CN102037056B - 制备高纯度聚乙二醇醛衍生物的方法 - Google Patents

制备高纯度聚乙二醇醛衍生物的方法 Download PDF

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CN102037056B
CN102037056B CN2009801183365A CN200980118336A CN102037056B CN 102037056 B CN102037056 B CN 102037056B CN 2009801183365 A CN2009801183365 A CN 2009801183365A CN 200980118336 A CN200980118336 A CN 200980118336A CN 102037056 B CN102037056 B CN 102037056B
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朴炳旭
金晟年
崔宇爀
张鹤淳
李宽淳
权世昌
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ID Biochem Inc
Hanmi Holdings Co Ltd
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Abstract

本发明提供一种制备高纯度聚乙二醇-亚烷基醛及其衍生物的方法。

Description

制备高纯度聚乙二醇醛衍生物的方法
技术领域
本发明涉及制备高纯度聚乙二醇醛衍生物的方法。
背景技术
聚乙二醇(PEG)是众所周知的代表性亲水聚合物，与天然聚合物和合成聚合物一样，聚乙二醇能与水分子形成氢键。
PEG可溶于许多有机溶剂，并且对人类几乎无毒。由于PEG在水中完全伸展，因此其可以与各种药物（蛋白质、肽、酶、基因等）缀合以通过空间位阻降低药物分子的毒性并保护药物分子的活性免受人体免疫系统的影响。因此，可将PEG应用于各种药物以减缓其从血液中的清除。
此外，当PEG连接于具有良好药效但具有高毒性和低溶解性的药物时，所得的PEG-药物具有改善的溶解性和降低的毒性。
为了将PEG引入药物，在PEG链末端连接各种官能团。
PEG-丙醛用于通过缀合来增加药物的溶解性和功效。
PEG-丙醛和甲氧基PEG-丙醛(mPEG-丙醛)可通过氧化PEG的末端羟基或引入缩醛基团随后水解而获得。例如，美国专利第6,465,694号公开了制备PEG-醛衍生物的方法，其中将氧气添加至PEG和催化剂的混合物中以将-CH2OH基团氧化为-CHO。然而，在大多数氧化条件下，PEG链会分解。并且，在PEG链末端引入缩醛基因为反应物昂贵而不适于商业化。
此外，关于PEG化或PEG与药物的共价连接，美国专利第4,002,531号(Pierce Chemical Company)公开了以MnO2氧化mPEG(1K)以制备mPEG醛并将其连接于胰蛋白酶（PEG化），从而用作药物递送系统的方法。然而，该氧化反应会导致PEG链的分解增加。而且，转化率并不高，为80%以下。
在J.Polym.Sci.Ed,1984,22,第341-352页中，通过下述方法制备了PEG-乙醛：使PEG(3.4K)与溴乙醛反应以制备PEG-缩醛，然后水解。根据该文献，末端醛基的活化度为约65%，其他的约35%仍是未反应的羟基。因此，不经过进一步的纯化，其不适用于药物递送系统。
在美国专利第4,002,531号(University of Alabama,Huntsville)中，当PEG与具有缩醛基的小分子反应时，PEG链末端的羟基被高反应性的巯基(-SH)取代。考虑到PEG-OH具有低反应性且难以通过亲核取代与单一分子反应，因此预计活化度与J.Polym.Sci.Ed,1984,22,第341-352页的报道（约65%）不会有太大差异。
