CN1042537C - 氮杂大环或无环氨基膦酸酯衍生物的制备方法 - Google Patents
氮杂大环或无环氨基膦酸酯衍生物的制备方法 Download PDFInfo
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Classifications
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- 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
-
- 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
- C07F9/6524—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen atoms as the only ring hetero atoms
-
- 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
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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Abstract
披露了一种新的制备氮杂大环或无环氨基磷酸酯的方法。该方法包括将适宜的氮杂大环或无环伯或仲胺与三烷基亚磷酸酯和多聚甲醛反应。
Description
本发明涉及氮杂大环或无环氨基膦酸酯衍生物的新制备方法。该方法可提供用于诊断或治疗剂的配位体。
作为诊断或治疗剂，大环氨基膦酸酯正受到极大关注。制备此类螯合剂的通常合成方法是将胺与亚磷酸、甲醛和盐酸反应而得到氨基膦酸，如1,4,7,10-四氮杂环十二烷基-1,4,7,10-四亚甲基膦酸(DOTMP)。另外，亚甲基膦基官能度的引入方法为在先前反应中的五磷酸处取代为亚磷酸二或三烷基酯而得到相应的膦酸乙烷基酯。可在碱性条件下将这些酯水解而得到单烷基膦酸半酯。另外，可在酸性条件下将这些全酯水解而得到膦酸，如DOTMP(参阅公开申请WO91/07911)。这种用二或三烷基亚磷酸酯制备氨基膦酸酯的通常合成方法被记录在有关各种线性胺的反应及使用普通方法的文献中。
本发明提供一种制备氮杂大环或无环氨基膦酸酯衍生物的方法，在该衍生物中，具有至少一个被至少一个下式取代的仲或伯氮原子
-CH2PO3RR1(1)其中R为H或C1-C5烷基；前提是所有的R必须为相同基团：
R1为C1-C5烷基、H、Na或K；前提是当R1为C1-C5烷基时所有的R和R1为相同的基团；该方法包括：将相应的未取代胺化合物与三烷基亚磷酸盐(酯)和多聚甲醛反应，从而得到式中所有R和R1均为C1-C5烷基的式(Ⅰ)衍生物；和
(a)随后选择性进行碱性水解从而得到式Ⅰ衍生物，其中R为C1-C5烷基和R1为H、Na或K；和/或
(b)随后选择性进行酸性水解从而得到式Ⅰ衍生物，其中R和R1均为H。
在上述式Ⅰ配位体中，
当(ⅰ)所有R和R1均为H，此配位体指膦酸；
(ⅱ)所有R为H,R1为C1-C5烷基，此配位体指膦酸半酯；
(ⅲ)所有R和R1为C1-C5烷基，此配位体指膦酸酯。
在一些我们未决申请和专利中，我们已经讨论过这些式(1)氮杂大环或无环氨基膦酸酯衍生物作为诊断试剂的应用。尤其当半酯与钆螯合后可用作组织特异磁共振成像(MRI)对照剂。多种氮杂大环或无环氨基膦酸，如DOTMP或EDTMP，当与钐153螯合后，可作为治疗癌症病人的钙化肿瘤止痛剂。
式Ⅰ代合物为氮杂大环或无环氨基膦酸酯衍生物，其中至少一个仲或伯氮原子被至少一个下式的部分取代
-CH2PO3RR1(1)其中，
R为H或C1-C5烷基；前提是所有R为相同基团；
R1为C1-C5烷基、H、Na或K；前提是当R1为C1-C5烷基时，所有的R和R1为相同基团。其包括已知配位体和那些在我们的未决申请中提出的配位体。
在本方法中，用于制备式(Ⅰ)化合物的起始原料的配位体为已知配位体。这些无环胺配位体的一些实例为：
乙二胺(EDA)
二亚乙基三胺(DTA)
三亚乙基四胺(TTA)及各种已知的线性或支链伯或仲胺。
氮杂大环胺配位体的一些实例为：
1,4,7,10-四氮杂环十二烷(环烯)Cyclen；及其他已知的仲氮杂大环胺。
含部分式Ⅰ的氮杂大环或无环氮基膦酸酯衍生物应含至少一个被部分式Ⅰ取代的仲或伯氮原子。可被部分式Ⅰ取代的氮原子的数目为2-10，优选2-6。通常这些氮原子之间隔有2个以上的碳原子。因而这些衍生物可被下式表示：
A-(N-CH2CH2-N)q-Z(Ⅱ)其中
q为1-5的整数；
A可为0,1,2份式Ⅰ或氢；
Z可为0,1,2份式Ⅰ或氢；前提是至少有一个式Ⅰ的A部分或Z部分存在；
