CN113402547B - 一种n-酰基磷酰胺类化合物的合成方法 - Google Patents
一种n-酰基磷酰胺类化合物的合成方法 Download PDFInfo
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- CN113402547B CN113402547B CN202110587708.1A CN202110587708A CN113402547B CN 113402547 B CN113402547 B CN 113402547B CN 202110587708 A CN202110587708 A CN 202110587708A CN 113402547 B CN113402547 B CN 113402547B
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/36—Amides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B47/00—Formation or introduction of functional groups not provided for in groups C07B39/00 - C07B45/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2479—Compounds containing the structure P(=X)n-N-acyl, P(=X)n-N-heteroatom, P(=X)n-N-CN (X = O, S, Se; n = 0, 1)
- C07F9/2487—Compounds containing the structure P(=X)n-N-acyl, P(=X)n-N-heteroatom, P(=X)n-N-CN (X = O, S, Se; n = 0, 1) containing the structure P(=X)n-N-C(=X) (X = O, S, Se; n = 0, 1)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
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Abstract
本发明公开了一种N‑酰基磷酰胺类化合物的合成方法:羧酸、叠氮化合物、磷氯化合物、碱和反应溶剂混合,在室温或加热条件下搅拌反应2‑12小时,使叠氮底物反应转化完全,然后将反应液进行柱层析分离,得到N‑酰基磷酰胺类化合物。与现有技术相比,本发明的方法有如下优点:原料廉价易得、反应条件温和,反应效率高,以三乙胺作为碱,无需任何催化剂,反应的副产物为易于分离除去的碱‑盐酸盐和氮气,不存在环境污染等问题,绿色环保并且原子经济性较好。
Description
技术领域
本发明涉及一种N-酰基磷酰胺类化合物的合成方法,属有机合成领域。
背景技术
由于磷酰胺骨架在许多药物分子和功能性材料分子结构中发挥着不可替代的作用,因此,磷酰胺类化合物成为医药、农业、材料以及有机合成等领域的重点研究对象之一。在诸多的磷酰胺化合物中,N-酰基磷酰胺类化合物是非常独特和重要的一类,许多抗生素的分子结构中具有N-酰基磷酰胺骨架。已报道的磷酰胺类化合物合成的方法如下式所示:
1)经典的合成方法是:在碱的作用下,胺和三价磷氯之间脱除一分子氯化氢,然后再进行氧化得到相应的磷酰胺类化合物。这种方法需要两步过程,多数需要在高温下进行反应,尤其是以酰胺作为底物,反应时间比较长,底物适用范围十分有限。
2)微波条件下,磷酸与胺的脱水缩合反应。此类方法反应温度在220度左右,并且转化率极低。后来通过使用丙烷磷酸酐来活化磷酸,能够将反应温度降低到室温,尽管如此,反应过程中还是需要两倍以上的碱来催化反应,并且底物适用范围也十分有限。
3)磷氯与羟胺的氧化重排:三价磷氯与羟胺在碱的作用下脱除一分子氯化氢,然后在加热的条件下发生重排得到相应的磷酰胺类化合物。此方法需要预先合成羟胺类底物,并且反应对羟胺类化合物的结构要求比较高,普适性比较低。
4)其它方法:磷氢与苯甲酰羟胺的偶联、重氮或偶氮的磷氢化。
上述几种方法通常都采用分步法,底物适用范围窄,反应条件苛刻,转化率低。
发明内容
本发明要解决的技术问题是克服现有的缺陷,提供一种操作简单、反应效率高,并且具有广普性的N-酰基磷酰胺类化合物的合成方法。
本发明的目的通过以下技术方案来具体实现:
一种N-酰基磷酰胺类化合物的合成方法,所述方法为:将羧酸、叠氮化合物、磷氯化合物、碱和反应溶剂混合反应即得,所述反应结构式如下所示:
其中,R选自苯基或者乙氧基;R'羧酸选自苯甲酸、可取代的芳基甲酸或者烷基羧酸,含羧基的药物分子或天然产物;R”选自苄基、芳基、各种氨基酸及天然产物骨架基团。
优选地,所述的反应溶剂为甲苯、氯苯、二氯甲烷、乙醚或乙腈中的任一种或几种的组合。
优选地,所述的反应溶剂为甲苯。
优选地,所述碱包括三乙胺、二异丙基乙胺、二乙胺、三乙烯二胺、1,8-二氮杂二环十一碳-7-烯、4-二甲氨基吡啶或四甲基胍。
优选地,所述碱包括三乙胺。
优选地,所述叠氮化合物包括苄基叠氮、苯基叠氮、各种氨基酸衍生的叠氮、酒石酸衍生的叠氮、alpha-D-吡喃糖衍生的叠氮、尿嘧啶核苷衍生的叠氮。
优选地,所述羧酸包括苯甲酸、苯环不同位置各种取代的苯甲酸、间二苯甲酸、2-萘甲酸、呋喃-2-甲酸、噻吩-2-甲酸、吡啶-2-甲酸、吡啶-2,6-二甲酸、喹啉-2-甲酸、咕吨-9-甲酸、4-甲基苯乙酸、苯甲酰甲酸、乙酸、丙酸、2-溴-己酸、三氟乙酸、肉桂酸、1-环己烯甲酸、雌酚酸、非布索坦、吲哚美辛、舒林酸、维A酸。
优选地,所述磷氯化合物包括二苯基氯化磷、二乙基亚磷酰氯。
优选地,所述的叠氮化合物、磷氯化合物、羧酸和碱的摩尔比为1.0:1.2:1.2:1.2-1.0:1.2:1.2:1.5。
优选地,所述的叠氮化合物、磷氯化合物、羧酸和碱的摩尔比为1.0:1.2:1.2:1.2
优选地,所述反应体系中叠氮化合物的反应浓度为0.05-0.4摩尔每升。
优选地,所述反应体系中叠氮化合物的反应浓度为0.2摩尔每升。
优选地,所述反应气氛为氩气条件;反应时间为2-12小时。
优选地,所述磷氯化合物为二苯基氯化磷时,反应温度为25℃。
优选地,所述磷氯化合物为二乙基亚磷酰氯时,所述反应温度为50℃。
优选地,所述方法还包括:反应后将反应液进行柱层析,所述柱层析的洗脱剂为石油醚和乙酸乙酯,所述石油醚和乙酸乙酯的体积比为2:1-1:2。
本发明的有益效果是:与现有技术相比,本发明的方法有如下优点:原料廉价易得、反应条件温和,反应效率高,以三乙胺作为碱,无需任何催化剂,反应的副产物为易于分离除去的碱-盐酸盐和氮气,不存在环境污染等问题,绿色环保并且原子经济性较好。
附图说明
图1合成化合物所示结果1;
图2合成化合物所示结果2。
具体实施方式
以下对本发明的优选实施例进行说明,应当理解,此处所描述的优选实施例仅用于说明和解释本发明,并不用于限定本发明。
本发明根据所述方法具体合成了图1和图2所示的化合物,但并不局限于图1和图2中所示的化合物。
本发明实施例具体展示了其中31种化合物的合成。
实施例1