美国专利第5,990,237号(Shearwater Polymers,Inc)提出了这样的方法：将PEG醛与各种具有氨基的水溶性聚合物（蛋白、酶、多肽、药物、染料、核苷、寡核苷酸、脂质、磷脂、脂质体等）偶联，由此制备在水溶液中稳定、在聚合物链中不具有易水解基团（例如，酯基）的聚合物。然而，实施例中提供的PEG醛的纯度随反应条件变化(85%～98%)。
WO2004/013205 A1(F.Hoffmann-La Roche AG)和美国专利第6,956,135 B2号(Sun Bio,Inc)提出了在PEG链的末端具有醛基而在PEG链内含有羰基或氮的物质。这些物质可显示出与具有仅由氧和氢构成的PEG链的物质不同的性质。此外，由于PEG链的末端官能团未经中间纯化步骤而转化，因此有很高的产生副产物(未反应的PEG)的风险。
发明内容
技术问题
本发明的目的是提供制备聚乙二醇(PEG)醛衍生物的方法，所述方法能将PEG或PEG衍生物（PEG链末端的一个醇基被取代为烷氧基的衍生物，在本文中称为烷氧基-PEG）的羟基氧化为醛基。
更具体而言，本发明的目的是提供一种能经济地由PEG或烷氧基-PEG（如mPEG）制备不含杂质的PEG醛或烷氧基-PEG醛的制备方法，所述PEG醛或烷氧基-PEG醛用于通过与药物连接而改善药物的溶解性和功效。
技术方案
本发明的发明人已发现由PEG链的分解导致的低分子量PEG的产生可通过在温和的条件下氧化聚乙二醇(PEG)或烷氧基-PEG(Pfitzner-Moffatt氧化)以将末端羟基转化为醛基，或通过在PEG或烷氧基-PEG的末端引入羟基(C3-C10)烷基而后在温和条件下氧化(Pfitzner-Moffatt氧化)以将末端羟基转化为醛基而减至最少。
本发明的制备方法被认为是一种适于商业应用的经济型方法，因为大分子化合物的末端醇基可定量转化为醛基而不导致PEG链的分解，多数反应物是可商购的物质，并且所涉及的反应无需特殊的制备装置（例如，低温、高温、高压等）。
在第一实施方式中，本发明提供一种通过使化学式2表示的PEG衍生物与二甲亚砜和二环己基碳二亚胺反应而制备化学式1表示的PEG醛的方法：
[化学式1]
OHC-(CH2)m-1-O-(CH2CH2O)n-(CH2)m-1-CHO
[化学式2]
HO-(CH2)m-O-(CH2CH2O)n-(CH2)m-OH
其中，
n代表3～2000的整数，且
m代表2～10的整数。
在第二实施方式中，本发明提供一种通过使化学式11表示的PEG衍生物与二甲亚砜和二环己基碳二亚胺反应而制备化学式10表示的PEG醛的方法：
[化学式10]
R2O-(CH2CH2O)n-(CH2)m-1-CHO
[化学式11]
R2O-(CH2CH2O)n-(CH2)m-OH
其中，
n代表3～2000的整数，
m代表2～10的整数，且
R2选自(C1-C7)烷基或(C6-C20)芳基(C1-C7)烷基。
下面将具体描述本发明的实施方式。
除非另作规定，本发明中所用的所有术语（包括技术术语和科技术语）具有与本领域普通技术人员通常理解的含义相同的含义。在本说明书中，为避免使所述实施方式的不必要的模糊，可省略对公知特征和技术的详细描述。
本发明第一实施方式的制备PEG醛的方法使得能够将化学式2表示的化合物的醇基氧化为醛而不导致PEG链的分解，由此使得能够制备高纯度的化学式1表示的PEG醛，且含有较少的如由PEG链分解产生的低分子量PEG、PEG酸等杂质：
[化学式1]
OHC-(CH2)m-1-O-(CH2CH2O)n-(CH2)m-1-CHO
[化学式2]
HO-(CH2)m-O-(CH2CH2O)n-(CH2)m-OH
其中，
n代表3～2000的整数，且
m代表2～10的整数。
更具体而言，上述反应通过将化学式2表示的PEG衍生物与二甲亚砜、三氟乙酸和吡啶混合，然后添加二环己基碳二亚胺而进行。可选的是，在反应后可使用庚烷-异丙醇混合物对产物进行结晶并使用乙腈(AN)-甲基叔丁基醚(MTBE)混合物进行重结晶。
在本发明第一实施方式的制备PEG醛的方法中，制备在PEG末端具有C3-C10醛基的PEG醛的方法具体包括：在化学式3表示的PEG的末端引入羟基(C3-C10)烷基以制备化学式4表示的PEG衍生物；和使用二甲基砜和二环己基碳二亚胺氧化化学式4表示的衍生物以制备化学式1表示的PEG醛：