A和Z可共构成一个环状化合物。
在我们的未决申请中讨论的适当的氮杂大环胺配位体以下式表示：
下面进一步定义用于式Ⅰ和用于本发明的术语“C1-C5烷基”包括直链和支链烷基。“三烷基亚磷酸酯”包括在所得式Ⅰ产物中水解后具有所需水溶性的任何烷基，如三(C1-C10烷基)亚磷酸酯，优选三(C1-C4烷基)亚磷酸酯，也包括直链和支链烷基。
当制备式Ⅰ氮杂大环配位体的全酯(R和R1均为相同的C1-C5烷基)，压力无严格限定，因而使用环境压力。因为该反应为放热反应，控制在反应第一个小时内的温度在40℃以下，第一个小时后，升高温度以利于反应的完成，但不能超过90℃。此反应的pH值不是关键的，反应在无水条件下进行。反应在无水液体的存在下进行，如三烷基亚磷酸酯反应试剂或溶剂。优选使用溶剂。这种溶剂的实例为：非质子传递极性溶剂，如四氢呋喃(THF)，二噁烷，乙腈和其他类似惰性非水溶剂；烷基部分与得到的R相同的醇，如甲醇、乙醇和丙醇、溶剂优选THF。加入反应物和氮杂大环或无环氨基膦酸酯起始原料的顺序并无严格限定。
当制备式Ⅰ无环配位体全酯(R和R1均为C1-C5烷基)时，反应更剧烈放热。必须严格控制反应在第一个小时内的温度在40℃以下。有效控制温度的方法如已知方法，如冰水浴、溶剂稀释、或改变加入反应物的顺序和速度。如，一种方法为将三烷基亚磷酸酯和多聚甲醛混合，开始时冷却混和物，然后有控制地加入无环胺，用冰水浴保持温度。
通过碱性水解而制备成半酯(R=C1-C5烷基和R1=H,Na或K)的所有式Ⅰ配位体在相应的全酯形成后也完成制备。适宜的碱的实例为碱金属氢氧化物，如钠或钾氢氧化物。所用碱的量为：对于每当量仲胺为1-10当量或对于每当量的胺为2-20当量。当R或R1的烷基链长度为丙基或更长时，使用带水的助溶剂。该助溶剂的适宜实例为有机的与水混溶溶剂，如1,4-二噁烷、THF和丙酮。
可在已知酸性水解条件下(参阅公开申请WO91/07911)从相应的半酯或全酯制备式Ⅰ配位体的全酸。
本方法在本领域中比那些已知方法先进，原因如下：先有方法在水相条件下用二烷基亚磷酸酯对无环胺有较好的结果，但对大环配位体得到不理想的结果。而且当用大环配位体环烯时，分离不出所需的酯。与先有方法比较，当使用本方法时，在任何情况下均能以大于90％的收率得到所需的式Ⅰ产物。
本发明将用下列实例进一步说明，这些实例拟成为本发明的真正实例。将在下列实例中使用的一些名词定义为：g=克；mg=毫克；kg=千克；ml=毫升；μl=微升。通常的原料和方法
所有反应试剂可从供应商购得，无需进一步纯化即可使用。除非另外指出，NMR谱用配有多核四探头(1H、13C、31P、19F)的Bruk-er Ac-250MHz色谱仪在297K下记录。1H谱(D20)以溶剂抑制脉部序列(solvent suyyuession prlse sequence)(“PRESAT”，同核预饱合)记录。1H谱在δ7.26处为残留氯仿(CDCl3)或在δ3.55处为外部二恶烷(D20)作参比。13C和31P谱以去偶质子(宽谱)来记录。用DEPT(Diuatovtionless Enhahcement by PolarigationTsansfcr)实验来测定13C{1H}的化学位移。13C{1H}谱以δ77.00的CDCl3中间峰(在CDCl3中)和δ66.66的外部二恶烷(在D20中)作参比。31P{1H}谱以80.00的外部85％H3PO4作参比。用毛细管熔融法测定熔点并未校正。在低压下(＜600psi)进行半制备的离子交换色谱分离，选用标准的手填Q-Seoherose(阴离子交换)或SP-Sepharose(阳离子交换)玻璃柱，并选用联机紫外检测器在263nm处进行洗脱监测。在Hewlett Packard(惠普)S890A气相色谱/5970质量选择检测器来测定GC/MS谱。
在前文已经讨论过制备式Ⅰ全酯衍生物的方法。典型方法如下：实例1：1,4,7,10-四氮杂环十二烷基-1,4,7,10-亚甲基二丁基
膦酸酯
将10g(58mmol)环烯、62g(246mmol)三丁基亚磷酸酯和7.4g(246mmol)多聚甲醛溶于70ml THF中，在室温(将温度保持在40℃以下)下搅拌24小时。将均相溶液减压浓缩而得到粘性油状物(计量收率)，特征如下：1H NMR(CDCl3)δ0.88(m,24H),1.33(m,16H),1.59(m,16H),280(s,16H),2.90(d,8H),4.00(m,16H)；and13C{1H}NMR(CDCl3)δ13.51,18.65,32.49,32.57,49.04,51.45,53.10,53.18；and31P NMR(CDCl3)δ26.16(s,4p)；
并以下式说明：
实例2：制备1,4,7,10-四氮杂环十二烷基-1,4,7,10-亚甲基二