在反应器中,加入0.24毫摩尔对甲基苯甲酸和1毫升甲苯,然后加入0.24毫摩尔二苯基氯化磷和0.24毫摩尔三乙胺,室温搅拌10分钟后,加入0.2毫摩尔(S)-2,6-二氮杂己酸甲酯、在25℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4aaa,产率为96%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ8.13(dd,J=12.4,7.6Hz,2H),7.85(dd,J=13.6,7.2Hz,2H),7.61-7.57(m,1H),7.51-7.46(m,2H),7.40-7.36(m,1H),7.33-7.29(m,2H),7.17-7.12(m,3H),7.06(t,J=7.4Hz,2H),6.98(d,J=8.0Hz,2H),6.53(d,J=7.2Hz,2H),4.76-4.68(m,1H),3.92(s,3H),3.52(dd,J=14.8,4.0Hz,1H),3.24(dd,J=14.8,10.4Hz,1H),2.26(s,3H).13C NMR(100MHz,CDCl3)δ174.8(d,JC-F=4.0Hz),171.3,141.1,137.1,133.8,133.7,132.8(d,JC-F=3.0Hz),131.9(d,JC-F=3.0Hz),132.2,131.6,131.5,129.4,128.6,128.5,128.4,128.3,128.1,127.7,126.6,62.8(d,JC-F=2.0Hz),52.8,36.9,21.5.31P NMR(162MHz,CDCl3)δ32.63.HRMS(ESI)m/z calcd for C30H29NO4P[M+H]+:498.1829,found 498.1833。
产物结构式如下:
实施例2
在反应器中,加入0.24毫摩尔对甲基苯甲酸和1毫升甲苯,然后加入0.24毫摩尔二乙基亚磷酰氯和0.24毫摩尔三乙胺,室温搅拌30分钟后,加入0.2毫摩尔(S)-2,6-二氮杂己酸甲酯、在50℃反应6小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4aa’a,产率为82%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.33-7.26(m,2H),7.22(q,J=7.5Hz,5H),7.10(d,J=7.6Hz,2H),5.08-5.01(m,1H),4.04-3.92(m,2H),3.82(s,3H),3.76-3.70(m,1H),3.56(dd,J=14.4,4.4Hz,1H),3.50-3.43(m,1H),3.41-3.34(m,1H),2.35(s,3H),1.11-1.03(m,6H).13C NMR(100MHz,CDCl3)δ172.8(d,JC-F=6.0Hz),171.0(d,JC-F=1.0Hz),141.3,138.1,133.2,129.8,128.5,128.3,127.7,126.7,64.0(d,JC-F=6.0Hz),63.5(d,JC-F=6.0Hz),61.4(d,JC-F=4.0Hz),52.5,35.2,21.6,15.8(d,JC-F=8.0Hz),15.7(d,JC-F=8.0Hz).31P NMR(162MHz,CDCl3)δ1.12.HRMS(ESI)m/z calcd for C22H29NO6P[M+H]+:434.1727,found 434.1730。产物结构式如下:
实施例3
在反应器中,加入0.24毫摩尔对乙烯基苯甲酸和1毫升甲苯,然后加入0.24毫摩尔二苯基氯化磷和0.24毫摩尔三乙胺,室温搅拌10分钟后,加入0.2毫摩尔(S)-2,6-二氮杂己酸甲酯、在25℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4aaj,产率为88%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ6.86(dd,J=16.6,10.2Hz,2H),6.59(dd,J=18.0,9.6Hz,2H),6.37-6.33(m,1H),6.27-6.22(m,2H),6.12-6.05(m,3H),5.93-5.90(m,5H),5.86-5.81(m,2H),5.40-5.29(m,3H),4.47(d,J=23.6Hz,1H),4.02(d,J=14.8Hz,1H),3.46-3.36(m,1H),2.67(s,3H),2.26(dd,J=19.6,4.8Hz,1H),1.99(dd,J=19.6,14.0Hz,1H).13C NMR(100MHz,CDCl3)δ173.3(d,JC-F=5.0Hz),170.1,138.7,136.0,134.9,133.1,132.7,132.6,131.8,130.9(d,JC-F=4.0Hz),,130.6,129.5,128.3,127.5,127.4,127.4,127.3,127.1,127.1,125.7,124.6,114.8,61.7,51.8,35.7.31P NMR(162MHz,CDCl3)δ31.24.HRMS(ESI)m/z calcd for C31H29NO4P[M+H]+:510.1829,found 510.1833。
产物结构式如下:
实施例4
在反应器中,加入0.24毫摩尔2-萘甲酸和1毫升甲苯,然后加入0.24毫摩尔二苯基氯化磷和0.24毫摩尔三乙胺,室温搅拌10分钟后,加入0.2毫摩尔(S)-2,6-二氮杂己酸甲酯、在25℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4aal,产率为91%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.92(dd,J=16.6,10.2Hz,2H),7.61(dd,J=18.0,9.2Hz,2H),7.47-7.42(m,3H),7.33-7.16(m,7H),7.05-6.92(m,4H),6.81(t,J=10.0Hz,2H),6.28(d,J=9.6Hz,2H),4.52-4.42(m,1H),3.67(s,3H),3.27(dd,J=19.6,5.2Hz,1H),3.06(dd,J=19.4,14.2Hz,1H).13C NMR(100MHz,CDCl3)δ174.6(d,JC-F=4.8Hz),171.1,137.0,133.8,133.7,133.6,132.8,132.5,132.2,131.9,131.8,131.6,131.4,130.8,130.8,129.4,128.9,128.6,128.4,128.3,128.1,127.8,127.6,126.7,126.6,123.9,62.7(d,JC-F=3.3Hz),52.8,36.7.31P NMR(162MHz,CDCl3)δ32.37.HRMS(ESI)m/zcalcd for C33H29NO4P[M+H]+:534.1829,found 534.1833。
产物结构式如下:
实施例5
在反应器中,加入0.24毫摩尔肉桂酸和1毫升甲苯,然后加入0.24毫摩尔二苯基氯化磷和0.24毫摩尔三乙胺,室温搅拌10分钟后,加入0.2毫摩尔(S)-2,6-二氮杂己酸甲酯、在25℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4aam,产率为80%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.96(dd,J=16.0,10.0Hz,2H),7.59-7.53(m,2H),7.48-7.45(m,1H),7.43-7.35(m,5H),7.27-7.22(m,9H),7.04-7.02(m,2H),6.90(d,J=20.4Hz,1H),4.57-4.37(m,1H),3.83(s,3H),3.54(dd,J=19.0,6.2Hz,1H),3.30(dd,J=19.0,12.6Hz,1H).13C NMR(100MHz,CDCl3)δ171.2,168.9(d,JC-F=5.6Hz),144.3,137.4,134.3,132.6,132.3,132.2,132.1,130.3,129.9,128.7,128.6,128.2,126.9,120.1,60.7,52.6,36.1.31P NMR(162MHz,CDCl3)δ30.61.HRMS(ESI)m/z calcd forC31H29NO4P[M+H]+:510.1829,found 510.1832。
产物结构式如下:
实施例6
在反应器中,加入0.24毫摩尔1-环己烯甲酸和1毫升甲苯,然后加入0.24毫摩尔二苯基氯化磷和0.24毫摩尔三乙胺,室温搅拌10分钟后,加入0.2毫摩尔(S)-2,6-二氮杂己酸甲酯、在25℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4aan,产率为79%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.97(dd,J=16.8,10.4Hz,2H),7.86(dd,J=16.4,9.6Hz,2H),7.50-7.41(m,6H),7.29-7.27(m,3H),6.93-6.91(m,2H),6.46-6.43(m,2H),4.32-4.25(m,1H),3.83(s,3H),3.47(dd,J=19.0,5.8Hz,1H),3.16(dd,J=19.2,13.2Hz,1H),1.93-1.85(m,3H),1.65-1.58(m,1H),1.38-1.23(m,2H),1.15-1.09(m,1H),0.91-0.91(m,1H).13C NMR(100MHz,CDCl3)δ175.3(d,JC-F=6.5Hz),171.0,137.6,136.9,133.9,133.0,132.9,132.5,131.9,131.7,131.5,131.1,129.6,128.7,128.5,128.4,127.0,61.8,52.6,36.1,24.8,24.7,21.4,21.0.31P NMR(162MHz,CDCl3)δ27.64.HRMS(ESI)m/z calcd for C29H31NO4P[M+H]+:488.1985,found 488.1990。
产物结构式如下:
实施例7
在反应器中,加入0.2毫摩尔间二苯甲酸和1毫升甲苯,然后加入0.4毫摩尔二苯基氯化磷和0.48毫摩尔三乙胺,室温搅拌10分钟后,加入0.4毫摩尔(S)-2,6-二氮杂己酸甲酯、在25℃反应6小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=1:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4aao,产率为93%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ8.14(dd,J=14.8,10.8Hz,4H),7.87(dd,J=17.8,5.4Hz,4H),7.65-7.60(m,2H),7.53-7.49(m,5H),7.35-7.35(m,6H),7.12-7.08(m,2H),6.99-6.89(m,7H),6.44(s,4H),4.61-4.53(m,2H),3.98(s,6H),3.52(dd,J=20.2,4.6Hz,2H),3.22(dd,J=19.6,14.0Hz,2H).13C NMR(100MHz,CDCl3)δ173.5(d,JC-F=3.6Hz),171.0,137.0,134.7,133.9,133.7,133.2,132.6,132.3,131.8,131.6,130.9,130.8,130.5,129.4,129.1,128.8,128.6,128.5,128.4,126.7,63.0,53.1,36.9.31P NMR(162MHz,CDCl3)δ33.40.HRMS(ESI)m/z calcd for C52H47N2O8P2[M+H]+:889.2802,found889.2807。
产物结构式如下:
实施例8
在反应器中,加入0.24毫摩尔4-甲基苯乙酸和1毫升甲苯,然后加入0.24毫摩尔二苯基氯化磷和0.24毫摩尔三乙胺,室温搅拌10分钟后,加入0.2毫摩尔(S)-2,6-二氮杂己酸甲酯、在25℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4aap,产率为80%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ8.05-7.99(m,2H),7.51-7.44(m,6H),7.35-7.32(m,2H),7.25-7.22(m,3H),7.04(d,J=10.4Hz,2H),6.93(d,J=10.4Hz,2H),6.79(d,J=9.6Hz,2H),4.22(s,1H),3.74(s,4H),3.48-3.40(m,2H),3.14(dd,J=19.0,12.6Hz,1H),2.26(s,3H).13C NMR(100MHz,CDCl3)δ175.4(d,JC-F=7.2Hz),171.3(d,JC-F=4.8Hz),137.9,136.9,133.5,133.1,133.0,133.0,132.8,132.6,132.5,131.8,131.1,130.3,130.0,129.4,129.2,129.0,129.0,127.3,62.1,52.9,43.9,36.3,21.5.31P NMR(162MHz,CDCl3)δ31.37.HRMS(ESI)m/z calcd for C31H31NO4P[M+H]+:512.1985,found512.1989。
产物结构式如下:
实施例9
在反应器中,加入0.24毫摩尔苯甲酰甲酸和1毫升甲苯,然后加入0.24毫摩尔二苯基氯化磷和0.24毫摩尔三乙胺,室温搅拌10分钟后,加入0.2毫摩尔(S)-2,6-二氮杂己酸甲酯、在25℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4aaq,产率为71%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.83-7.74(m,2H),7.64(dd,J=12.6,7.8Hz,2H),7.57-7.55(m,2H),7.50-7.42(m,3H),7.30-7.26(m,6H),7.11-7.04(m,5H),5.23-5.16(m,1H),7.77-7.72(m,4H),3.39(s,1H).13C NMR(100MHz,CDCl3)δ187.8,170.4(d,JC-F=2.0Hz),169.5(d,JC-F=5.0Hz),137.4,134.3,133.4,133.3,133.0(d,JC-F=2.0Hz),132.7,132.4,130.1,129.5,128.5,128.4,128.3,128.3,128.2,126.9,59.4,52.7,36.6.31P NMR(162MHz,CDCl3)δ33.90.HRMS(ESI)m/z calcd for C30H27NO5P[M+H]+:512.1621,found 512.1626。
产物结构式如下:
实施例10
在反应器中,加入0.24毫摩尔三氟乙酸和1毫升甲苯,然后加入0.24毫摩尔二苯基氯化磷和0.24毫摩尔三乙胺,室温搅拌10分钟后,加入0.2毫摩尔(S)-2,6-二氮杂己酸甲酯、在25℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4aar,产率为32%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ8.03(dd,J=12.8,7.6Hz,2H),7.84(dd,J=13.2,7.2Hz,1H),7.73-7.66(m,2H),7.57-7.54(m,3H),7.45-7.43(m,2H),7.15-7.14(m,3H),6.92-6.92(m,2H),5.07-4.99(m,1H),3.89(dd,J=14.8,5.6Hz,1H),3.84(s,3H),3.23(dd,J=14.4,8.0Hz,1H).13C NMR(100MHz,CDCl3)δ170.0,136.9,133.4(d,JC-F=3.0Hz),133.2,133.1,132.8(d,JC-F=3.0Hz),132.0,131.9,131.5(d,JC-F=10.0Hz),129.4,129.0,128.8,128.7,128.6,128.5,128.5,128.3,126.9,60.8,53.0,38.1.31P NMR(162MHz,CDCl3)δ37.30.19F NMR(376MHz,CDCl3)δ-68.83.HRMS(ESI)m/z calcd forC24H22F3NO4P[M+H]+:476.1233,found 476.1237。