[化学式3]
HO-(CH2CH2O)n-H
[化学式4]
HO-(CH2)k-O-(CH2CH2O)n-(CH2)k-OH
其中，
n代表3～2000的整数，且
k代表3～10的整数。
具体而言，制备化学式4表示的PEG衍生物的方法包括：
(a)使化学式3表示的PEG与化学式5表示的氰基烯反应以制备化学式6表示的氰烷基-PEG；
(b)由所述化学式6表示的氰烷基-PEG制备化学式7表示的PEG-羧酸；
(c)使化学式7表示的PEG-羧酸与化学式8表示的醇反应以制备化学式9表示的PEG-酯化合物；和
(d)还原化学式9表示的PEG-酯化合物以制备化学式4表示的PEG衍生物：
[化学式3]
HO-(CH2CH2O)n-H
[化学式4]
HO-(CH2)k-O-(CH2CH2O)n-(CH2)k-OH
[化学式5]
Figure GDA00002025293100051
[化学式6]
NC-(CH2)k-1-O-(CH2CH2O)n-(CH2)k-1-CN
[化学式7]
HOOC-(CH2)k-1-O-(CH2CH2O)n-(CH2)k-1-COOH
[化学式8]
R1-OH
[化学式9]
R1OOC-(CH2)k-1-O-(CH2CH2O)n-(CH2)k-1-COOR1
其中，
n代表3～2000的整数，
k代表3～10的整数，并且
R1选自(C1-C7)烷基或(C6-C20)芳基(C1-C7)烷基。
当制备化学式4表示的PEG衍生物时，在步骤(b)～(d)中的一步或多步之后，还可以包括通过使用离子交换树脂柱分离反应副产物（特别是PEG和PEG酸）而纯化产物的步骤。
本发明第二实施方式的制备PEG醛的方法使得能够将化学式11表示的化合物的醇基氧化为醛而不导致PEG链的分解，由此使得能够制备高纯度的化学式10表示的PEG醛，且含有较少的如由PEG链分解产生的低分子量PEG、PEG酸等杂质：
[化学式10]
R2O-(CH2CH2O)n-(CH2)m-1-CHO
[化学式11]
R2O-(CH2CH2O)n-(CH2)m-OH
其中，
n代表3～2000的整数，
m代表2～10的整数，且
R2选自(C 1-C7)烷基或(C6-C20)芳基(C 1-C7)烷基。
更具体而言，在化学式11中，R2可以是例如甲基、乙基、丙基、丁基和苄基。
更具体而言，上述反应通过将化学式11表示的PEG衍生物与二甲亚砜、三氟乙酸和吡啶混合，然后添加二环己基碳二亚胺而进行。可选的是，在反应后可使用庚烷-异丙醇混合物对产物进行结晶并使用AN-MTBE混合物进行重结晶。
在本发明第二实施方式的制备PEG醛的方法中，制备在PEG末端具有C3-C10醛基的PEG醛的方法具体包括：在化学式12表示的烷氧基-PEG的末端引入羟基(C3-C10)烷基以制备化学式13表示的烷氧基-PEG衍生物；和使用二甲亚砜和二环己基碳二亚胺氧化化学式13表示的衍生物以制备化学式10表示的PEG醛：
[化学式12]
R2O-(CH2CH2O)n-H
[化学式13]
R2O-(CH2CH2O)n-(CH2)k-OH
其中，
n代表3～2000的整数，
k代表3～10的整数，且
R2选自(C1-C7)烷基或(C6-C20)芳基(C1-C7)烷基。
更具体而言，在化学式12和13中，R2可以是例如甲基、乙基、丙基、丁基和苄基。
具体而言，制备化学式13表示的烷氧基-PEG衍生物的方法包括：
(a)使化学式12表示的烷氧基-PEG与化学式5表示的氰基烯反应以制备化学式14表示的烷氧基-PEG腈化合物；
(b)由所述化学式14表示的烷氧基-PEG腈化合物制备化学式15表示的烷氧基-PEG羧酸；
(c)使化学式15表示的烷氧基-PEG羧酸与化学式8表示的醇反应以制备化学式16表示的烷氧基-PEG酯化合物；和
(d)还原化学式16表示的烷氧基-PEG酯化合物以制备化学式13表示的PEG衍生物：
[化学式12]
R2O-(CH2CH2O)n-H
[化学式13]
R2O-(CH2CH2O)n-(CH2)k-OH