乙基膦酸酯
当将实例1的三丁基亚磷酸酯换为三乙基亚磷酸酯后再进行如实例1的制备，得到＞98％收率的呈粘性油状物的标题化合物，特征如下：
1H NMR(CDCl3)
δ1.19(m,24H),2.71(s,16H),2.80(d,8H),4.01(m,16H)；and
13C{1H}NMR(CDCl3)
δ15.32,15.42,42.23,51.67,53.18,53.28,61.34,61.45；and
31P NMR(CDCl3)
δ26.02(s,4P)；
并以下式说明：
实例3：N,N′-二(亚甲基二甲基膦酸酯)-2,11-二氮杂〔3,3〕
(21,6)吡啶并烷(pydinophane)的制备
当将实例1中的三丁基亚磷酸酯换为三甲基亚磷酸酯和将环烯换为〔3,3〕(2,6)吡啶并烷后，再进行如实例1的制备，得到收率大于95％的呈很粘油状物的标题化合物，特征如下：
1H NMR(CDCl3)
δ3.39(d,4H),3.88(d,12H),4.08(s,8H),6.84(d,4H),7.13(t,2H)；and
13C{1H}NMR(CDCl3)
δ52.75(d),54.88(d),65.21(d),122.71,135.69,157.14；and
31P NMR(CDCl3)
δ27.22；
并以下式说明：实例4：N,N′-二(亚甲基二乙基膦酸酯)-2,11-二氮杂〔3,3〕(2,
6)吡啶并烷的制备
当将实例1中的三丁基亚磷酸酯换为三乙基亚磷酸酯和将环烯换为2,11-二氮杂〔3,3〕(2,6)吡啶并环后再进行实例1的制备，得到收率大于95％的呈很粘的油状物的标题化合物，特征如下：
1H NMR(CDCl3)
δ1.24(t,12H),3.20(d,4H),3.94(s,8H),4.07(q,8H),6.71(d,4H),6.98(t,2H)；and
13C{1H}NMR(CDCl3)
δ16.48,55.36(d),61.75(d),65.14(d),122.52,135.41,157.04；and
31P{1H}NMR(CDCl3)
δ24.60；
并以下式说明：实例5：N-(2-吡啶基甲基)-N′,N″,N-三(亚甲基二乙基
膦酸酯)-1,4,7,10-四氮杂环十二烷
当将实例1的三丁基亚磷酸酯换为三乙基亚磷酸酯和将环烯换为N-(2-吡啶基甲基)-1,4,7,-10-四氮杂环十二烷后；再进行如实例1的制备，得到收率大于95％的呈很粘油状物的标题化合物，特征如下：
1H NMR(CDCl3)
δ1.25-1.39(m,18H),2.66-2.95(m,22H),3.71(s,2H),4.01-4.22(m,12H),7.10-7.15(m,1H),
7.57-7.65(m,2H),8.46-8.52(m,1H)；
13C{1H}NMR(CDCl3)
δ16.38,16.46,50.45,50.67,52.41,53.19,53.29,53.48,53.58,61.37,61.47,61.52,121.67,123.28,
136.19,148.61,159.90；and
31P{1H}NMR(CDCl3,297°K)
δ26.21；
31P{1H}NMR(CDCl3,217°K)
δ24.18(1P),24.32(2P)；
并以下式说明：
实例6：N-(2-吡啶基甲基)-N′,N″,N-三(亚甲基)二丙基膦酸
酯)-1,4,7,10-四氮杂环十二烷的制备
当将实例1的三丁基亚磷酸酯换为三丙基亚磷酸酯和将环烯换为N-(2-吡啶基甲基-1,4,7,10-四氮杂环十二烷后，再进行如实例1的制备，得到收率大于95％呈粘性油状物的标题化合物，特征如下：
1H NMR(CDCl3)
δ0.91-1.00(m,18H),1.60-1.76(m,12H),2.67-2.99(m,22H),3.73(s,2H),3.94-4.08(m,12H),
7.12-7.15(m,1H),7.46-7.67(m,2H),8.48-8.52(m,1H)；
13C{1H}NMR(CDCl3)
δ9.93,10.21,23.71,23.80,50.17,50.44,52.38,53.09,53.44,61.44,66.79,66.83,121.61,123.23,
136.14,148.54,159.92；and
31P{1H}NMR(CDCl3)
δ26.20(1P),26.23(2P)；
并以下式说明：实例7：3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13，三烯-
3,6,9-亚甲基二乙基膦酸酯的制备
当将实例1的三丁基亚磷酸酯换为三乙基亚磷酸酯和将环烯换为3,6,9,15-四氮杂双环〔9,3,1〕十五-1(15),11,13-三烯后，再进行如实例1的制备，得到收率大于95％的呈粘性油状物的标题化合物，特征如下：
