd.For C35H57NaIO3[M+Na]+:675.3242;found:675.3241.
(26)本组α-卤代酮化合物采用对应的烯氧基吡啶鎓盐根据上述合成方法合成:
化合物26a:
(4S,5′R,6aS,8aS,8bR,9S,10R,11aS,12aS,12bR)-5′,6a,8a,9-tetramethyl-2a,3,3′,4,4′,5,5′,6,6a,6b,6′,7,8,8a,8b,9,11a,12,12a,12b-icosahydrospiro[naphtho[2′,1′:4,5]indeno[2,1-b]furan-10,2′-pyran]-4-yl 6-chloro-5-oxohexanoate
柱层析纯化后的白色固体(石油醚/乙酸乙酯=30/1);98.8mg产率88%.m.p117.9-121.2℃.1H NMR(400MHz,Chloroform-d)δ5.37(d,J=4.9Hz,1H),4.67-4.54(m,1H),4.41(q,J=7.6Hz,1H),4.07(s,2H),3.47(dd,J=4.1,10.8Hz,1H),3.37(t,J=10.9Hz,1H),2.68(t,J=7.2Hz,2H),2.33(q,J=5.3,6.2Hz,4H),1.99-1.91(m,3H),1.89-1.81(m,3H),1.80-1.71(m,2H),1.65-1.58(m,5H),1.56(s,4H),1.46(ddd,J=5.7,12.4,21.1Hz,3H),1.33-1.24(m,1H),1.20-1.06(m,3H),1.04(s,3H),0.97(d,J=6.9Hz,3H),0.79(t,J=3.1Hz,6H).13C NMR(101MHz,Chloroform-d)δ202.18,172.46,139.72,122.57,109.40,80.91,74.14,66.96,62.18,56.54,50.03,48.24,41.72,40.37,39.83,38.64,38.21,37.04,36.84,33.41,32.15,31.95,31.50,30.41,28.91,27.87,20.92,19.45,18.89,17.26,16.40,14.65.IR(cm-1):3851,3709,3626,2351,1732,1681,1651,1573,1504,920,864,840,758,478;HRMS(ESI+)m/z calcd.For C33H49NaClO5[M+Na]+:583.3161;found:583.3157.
化合物26b:
(4S,5′R,6aS,8aS,8bR,9S,10R,11aS,12aS,12bR)-5′,6a,8a,9-tetramethyl-2a,3,3′,4,4′,5,5′,6,6a,6b,6′,7,8,8a,8b,9,11a,12,12a,12b-icosahydrospiro[naphtho[2′,1′:4,5]indeno[2,1-b]furan-10,2′-pyran]-4-yl 6-bromo-5-oxohexanoate
柱层析纯化后的白色固体(石油醚/乙酸乙酯=1/1);101.7mg产率84%.m.p114.2-116.5℃.
1H NMR(400MHz,Chloroform-d)δ5.37(d,J=3.6Hz,1H),4.61(dd,J=5.6,10.8Hz,1H),4.40(q,J=7.2Hz,1H),3.88(s,2H),3.47(d,J=9.9Hz,1H),3.42-3.32(m,1H),2.74(t,J=7.0Hz,2H),2.35-2.29(m,4H),1.98-1.90(m,3H),1.86(t,J=8.5Hz,3H),1.80-1.73(m,2H),1.66-1.52(m,9H),1.48(d,J=14.3Hz,3H),1.28(s,1H),1.19-1.08(m,3H),1.03(s,3H),0.97(d,J=6.8Hz,3H),0.78(s,6H).13C NMR(101MHz,CHLOROFORM-D)δ201.61,172.51,139.74,122.59,109.43,80.94,74.15,66.97,62.18,56.54,50.04,41.73,40.38,39.84,38.76,38.23,37.05,36.85,34.25,33.40,32.16,31.96,31.51,30.42,29.84,28.92,27.89,20.93,19.46,19.15,17.27,16.42,14.66.IR(cm-1):3851,3647,2937,1732,1558,1506,1456,1205,1053,983,900,740,569;HRMS(ESI+)m/z calcd.ForC33H49NaBrO5[M+Na]+:627.2656;found:627.2653.