[化学式5]
Figure GDA00002025293100071
[化学式14]
R2O-(CH2CH2O)n-(CH2)k-1-CN
[化学式15]
R2O-(CH2CH2O)n-(CH2)k-1-COOH
[化学式8]
R1-OH
[化学式16]
R2O-(CH2CH2O)n-(CH2)k-1-COOR1
其中，
n代表3～2000的整数；
k代表3～10的整数；并且
R1和R2独立地选自(C1-C7)烷基或(C6-C20)芳基(C1-C7)烷基。
更具体而言，在化学式5、8和12～16中，R1和R2可以是例如甲基、乙基、丙基、丁基和苄基。
当制备化学式13表示的PEG衍生物时，在步骤(b)～(d)中的一步或多步之后，还可以包括通过使用离子交换树脂柱分离反应副产物（特别是PEG和PEG酸）而纯化产物的步骤。
有利效果
在本发明中，由聚乙二醇(PEG)或烷氧基-PEG通过氰化、水解、酯化、还原和氧化制备PEG醛或烷氧基-PEG醛。由水解和还原产生的副产物（特别是PEG和PEG酸）可通过使用离子交换树脂柱进行分离纯化而减至最少。大分子化合物的末端醇基可定量转化为醛基而不导致PEG链的分解。本发明的制备方法被认为是一种适于商业应用的经济型方法，因为反应物是可商购获得的物质，并且所涉及的反应无需特殊的制备装置（例如，低温、高温、高压等）。
具体实施方式
现在将描述实施例和实验。下述实施例和实验均仅处于描述目的而非旨在限制本发明的范围。除非另外规定，否则%表示摩尔%。
[实施例1]PEG丙醛的制备
Figure GDA00002025293100091
根据上述反应式制备PEG丙醛。下面将对各步骤进行详细描述。
氰化
将PEG（数均分子量＝3.4K，100g）溶解在反应器中的蒸馏水(600mL)中。添加KOH(45g)并将混合物冷却至1℃～5℃。冷却后，添加丙烯腈(16g)并使混合物反应3天。反应完成后，以MC(400mL)将混合物萃取3遍，并完全除去溶剂。
产量：110g。
1H-NMR(200MHz,CDCl3):PEG骨架(m,3.20-4.20ppm),-OCH2 CH 2 CN(t,2.63ppm)
水解和纯化
将浓HCl(500mL)添加至浓缩残余物(110g)中并使混合物在室温反应2天。以MC(400mL)萃取3遍后，将MC彻底浓缩。将10%的KOH溶液(600mL)添加至浓缩残余物(95g)中，并使混合物在室温反应2天。反应完成后，以MC(300mL)将混合物萃取3遍，并浓缩溶剂层。添加乙醚(1.2L)并通过在0℃结晶、过滤和干燥得到白色粉末(88g)。使用离子交换树脂柱纯化干燥的白色粉末。
产量：52g(HPLC纯度：99.94%)
1H-NMR(200MHz,CDCl3):PEG骨架(m,3.20-4.20ppm),-OCH2 CH 2 C(O)OH(t,2.60ppm)
酯化
将MeOH(400mL)和H2SO4(2.25g)添加至纯化的PEG二酸(52g)中并使混合物在室温反应2天。以MC(300mL)萃取3遍后，彻底浓缩溶剂层。
产量：51g
1H-NMR(200MHz,CDCl3):PEG骨架(m,3.20-4.20ppm),-OCH3(s,3.50ppm)，-OCH2 CH 2 C(O)OCH3(t,2.60ppm)
还原和纯化
将MC(30mL)和MeOH(30mL)添加至浓缩残余物(51g)中。搅拌30分钟后，添加NaBH4(3g)并使混合物反应24小时。反应完成后，除去大部分溶剂，添加1N-NaOH溶液(400mL)后，将混合物于80℃的内部温度搅拌1小时。冷却后，添加浓盐酸以将pH调节至1.5～2，并以MC(200mL)将混合物萃取3遍。通过以甲基叔丁基醚(MTBE,600mL)结晶、而后过滤并干燥而获得白色粉末(42g)。使用离子交换树脂柱纯化干燥的白色粉末。
产量：30g(HPLC纯度：100%)
GPC:Mn(3023),PDI(多分散指数)=1.02
1H-NMR(200MHz,CDCl3):PEG骨架(m,3.20-4.20ppm),-OCH2CH2 CH 2 OH(t,2.62ppm),-OCH2 CH 2 CH2OH(t,1.83ppm)
