TWI397543B - 製備高純度聚乙二醇醛衍生物之方法 - Google Patents
製備高純度聚乙二醇醛衍生物之方法 Download PDFInfo
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Description
本發明係關於一種製備高純度聚乙二醇醛衍生物之方法。
聚乙二醇(PEGs)係眾所周知為代表性之親水性聚合物,其可連同天然聚合物及合成聚合物與水分子形成氫鍵。
它們可溶在許多有機溶劑中,且幾乎對於人類不具毒性。由於聚乙二醇在水中係完全地伸展,故其可與各種藥物(蛋白質、胜肽、酵素、基因等)結合(conjugated),藉由立體阻礙降低藥物分子的毒性,以及保護藥物分子的活性,使其免於人體免疫系統的作用。因此,它可應用於各種藥物,以減緩藥物自血液中清除的速度。
另外,當聚乙二醇連接至具有優異藥物療效,但毒性高且溶解度低之藥物時,所合成的聚乙二醇-藥物具有增進之溶解度及降低之毒性。
為了將聚乙二醇引至藥物上,各種官能基係連接在聚乙二醇鏈的末端。
聚乙二醇-丙醛係藉由結合(conjugation)而用於增加藥物的溶解度及效率。
可藉由氧化聚乙二醇末端之羥基,或引入一縮醛基,接著進行水解,以獲得聚乙二醇-丙醛及甲氧基聚乙二醇-丙醛(mPEG-propionaldehyde)。舉例言之,美國專利第6,465,694號揭露一種製備聚乙二醇-醛衍生物的方法,其中於一聚乙二醇與一催化劑的混合物中加入氧氣,以將-CH2
OH基氧化為-CHO。然而,於大部分的氧化條件下,聚乙二醇鏈會分解。另外,因為反應物昂貴,所以在聚乙二醇鏈的末端引入一縮醛基在商業上係不適用的。
此外,關於聚乙二醇化(PEGylation),或將聚乙二醇共價連接至藥物上,美國專利第4,002,531號(皮爾斯(Pierce)化學公司)揭露一種以二氧化錳氧化甲氧基聚乙二醇(1K)以製備甲氧基聚乙二醇乙醛,並將其連接至酵素胰蛋白酶(聚乙二醇化)以用作藥物遞送系統的製程。然而,此氧化反應會使聚乙二醇鏈的分解增加。另外,轉換速率並不高,為80%或更低。
在J. Polym. Sci.
Ed,1984,22,第341至352頁中,聚乙二醇-乙醛係從聚乙二醇(3.4K)與溴乙醛製備聚乙二醇-縮醛的反應,接著進行水解而製得。根據該論文,在末端基上之醛的活化程度大約為65%,剩下的-35%殘留為未反應的羥基。因此,在沒有進一步之純化前,它不適用於藥物遞送系統。
在美國專利第4,002,531號(位於亨茨維爾(Huntsville)的阿拉巴馬大學)中,當聚乙二醇與一具有一縮醛基的小分子反應時,該聚乙二醇鏈末端上的羥基係經高反應性的硫醇基(-SH)取代。鑒於聚乙二醇-OH具有低反應性,且不易藉由親核性取代反應使其與一單一分子反應,可預期活化的程度不會與J. Polym. Sci.