化合物26c:
(4S,5′R,6aS,8aS,8bR,9S,10R,1laS,12aS,12bR)-5′,6a,8a,9-tetramethyl-2a,3,3′,4,4′,5,5′,6,6a,6b,6′,7,8,8a,8b,9,l1a,12,12a,12b-icosahydrospiro[naphtho[2′,1′:4,5]indeno[2,1-b]furan-10,2′-pyran]-4-yl 6-iodo-5-oxohexanoate
柱层析纯化后的白色固体(CH2Cl2);111.0mg产率85%.m.p 143.3-145.1℃.1HNMR(400MHz,Chloroform-d)δ5.37(d,J=4.1Hz,1H),4.67-4.53(m,1H),4.40(q,J=7.2Hz,1H),3.80(s,2H),3.47(dd,J=3.0,11.1Hz,1H),3.37(t,J=10.8Hz,1H),2.80(t,J=7.0Hz,2H),2.32(t,J=7.1Hz,4H),1.99-1.91(m,3H),1.85(d,J=10.7Hz,3H),1.76(dd,J=11.2,19.1Hz,2H),1.62(d,J=12.6Hz,9H),1.52-1.40(m,3H),1.26(dd,J=6.2,12.6Hz,1H),1.20-1.05(m,3H),1.03(s,3H),0.97(d,J=6.8Hz,3H),0.78(s,6H).13C NMR(101MHz,CHLOROFORM-D)δ202.62,172.52,139.75,122.58,109.44,80.95,74.13,66.98,62.17,56.55,50.04,41.73,40.38,39.84,38.25,38.18,37.06,36.86,33.39,32.17,31.96,31.51,30.42,28.92,27.90,20.93,19.48,19.41,17.28,16.42,14.67,6.13.IR(cm-1):3851,3626,2949,1732,1681,1651,1556,1456,1273,1080,900,866,798;HRMS(ESI+)m/zcalcd.For C33H49NaIO5[M+Na]+:675.2517;found:675.2513.
3、替洛利生的合成
本发明提供的α-卤代酮可用于制备替洛利生,合成路线如下:
采用本发明提供的上述合成方法得到α-卤代酮A,使其与哌啶进行亲核取代反应产生化合物B(分离产率可达到90%以上);随后,使化合物B与NH2NHTs进行脱水缩合,得到化合物C(分离产率54%以上);最后,使用硼氢化钠作为还原剂与化合物C进行反应,得到替洛利生(分离产率46%以上)。上述替洛利生的合成路线起始原料和试剂易于获得,合成步骤简单,因而具有潜在的工业化前景。
此外,本案发明人还参照前述实施例,以本说明书述及的其它原料、工艺操作、工艺条件进行了试验,并均获得了较为理想的结果。
尽管已参考说明性实施例描述了本发明,但所属领域的技术人员将理解,在不背离本发明的精神及范围的情况下可做出各种其它改变、省略及/或添加且可用实质等效物替代所述实施例的元件。另外,可在不背离本发明的范围的情况下做出许多修改以使特定情形或材料适应本发明的教示。因此,本文并不打算将本发明限制于用于执行本发明的所揭示特定实施例,而是打算使本发明将包含归属于所附权利要求书的范围内的所有实施例。此外,除非具体陈述,否则术语第一、第二等的任何使用不表示任何次序或重要性,而是使用术语第一、第二等来区分一个元素与另一元素。
Claims (10)
1.一种α-卤代酮的高效合成方法,其特征在于,包括:使包含烯氧基吡啶鎓盐和卤化季铵盐的均匀混合反应体系于室温下进行反应,获得α-卤代酮;
所述烯氧基吡啶鎓盐具有式I所示结构:
其中,R包括H、卤素、取代或未取代的烷基、取代或未取代的芳基、取代或未取代的杂环基、取代或未取代的烯基、炔基、酯基、氨基或氰基;R1包括H或甲基;Xa -包括负电性基团。
2.根据权利要求1所述的α-卤代酮的高效合成方法,其特征在于,所述卤化季铵盐包括四丁基卤化铵,所述四丁基卤化铵具有式II所示结构:
其中,Xb包括Cl、Br或I。
3.根据权利要求1所述的合成方法,其特征在于:所述卤化季铵盐与烯氧基吡啶鎓盐的摩尔比为1.1~2∶1;和/或,所述反应的反应时间为5-15min。
4.根据权利要求1所述的合成方法,其特征在于:Xa -包括-NTf2。
5.根据权利要求1所述的合成方法,其特征在于:所述均匀混合反应体系还包括有机溶剂。
6.根据权利要求5所述的合成方法,其特征在于:所述有机溶剂包括四氢呋喃、二氯甲烷、二氯乙烷、乙腈、甲醇和六氟异丙醇中的一种或多种。
7.根据权利要求5或6所述的合成方法,其特征在于:所述卤化季铵盐为Bu4NXb;
当Xb为Cl时,所述有机溶剂选自四氢呋喃、二氯甲烷和甲醇中的至少一种;
当Xb为Br或I时,所述有机溶剂包括六氟异丙醇。
8.一种α-卤代酮,其特征在于,所述α-卤代酮具有式III所示结构:
其中,R包括H、卤素、取代或未取代的烷基、取代或未取代的芳基、取代或未取代的杂环基、取代或未取代的烯基、炔基、酯基、氨基或氰基;X包括Cl、Br或I。
9.根据权利要求8所述的α-卤代酮,其特征在于,所述α-卤代酮包括下列任一种化合物:
10.权利要求8-9中任一项所述的α-卤代酮在制备替洛利生中的用途。
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