氧化
将PEG丙醇(42g)溶解在MC中(80mL)。添加DMSO(94mL)后，将内部温度降低至0℃～5℃。添加吡啶(3g)和三氟乙酸(TFA,4g)后，在同样的温度搅拌混合物1小时。添加二环己基碳二亚胺(DCC,10g)后，使混合物在室温反应24小时。反应完成后，通过过滤除去沉淀的二环己基脲(DCU)。然后，添加预先配制的庚烷-异丙醇(IPA)(7:3体积%,1088mL)，并通过冷却和结晶获得固体产物。使用AN-MTBE(5:1)重结晶所得固体，并干燥。
产量：25g(NMR纯度：99.73%)
GPC(mPEG):Mn(3156),PDI=1.02
GPC:Mn(3010),PDI=1.02
1H-NMR(500MHz,CDCl3):-C(O)H(s,9.80ppm),PEG骨架(m,3.20-4.20ppm),-OCH2 CH 2 C(O)H(t,2.60ppm)
[实施例2]mPEG-丙醛的制备
以与实施例1相同的方式由mPEG(数均分子量＝20K)制备mPEG(数均分子量＝20K)丙醛。
产率：60%(由mPEG算起，NMR纯度：99.73%)
1H-NMR(500MHz,CDCl3):-C(O)H(s,9.80ppm),PEG骨架(m,3.20-4.20ppm),-OCH2 CH 2 C(O)H(t,2.60ppm)
[实施例3]mPEG-乙醛的制备
通过与实施例1相同的氧化步骤由mPEG(数均分子量＝5K)制备mPEG乙醛。下面进行详细描述。
将mPEG(数均分子量＝5K，50g)溶解在MC中(100mL)。添加DMSO(100mL)后，将内部温度降低至0℃～5℃。添加吡啶(5g)和三氟乙酸(TFA,7g)后，在同样的温度搅拌混合物1小时。添加二环己基碳二亚胺(DCC,15g)后，使混合物在室温反应24小时。反应完成后，通过过滤除去沉淀的二环己基脲(DCU)。然后，添加预先配制的庚烷-IPA(7:3体积%,1000mL)，并通过冷却和结晶获得固体产物。使用AN-MTBE(5:1)重结晶所得固体，并干燥。
产率：95%(由mPEG算起，NMR纯度：99.73%)
1H-NMR(200MHz,CDCl3):-C(O)H(s,9.67ppm),PEG骨架(m,3.20-4.20ppm),-OCH 2 C(O)H(s,4.18ppm)

Claims (11)

1.一种化学式1表示的PEG醛的制备方法，所述方法通过使化学式4表示的PEG衍生物与二甲亚砜和二环己基碳二亚胺反应而进行：
[化学式1]
OHC-(CH2)k-1-O-(CH2CH2O)n-(CH2)k-1-CHO
[化学式4]
HO-(CH2)k-O-(CH2CH2O)n-(CH2)k-OH
其中，
n代表3～2000的整数，且
k代表3～10的整数。
2.如权利要求1所述的PEG醛的制备方法，其中，将所述化学式4表示的PEG衍生物与二甲亚砜、三氟乙酸和吡啶混合，然后向其中添加二环己基碳二亚胺。
3.如权利要求1所述的PEG醛的制备方法，其中，在所述反应后，使用庚烷-异丙醇混合物进行结晶并使用乙腈-甲基叔丁基醚混合物进行重结晶。
4.如权利要求1所述的PEG醛的制备方法，其中，所述化学式4表示的PEG衍生物通过包括下述步骤的方法制备：
使化学式3表示的PEG与化学式5表示的氰基烯反应以制备化学式6表示的氰烷基-PEG；
由所述化学式6表示的氰烷基-PEG制备化学式7表示的PEG-羧酸；
使所述化学式7表示的PEG-羧酸与化学式8表示的醇反应以制备化学式9表示的PEG-酯化合物；和
还原所述化学式9表示的PEG-酯化合物以制备所述化学式4表示的PEG衍生物：
[化学式3]
HO-(CH2CH2O)n-H
[化学式4]
HO-(CH2)k-O-(CH2CH2O)n-(CH2)k-OH
[化学式5]
[化学式6]
NC-(CH2)k-1-O-(CH2CH2O)n-(CH2)k-1-CN
[化学式7]
HOOC-(CH2)k-1-O-(CH2CH2O)n-(CH2)k-1-COOH