Ed,1984,22,第341至352頁所記載的活化程度(-65%)有很大的差異。
美國專利第5,990,237號(海鷗(Shearwater)聚合物公司)提出一種偶合聚乙二醇醛類至各種具有胺基之水溶性聚合物(蛋白質、酵素、多胜肽、藥物、色素、核苷酸、寡核苷酸、脂質、磷脂質、脂質體等)的方法,從而製備於含水溶液中穩定的聚合物,而在聚合物鏈上沒有可容易水解的基團,例如酯。然而,在該些例子中所提供之聚乙二醇醛類的純度係依照反應條件而變化(85至98%)。
WO 2004/013205 A1(F. Hoffmann-La Roche AG)以及美國專利第6,956,135 B2(Sun Bio公司)提出在聚乙二醇鏈的末端上具有一醛基,但在該聚乙二醇鏈中包含羰基或氮的物質。它們可顯現出與具有一僅由氧與氫所組成之聚乙二醇鏈之物質不同的特性。另外,由於該聚乙二醇鏈的末端官能基係不經中間的純化步驟而轉換,故有產生副產物(未反應的聚乙二醇)的高風險。
本發明之一目的在於提供一種製備聚乙二醇(PEG)醛衍生物之方法,其能將聚乙二醇或衍生物(聚乙二醇鏈末端之醇基的其中一者係經烷氧基取代(下文稱為烷氧基-聚乙二醇))的羥基轉換為醛基。
特定言之,本發明之一目的在於提供一種能夠從聚乙二醇或烷氧基-聚乙二醇(例如甲氧基聚乙二醇)經濟地製備聚乙二醇醛類或烷氧基-聚乙二醇醛類之製備方法,其係藉由將聚乙二醇醛類或烷氧基-聚乙二醇醛類連接至藥物上,以用於改善藥物的溶解度及效率,而沒有雜質。
本案發明人發現,由分解聚乙二醇鏈所造成之低分子量聚乙二醇的產生,可以下述方式減至最小:於一溫和條件(Pfitzner-Moffatt氧化反應)下,氧化聚乙二醇(PEG)或烷氧基-聚乙二醇,以使末端羥基轉換為醛基;或於聚乙二醇或烷氧基-聚乙二醇之末端上,引入一羥基(C3
至C10
)烷基,接著於一溫和條件(Pfitzner-Moffatt氧化反應)下將其氧化,使末端羥基轉換為醛基。
因為可定量地將巨分子的末端醇基轉換為醛基,而不分解聚乙醇鏈,大部分的反應物係市面上可取得的物質,且所涉及之反應不需要特別的製備設備(例如低溫、高溫、高壓等),因此根據本發明之製備方法係被視為在商業上適用且經濟之方法。
於第一實施態樣中,本發明提供一種製備由化學式1所示之聚乙二醇醛之方法,其係使一由化學式2所示之聚乙二醇衍生物與二甲基亞碸(dimethyl sulfoxide)及二環己碳二亞胺反應:
[化學式1]
OHC-(CH2
)m-1
-O-(CH2
CH2
O)n
-(CH2
)m-1
-CHO
[化學式2]
HO-(CH2
)m
-O-(CH2
CH2
O)n
-(CH2
)m
-OH
其中,n代表一3至2000之整數,且m代表一2至10之整數。
於第二實施態樣中,本發明提供一種製備由化學式10所示之聚乙二醇醛之方法,其係使一由化學式11所示之聚乙二醇衍生物與二甲基亞碸及二環己碳二亞胺反應:
[化學式10]
R2
O-(CH2
CH2
O)n
-(CH2
)m-1
-CHO
[化學式11]
R2
O-(CH2
CH2
O)n
-(CH2
)m
-OH
其中,n代表一3至2000之整數;m代表一2至10之整數;且R2
係選自(C1
至C7
)烷基或(C6
至C20
)芳基(C1
至C7
)烷基。
下文將詳細描述本發明之實施態樣。
除非另外定義,於此所使用之全部詞彙(包括技術及科學的詞彙)具有與一般熟於此項技藝人士之通常所瞭解的相同的意義。於本敘述中,可能省略眾所周知之特徵與技術的細節,以避免不必要地混淆所呈現之實施態樣。