1H NMR(CDCl3)
δ1.23(m,18H),2.77(m,12H),3.04(d,6H),4.13(m,12H),7.17(d,2H),7.60(t,1H)；and
13C NMR(CDCl3)
δ16.43,50.03,50.31,50.43,50.77,51.23,51.38,52.63,53.30,60.86,60.92,61.63,61.74,61.83,
61.93,62.32,76.46,76.97,77.18,77.48,122.50,137.10,157.18；and
31P NMR(CDCl3)
δ24.92(s,2P),24.97(s,1P)；
并以下式说明：
实例8：3,6,9,15-四氮杂双环〔9,3,1〕十五-1(15),11,13-三烯
-3,6,9-亚甲基二(正丙基)膦酸酯的制备
当将实例1的三丁基亚磷酸酯换为三丙基亚磷酸酯和将环烯换为3,6,9,15-四氮杂二环〔9,3,1〕十五-(15),11,13-三烯后，再进行如实例1的制备，得到收率大于95％的呈粘性油状物的标题化合物，特征如下：1H NMR(CDCl3)δ0.88(m,18H),1.61(m,12H),2.72(m,12H),3.03(d,6H),3.97(m,12H),7.13(d,2H),7.55(t,1H)；and13C NMR(CDCl3)δ9.96,23.73,49.84,50.14,50.26,50.57,51.11,51.23,52.43,53.01,60.78,60.84,67.27,67.40,122.48,137.04,157.16；and31P NMR(CDCl3)δ24.98(3P)；
并以下式说明：
实例9：3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13-三烯
-3,6,9-亚甲基二(正丁基)膦酸酯制备
当将实例1的三丁基亚磷酸酯换为三丁基亚磷酸酯和将环烯换为3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13-三烯后，再进行如实例1的制备，得到收率大于95％的呈粘性油状物的标题化合物，特征如下：1H NMR(CDCl3)δ0.84(m,18H),1.27(m,12H),1.58(m,12H),2.57(m,12H),3.01(d,6H),3.99(m,12H),7.12(d,2H),7.54(t,1H)；and13C NMR(CDCl3)δ13.42,13.46,18.50,18.59,32.16,32.43,49.88,50.03,50.16,50.63,51.11,51.27,52.48,53.16,60.71,60.78,65.38,65.48,65.58,122.46,136.96,157.14；and31P NMR(CDCl3)δ24.88(2P),24.93(1P)；
并以下式说明：
前文已讨论过用碱将式1全酯衍生物水解而制备式(Ⅰ)半酯的方法。典型方法如下：实例10：1,4,7,10-四环十二烷基-1,4,7,10-四亚甲基丁基膦酸
酯的钾盐的制备
将3g(3mmol)实例1所制备的酯与3g(48mmol)KOH合并在二恶烷的水溶液(100ml水∶25ml二恶烷)，回流搅拌此溶液16小时，得到固态的所需标题产物(收率为94％)，特征如下：
31PNMR(D20)
δ21.87(S,4P)，并以下式说明：
为制备烷基酯为C1-C3烷基的其他酯衍生物，可在无二恶烷助溶剂的条件下进行水解。实例11：N,N′-二(亚甲基膦酸乙酯)-2,11-二氮杂〔3,3〕(2,6)吡
啶并烷(BPZEP)的制备
当用实例4的酯进行实例10的制备时，可得到收率大于95％的固态标题化合物，特征如下：
1H NMR(D2O)
δ1.10(t,6H),2.97(d,4H),3.81(q,4H),3.84(s,8H),6.73(d,4H),7.09(t,2H)；and
13C{1H}NMR(D2O)
δ18.98,58.76(d),63.69(d),66.53(d),126.35,140.09,159.37；and
31P{1H}NMR(D2O)
δ20.65；
并以下式说明：实例12：3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13-三烯
-3,6,9-亚甲基(正丁基)膦酸酯三钾盐(PMBHE)的制
备
当用实例3的酯进行实例10的制备时，可得到大于95％的固态标题化合物，特征如下：
1H NMR(D2O)
δ0.68(m,9H),1.14(m,6H),1.37(m,6H),2.76(d,6H),3.41(m,12H),3.73(m,6H),7.24(d,2H),