[化学式8]
R1-OH
[化学式9]
R1OOC-(CH2)k-1-O-(CH2CH2O)n-(CH2)k-1-COOR1
其中，
n代表3～2000的整数，
k代表3～10的整数，并且
R1选自C1-C7烷基或C6-C20芳基C1-C7烷基。
5.如权利要求4所述的PEG醛的制备方法，所述方法还包括：在所述制备化学式7表示的PEG-羧酸的步骤和/或在所述还原化学式9表示的PEG-酯化合物的步骤之后，使用离子交换树脂柱分离反应副产物。
6.一种化学式10表示的PEG醛的制备方法，所述方法通过使化学式11表示的PEG衍生物与二甲亚砜和二环己基碳二亚胺反应而进行：
[化学式10]
R2O-(CH2CH2O)n-(CH2)m-1-CHO
[化学式11]
R2O-(CH2CH2O)n-(CH2)m-OH
其中，
n代表3～2000的整数，
m代表2～10的整数，且
R2选自C1-C7烷基或C6-C20芳基C1-C7烷基。
7.如权利要求6所述的PEG醛的制备方法，其中，将所述化学式11表示的PEG衍生物与二甲亚砜、三氟乙酸和吡啶混合，然后向其中添加二环己基碳二亚胺。
8.如权利要求6所述的PEG醛的制备方法，其中，在所述反应后，使用庚烷-异丙醇混合物进行结晶并使用乙腈-甲基叔丁基醚混合物进行重结晶。
9.如权利要求6所述的PEG醛的制备方法，其中，所述化学式11表示的PEG衍生物是化学式13表示的PEG衍生物：
[化学式13]
R2O-(CH2CH2O)n-(CH2)k-OH
其中，
n代表3～2000的整数，
k代表3～10的整数，并且
R2选自C1-C7烷基或C6-C20芳基C1-C7烷基。
10.如权利要求9所述的PEG醛的制备方法，其中，所述化学式13表示的PEG衍生物通过包括下述步骤的方法制备：
使化学式12表示的化合物与化学式5表示的氰基烯反应以制备化学式14表示的化合物；
由所述化学式14表示的化合物制备化学式15表示的化合物；
使所述化学式15表示的化合物与化学式8表示的醇反应以制备化学式16表示的化合物；和
还原所述化学式16表示的化合物以制备所述化学式13表示的PEG衍生物：
[化学式12]
R2O-(CH2CH2O)n-H
[化学式13]
R2O-(CH2CH2O)n-(CH2)k-OH
[化学式5]
[化学式14]
R2O-(CH2CH2O)n-(CH2)k-1-CN
[化学式15]
R2O-(CH2CH2O)n-(CH2)k-1-COOH
[化学式8]
R1-OH
[化学式16]
R2O-(CH2CH2O)n-(CH2)k-1-COOR1
其中，
n代表3～2000的整数，
k代表3～10的整数，并且
R1和R2独立地选自C1-C7烷基或C6-C20芳基C1-C7烷基。
11.如权利要求10所述的PEG醛的制备方法，所述方法还包括：在所述制备化学式15表示的化合物的步骤和/或在所述还原化学式16表示的化合物的步骤之后，使用离子交换树脂柱分离反应副产物。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0372752B1 (en) * 1988-11-23 1993-05-05 Genentech, Inc. Cd4 polypeptide derivatives
CN1360611A (zh) * 1999-07-14 2002-07-24 阿尔萨公司 中性脂质聚合物以及含中性脂质聚合物的脂质体组合物
US6465694B1 (en) * 1998-10-26 2002-10-15 University Of Utah Research Foundation Method for preparation of polyethylene glycol aldehyde derivatives

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1000000A (en) * 1910-04-25 1911-08-08 Francis H Holton Vehicle-tire.