产物结构式如下:
实施例11
在反应器中,加入0.24毫摩尔咕吨-9-甲酸和1毫升甲苯,然后加入0.24毫摩尔二苯基氯化磷和0.24毫摩尔三乙胺,室温搅拌10分钟后,加入0.2毫摩尔(S)-2,6-二氮杂己酸甲酯、在25℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4aat,产率为81%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ8.48-8.40(m,4H),8.35-7.95(m,4H),7.93-7.62(m,4H),7.52-7.47(m,4H),7.47-7.25(m,3H),7.26-7.20(m,2H),7.16-7.12(m,3H),6.73-6.73(m,1H),6.66(d,J=9.6Hz,2H),5.70(s,1H),5.61-5.61(m,1H),4.00-3.91(m,1H),3.58(s,3H),3.24(dd,J=19.6,7.6Hz,1H),2.62(dd,J=21.2,9.2Hz,1H).13C NMR(100MHz,CDCl3)δ177.0(d,JC-F=10.6Hz),171.1,153.2(d,JC-F=49.3Hz),138.4,133.8,133.6,133.1(d,JC-F=14.4Hz),130.4,130.1,130.0,129.6(d,JC-F=16.9Hz),129.2,129.1,128.7,127.3,123.6,123.3,121.0,120.7,117.8,117.6,63.4(d,JC-F=2.3Hz),53.1,47.7,36.2.31P NMR(162MHz,CDCl3)δ30.72.HRMS(ESI)m/z calcd for C36H31NO5P[M+H]+:588.1934,found 588.1940。
产物结构式如下:
实施例12
在反应器中,加入0.2毫摩尔2,6-吡啶二甲酸和1毫升甲苯,然后加入0.4毫摩尔二苯基氯化磷和0.48毫摩尔三乙胺,室温搅拌10分钟后,加入0.4毫摩尔(S)-2,6-二氮杂己酸甲酯、在25℃反应6小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=1:2)通过硅胶柱层析得到N-酰基磷酰胺化合物4aaw,产率为84%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ8.15-8.10(m,4H),7.85-7.83(m,4H),7.63-7.60(m,2H),7.54-7.48(m,4H),7.35-7.35(m,6H),7.26-7.19(m,3H),7.00-6.82(m,7H),6.57(s,3H),5.41(s,2H),3.82(s,6H),3.65(d,J=12.4Hz,2H),3.27(t,J=12.2Hz,2H).13C NMR(100MHz,CDCl3)δ170.6,170.1,150.8,137.4,133.7(d,JC-F=10.0Hz),132.9,132.2,131.9,131.8,131.6,131.3(d,JC-F=11.0Hz),129.5,129.3,128.4,128.3,128.2,126.4,125.3,61.3,52.7,37.8.31P NMR(162MHz,CDCl3)δ35.68.HRMS(ESI)m/z calcd forC51H46N3O8P2[M+H]+:890.2755,found 890.2760。
产物结构式如下:
实施例13
在反应器中,加入0.24毫摩尔对甲基苯甲酸和1毫升甲苯,然后加入0.24毫摩尔二苯基氯化磷和0.24毫摩尔三乙胺,室温搅拌10分钟后,加入0.2毫摩尔、在25℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4maa,产率为71%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.95(dd,J=13.0,7.0Hz,4H),7.52-7.48(m,2H),7.45-7.41(m,4H),7.29-7.27(m,2H),7.23-7.14(m,5H),6.93(d,J=8.0Hz,2H),2.19(s,3H).13C NMR(100MHz,CDCl3)δ173.1(d,JC-F=3.0Hz),141.6,138.2,132.2,132.1,132.0,131.7,131.6,131.6,130.7(d,JC-F=2.0Hz),130.3,129.3,128.9,128.6,128.4,128.3,127.8,21.4.31P NMR(162MHz,CDCl3)δ29.85.HRMS(ESI)m/z calcd forC26H23NO2P[M+H]+:412.1461,found 412.1464。
产物结构式如下:
实施例14
在反应器中,加入0.24毫摩尔对甲基苯甲酸和1毫升甲苯,然后加入0.24毫摩尔二苯基氯化磷和0.24毫摩尔三乙胺,室温搅拌10分钟后,加入0.2毫摩尔苄基叠氮、在25℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4naa,产率为74%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.83(dd,J=12.0,8.0Hz,4H),7.48-7.44(m,2H),7.39-7.33(m,6H),7.12-7.12(m,3H),7.09-7.06(m,4H),4.97(d,J=12.0Hz,2H),2.30(s,3H).13C NMR(100MHz,CDCl3)δ175.3(d,JC-F=4.0Hz),141.5,137.7,132.9,132.9,132.1,132.1,132.0,131.8,130.5,128.9,128.3,128.3,128.2,128.1,128.0,127.3,50.3(d,JC-F=3.0Hz),21.5.31P NMR(162MHz,CDCl3)δ30.07.HRMS(ESI)m/z calcdfor C27H25NO2P[M+H]+:426.1617,found 426.1621。
产物结构式如下:
实施例15
在反应器中,加入0.24毫摩尔丙酸和1毫升甲苯,然后加入0.24毫摩尔二苯基氯化磷和0.24毫摩尔三乙胺,室温搅拌10分钟后,加入0.2毫摩尔苄基叠氮、在25℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4nay,产率为96%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.75(dd,J=13.0,7.8Hz,4H),7.55-7.51(m,2H),7.44-7.40(m,4H),7.23-7.21(m,3H),7.10-7.08(m,2H),4.89(d,J=11.2Hz,2H),2.51(q,J=10.8Hz,2H),0.99(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3)δ178.3(d,JC-F=4.0Hz),137.9,132.4,132.4,132.1,132.0,131.6,130.3,128.5,128.4,127.2,126.9,48.0,29.9,8.8.31P NMR(162MHz,CDCl3)δ31.75.HRMS(ESI)m/z calcd for C22H23NO2P[M+H]+:364.1461,found 364.1465。