根據本發明之第一實施態樣之製備聚乙二醇醛的方法,能夠將由化學式2所示之化合物的醇基氧化為醛基,而不分解聚乙二醇鏈,從而能夠製備高純度之由化學式1所示之聚乙二醇醛,且具有較少的雜質,例如由聚乙二醇鏈分解所產生之低分子量的聚乙二醇、聚乙二醇酸等:
[化學式1]
OHC-(CH2
)m-1
-O-(CH2
CH2
O)n
-(CH2
)m-1
-CHO
[化學式2]
HO-(CH2
)m
-O-(CH2
CH2
O)n
-(CH2
)m
-OH
其中,n代表一3至2000之整數,且m代表一2至10之整數。
特定言之,上述反應係使一由化學式2所示之聚乙二醇衍生物與二甲基亞碸、三氟乙酸及吡啶混合,接著添加二環己碳二亞胺來進行。視需要地,於反應後,可使用一庚烷-異丙醇混合物使產物結晶,並使用一乙腈(AN)-甲基三級丁基醚(MTBE)混合物使產物再結晶。
根據本發明之第一實施態樣之製備聚乙二醇醛的方法,該製備於聚乙二醇末端上具有一C3
至C10
醛基之聚乙二醇醛的方法,特別包含:於由化學式3所示之聚乙二醇之末端上,引入一羥基(C3
至C10
)烷基,以製備一由化學式4所示之聚乙二醇衍生物;以及使用二甲基亞碸與二環己碳二亞胺,氧化由化學式4所示之衍生物,以製備由化學式1所示之聚乙二醇醛:
[化學式3]
HO-(CH2
CH2
O)n
-H
[化學式4]
HO-(CH2
)k
-O-(CH2
CH2
O)n
-(CH2
)k
-OH
其中,n代表一3至2000之整數,且k代表一3至10之整數。
特定言之,製備一由化學式4所示之聚乙二醇衍生物之方法包含:
a)使一由化學式3所示之聚乙二醇與一由化學式5所示之氰基烯反應,以製備一由化學式6所示之氰基烷基-聚乙二醇;
b)自該由化學式6所示之氰基烷基-聚乙二醇製備一由化學式7所示之聚乙二醇-羧酸;
c)使該由化學式7所示之聚乙二醇-羧酸與一由化學式8所示之醇反應,以製備一由化學式9所示之聚乙二醇-酯化合物;以及
d)還原該由化學式9所示之聚乙二醇-酯化合物,以製備該由化學式4所示之聚乙二醇衍生物;
[化學式3]
HO-(CH2
CH2
O)n
-H
[化學式4]
HO-(CH2
)k
-O-(CH2
CH2
O)n
-(CH2
)k
-OH
[化學式6]
NC-(CH2
)k-1
-O-(CH2
CH2
O)n
-(CH2
)k-1
-CN
[化學式7]
HOOC-(CH2
)k-1
-O-(CH2
CH2
O)n
-(CH2
)k-1
-COOH
[化學式8]
R1
-OH
[化學式9]
R1
OOC-(CH2
)k-1
-O-(CH2
CH2
O)n
-(CH2
)k-1
-COOR1
其中,n代表一3至2000之整數,k代表一3至10之整數,且R1
係選自(C1
至C7
)烷基或(C6
至C20
)芳基(C1
至C7
)烷基。
當製備由化學式4所示之聚乙二醇衍生物時,於步驟b)至d)之一或多者之後,可更包含一純化產物之步驟,其係利用一離子交換樹脂管柱分離反應副產物,尤其是聚乙二醇以及聚乙二醇酸。
根據本發明之第二實施態樣之製備聚乙二醇醛的方法,能夠將由化學式11所示之化合物的醇基氧化為醛,而不分解聚乙二醇鏈,從而能夠製備高純度之由化學式10所示之聚乙二醇醛,且具有較少的雜質,例如由聚乙二醇鏈分解所產生之低分子量的聚乙二醇、聚乙二醇酸等;
[化學式10]
R2
O-(CH2
CH2
O)n
-(CH2
)m-1
