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1. 发明授权

US08138330B2 Process for the synthesis of oligonucleotides 失效
标题翻译：合成寡核苷酸的方法
公开(公告)号：US08138330B2
公开(公告)日：2012-03-20
申请号：US11853662
申请日：2007-09-11
申请人： Michael Leuck , Andreas Wolter , Alfred Stumpe
发明人： Michael Leuck , Andreas Wolter , Alfred Stumpe
IPC分类号： C07H21/02 , C07H21/04
CPC分类号： C07H21/00 , Y02P20/55
摘要： The present invention discloses novel methods for the synthesis of oligonucleotides with nucleoside phosphoramidites on solid supports. The methods comprise the stepwise chain assembly of oligonucleotides on supports with 5′-acyl phosphoramidites. The synthesis cycles consist of a front end deprotection step which is conducted with a solution of a primary amine or a phenolate, a phosphoramidite coupling step with a 5′-acyl nucleoside phosphoramidite in the presence of an activator, a phosphite oxidation step and an optional capping step. The novel methods improve the quality of synthetic oligonucleotides due to the irreversibility of the front end deprotection step, which prevents the formation of deletion sequences, and due to the avoidance of acidic reagents in the synthesis cycles, which prevent the formation of depurination side products. The invention further discloses novel nucleoside phosphoramidite compositions wherein the phosphoramidites carry acyl front end protective groups which are cleavable with primary amines or phenolates. The invention is applicable to the synthesis of oligodeoxyribonucleotides, oligoribonucleotides and oligonucleotides with modifications in their sugar or phosphate groups.
摘要翻译：本发明公开了在固体支持物上合成具有核苷亚磷酰胺的寡核苷酸的新方法。所述方法包括在载体上用5'-酰基亚磷酰胺逐步链组装寡核苷酸。合成循环由在活化剂存在下用伯胺或酚盐溶液，亚磷酰胺偶联步骤与5'-酰基核苷亚磷酰胺进行的前端去保护步骤，亚磷酸酯氧化步骤和任选的封顶步新方法由于前端脱保护步骤的不可逆性而改善了合成寡核苷酸的质量，这防止了缺失序列的形成，并且由于避免了在合成循环中的酸性试剂，从而防止了形成脱嘌呤产物。本发明进一步公开了新的核苷亚磷酰胺组合物，其中亚磷酰胺携带可与伯胺或酚盐切割的酰基前端保护基。本发明适用于寡脱氧核糖核苷酸，寡核糖核苷酸和其糖或磷酸基团修饰的寡核苷酸的合成。

2. 发明授权

US07897758B2 Activators for oligonucleotide and phosphoramidite synthesis 有权
标题翻译：用于寡核苷酸和亚磷酰胺合成的活化剂
公开(公告)号：US07897758B2
公开(公告)日：2011-03-01
申请号：US11380227
申请日：2006-04-26
申请人： Andreas Wolter , Michael Leuck
发明人： Andreas Wolter , Michael Leuck
IPC分类号： C07H21/02 , C07H21/04
CPC分类号： C07H21/02 , C07H21/04
摘要： The present invention discloses novel methods for the synthesis of oligonucleotides and nucleoside phosphoramidites. The methods are based on employing aryl-substituted 5-phenyl-1H-tetrazoles with perfluoroalkyl groups on the aromatic ring as activators. In one aspect the novel activators are used in the synthesis of oligonucleotides via the phosphoramidite approach. In this aspect the activators are highly efficient and can be applied with very short coupling times. In a further aspect, the activators of the invention are used in the synthesis of phosphoramidites through the reaction of nucleosides comprising a free hydroxyl group with phosphitylating agents. In this aspect the activators provide very pure phosphoramidites under mild conditions. The activators of the invention are further characterized by being highly soluble, non-hygroscopic and non-hazardous.
摘要翻译：本发明公开了合成寡核苷酸和核苷亚磷酰胺的新方法。该方法基于在芳环上使用具有全氟烷基的芳基取代的5-苯基-1H-四唑作为活化剂。在一个方面，新的活化剂用于通过亚磷酰胺方法合成寡核苷酸。在这方面，活化剂是高效的并且可以以非常短的偶联时间施用。在另一方面，本发明的活化剂用于通过包含游离羟基的核苷与磷酸化剂的反应来合成亚磷酰胺。在这方面，活化剂在温和条件下提供非常纯的亚磷酰胺。本发明的活化剂的特征还在于高溶解性，非吸湿性和非危险性。