产物结构式如下:
实施例16
在反应器中,加入0.24毫摩尔2-溴己酸和1毫升甲苯,然后加入0.24毫摩尔二乙基亚磷酰氯和0.24毫摩尔三乙胺,室温搅拌30分钟后,加入0.2毫摩尔苄基叠氮、在50℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4na’z,产率为53%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.29-7.22(m,5H),5.30-5.17(m,3H),4.24-4.10(m,4H),1.42-1.27(m,11H),0.95-0.91(m,4H).13C NMR(100MHz,CDCl3)δ172.1,134.3,128.5,128.1,127.6,64.7(d,JC-F=4.0Hz),64.6(d,JC-F=3.0Hz),43.8,43.2,33.7,29.4,22.2,16.3,16.2,13.8.31P NMR(162MHz,CDCl3)δ1.54.HRMS(ESI)m/z calcd forC17H28BrNO4P[M+H]+:420.0934,found 420.0936。
产物结构式如下:
实施例17
在反应器中,加入0.24毫摩尔乙酸和1毫升甲苯,然后加入0.24毫摩尔二乙基亚磷酰氯和0.24毫摩尔三乙胺,室温搅拌30分钟后,加入0.2毫摩尔2-溴苯基叠氮、在50℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物6oa’a,产率为71%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.68(d,J=8.0Hz,1H),7.41-7.34(m,2H),7.28-7.24(m,1H),4.32-4.17(m,4H),2.09(s,3H),1.29(q,J=7.5Hz,6H).13C NMR(100MHz,CDCl3)δ172.6(d,JC-F=5.0Hz),138.3,133.7,130.9,130.0,128.7,124.4(d,JC-F=3.0Hz),124.3,64.7(d,JC-F=6.0Hz),64.6(d,JC-F=7.0Hz),24.0(d,JC-F=4.0Hz),16.1,16.0.31P NMR(162MHz,CDCl3)δ-0.94.HRMS(ESI)m/z calcd for C12H18BrNO4P[M+H]+:350.0151,found 350.0158。
产物结构式如下:
实施例18
在反应器中,加入0.24毫摩尔丙烯酸和1毫升甲苯,然后加入0.24毫摩尔二乙基亚磷酰氯和0.24毫摩尔三乙胺,室温搅拌30分钟后,加入0.2毫摩尔苯基叠氮、在50℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物6ma’b,产率为66%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.45-7.38(m,3H),7.27-7.24(m,2H),6.46(dd,J=16.8,1.6Hz,1H),6.19(dd,J=16.6,10.2Hz,1H),5.68-5.64(m,1H),4.27-4.23(m,2H),4.22-4.11(m,2H),1.29-1.25(m,6H).13C NMR(100MHz,CDCl3)δ167.9(d,JC-F=5.0Hz),138.0,130.6,129.5,129.4(d,JC-F=2.0Hz),128.5,128.4(d,JC-F=5.0Hz),64.5,64.5,16.1,16.0.31P NMR(162MHz,CDCl3)δ-1.14.HRMS(ESI)m/z calcd for C13H19NO4P[M+H]+:284.1046,found 284.1051。
产物结构式如下:
实施例19
在反应器中,加入0.4毫摩尔对甲基苯甲酸和1毫升甲苯,然后加入0.4毫摩尔二乙基亚磷酰氯和0.48毫摩尔三乙胺,室温搅拌30分钟后,加入0.2毫摩尔酒石酸衍生的叠氮,在50℃反应6小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=1:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4pa’a,产率为58%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.49(d,J=8.4Hz,4H),7.20(d,J=8.0Hz,4H),4.14-4.09(m,4H),4.07-4.04(m,2H),4.03-3.98(m,4H),3.58(dd,J=13.2,3.2Hz,2H),3.33(dd,J=13.0,5.0Hz,2H),2.39(s,6H),1.43(s,3H),1.39(s,3H),1.27(t,J=7.2Hz,6H),1.23(t,J=7.0Hz,6H).13C NMR(100MHz,CDCl3)δ173.7(d,JC-F=7.0Hz),141.5,133.4,128.6,127.9,109.9,78.1,64.1(d,JC-F=6.0Hz),64.0(d,JC-F=6.0Hz),51.7,47.9(d,JC-F=4.0Hz),27.0,26.9,21.5,16.0(d,JC-F=7.0Hz),15.9(d,JC-F=7.0Hz).31PNMR(162MHz,CDCl3)δ1.78.HRMS(ESI)m/z calcd for C31H47N2O10P2[M+H]+:669.2700,found 669.2706。
产物结构式如下:
实施例20
在反应器中,加入0.24毫摩尔对甲基苯甲酸和1毫升甲苯,然后加入0.24毫摩尔二乙基亚磷酰氯和0.24毫摩尔三乙胺,室温搅拌30分钟后,加入0.2毫摩尔α-D-吡喃糖衍生的叠氮,在50℃反应6小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4qa’a,产率为61%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.51(d,J=8.4Hz,2H),7.15(d,J=8.0Hz,2H),5.62(t,J=9.2Hz,1H),5.13-5.02(m,3H),4.24(dd,J=12.4,5.2Hz,1H),4.18-4.05(m,5H),3.62-3.58(m,1H),2.33(s,3H),2.04(s,3H),1.96(s,3H),1.94(s,3H),1.91(s,3H),1.27-1.23(m,6H).13C NMR(100MHz,CDCl3)δ173.6,170.4,170.3,169.2,169.0,142.6,132.4,128.9,128.2,85.0,74.3,74.2,69.6,67.7,64.8(d,JC-F=6.0Hz),64.1(d,JC-F=6.0Hz),62.0,21.6,20.7,20.6,20.5,16.1(d,JC-F=7.0Hz),15.9(d,JC-F=7.0Hz).31PNMR(162MHz,CDCl3)δ1.12.HRMS(ESI)m/z calcd for C26H37NO13P[M+H]+:602.1997,found602.2001。
产物结构式如下:
实施例21