-CHO
[化學式11]
R2
O-(CH2
CH2
O)n
-(CH2
)m
-OH
其中,n代表一3至2000之整數,m代表一2至10之整數,且R2
係選自(C1
至C7
)烷基或(C6
至C20
)芳基(C1
至C7
)烷基。
進一步言之,於化學式11中,R2
可例示為甲基、乙基、丙基、丁基及苯甲基。
特定言之,上述反應係藉由混合由化學式11所示之聚乙二醇衍生物與二甲基亞碸、三氟乙酸以及吡啶,接著添加二環己碳二亞胺來進行。視需要地,於反應後,可使用一庚烷-異丙醇混合物使產物結晶,並使用一乙腈-甲基三級丁基醚(AN-MTBE)混合物使產物再結晶。
根據本發明之第二實施態樣之製備聚乙二醇醛的方法,該製備於聚乙二醇末端上具有一C3
至C10
醛基之聚乙二醇醛的方法,係特別包含:於由化學式12所示之烷氧基-聚乙二醇之末端上,引入一羥基(C3
至C10
)烷基,以製備一由化學式13所示之烷氧基-聚乙二醇衍生物;以及使用二甲基亞碸及二環己碳二亞胺氧化該由化學式13所示之衍生物,以製備一由化學式10所示之聚乙二醇醛:
[化學式12]
R2
O-(CH2
CH2
O)n
-H
[化學式13]
R2
O-(CH2
CH2
O)n
-(CH2
)k
-OH
其中,n代表一3至2000之整數,k代表一3至10之整數,且R2
係選自(C1
至C7
)烷基或(C6
至C20
)芳基(C1
至C7
)烷基。
進一步言之,於化學式12與13中,R2
可例示為甲基、乙基、丙基、丁基及苯甲基。
特定言之,製備一由化學式13所示之烷氧基-聚乙二醇衍生物的方法包含:
a)使一由化學式12所示之烷氧基-聚乙二醇與一由化學式5所示之氰基烯反應,以製備一由化學式14所示之烷氧基-聚乙二醇腈(alkoxy-PEG nitrile)化合物;
b)自該由化學式14所示之烷氧基-聚乙二醇腈化合物製備一由化學式15所示之烷氧基-聚乙二醇羧酸;
c)使該由化學式15所示之烷氧基-聚乙二醇羧酸與一由化學式8所示之醇反應,以製備一由化學式16所示之烷氧基-聚乙二醇酯化合物;以及
d)還原該由化學式16所示之烷氧基-聚乙二醇酯化合物,以製備該由化學式13所示之聚乙二醇衍生物;
[化學式12]
R2
O-(CH2
CH2
O)n
-H
[化學式13]
R2
O-(CH2
CH2
O)n
-(CH2
)k
-OH
[化學式14]
R2
O-(CH2
CH2
O)n
-(CH2
)k-1
-CN
[化學式15]
R2
O-(CH2
CH2
O)n
-(CH2
)k-1
-COOH
[化學式8]
R1
-OH
[化學式16]
R2
O-(CH2
CH2
O)n
-(CH2
)k-1
-COOR1
其中,n代表一3至2000之整數,k代表一3至10之整數,且R1
與R2
係獨立選自(C1
至C7
)烷基或(C6
至C20
)芳基(C1
至C7
)烷基。
進一步言之,於化學式5、8以及12至16中,R1
與R2
可例示為甲基、乙基、丙基、丁基及苯甲基。
當製備由化學式13所示之聚乙二醇衍生物時,於步驟b)至d)之一或多者之後,可更包含一純化產物之步驟,其係利用一離子交換樹脂管柱分離反應副產物,尤其是聚乙二醇及聚乙二醇酸。
[有利效應]
於本發明中,聚乙二醇(PEG)醛類或烷氧基-聚乙二醇醛類係由聚乙二醇或烷氧基-聚乙二醇藉由氰化、水解、酯化、還原以及氧化製備而成。可利用一離子交換樹脂管柱,藉由分離及純化,使由水解及還原所產生的副產物(尤其是聚乙二醇以及聚乙二醇酸)減至最少。可將巨分子的末端醇基定量地轉換為醛基,而不分解聚乙二醇鏈。由於反應物係可自市面上取得之物質,且所涉及之反應不需要特別的製備設備(例如低溫、高溫、高壓等),故根據本發明之製備方法係被視為商業上適用且經濟之方法。