7.76(t,1H)；and
13C NMR(D2O)
δ15.76,15.80,21.12,21.20,34.96,35.06,35.14,52.08,52.53,53.38,53.48,54.49,54.75,57.70,
57.76,61.86,67.65,67.75,67.98,68.08,125.15,142.93,152.25；and
31P NMR
δ9.73(s,2P),21.00(s,1P)；
并以下式说明：
实例13：3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13三烯-
3,6,9-亚甲基(正丙基)膦酸酯三钾盐(PMPHE)的制备
当用实例8的酯进行实例10的制备时，可得到大于95％的固态标题化合物，特征如下：
31P︳NMR
δ20.49(S,3P)；并以下式说明：实例14：3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13-三烯
-3,6,9-亚甲基乙基膦酸酯三钾盐(PMEHE)的制备
当用实例7的酯进行实例10的制备时，可得到大于95％的固态标题化合物，特征如下：
13C NMR(D2O)
δ18.98,19.82,51.78,52.06,53.08,54.46,54.68,57.01,58.22,60.24,63.19,63.25,63.36,63.49,
63.59,63.95,64.18,64.25,66.80,126.62,141.63,159.40；and
31P NMR(D2O)
δ20.58(s,2P),20.78(s,1P)；
并以下式说明：
实例15：N-(2-吡啶基甲基)-N′,N″,N-三(亚甲基膦酸乙酯)
-1,4,7,10-四氮杂环十二烷(PD3EP)
当用实例5的酯进行实例10的制备时，可得到大于95％的固态标题化合物，特征如下：1H NMR(D2O,338°K)δ1.41-1.57(m,9H),3.28-3.89(m,22H),4.09-4.64(m,8H),8.22-8.26(m,2H),8.70-8.75(m,1H),9.00-9.12(m,1H)；and13C{1H}NMR(D2O,338°K)δ19.41,19.51,52.58,53.00,52.31,53.75,53.82,56.04,59.53,64.60,64.76,129.86,131.41,147.31,149.06,154.34；and31P{1H}NMR(D2O,338°K)δ9.64(2P),19.79(1P)；
并以下式说明：实例16：N-(2-吡啶基甲基)-N′,N″,N-三(亚甲基膦酸丙酯)-1,4,7,10-四氮杂环十二烷(PD3PP)的制备
当用实例6的酯进行实例10的制备，可得到大于95％的固态标题化合物，特征如下：1H NMR(D2O,353°K)δ1.24-1.36(m,9H),1.95-2.04(m,6H),3.03-3.29(m,22H),4.10-4.25(m,8H),7.74-7.92(m,2H),8.23-8.29(m,1H),8.87-8.96(m,1H)；and13C{1H}NMR(D2O,353°K)δ13.15,27.20,50.43,53.89,54.48,54.98,55.42,64.33,69.41,126.38,128.30,141.24,152.46,161.45；and31P{1H}NMR(D2O,353°K)δ21.61(2P),21.95(1P)；
并以下式说明：
前文已讨论过制备式(a)膦酸衍生物的方法。典型方法如下：实例17：N,N′-二(亚甲基膦酸)-2,11-二氮杂〔3,3〕(2,6)吡啶
并烷(BP2P)的制备
将实例3制备的N,N′-2(亚甲基二甲基膦酸酯)-2,11-二氮杂〔3,3〕(2,6)吡啶并烷(255mg,0.53mmol)的浓HCl溶液(37％,4ml)加热回流2.5小时。冷却后，将溶液蒸发至干，然后与新鲜的去离子水(3×2ml)一起蒸发以除去过量HCl。将浓缩水溶液冷冻干燥，分离出呈吸湿的棕色固体的最终产物，特征如下：
1H NMR(D2O)
δ3.55(d,4H),4.46(br s,8H),6.90(d,4H),7.37(t,2H)；and
13C{1H}NMR(D2O)
δ57.80(d),63.74(d),127.02,144.18,152.96；and
31P{1H}NMR(D2O)
δ11.71；
并以下式说明：实例18：乙二胺基四亚甲基膦酸(EDTMP)的制备
在搅拌下，将乙二胺(2g,33.3mmo1)加到三乙基亚磷酸酯(23g,140mmol)和多聚甲醛(4.2g,140mmol)的冷却(0℃)THF溶液(20ml)中。添加完全后，将溶液逐步加热至室温并持续搅拌12小时。将此溶液真空浓缩，得到呈粘性油状物的四乙基膦酸酯。
