CN107501323B - 一种三环膦酸酯类化合物的制备方法 - Google Patents
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- CAIZIGKCPQJNCW-UHFFFAOYSA-N nitric acid;pyridine Chemical compound O[N+]([O-])=O.C1=CC=NC=C1 CAIZIGKCPQJNCW-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
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- 238000012805 post-processing Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
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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
- C07F9/547—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
- C07F9/576—Six-membered rings
- C07F9/5765—Six-membered rings condensed with carbocyclic rings or carbocyclic ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Materials For Photolithography (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种三环膦酸酯类化合物(I)的制备方法。该方法以三环酮为起始原料,在无溶剂或适当溶剂中以酸性化合物为催化剂条件下与相应的亚磷酸酯类化合物反应,一步即可得到三环膦酸酯类化合物(I);式中:R表示C1‑12烷基、苄基。
Description
技术领域
本发明属药物化学领域,涉及一类化学结构如(I)所示的三环膦酸酯类化合物的制备方法,
式中:R表示C1-12烷基、苄基。
背景技术
氯雷他定(Loratadine),化学名为:4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚烷并[1,2-b]吡啶-11-亚基)-1-哌啶羧酸乙酯,是一种长效非镇静三环类抗组胺药物,可竞争性地抑制组胺H1受体,抑制组胺所引起的过敏症状,在临床使用中具有疗效确切、服用方便、毒副作用低等特点。
目前,已有较多文献报道了氯雷他定的合成方法(参见文献:庄守群等. 氯雷他定合成工艺研究进展. 中国医药工业杂志2013,44(12),1291-1299),在这些方法中,最具应用潜力的是以三环膦酸酯类化合物(I)为关键中间体的制备方法。该方法以氯代三环化合物(1)为起始原料,先在NaH作用下与亚磷酸三甲酯反应得到三环膦酸二甲酯(2),然后再与相应的哌啶酮(3)经Wittig-Horner反应即可得到氯雷他定(参见文献:Tamarang SA. ES2040177),其合成路线如下:
而氯代三环化合物(1)可按照现有技术,以相应的三环酮(4)为原料,先用NaBH4将其还原为相应的三环醇,然后进一步经氯化亚砜氯代得到(参见文献:Bishop WR. U.S5719148)。
显然,上述制备三环膦酸酯类化合物(I)的方法存在反应步骤多、反应条件苛刻、反应操作及后处理过程繁琐、制备过程中“三废”排放严重等不足,使三环膦酸酯类化合物(I)的合成成本较高,大量制备受到限制。因此,本领域仍需开发原料价廉易得、反应条件温和、操作简便、化学收率高、“绿色环保”的三环膦酸酯类化合物(I)制备新方法。
发明内容
本发明的目的是在于避免现有方法的不足,提供一种反应步骤少、反应环境友好、反应操作及后处理简便、成本低、可大量制备三环膦酸酯类化合物(I)的合成新方法。
本发明所提出的制备三环膦酸酯类化合物(I)新方法,是以三环酮(4)为起始原料,在无溶剂或适当溶剂中以酸性化合物为催化剂条件下与相应的亚磷酸酯类化合物(5)反应,一步即可得到三环膦酸酯类化合物(I),其合成路线如下:
式中:R表示C1-12烷基、苄基。