3. 发明授权

US07098326B2 Methods for the integrated synthesis and purification of oligonucleotides 有权
公开(公告)号：US07098326B2
公开(公告)日：2006-08-29
申请号：US10349195
申请日：2003-01-22
申请人： Wolfgang Pieken , Andreas Wolter , Michael Leuck
发明人： Wolfgang Pieken , Andreas Wolter , Michael Leuck
IPC分类号： C07H21/00 , C07H21/02 , C07H21/04
CPC分类号： C07H21/00 , C07H21/04
摘要： The present invention discloses novel methods for the integrated synthesis and purification of oligonucleotides. The methods employ novel capping reagents carrying two functional groups. The first functional group provides for a smooth and efficient capping process and incorporates the second functional group into contaminant oligonucleotides during solid phase oligonucleotide synthesis. The second functional group functions as a chemical purification handle in the trapping of truncated oligonucleotides (failure sequences) on a solid support. The trapping process creates covalent bonds between the solid support and the truncated oligonucleotides and therefore allows the removal of the truncated sequences from the desired full length oligonucleotide product by filtration. The chemical trapping process employed in this invention is based on cycloaddition reactions, particularly Diels-Alder reactions between the truncated oligonucleotides and the trapping agent. The invention includes novel solid support compositions that carry covalently attached Diels-Alder reaction components.

4. 发明授权

US07276598B2 Phosphorylation reagents for improved processes to convert terminal hydroxyl groups of oligonucleotides into phosphate monoesters 有权
标题翻译：用于将寡核苷酸的末端羟基转化成磷酸酯单酯的改进方法的磷酸化试剂
公开(公告)号：US07276598B2
公开(公告)日：2007-10-02
申请号：US10821631
申请日：2004-04-09
申请人： Kurt Vagle , Michael Leuck , Andreas Wolter
发明人： Kurt Vagle , Michael Leuck , Andreas Wolter
IPC分类号： C07H5/06 , C07H21/04
CPC分类号： C07H5/06 , C07H21/04 , Y02P20/55
摘要： The present invention discloses novel phosphoramidite reagents for use in oligonucleotide synthesis. The present invention further discloses novel methods for the conversion of terminal hydroxyl groups of oligonucleotides into phosphate monoesters. By employing novel reagents, as also disclosed herein, the methods are fully compatible with standard procedures for solid phase oligonucleotide synthesis and do not require additional processing steps. The inventive reagents to phosphorylate terminal hydroxyl groups of oligonucleotides are superior to the prior art in that they for the first time combine the desired attributes of being a solid compound for facile handling, comprising two β-eliminating protective groups removable as fast or faster than the standard cyanoethyl group, providing a DMT-group for easy monitoring of the coupling efficiency, and enabling a fast final deprotection of the phosphorylated oligonucleotide without any extra manipulation steps.
摘要翻译：本发明公开了用于寡核苷酸合成的新型亚磷酰胺试剂。本发明还公开了将寡核苷酸的末端羟基转化成磷酸酯单酯的新方法。通过使用本文也公开的新型试剂，所述方法与固相寡核苷酸合成的标准方法完全相容，并且不需要额外的加工步骤。使寡核苷酸的末端羟基磷酸化的本发明试剂优于现有技术，因为它们首次将作为固体化合物的所需属性与易于处理组合在一起，包括可以快速或快速移除的两个β-消除保护基团标准氰乙基，提供DMT基团，以便于监测偶联效率，并且能够快速地最终去除磷酸化寡核苷酸，而无需任何额外的操作步骤。