在反应器中,加入0.24毫摩尔对甲基苯甲酸和1毫升甲苯,然后加入0.24毫摩尔二乙基亚磷酰氯和0.24毫摩尔三乙胺,室温搅拌30分钟后,加入0.2毫摩尔尿苷衍生的叠氮,在50℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=1:2)通过硅胶柱层析得到N-酰基磷酰胺化合物4ra’a,产率为47%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.42(d,J=8.0Hz,2H),7.22(d,J=8.0Hz,1H),7.14(d,J=8.0Hz,2H),5.74(d,J=8.0Hz,1H),5.58(s,1H),4.94-4.93(m,1H),4.82-4.79(m,1H),4.43-4.39(m,1H),4.17-4.03(m,6H),3.19(s,3H),2.37(s,3H),1.54(s,3H),1.33(s,3H),1.27-1.23(m,6H).13C NMR(100MHz,CDCl3)δ173.8(d,JC-F=5.0Hz),162.7,150.6,141.5,140.2,133.3,128.5,128.0,114.4,101.9,95.5,86.8,84.8,82.3,64.0(d,JC-F=7.0Hz),64.0(d,JC-F=6.0Hz),48.6,27.4,27.1,25.3,21.5,16.0,15.9.31PNMR(162MHz,CDCl3)δ2.19.HRMS(ESI)m/z calcd for C25H35N3O9P[M+H]+:552.2105,found552.2110。
产物结构式如下:
实施例22
在反应器中,加入0.24毫摩尔对甲基苯甲酸和1毫升甲苯,然后加入0.24毫摩尔二乙基亚磷酰氯和0.24毫摩尔三乙胺,室温搅拌30分钟后,加入0.2毫摩尔L-苯丙氨酸薄荷醇酯衍生的叠氮,在50℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4sa’a,产率为72%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.32-7.29(m,2H),7.27-7.24(m,3H),7.21(d,J=8.0Hz,2H),7.10(d,J=8.0Hz,2H),5.03(td,J=12.0,4.76Hz,1H),7.84(td,J=13.0,7.4Hz,1H),3.98-3.88(m,2H),3.64-3.55(m,2H),3.42-3.34(m,2H),2.35(s,3H),2.19-2.13(m,3H),1.70(d,J=12.0Hz,2H),1.38(s,1H),1.38(t,J=11.6Hz,1H),1.06(t,J=7.0Hz,3H),1.00(t,J=7.0Hz,3H),0.94-0.90(m,8H),0.83(d,J=6.8Hz,4H).13C NMR(100MHz,CDCl3)δ172.4(d,JC-F=6.0Hz),170.0,140.9,138.5,133.5,129.9,128.4,128.1,127.5,126.5,75.5,63.7(d,JC-F=6.0Hz),63.3(d,JC-F=5.0Hz),61.6(d,JC-F=4.0Hz),47.4,40.8,35.1,34.4,31.5,25.8,23.2,22.1,21.5,21.0,16.0,15.8(d,JC-F=7.0Hz),15.7(d,JC-F=8.0Hz).31P NMR(162MHz,CDCl3)δ1.34.HRMS(ESI)m/z calcd for C31H45NO6P[M+H]+:558.2979,found 558.2984。
产物结构式如下:
实施例23
在反应器中,加入0.24毫摩尔对甲基苯甲酸和1毫升甲苯,然后加入0.24毫摩尔二乙基亚磷酰氯和0.24毫摩尔三乙胺,室温搅拌30分钟后,加入0.2毫摩尔L-苯丙氨酸胆甾醇酯衍生的叠氮,在50℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物4ta’a,产率为69%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.23-7.21(m,2H),7.19-7.17(m,3H),7.15-7.13(m,2H),7.03(d,J=8.0Hz,2H),5.35(s,1H),4.92(td,J=12.0,4.5Hz,1H),4.74-4.66(m,1H),3.96-3.85(m,2H),3.67-3.61(m,1H),3.53-3.48(m,1H),3.43-3.37(m,1H),3.32-3.23(m,1H),2.42-2.32(m,2H),2.29(s,3H),1.97-1.89(m,3H),1.84-1.75(m,2H),1.54-1.37(m,8H),1.32-1.19(m,4H),1.10-1.02(m,10H),0.99-0.96(m,8H),0.86(d,J=6.5Hz,3H),0.80(dd,J=6.5,1.3Hz,6H),0.62(s,3H).13C NMR(100MHz,CDCl3)δ172.6(d,JC-F=6.0Hz),169.8,140.9,139.5,138.4,133.4,129.9,128.4,128.2,127.5,126.6,122.8,75.2,63.9(d,JC-F=6.0Hz),63.4(d,JC-F=6.0Hz),61.6,56.7,56.2,50.0,42.3,39.7,39.5,38.0,37.0,36.6,36.2,35.8,35.4,31.9,31.9,28.2,28.0,27.8,24.3,23.8,22.8,22.6,21.5,21.1,19.3,18.7,15.8(d,JC-F=7.0Hz),15.7(d,JC-F=7.0Hz),11.9.31PNMR(162MHz,CDCl3)δ1.21.HRMS(ESI)m/z calcd for C48H71NO6P[M+H]+:788.5014,found788.5016。
产物结构式如下:
实施例24
在反应器中,加入0.24毫摩尔雌酚酸和1毫升甲苯,然后加入0.24毫摩尔二乙基亚磷酰氯和0.24毫摩尔三乙胺,室温搅拌30分钟后,加入0.2毫摩尔L-苯丙氨酸甲酯衍生的叠氮,在50℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物6aa’c,产率为69%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ4.12-4.02(m,4H),4.45(dd,J=13.2,9.2Hz,1H),3.76(s,3H),7.52(d,J=8.0Hz,2H),7.18(d,J=7.6Hz,2H),2.43-2.39(m,4H),1.68-1.62(m,1H),1.24(t,J=7.0Hz,3H),1.19(t,J=7.4Hz,3H),1.16(d,J=6.5Hz,3H),0.98-0.88(m,4H).13C NMR(100MHz,CDCl3)δ220.6,172.8(d,JC-F=7.0Hz),171.0,142.8,138.1,135.8,133.5,129.9,128.4,128.4,126.7,125.0,124.6,64.0(d,JC-F=6.0Hz),63.5(d,JC-F=5.0Hz),61.4,52.5,50.5,47.9,44.4,37.8,35.8,35.2,31.5,29.2,26.3,25.5,21.6,15.9(d,JC-F=8.0Hz),15.8(d,JC-F=8.0Hz),13.8.31P NMR(162MHz,CDCl3)δ2.04.HRMS(ESI)m/z calcd for C33H43NO7P[M+H]+:596.2772,found 596.2775。
产物结构式如下:
实施例25