将四乙基膦酸酯(2g)在12MHCl(50ml)中加热至100℃并持续6小时。在冰水浴中冷却此溶液而得到呈白色结晶固体的EDTMP。
对于那些本领域技术人员讲从在此公开的本发明说明书及实践中导出本发明的其他应用也是显而易见的。即这些说明和实例只是用作举例说明，而本发明的实际应用范围和真正内含将在下面的权利要求中描述。
Claims (33)
1．制备式Ⅱ氮杂大环或无环氨基膦酸酯衍生物的方法，
A-(N-CH2CH2-N)q-Z(Ⅱ)其中q为1-5的整数，A为式(Ⅰ)的0,1或2份或氢，Z为式(Ⅰ)的0,1或2份或氢，前提为至少一个式(Ⅰ)的A或Z部分存在；且A和Z可共同形成一个环化合物，该衍生物至少有一个仲或伯氮原子被至少下式的一部分取代
-CH2PO3RR1 (Ⅰ)其中，
R为H或C1-C5烷基；前提是每个R都相同，
R1为C1-C5烷基、H、Na或K；前提是当R1为C1-C5烷基时所有的R和R1为相同基团；该方法包括：于低于40℃温度下将相应的未取代的胺化合物与三烷基亚磷酸酯和多聚甲醛先反应1小时，得到至少一部分所有R和R1为C1-C5烷基的式(Ⅰ)取代的衍生物；和
(a)可进一步选择性碱性水解而得到被两部分R为C1-C5烷基和R1为H、Na或K的式(Ⅰ)取代的衍生物；和/或
(b)可进一步选择性酸性水解而得到被两部分所有R和R1为H的式(Ⅰ)取代的衍生物。
2．权利要求1所述的方法，其中式(Ⅰ)衍生物产物的所有R和R1为C1-C5烷基。
3．权利要求1的方法，其包括将环烯与三丁基亚磷酸酯和多聚甲醛在THF中反应制备1,4,7,10-四氮杂环十二烷基-1,4,7,10-亚甲基二丁基膦酸酯。
4．权利要求1方法，其包括将环烯与三乙基亚磷酸酯和多聚甲醛在THF中反应制备1,4,7,10-四氮杂环十二烷基-1,4,7,10-亚甲基-二乙基膦酸酯。
5．权利要求1方法，其包括将2,11-二氮杂〔3,3〕(2,6)吡啶并烷与三甲基亚磷酸酯和多聚甲醛在THF反应制备N,N′-二(亚甲基二甲基膦酸酯-2,11-二氮杂〔3,3〕(2,6)吡啶并烷。
6．权利要求1所述方法，其包括将2,11-二氮杂〔3,3〕(2,6)吡啶并烷与三乙基亚膦酸酯和多聚甲醛在THF中反应制备N,N′-二(亚甲基二乙基膦酸酯-2,11-二氮杂〔3,3〕(2,6)吡啶并烷。
7．权利要求1所述方法，其包括将N-(2-吡啶基甲基)-1,4,7,10-四氮杂环十二烷与三乙基亚磷酸酯和多聚甲醛在THF中反应制备N-(2-吡啶基甲基)-N′,N″,N-三(亚甲基二乙基膦酸酯)-1,4,7,10-四氮杂环十二烷。
8．权利要求1所述方法，其包括将N-(2-吡啶基甲基)-1,4,7,10-四氮杂环十二烷与三丙基亚磷酸酯和多聚甲醛在THF中反应制备N-(2-吡啶基甲基)-N′,N″,N-三(亚甲基二丙基膦酸酯)-1,4,7,10-四氮杂环十二烷。
9．权利要求1所述方法，其包括将3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13-三烯与三乙基亚膦酸酯和多聚甲醛在THF中反应制备3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13-三烯-3,6,9-亚甲基二乙基膦酸酯。
10．权利要求1所述方法，其包括将3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13-三烯与三丙基亚膦酸酯和多聚甲醛在THF中反应制备3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13-三烯-3,6,9-亚甲基二(正丙基)膦酸酯。
11．权利要求1所述方法，其包括将3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13-三烯与三丁基亚膦酸酯和多聚甲醛在THF中反应制备3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13-三烯-3,6,9-亚甲基二(正丁基)膦酸酯。
12．如权利要求1所述方法，其中式(1)衍生物产物的所有R为H、Na或K和所有R1为C1-C5烷基。
13．权利要求1所述方法，其包括将环烯与三丁基亚磷酸酯和多聚甲醛在THF中反应而得到1,4,7,10-四氮杂环十二烷基-1,4,7,10-亚甲基二丁基膦酸酯，分离出得到的中间体，在水和二噁烷的共溶剂中用KOH进行碱性水解，从而得到1,4,7,10-四环十二烷基-1,4,7,10-四亚甲基丁基膦酸酯四钾盐。