[發明態樣]
於此,將描述實施例及實驗。以下實施例及實驗僅係用於例示目的,且非意於限制本發明之範疇。除非另外指明,否則%即代表莫耳%。
[實施例1]製備聚乙二醇-丙醛
聚乙二醇-丙醛係根據上述反應流程而製備。以下將提供各步驟的詳細敘述。
[氰化反應]
將聚乙二醇(數目平均分子量=3.4 K,100公克)溶解於一反應器內之蒸餾水(600毫升)中。添加氫氧化鉀(45公克)且將混
合物冷卻到1至5℃。在冷卻後,添加丙烯腈(16公克),並讓該混合物反應3天。在反應完成後,立即以二氯甲烷(methylene chloride,MC)(400毫升)萃取混合物3次,且完全地移除溶劑。
產量:110公克
1
H-NMR(200 MHz,CDCl3
):聚乙二醇主幹(m,3.20-4.20 ppm),-OCH2 CH 2
CN(t,2.63 ppm)。
[水解與純化]
將濃鹽酸(500毫升)添加至經濃縮的殘餘物(110公克)中,並讓該混合物在室溫下反應2天。在以MC(400毫升)萃取3次後,完全地濃縮MC。添加10%的氫氧化鉀溶液(600毫升)至經濃縮的殘餘物(95公克)中,並讓該混合物在室溫下反應2天。在反應完成後,立即以MC(300毫升)萃取混合物3次,並濃縮溶劑層。添加乙醚(1.2公升),並藉由在0℃下結晶、過濾以及乾燥獲得白色粉末(88公克)。該經乾燥的白色粉末係利用一離子交換樹脂管柱加以純化。
產量:52公克(高效能液相層析儀(HPLC)測得的純度:99.94%)
1
H-NMR(200 MHz,CDCl3
):聚乙二醇主幹(m,3.20-4.20 ppm),-OCH2 CH 2
C(O)OH(t,2.60 ppm)。
[酯化反應]
將甲醇(400毫升)以及硫酸(2.25公克)加入至經純化的聚乙二醇二酸(52公克)中,並讓該混合物在室溫下反應2天。以MC(300毫升)進行MC萃取3次後,完全地濃縮溶劑層。
產量:51公克
1
H-NMR(200 MHz,CDCl3
):聚乙二醇主幹(m,3.20-4.20 ppm),-OCH3
(s,3.50ppm)-OCH2 CH 2
C(O)OCH3
(t,2.60ppm)。
[還原與純化]
將MC(30毫升)以及甲醇(30毫升)加入至經濃縮的殘餘物(51公克)中。在攪拌30分鐘後,添加硼氫化鈉(3公克),並讓該混合物反應24小時。在反應完成後,立即移除大部分的溶劑,以及在添加1當量濃度之氫氧化鈉溶液(400毫升)後,在一80℃之內部溫度下將該混合物攪拌1小時。在冷卻後。添加濃鹽酸以調整pH為1.5至2,並以MC(200毫升)萃取該混合物3次。以甲基三級丁基醚(MTBE,600毫升)進行結晶,接著過濾及乾燥,以獲得白色粉末(42公克)。該經乾燥的白色粉末係利用一離子交換樹脂管柱加以純化。
產量:30公克(高效能液相層析儀(HPLC)測得的純度:100%)。
凝膠滲透層析儀(GPC):數目平均分子量(Mn
)(3023),聚合度分佈性指數(PDI)=1.02。
1
H-NMR(200MHz,CDCl3
):聚乙二醇主幹(m,3.20-4.20ppm),-OCH2
CH2 CH 2
OH(t,2.62ppm),-OCH2 CH 2
CH2
OH(t,1.83ppm)。