在反应器中,加入0.24毫摩尔非布索坦和1毫升甲苯,然后加入0.24毫摩尔二乙基亚磷酰氯和0.24毫摩尔三乙胺,室温搅拌30分钟后,加入0.2毫摩尔L-苯丙氨酸甲酯衍生的叠氮,在50℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=1:1)通过硅胶柱层析得到N-酰基磷酰胺化合物6aa’d,产率为80%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ8.07-8.05(m,1H),8.03(d,J=2.3Hz,1H),7.37-7.33(m,2H),7.30-7.26(m,3H),7.01(d,J=8.8Hz,1H),5.16-5.09(m,1H),4.13-4.05(m,2H),3.90(d,J=6.4Hz,2H),3.85(s,3H),3.80-3.74(m,1H),3.61-3.51(m,2H),3.43-3.37(m,1H),2.36(s,3H),2.36-2.17(m,1H),4.45(td,J=16.0,6.7Hz,3H),1.14-1.09(m,9H).13C NMR(100MHz,CDCl3)δ170.5(d,JC-F=1.0Hz),165.0(d,JC-F=6.0Hz),165.0,162.2,156.6,137.7,132.4,131.8,129.7,128.7,126.9,125.9,124.0,115.5,112.7,102.8,75.7,64.6(d,JC-F=6.0Hz),64.0(d,JC-F=5.0Hz),61.7(d,JC-F=3.0Hz),52.6,35.2,28.2,19.1,16.7,16.0(d,JC-F=3.0Hz),15.9(d,JC-F=2.0Hz).31P NMR(162MHz,CDCl3)δ0.37.HRMS(ESI)m/z calcd for C30H37N3O7PS[M+H]+:614.2084,found 614.2088。
产物结构式如下:
实施例26
在反应器中,加入0.24毫摩尔吲哚美辛和1毫升甲苯,然后加入0.24毫摩尔二乙基亚磷酰氯和0.24毫摩尔三乙胺,室温搅拌30分钟后,加入0.2毫摩尔L-苯丙氨酸甲酯衍生的叠氮,在50℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=1:1)通过硅胶柱层析得到N-酰基磷酰胺化合物6aa’e,产率为67%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.69(d,J=8.4Hz,2H),7.47(d,J=8.4Hz,2H),7.32-7.29(m,2H),7.24-7.21(m,3H),6.85-6.82(m,2H),6.66(dd,J=8.8,2.4Hz,1H),5.18(td,J=10.0,5.3Hz,1H),4.35-4.27(m,2H),3.83-3.79(m,5H),3.77-3.72(m,4H),3.49-3.40(m,2H),3.36-3.30(m,1H),2.33(s,3H),1.42(t,J=7.2Hz,3H),1.18(t,J=7.0Hz,3H).13C NMR(100MHz,CDCl3)δ172.0(d,JC-F=8.0Hz),170.9(d,JC-F=3.0Hz),168.3,156.0,139.1,138.0,136.2,134.0,131.2,131.1,130.9,129.8,129.1,128.5,126.6,115.0,113.1,110.9,102.0,64.4(d,JC-F=5.0Hz),63.8(d,JC-F=5.0Hz),60.9(d,JC-F=4.0Hz),55.7,52.4,35.3,31.6,16.2(d,JC-F=8.0Hz),16.1(d,JC-F=8.0Hz),13.4.31PNMR(162MHz,CDCl3)δ2.78.HRMS(ESI)m/z calcd for C33H37ClN2O8P[M+H]+:655.1971,found655.1976。
产物结构式如下:
实施例27
在反应器中,加入0.24毫摩尔舒林酸和1毫升甲苯,然后加入0.24毫摩尔二乙基亚磷酰氯和0.24毫摩尔三乙胺,室温搅拌30分钟后,加入0.2毫摩尔L-苯丙氨酸甲酯衍生的叠氮,在50℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=1:2)通过硅胶柱层析得到N-酰基磷酰胺化合物6aa’f,产率为73%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.72(d,J=8.0Hz,2H),7.67(d,J=8.4Hz,2H),7.32(t,J=7.2Hz,2H),7.25-7.20(m,3H),7.15(t,J=6.8Hz,2H),6.65(dd,J=8.8,1.6Hz,1H),6.56(td,J=8.7,1.9Hz,1H),5.19(td,J=10.7,5.3Hz,1H),4.33-4.28(m,2H),3.84-3.69(m,6H),3.50-3.43(m,2H),3.41-3.34(m,1H),2.81(s,3H),2.15(s,3H),1.42(t,J=7.0Hz,3H),1.17(t,J=7.0Hz,3H).13C NMR(100MHz,CDCl3)δ171.4(d,JC-F=8.0Hz),170.8(d,JC-F=3.0Hz),163.3(d,JC-F=244.0Hz),147.0(d,JC-F=8.0Hz),145.4,141.8,139.8,138.4,137.9,132.5(d,JC-F=2.0Hz),130.3,129.8,129.6(d,JC-F=2.0Hz),128.5,128.0,126.7,123.8,123.7(d,JC-F=9.0Hz),110.7(d,JC-F=23.0Hz),105.8(d,JC-F=24.0Hz),64.5(d,JC-F=6.0Hz),63.9(d,JC-F=5.0Hz),60.8,52.4,43.9,35.2,33.0,16.2(d,JC-F=8.0Hz),16.1(d,JC-F=8.0Hz),10.6.31P NMR(162MHz,CDCl3)δ2.71.19F NMR(376MHz,CDCl3)δ-113.31.HRMS(ESI)m/z calcd for C34H38FNO7PS[M+H]+:654.2085,found654.2090。
产物结构式如下:
实施例28
在反应器中,加入0.24毫摩尔维A酸和1毫升甲苯,然后加入0.24毫摩尔二乙基亚磷酰氯和0.24毫摩尔三乙胺,室温搅拌30分钟后,加入0.2毫摩尔L-苯丙氨酸甲酯衍生的叠氮,在50℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=2:1)通过硅胶柱层析得到N-酰基磷酰胺化合物6aa’g,产率为81%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.28-7.16(m,5H),6.99(dd,J=15.0,11.4Hz,1H),6.30-6.23(m,3H),6.16-6.11(m,2H),5.09(td,J=10.5,5.1Hz,1H),4.19-4.12(m,2H),3.76(s,3H),3.59-3.51(m,2H),3.38-3.32(m,1H),3.20-3.14(m,1H),2.27(s,2H),2.06-2.01(m,5H),1.71(s,3H),1.65-1.59(m,2H),1.48-1.45(m,2H),1.26(t,J=7.0Hz,3H),1.07-1.03(m,9H).13C NMR(100MHz,CDCl3)δ171.4(d,JC-F=3.0Hz),167.9(d,JC-F=6.0Hz),151.3,139.6,138.3,137.7,137.3,135.4,131.0,130.1,129.8,129.5,128.7,128.4,126.4,120.5,63.8(d,JC-F=5.0Hz),63.1(d,JC-F=5.0Hz),60.5(d,JC-F=4.0Hz),52.3,39.6,35.4,34.3,33.1,29.0,21.8,19.2,16.0(d,JC-F=8.0Hz),16.0(d,JC-F=7.0Hz),14.6,12.9.31P NMR(162MHz,CDCl3)δ2.22.HRMS(ESI)m/z calcd for C34H49NO6P[M+H]+:598.3292,found 598.3296。