14．权利要求1所述方法，其包括将2,11-二氮杂〔3,3〕(2,6)吡啶并烷与三乙基亚磷酸酯和多聚甲醛在THF反应而得到N,N′-二亚甲基二乙基膦酸酯)-2,11-二氮杂〔3,3〕(2,6)吡啶并烷，分离出得到的中间体，在水中用KOH进行碱性水解，而得到N,N′-二(亚甲基膦酸乙酯)-2,11-二氮杂〔3,3〕(2,6)吡啶并烷。
15．权利要求1所述方法，其包括将3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13-三烯与三丁基亚磷酸酯和多聚甲醛在THF中反应而得到3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13,-三烯-3,6,9-亚甲基(正丁基)膦酸酯，分离出所得的中间体，在水和二噁烷的混合溶剂中用KOH进行碱性水解而得到3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13-三烯-3,6,9-亚甲基(正丁基)膦酸酯三钾盐。
16．权利要求1所述方法，其包括将3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13-三烯与三丙基亚磷酸酯和多聚甲醛在THF中反应，得到3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13,-三烯-3,6,9-亚甲基二(正丙基)膦酸酯，分离出得到的中间体，在水中用KOH进行碱性水解而得到3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13-三烯-3,6,9-亚甲基(正丙基)膦酸酯三钾盐。
17．权利要求1所述方法，其包括将3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13-三烯与三乙基亚磷酸酯和多聚甲醛在THF中反应，得到3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13,-三烯-3,6,9-亚甲基二乙基膦酸酯，分离出所得中间体，在水中用KOH进行碱性水解，从而得到3,6,9,15-四氮杂二环〔9,3,1〕十五-1(15),11,13-三烯-3,6,9-亚甲基乙基膦酸酯三钾盐。
18．权利要求1所述方法，其包括将N-(2-吡啶基甲基)-1,4,7,10-四氮杂环十二烷与三乙基亚磷酸酯和多聚甲醛在THF中反应，得到N-(2-吡啶基甲基)-N′,N″,N-三(亚甲基二乙基膦酸酯)-1,4,7,10-四氮杂环十二烷，分离出所得中间体，在水中用KOH进行碱性水解，得到N-(2-吡啶基甲基)-N′,N″,N三(亚甲基膦酸乙酯)-1,4,7,10-四氮杂环十二烷。
19．权利要求1所述方法，其包括将N-(2-吡啶基甲基)-1,4,7,10-四氮杂环十二烷与三丙基磷酸酯和多聚甲醛在THF中反应，得到N-(2-吡啶基甲基)-N′,N″,N-三(亚甲基二丙基膦酸酯)-1,4,7,10-四氮杂环十二烷，分离出得到的中间体，在水中用KOH进行碱性水解，得到N-(2-吡啶基甲基)-N′,N″,N三(亚甲基膦酸丙酯)-1,4,7,10-四氮杂环十二烷。
20．权利要求1所述方法，其中式(1)衍生物产物的所有R和R1均为H、Na或K。
21．权利要求20所述方法，其包括将2,11-二氮杂〔3,3〕(2,6)吡啶并烷与三甲基亚磷酸酯和多聚甲醛在THF中反应，得到N,N′-二(亚甲基二甲基膦酸酯)-2,11-二氮杂〔3,3〕(2,6)吡啶并烷，用加热的HCl将中间体进行酸性水解，分离出N,N′-二(亚甲基膦酸)-2,11-二氮杂〔3,3〕(2,6)吡啶并烷。
22．权利要求1所述方法，其中三烷基亚磷酸酯为(C1-C4烷基)亚磷酸酯。
23．权利要求1中部分(a)所述方法，其中水溶性碱是碱金属氢氧化物。
24．权利要求1中部分(a)所述方法，其中R或R1为C3-C5烷基，而且存在有有机/水混溶溶剂。
25．权利要求1所述方法，其中式(1)衍生物为R和R1-均为C1-C5烷基的氮杂大环配位体，在反应的最初一小时内将温度保持在40℃以下。
26．权利要求1所述方法，其中式(1)衍生物为R和R1均为C1-C5烷基的氮杂大环配位体，而且存在有非水性液体。
27．权利要求26所述方法，其中液体为非质子传递溶剂或醇类。
28．权利要求27所述方法，其中溶剂为THF。
29．权利要求1所述方法，其中式(1)衍生物为R和R1均为C1-C5烷基的无环胺，在反应的最初一个小时内温度保持在40℃以下。
30．权利要求29所述方法，其中三烷基亚磷酸酯和多聚甲醛混合并冷却，逐渐加入无环胺，用冰水浴保持温度。
31．权利要求29所述方法，其中无环胺为乙二胺，二亚乙基三胺、三亚乙基四胺。
32．权利要求31所述方法，其中通过碱性水解得到单烷基膦酸酯。