[氧化反應]
將聚乙二醇丙醇(42公克)溶解於MC(80毫升)中。在添加二甲基亞碸(DMSO,94毫升)後,將內部溫度降為0至5℃。在添加吡啶(3公克)以及三氟乙酸(TFA,4公克)後,於相同溫度下攪拌該混合物1小時。在添加二環己碳二亞胺(DCC,10公克)後,讓該混合物在室溫下反應24小時。在反應完成後,立即以過濾方式移除沉澱的二環已基尿素(dicyclohexylurea,DCU)。之後,添加預先製備的庚烷-異丙醇(IPA)(7:3體積%,1088毫升),並藉由冷卻及結晶獲得固體產物。該固體係使用乙腈-甲基三級丁基醚(5:1)再結晶,並加以乾燥。
產量:25公克(根據核磁共振光譜(NMR)測得之純度:99.73%)
凝膠滲透層析儀(GPC)(甲氧基聚乙二醇):數目平均分子量Mn(3156),PDI=1.02。
凝膠滲透層析儀(GPC):數目平均分子量Mn(3010),PDI=1.02
1
H-NMR(500MHz,CDCl3
):-C(O)H(s,9.80ppm),聚乙二醇主幹(m,3.20-4.20ppm),-OCH2 CH 2
C(O)H(t,2.60ppm)。
[實施例2]製備甲氧基聚乙二醇-丙醛
甲氧基聚乙二醇(數目平均分子量=20K)-丙醛係以與實施例1同樣的方式,由甲氧基聚乙二醇(數目平均分子量=20K)製備而成。
產量:60%(來自甲氧基聚乙二醇,根據核磁共振光譜(NMR)測得之純度:99.73%)。
1
H-NMR(500MHz,CDCl3
):-C(O)H(s,9.80ppm),聚乙二醇主幹(m,3.20-4.20ppm),-OCH2 CH 2
C(O)H(t,2.60ppm)。
[實施例3]製備甲氧基聚乙二醇-乙醛
甲氧基聚乙二醇-乙醛係藉由與實施例1中同樣的氧化過程,由甲氧基聚乙二醇(數目平均分子量=5K)製備而成。以下將提供詳細的敘述。
甲氧基聚乙二醇(數目平均分子量=5K,50公克)係溶解在MC(100毫升)中。添加二甲基亞碸(DMSO,100毫升),並將內部溫度降為0至5℃。在添加吡啶(5公克)以及三氟乙酸(TFA,7公克)後,在相同溫度下攪拌該混合物1小時。在添加二環己碳二亞胺(DCC,15公克)後,讓該混合物在室溫下反應24小時。在反應完成後,以過濾方式移除沉澱之二環已基尿素(DCU)。之後,添加預先製備的庚烷-異丙醇(IPA)(7:3體積%,1000毫升),並藉由冷卻及結晶獲得固體產物。該固體係使用乙腈-甲基三級丁基醚(5:1)進行再結晶,並加以乾燥。
產量:95%(來自甲氧基聚乙二醇,根據核磁共振光譜(NMR)測得之純度:99.73%)。
1
H-NMR(200MHz,CDCl3
):-C(O)H(s,9.67ppm),聚乙二醇主幹(m,3.20-4.20ppm),-OCH 2
C(O)H(S,4.18ppm)。
Claims (10)
- 一種製備聚乙二醇醛之方法,其中係使一由化學式4所示之聚乙二醇衍生物與二甲基亞碸(dimethyl sulfoxide)、三氟乙酸(trifluoroacetic acid)及吡啶混合,且加入二環己碳二亞胺:[化學式1]OHC-(CH2 )k-1 -O-(CH2 CH2 O)n -(CH2 )k-1 -CHO [化學式4]HO-(CH2 )k -O-(CH2 CH2 O)n -(CH2 )k -OH其中,n代表一3至2000之整數,且k代表一3至10之整數。