产物结构式如下:
实施例29
在反应器中,加入0.24毫摩尔3-(环丙基甲氧基)-4-(二氟甲氧基)苯甲酸和1毫升甲苯,然后加入0.24毫摩尔二乙基亚磷酰氯和0.24毫摩尔三乙胺,室温搅拌30分钟后,加入0.2毫摩尔4-叠氮基-3,5-二氯吡啶,在50℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=1:1)通过硅胶柱层析得到N-酰基磷酰胺化合物6ua’h,产率为75%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ8.51(s,2H),7.15(s,1H),7.11-7.09(m,1H),7.04-7.02(m,1H),6.63(t,J=74.6Hz,1H),4.36-4.29(m,4H),3.79(d,J=6.8Hz,2H),1.33(t,J=7.0Hz,6H),1.27-1.20(m,1H),0.66-0.62(m,2H),0.35-0.33(m,2H).13CNMR(100MHz,CDCl3)δ169.8,149.8,148.8,142.8(q,JC-F=3.0Hz),132.7,132.7,131.8,121.4,120.4,118.2,115.6,113.5,113.0,74.0,65.6,65.5,16.1,16.0,9.9,3.2.31P NMR(162MHz,CDCl3)δ-4.42.19F NMR(376MHz,CDCl3)δ-82.00.HRMS(ESI)m/z calcd for C21H24Cl2F2N2O6P[M+H]+:539.0712,found 539.0718。
产物结构式如下:
实施例30
在反应器中,加入0.24毫摩尔乙酸和1毫升甲苯,然后加入0.24毫摩尔二乙基亚磷酰氯和0.24毫摩尔三乙胺,室温搅拌30分钟后,加入0.2毫摩尔吗啉衍生的叠氮,在50℃反应4小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=1:1)通过硅胶柱层析得到N-酰基磷酰胺化合物6va’a,产率为47%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ7.43(dd,J=14.4,2.4Hz,1H),7.12-7.10(m,1H),6.92(t,J=9.0Hz,1H),4.92-4.85(m,1H),4.32-4.19(m,4H),4.07-3.99(m,2H),3.88-3.86(m,6H),3.69-3.66(m,1H),3.06-3.04(m,4H),2.40(s,3H),1.41-1.40(m,6H).13C NMR(100MHz,CDCl3)δ172.9(d,JC-F=8.0Hz),155.5(d,JC-F=245.0Hz),154.0,136.4(d,JC-F=9.0Hz),133.3(d,JC-F=10.0Hz),118.8(d,JC-F=4.0Hz),113.9(d,JC-F=3.0Hz),107.5(d,JC-F=26.0Hz),70.5,67.0,64.7(d,JC-F=6.0Hz),64.2(d,JC-F=6.0Hz),51.0(d,JC-F=3.0Hz),48.5,48.3(d,JC-F=4.0Hz),24.5,16.1(d,JC-F=4.0Hz),16.0(d,JC-F=4.0Hz).31P NMR(162MHz,CDCl3)δ2.45.19F NMR(376MHz,CDCl3)δ-120.42.HRMS(ESI)m/zcalcd for C21H31FN2O7P[M+H]+:473.1847,found 473.1849。
产物结构式如下:
实施例31
在反应器中,加入0.2毫摩尔3,3',3”-(((2,4,6-三甲基苯-1,3,5-三基)三(亚甲基))三(氧基))三苯甲酸和1毫升甲苯,然后加入0.6毫摩尔二苯基氯化磷和0.72毫摩尔三乙胺,室温搅拌10分钟后,加入0.6毫摩尔L-苯丙氨酸甲酯衍生的叠氮,在25℃反应8小时后,反应液直接使用洗脱剂(V石油醚:V乙酸乙酯=1:4)通过硅胶柱层析得到N-酰基磷酰胺化合物6aai,产率为63%,无色油状液体。
产物检测数据为:1H NMR(400MHz,CDCl3)δ8.12(dd,J=11.8,7.8Hz,6H),7.88(dd,J=13.6,7.2Hz,6H),7.64-7.60(m,3H),7.54-7.50(m,6H),7.41-7.38(m,3H),7.35-7.31(m,6H),7.20-7.12(m,12H),7.00(d,J=7.2Hz,3H),6.92(d,J=6.8Hz,3H),6.81(s,3H),6.66(s,6H),4.95(q,J=10.0Hz,6H),4.71(t,J=11.4Hz,3H),3.93(s,9H),3.54(dd,J=14.6,3.8Hz,3H),3.29(dd,J=14.6,10.6Hz,3H),2.41(s,9H).13C NMR(100MHz,CDCl3)δ174.3(d,JC-F=3.0Hz),171.1,158.5,139.4,137.2,136.4,133.6(d,JC-F=11.0Hz),132.8,132.0,131.8,131.7,131.5,129.5,129.1,128.6,128.4,128.3,128.2,126.7,120.3,118.6,112.7,65.0,62.7,52.9,36.6,16.0.31P NMR(162MHz,CDCl3)δ30.99.HRMS(ESI)m/zcalcd for C99H91N3O15P3[M+H]+:1654.5658,found 1654.5661。
产物结构式如下:
最后应说明的是:以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (7)
1.一种N-酰基磷酰胺类化合物的合成方法,其特征在于,所述方法为:将羧酸、叠氮化合物、磷氯化合物、碱和反应溶剂混合反应即得,所述反应结构式如下所示:
其中,R选自苯基或者乙氧基;R'羧酸选自苯甲酸、苯环不同位置各种取代的苯甲酸、2-萘甲酸、呋喃-2-甲酸、噻吩-2-甲酸、吡啶-2-甲酸、吡啶-2,6-二甲酸、喹啉-2-甲酸、咕吨-9-甲酸、4-甲基苯乙酸、乙酸、丙酸、2-溴-己酸、三氟乙酸、肉桂酸、1-环己烯甲酸、非布索坦、吲哚美辛、舒林酸、维A酸;;R”叠氮选自苄基叠氮、苯基叠氮、氨基酸衍生的叠氮、酒石酸衍生的叠氮、alpha-D-吡喃糖衍生的叠氮、尿嘧啶核苷衍生的叠氮;所述碱选自三乙胺、二异丙基乙胺、二乙胺、三乙烯二胺、1,8-二氮杂二环十一碳-7-烯、4-二甲氨基吡啶或四甲基胍。
2.如权利要求1所述的合成方法,其特征在于,所述的反应溶剂为甲苯、氯苯、二氯甲烷、乙醚或乙腈中的任一种或几种的组合。
3.如权利要求1所述的合成方法,其特征在于,所述磷氯化合物选自二苯基氯化磷、二乙基亚磷酰氯。
4.如权利要求1所述的合成方法,其特征在于,所述的叠氮化合物、磷氯化合物、羧酸和碱的摩尔比为1.0:1.2:1.2:1.2-1.0:1.2:1.2:1.5。
5.如权利要求1所述的合成方法,其特征在于,所述反应体系中叠氮化合物的反应浓度为0.05-0.4摩尔每升。
6.如权利要求1-5任一所述的合成方法,其特征在于,所述反应气氛为氩气条件;反应时间为2-12小时。
7.如权利要求6所述的合成方法,其特征在于,所述方法还包括:反应后,将反应液进行柱层析,所述柱层析的洗脱剂为石油醚和乙酸乙酯,所述石油醚和乙酸乙酯的体积比为2:1-1:2。
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