5. 发明授权

US07427678B2 Method for immobilizing oligonucleotides employing the cycloaddition bioconjugation method 有权
标题翻译：使用环加成生物共轭法固定寡核苷酸的方法
公开(公告)号：US07427678B2
公开(公告)日：2008-09-23
申请号：US09845742
申请日：2001-05-01
申请人： Wolfgang Pieken , Andreas Wolter , David P. Sebesta , Michael Leuck , Hallie A. Latham-Timmons , John Pilon , Gregory M. Husar
发明人： Wolfgang Pieken , Andreas Wolter , David P. Sebesta , Michael Leuck , Hallie A. Latham-Timmons , John Pilon , Gregory M. Husar
IPC分类号： C07H21/00 , A61K38/00 , C07K1/00
CPC分类号： C40B50/18 , C07B2200/11 , C07C215/10 , C07C271/16 , C07C2601/16 , C07D207/46 , C07F7/1804 , C07F9/2408 , C07H21/00 , C40B40/04 , C40B40/06
摘要： This invention discloses a novel method for immobilizing molecules to a support. Specifically, this invention discloses a method of immobilizing derivatized biomolecules, such as oligonucleotides, using cycloaddition reactions, such as the Diels-Alder reaction. Included in this invention are the novel immobilized biomolecules that can be prepared according to the method of this invention.
摘要翻译：本发明公开了一种将分子固定在载体上的新方法。具体地说，本发明公开了一种使用诸如Diels-Alder反应的环加成反应固定衍生的生物分子如寡核苷酸的方法。本发明包括可根据本发明方法制备的新型固定化生物分子。

6. 发明申请

US20060247431A1 ACTIVATORS FOR OLIGONUCLEOTIDE AND PHOSPHORAMIDITE SYNTHESIS 有权
标题翻译：用于寡核苷酸和磷酰胺合成的激活剂
公开(公告)号：US20060247431A1
公开(公告)日：2006-11-02
申请号：US11380227
申请日：2006-04-26
申请人： Andreas Wolter , Michael Leuck
发明人： Andreas Wolter , Michael Leuck
IPC分类号： C07H21/02
CPC分类号： C07H21/02 , C07H21/04
摘要： The present invention discloses novel methods for the synthesis of oligonucleotides and nucleoside phosphoramidites. The methods are based on employing aryl-substituted 5-phenyl-1H-tetrazoles with perfluoroalkyl groups on the aromatic ring as activators. In one aspect the novel activators are used in the synthesis of oligonucleotides via the phosphoramidite approach. In this aspect the activators are highly efficient and can be applied with very short coupling times. In a further aspect, the activators of the invention are used in the synthesis of phosphoramidites through the reaction of nucleosides comprising a free hydroxyl group with phosphitylating agents. In this aspect the activators provide very pure phosphoramidites under mild conditions. The activators of the invention are further characterized by being highly soluble, non-hygroscopic and non-hazardous.
摘要翻译：本发明公开了合成寡核苷酸和核苷亚磷酰胺的新方法。该方法基于在芳环上使用具有全氟烷基的芳基取代的5-苯基-1H-四唑作为活化剂。在一个方面，新的活化剂用于通过亚磷酰胺方法合成寡核苷酸。在这方面，活化剂是高效的并且可以以非常短的偶联时间施用。在另一方面，本发明的活化剂用于通过包含游离羟基的核苷与磷酸化剂的反应来合成亚磷酰胺。在这方面，活化剂在温和条件下提供非常纯的亚磷酰胺。本发明的活化剂的特征还在于高溶解性，非吸湿性和非危险性。