其具体制备方法如下:以三环酮(4)为起始原料,在无溶剂或适当溶剂中以酸性化合物为催化剂条件下与相应的亚磷酸酯类化合物(5)反应,得三环膦酸酯类化合物(I);其中,反应所用溶剂为:C5-10脂肪烷烃或环烷烃(如:正己烷、正庚烷等)、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、乙腈、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、乙二醇二甲醚、1,4-二氧六环、C1-6脂肪酸与C1-6脂肪醇所形成酯、卤代烃(如:二氯甲烷、氯仿、1,2-二氯乙烷、氯苯、邻二氯苯等)、苯、甲苯或二甲苯;反应在上述单一溶剂中进行,或者在上述溶剂的任意两种混合溶剂中进行,混合溶剂的体积比为1:0.1~10,优选溶剂为:正庚烷、1,4-二氧六环、N,N-二甲基甲酰胺、二氯甲烷、氯仿、氯苯或甲苯;所用酸性化合物为:硫酸、磷酸、硝酸、盐酸、高氯酸、甲烷磺酸、苯磺酸、对甲苯磺酸、硼酸、苯硼酸、吡啶盐酸盐、吡啶硫酸盐、吡啶硝酸盐、吡啶高氯酸盐、吡啶对甲苯磺酸盐、吡啶苯磺酸盐、ZnCl2、TiCl4、SnCl4、SnCl2、NiCl2、FeCl3、BF3、BF3乙醚、AlCl3、CuCl2、CuBr2、金属离子三氟甲磺酸盐、金属离子乙酸盐,优选酸性化合物为:硫酸、磷酸、高氯酸、甲烷磺酸、对甲苯磺酸、硼酸、吡啶硫酸盐、吡啶高氯酸盐、ZnCl2、TiCl4、BF3乙醚、三氟甲磺酸锂、乙酸锌或乙酸铜;三环酮(4):亚磷酸酯类化合物(5):酸性化合物的摩尔投料比为1.0:0.8~20.0:0.05~8.0,优选摩尔投料比为1.0:1.0~8.0:0.1~4.0;反应温度为-20℃~150℃,优选为0℃~100℃;反应时间为20分钟~72小时,优选为1~42小时。
采用上述方法所制备得到的三环膦酸酯类化合物(I)的化学纯度均大于98.5%。本发明的优点在于:与现有技术相比,该方法具有反应步骤短、原料价廉易得,反应条件温和、操作简便且环境友好,无需高温和无水反应条件,适合较大规模制备三环膦酸酯类化合物(I)。
具体实施方式
通过下面的实施例可对本发明进行进一步的描述,然而,本发明的范围并不限于下述实施例。本领域的专业人员能够理解,在不背离本发明的精神和范围的前提下,可以对本发明进行各种变化和修饰。
实施例1
(8-氯-6,11-二氢-5H-苯并[5,6]环庚烷并[1,2-b]吡啶-11-基)膦酸二甲酯(Ia)的制备
在反应瓶中加入三环酮(4)(10.0 mmol)、氯仿(30.0 ml)和P(OMe)3(26.0 mmol),搅拌均匀后,加入磷酸(10.0 mmol),室温搅拌反应12 h。反应结束后,反应液依次用去离子水(30 ml)、10%碳酸钠水溶液(30 ml)和饱和NaCl水溶液(25 ml)洗涤,有机层经无水Na2SO4干燥,过滤,减压蒸除溶剂,残余物经硅胶柱层析纯化,得浅黄色产物,收率65.0%;HRMS(ESI) calcd for C16H18ClNO3P [M+H]+ 338.0713, found 338.0706。
实施例2
(8-氯-6,11-二氢-5H-苯并[5,6]环庚烷并[1,2-b]吡啶-11-基)膦酸二乙酯(Ib)的制备
在反应瓶中加入三环酮(4)(10.0 mmol)、甲苯(40.0 ml)和P(OEt)3(12.0 mmol),搅拌均匀后,加入对甲苯磺酸(5.0 mmol),室温搅拌反应24 h。反应结束后,反应液依次用去离子水(30 ml)、10%碳酸钠水溶液(30 ml)和饱和NaCl水溶液(30 ml)洗涤,有机层经无水Na2SO4干燥,过滤,减压蒸除溶剂,残余物经硅胶柱层析纯化,得浅黄色产物,收率73.8%;mp 77.0~78.5℃;1H NMR(CDCl3) d: 8.40(d, J=4.4 Hz, 1H), 7.47(d, J=7.6 Hz, 1H),7.21(d, J=8.0 Hz, 1H), 7.16(s, 1H), 7.15(d, J=8.0 Hz, 1H), 7.14(t, J=7.6 Hz,1H), 5.01(d, J=32.4 Hz, 1H), 4.01~3.91(m, 3H), 3.88~3.76(m, 3H), 2.87~2.81(m,2H), 1.15(t, J=7.2 Hz, 3H), 1.13(t, J=7.2 Hz, 3H); 13C NMR(CDCl3) d: 152.38,146.64, 142.77, 138.48, 136.82, 133.58, 133.04, 130.53, 130.19, 126.04,122.55, 62.77, 62.56, 57.047(d, J=128.0 Hz), 32.15, 31.33, 16.16, 16.11; HRMS(ESI) calcd for C18H22ClNO3P [M+H]+ 366.1026, found 366.1023。