- 如請求項1所述之製備聚乙二醇醛之方法,其中,於反應之後,使用一庚烷-異丙醇混合物進行結晶,並使用一乙腈-甲基三級丁基醚混合物進行再結晶。
- 如請求項1所述之製備聚乙二醇醛之方法,其中該由化學式4所示之聚乙二醇衍生物係由以下製程所製得,包含:使一由化學式3所示之聚乙二醇與一由化學式5所示之氰基烯反應,以製備一由化學式6所示之氰基烷基-聚乙二醇;自該由化學式6所示之氰基烷基-聚乙二醇製備一由化學式7所示之聚乙二醇-羧酸;使該由化學式7所示之聚乙二醇-羧酸與一由化學式8所示之醇反應,以製備一由化學式9所示之聚乙二醇-酯化合物;以及還原該由化學式9所示之聚乙二醇-酯化合物,以製備該由化學式4所示之聚乙二醇衍生物;[化學式3] HO-(CH2 CH2 O)n -H [化學式4]HO-(CH2 )k -O-(CH2 CH2 O)n -(CH2 )k -OH
- 如請求項3所述之製備聚乙二醇醛之方法,更包含於所述製備該由化學式7所示之聚乙二醇-羧酸及所述還原該由化學式9所示之聚乙二醇-酯化合物之一或多者之後,利用一離子交換樹脂管柱分離反應副產物。
- 一種製備由化學式10所示之聚乙二醇醛之方法,其係使一由化學式11所示之聚乙二醇衍生物與二甲基亞碸及二環己碳二亞胺反應:[化學式10]R2 O-(CH2 CH2 O)n -(CH2 )m-1 -CHO [化學式11]R2 O-(CH2 CH2 O)n -(CH2 )m -OH其中,n代表一3至2000之整數,m代表一2至10之整數, 且R2 係選自(C1 至C7 )烷基或(C6 至C20 )芳基(C1 至C7 )烷基。
- 如請求項5所述之製備聚乙二醇醛之方法,其中該由化學式11所示之聚乙二醇衍生物係與二甲基亞碸、三氟乙酸及吡啶混合,並添加二環己碳二亞胺。
- 如請求項5所述之製備聚乙二醇醛之方法,其中,於反應之後,使用一庚烷-異丙醇混合物進行結晶,並使用一乙腈-甲基三級丁基醚混合物進行再結晶。
- 如請求項5所述之製備聚乙二醇醛之方法,其中該由化學式11所示之聚乙二醇衍生物係一由化學式13所示之聚乙二醇衍生物:[化學式13]R2 O-(CH2 CH2 O)n -(CH2 )k -OH其中,n代表一3至2000之整數,k代表一3至10之整數,且R2 係選自(C1 至C7 )烷基或(C6 至C20 )芳基(C1 至C7 )烷基。
- 如請求項8所述之製備聚乙二醇醛之方法,其中該由化學式13所示之聚乙二醇衍生物係由以下製程所製得,包含:使一由化學式12所示之烷氧基-聚乙二醇與一由化學式5所示之氰基烯反應,以製備一由化學式14所示之烷氧基-聚乙二醇腈(alkoxy-PEG nitrile)化合物;自該由化學式14所示之烷氧基-聚乙二醇腈化合物製備一由化學式15所示之烷氧基-聚乙二醇羧酸;使該由化學式15所示之烷氧基-聚乙二醇羧酸與一由化 學式8所示之醇反應,以製備一由化學式16所示之烷氧基-聚乙二醇酯化合物;以及還原該由化學式16所示之烷氧基-聚乙二醇酯化合物,以製備該由化學式13所示之聚乙二醇衍生物;[化學式12]R2 O-(CH2 CH2 O)n -H [化學式13]R2 O-(CH2 CH2 O)n -(CH2 )k -OH
- 如請求項9所述之製備聚乙二醇醛之方法,更包含於所述製備該由化學式15所示之烷氧基-聚乙二醇羧酸及所述還原該由化學式16所示之烷氧基-聚乙二醇酯化合物之一或多者之後,利用一離子交換樹脂管柱分離反應副產物。
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