33．权利要求32所述方法，其中通过酸性水解得到相应的乙二胺四亚甲基膦酸、二亚乙基三胺五亚甲基膦酸或三亚乙基四胺六亚甲基膦酸。
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| US08/065,963 US5714604A (en) | 1993-05-06 | 1993-05-06 | Process for the preparation of azamacrocyclic or acyclic aminophosphonate ester derivatives |
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| CA2371728C (en) * | 1999-06-11 | 2009-06-02 | Neorx Corporation | High dose radionuclide complexes for bone marrow suppression |
| US7094885B2 (en) * | 1999-07-11 | 2006-08-22 | Neorx Corporation | Skeletal-targeted radiation to treat bone-associated pathologies |
| CA2382877A1 (en) * | 1999-10-18 | 2001-04-26 | Dow Global Technologies Inc. | Aminoalkylenephosphonates for treatment of bone disorders |
| US6794371B1 (en) * | 1999-10-18 | 2004-09-21 | The Dow Chemical Company | Aminoalkylenephosphonates for treatment of bone disorders |
| US6565828B2 (en) * | 2000-04-07 | 2003-05-20 | Bristol-Myers Squibb Company | Macrocyclic chelants for metallopharmaceuticals |
| WO2002062398A2 (en) | 2001-01-08 | 2002-08-15 | Neorx Corporation | Radioactively labelled conjugates of phosphonates |
| ATE329623T1 (de) * | 2001-10-22 | 2006-07-15 | Dow Global Technologies Inc | Radiopharmazeutishes mittel zur behandlung von krebs im frühstadium |
| US6962690B2 (en) | 2001-10-22 | 2005-11-08 | Dow Global Technologies Inc. | Tissue specific fluorescent chelates possessing long wavelength UV excitation |
| US7045116B2 (en) | 2001-12-13 | 2006-05-16 | Dow Global Technologies Inc. | Treatment of osteomyelitis with radiopharmaceuticals |
| US20050112066A1 (en) * | 2003-11-26 | 2005-05-26 | Concat Lp, A California Limited Partnership | Complexes of cyclic polyaza chelators with cations of alkaline earth metals for enhanced biological activity |
| EP1778699A4 (en) * | 2004-08-10 | 2009-02-25 | Dow Global Technologies Inc | TARGETING OF CHELANTS AND CHELATES |
| CN112442069A (zh) * | 2019-08-28 | 2021-03-05 | 广东广山新材料股份有限公司 | 一种带有胺基的含磷阻燃剂及其制备方法和应用 |
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