实施例3
(8-氯-6,11-二氢-5H-苯并[5,6]环庚烷并[1,2-b]吡啶-11-基)膦酸二丁酯(Ic)的制备
在反应瓶中加入三环酮(4)(10.0 mmol)、N,N-二甲基甲酰胺(20.0 ml)和P(OBu-n)3(15.0 mmol),搅拌均匀后,加入硼酸(5.0 mmol),升温至80~90℃保温搅拌反应6 h。反应结束后,冷却至室温,加入二氯甲烷(50.0 ml),反应液依次用去离子水(30 ml)、10%碳酸钠水溶液(30 ml)和饱和NaCl水溶液(30 ml)洗涤,有机层经无水Na2SO4干燥,过滤,减压蒸除溶剂,残余物经硅胶柱层析纯化,得浅黄色产物,收率55.2%;HRMS (ESI) calcd forC22H30ClNO3P [M+H]+ 422.1652, found 422.1648。
实施例4
(8-氯-6,11-二氢-5H-苯并[5,6]环庚烷并[1,2-b]吡啶-11-基)膦酸二苄酯(Id)的制备
在反应瓶中加入三环酮(4)(10.0 mmol)、1,4-二氧六环(20.0 ml)和P(OCH2Ph)3(15.0 mmol),搅拌均匀后,加入BF3乙醚(10.0 mmol),室温搅拌反应12 h。反应结束后,加入二氯甲烷(50.0 ml),反应液依次用去离子水(30 ml)、10%碳酸钠水溶液(30 ml)和饱和NaCl水溶液(30 ml)洗涤,有机层经无水Na2SO4干燥,过滤,减压蒸除溶剂,残余物经硅胶柱层析纯化,得浅黄色产物,收率60.0%;HRMS (ESI) calcd for C28H26ClNO3P [M+H]+490.1339, found 490.1348。
实施例5
(8-氯-6,11-二氢-5H-苯并[5,6]环庚烷并[1,2-b]吡啶-11-基)膦酸二乙酯(Ib)的制备
在反应瓶中加入三环酮(4)(10.0 mmol)、氯仿(40.0 ml)和P(OEt)3(20.0 mmol),搅拌均匀后,加入高氯酸(5.0 mmol),室温搅拌反应12 h。反应结束后,反应液依次用去离子水(30 ml)、10%碳酸钠水溶液(30 ml)和饱和NaCl水溶液(30 ml)洗涤,有机层经无水Na2SO4干燥,过滤,减压蒸除溶剂,残余物经硅胶柱层析纯化,得浅黄色产物,收率71.0%;mp77.0~78.5℃。
实施例6
(8-氯-6,11-二氢-5H-苯并[5,6]环庚烷并[1,2-b]吡啶-11-基)膦酸二乙酯(Ib)的制备
在反应瓶中加入三环酮(4)(10.0 mmol)、正庚烷(40.0 ml)和P(OEt)3(40.0mmol),搅拌均匀后,加入吡啶硫酸盐(5.0 mmol),室温搅拌反应12 h。反应结束后,反应液依次用去离子水(30 ml)、10%碳酸钠水溶液(30 ml)和饱和NaCl水溶液(30 ml)洗涤,有机层经无水Na2SO4干燥,过滤,减压蒸除溶剂,残余物经硅胶柱层析纯化,得浅黄色产物,收率57.0%;mp 77.1~78.5℃。
实施例7
(8-氯-6,11-二氢-5H-苯并[5,6]环庚烷并[1,2-b]吡啶-11-基)膦酸二乙酯(Ib)的制备
在反应瓶中加入三环酮(4)(10.0 mmol)、氯苯(40.0 ml)和P(OEt)3(12.0 mmol),搅拌均匀后,加入吡啶高氯酸盐(10.0 mmol),室温搅拌反应12 h。反应结束后,反应液依次用去离子水(30 ml)、10%碳酸钠水溶液(30 ml)和饱和NaCl水溶液(30 ml)洗涤,有机层经无水Na2SO4干燥,过滤,减压蒸除溶剂,残余物经硅胶柱层析纯化,得浅黄色产物,收率72.8%;mp 77.0~78.5℃。
实施例8
(8-氯-6,11-二氢-5H-苯并[5,6]环庚烷并[1,2-b]吡啶-11-基)膦酸二乙酯(Ib)的制备
在反应瓶中加入三环酮(4)(10.0 mmol)、二氯甲烷(40.0 ml)和P(OEt)3(20.0mmol),搅拌均匀后,加入TiCl4(10.0 mmol),室温搅拌反应8 h。反应结束后,反应液依次用去离子水(30 ml)、10%碳酸钠水溶液(30 ml)和饱和NaCl水溶液(30 ml)洗涤,有机层经无水Na2SO4干燥,过滤,减压蒸除溶剂,残余物经硅胶柱层析纯化,得浅黄色产物,收率58.2%;mp 77.0~79.0℃。
实施例9
(8-氯-6,11-二氢-5H-苯并[5,6]环庚烷并[1,2-b]吡啶-11-基)膦酸二乙酯(Ib)的制备