US3600121A (en) * 1967-11-27 1971-08-17 Dan River Inc Method for obtaining level dyeing on cellulosic fibers using polyethylene glycol carboxylic acid esters as unstable retarding agent
US4002531A (en) * 1976-01-22 1977-01-11 Pierce Chemical Company Modifying enzymes with polyethylene glycol and product produced thereby
SU1017701A1 (ru) * 1981-11-25 1983-05-15 Московский Ордена Ленина,Ордена Октябрьской Революции И Ордена Трудового Красного Знамени Государственный Университет Им.М.В.Ломоносова Способ получени альдегидных производных полигликолей
SU1085990A1 (ru) * 1983-01-21 1984-04-15 Московский Ордена Ленина,Ордена Октябрьской Революции И Ордена Трудового Красного Знамени Государственный Университет Им.М.В.Ломоносова Способ получени гидроксилсодержащих макроциклических полиэфиров
JPS61205294A (ja) * 1985-03-08 1986-09-11 Suntory Ltd アラビノホスホノヌクレオシドおよびその製法
JP2697495B2 (ja) * 1991-06-19 1998-01-14 富士レビオ株式会社 アルデヒド誘導体
US5622986A (en) * 1993-10-20 1997-04-22 Enzon, Inc. 2'-and/or 7-substituted taxanes
US5990237A (en) * 1997-05-21 1999-11-23 Shearwater Polymers, Inc. Poly(ethylene glycol) aldehyde hydrates and related polymers and applications in modifying amines
US7642323B2 (en) * 1997-11-06 2010-01-05 Nektar Therapeutics Heterobifunctional poly(ethylene glycol) derivatives and methods for their preparation
CA2444880C (en) * 2001-04-23 2009-11-24 Wisconsin Alumni Research Foundation Bifunctional-modified hydrogels
US6956135B2 (en) * 2001-12-11 2005-10-18 Sun Bio, Inc. Monofunctional polyethylene glycol aldehydes
PL371435A1 (en) * 2002-02-01 2005-06-13 Novo Nordisk A/S Amides of aminoalkyl-substituted azetidines, pyrrolidines, piperidines and azepanes
DE60309482T2 (de) * 2002-07-24 2007-06-28 F. Hoffmann-La Roche Ag Polyethylenglykol-aldehydderivate
EP1546235B1 (en) * 2002-09-09 2021-10-20 Nektar Therapeutics Water-soluble polymer alkanals
EP1761282A2 (en) * 2004-06-08 2007-03-14 Alza Corporation Preparation of macromolecular conjugates by four-component condensation reaction
CA2583700A1 (en) * 2004-08-11 2006-02-23 Arqule, Inc. Quinone prodrug compositions and methods of use
US7960498B2 (en) * 2006-06-30 2011-06-14 Actamax Surgical Materials, Llc Tissue adhesives with modified elasticity
US20090324726A1 (en) * 2008-05-01 2009-12-31 Fernandes Julio C Non-Viral Gene Therapy Using Chitosan-Containing Nanoparticles

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0372752B1 (en) * 1988-11-23 1993-05-05 Genentech, Inc. Cd4 polypeptide derivatives
US6465694B1 (en) * 1998-10-26 2002-10-15 University Of Utah Research Foundation Method for preparation of polyethylene glycol aldehyde derivatives
CN1360611A (zh) * 1999-07-14 2002-07-24 阿尔萨公司 中性脂质聚合物以及含中性脂质聚合物的脂质体组合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Samuel Zalipsky.Functionalized Poly(ethylene glycol) for Preparation of Biologically Relevant Conjugates.《Bioconjugate Chemistry》.1995,第6卷(第2期),第156页左栏倒数第1段至右栏第1段，方案6. *

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