7. 发明申请

US20080064867A1 PROCESS FOR THE SYNTHESIS OF OLIGONUCLEOTIDES 失效
标题翻译：合成寡核苷酸的方法
公开(公告)号：US20080064867A1
公开(公告)日：2008-03-13
申请号：US11853662
申请日：2007-09-11
申请人： Michael Leuck , Andreas Wolter , Alfred Stumpe
发明人： Michael Leuck , Andreas Wolter , Alfred Stumpe
IPC分类号： C07H21/00
CPC分类号： C07H21/00 , Y02P20/55
摘要： The present invention discloses novel methods for the synthesis of oligonucleotides with nucleoside phosphoramidites on solid supports. The methods comprise the stepwise chain assembly of oligonucleotides on supports with 5′-acyl phosphoramidites. The synthesis cycles consist of a front end deprotection step which is conducted with a solution of a primary amine or a phenolate, a phosphoramidite coupling step with a 5′-acyl nucleoside phosphoramidite in the presence of an activator, a phosphite oxidation step and an optional capping step. The novel methods improve the quality of synthetic oligonucleotides due to the irreversibility of the front end deprotection step, which prevents the formation of deletion sequences, and due to the avoidance of acidic reagents in the synthesis cycles, which prevent the formation of depurination side products. The invention further discloses novel nucleoside phosphoramidite compositions wherein the phosphoramidites carry acyl front end protective groups which are cleavable with primary amines or phenolates. The invention is applicable to the synthesis of oligodeoxyribonucleotides, oligoribonucleotides and oligonucleotides with modifications in their sugar or phosphate groups.
摘要翻译：本发明公开了在固体支持物上合成具有核苷亚磷酰胺的寡核苷酸的新方法。所述方法包括在载体上用5'-酰基亚磷酰胺逐步链组装寡核苷酸。合成循环由在活化剂存在下用伯胺或酚盐溶液，亚磷酰胺偶联步骤与5'-酰基核苷亚磷酰胺进行的前端去保护步骤，亚磷酸酯氧化步骤和任选的封顶步新方法由于前端脱保护步骤的不可逆性而改善了合成寡核苷酸的质量，这防止了缺失序列的形成，并且由于避免了在合成循环中的酸性试剂，从而防止了形成脱嘌呤产物。本发明进一步公开了新的核苷亚磷酰胺组合物，其中亚磷酰胺携带可与伯胺或酚盐切割的酰基前端保护基。本发明适用于寡脱氧核糖核苷酸，寡核糖核苷酸和其糖或磷酸基团修饰的寡核苷酸的合成。

8. 发明授权

US07329515B2 Solid support for the synthesis of 3′-amino oligonucleotides 有权
标题翻译：支持3'-氨基寡核苷酸的合成
公开(公告)号：US07329515B2
公开(公告)日：2008-02-12
申请号：US10830484
申请日：2004-04-21
申请人： Michael Leuck , Andreas Wolter
发明人： Michael Leuck , Andreas Wolter
IPC分类号： C12P19/34 , C07H21/02 , C07H21/04 , C07C229/56
CPC分类号： C07H21/02 , C07H21/04
摘要： The present invention discloses novel methods and solid supports for the synthesis of 3′-amino oligonucleotides. The novel supports are based on an unsubstituted or ring-substituted hydroxymethylbenzoyl linker element wherein the hydroxymethyl group is esterified to a solid phase bound carboxylic acid and the carbonyl group is linked to an amino alcohol as an amide. Oligonucleotides are conveniently synthesized on the novel supports with no modifications in the standard phosphoramidite synthesis scheme. The ester function of the support is cleaved under the alkaline deprotection conditions for oligonucleotides to provide a free hydroxymethyl group that aids in the release of the 3′-amino oligonucleotide products with a free amino group through neighbor group participation. The free amino group of the oligonucleotides is available for further conjugation reactions to haptens, reporter groups, surfaces or other small molecules or biomolecules. The methods provided are particularly mild, do not require any modifications in standard protocols for the synthesis and deprotection of oligonucleotides, provide the 3′-amino oligonucleotides free of side products and do not introduce chiral centers to the oligonucleotides.
摘要翻译：本发明公开了用于合成3'-氨基寡核苷酸的新方法和固体支持物。该新型载体是基于未取代的或环取代的羟甲基苯甲酰基接头元件，其中羟甲基被酯化成固相结合的羧酸，羰基连接到氨基醇作为酰胺。在新型载体上方便地合成寡核苷酸，在标准亚磷酰胺合成方案中没有修饰。在碱性脱保护条件下，对寡核苷酸的酯功能进行切割，提供游离羟甲基，有助于游离氨基的3'-氨基寡核苷酸产物通过邻群参与释放。寡核苷酸的游离氨基可用于进一步与半抗原，报告基团，表面或其他小分子或生物分子的缀合反应。所提供的方法特别温和，不需要对寡核苷酸的合成和去保护的标准方案进行任何修饰，提供不含副产物的3'-氨基寡核苷酸，并且不向寡核苷酸引入手性中心。

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