在反应瓶中加入三环酮(4)(10.0 mmol)、1,4-二氧六环(40.0 ml)和P(OEt)3(20.0 mmol),搅拌均匀后,加入ZnCl2(10.0 mmol),室温搅拌反应10 h。反应结束后,反应液依次用去离子水(30 ml)、10%碳酸钠水溶液(30 ml)和饱和NaCl水溶液(30 ml)洗涤,有机层经无水Na2SO4干燥,过滤,减压蒸除溶剂,残余物经硅胶柱层析纯化,得浅黄色产物,收率53.5%;mp 76.5~78.0℃。
实施例10
(8-氯-6,11-二氢-5H-苯并[5,6]环庚烷并[1,2-b]吡啶-11-基)膦酸二乙酯(Ib)的制备
在反应瓶中加入三环酮(4)(10.0 mmol)、二氯甲烷(40.0 ml)和P(OEt)3(20.0mmol),搅拌均匀后,加入BF3乙醚(10.0 mmol),室温搅拌反应12 h。反应结束后,反应液依次用去离子水(30 ml)、10%碳酸钠水溶液(30 ml)和饱和NaCl水溶液(30 ml)洗涤,有机层经无水Na2SO4干燥,过滤,减压蒸除溶剂,残余物经硅胶柱层析纯化,得浅黄色产物,收率61.9%;mp 76.5~78.0℃。
实施例11
(8-氯-6,11-二氢-5H-苯并[5,6]环庚烷并[1,2-b]吡啶-11-基)膦酸二乙酯(Ib)的制备
在反应瓶中加入三环酮(4)(10.0 mmol)、二氯甲烷(20.0 ml)、1,4-二氧六环(20.0 ml)和P(OEt)3(20.0 mmol),搅拌均匀后,加入甲烷磺酸(10.0 mmol),室温搅拌反应6 h。反应结束后,反应液依次用去离子水(30 ml)、10%碳酸钠水溶液(30 ml)和饱和NaCl水溶液(30 ml)洗涤,有机层经无水Na2SO4干燥,过滤,减压蒸除溶剂,残余物经硅胶柱层析纯化,得浅黄色产物,收率71.3%;mp 77.0~78.2℃。
实施例12
(8-氯-6,11-二氢-5H-苯并[5,6]环庚烷并[1,2-b]吡啶-11-基)膦酸二乙酯(Ib)的制备
在反应瓶中加入三环酮(4)(10.0 mmol)、氯仿(30.0 ml)、N,N-二甲基甲酰胺(10.0 ml)和P(OEt)3(20.0 mmol),搅拌均匀后,加入吡啶高氯酸盐(10.0 mmol),室温搅拌反应10 h。反应结束后,反应液依次用去离子水(30 ml)、10%碳酸钠水溶液(30 ml)和饱和NaCl水溶液(30 ml)洗涤,有机层经无水Na2SO4干燥,过滤,减压蒸除溶剂,残余物经硅胶柱层析纯化,得浅黄色产物,收率72.5%;mp 76.5~78.0℃。
实施例13
(8-氯-6,11-二氢-5H-苯并[5,6]环庚烷并[1,2-b]吡啶-11-基)膦酸二乙酯(Ib)的制备
在反应瓶中加入三环酮(4)(10.0 mmol)和P(OEt)3(80.0 mmol),搅拌均匀后,加入磷酸(10.0 mmol),室温搅拌反应10 h。反应结束后,反应液依次用去离子水(30 ml)、10%碳酸钠水溶液(30 ml)和饱和NaCl水溶液(30 ml)洗涤,有机层经无水Na2SO4干燥,过滤,减压蒸除溶剂,残余物经硅胶柱层析纯化,得浅黄色产物,收率70.9%;mp 77.0~78.0℃。
Claims (3)
1.一种三环膦酸酯类化合物(I)的制备方法,其特征在于以三环酮(4)为起始原料,在无溶剂或适当溶剂中以酸性化合物为催化剂条件下与相应的亚磷酸酯类化合物(5)反应得到;
式中:R表示C1-12烷基、苄基;所述酸性化合物为:磷酸、高氯酸、甲烷磺酸、对甲苯磺酸、硼酸、吡啶硫酸盐、吡啶高氯酸盐、ZnCl2、TiCl4、BF3乙醚。
2.如权利要求1所述的三环膦酸酯类化合物(I)的制备方法,其特征在于反应所用溶剂为:C5-10脂肪烷烃或环烷烃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、乙腈、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、乙二醇二甲醚、1,4-二氧六环、C1-6脂肪酸与C1-6脂肪醇所形成酯、二氯甲烷、氯仿、1,2-二氯乙烷、氯苯、邻二氯苯、苯、甲苯或二甲苯;反应在上述单一溶剂中进行,或者在上述溶剂的任意两种混合溶剂中进行,混合溶剂的体积比为1.0:0.1~10.0。
3.如权利要求1所述的三环膦酸酯类化合物(I)的制备方法,其特征在于三环酮(4):亚磷酸酯类化合物(5):酸性化合物的摩尔投料比为1.0:0.8~20.0:0.05~8.0;反应温度为-20℃~150℃;反应时间为20分钟~72小时。
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