The present disclosure provides a solid phase method of making oligonucleotides via sequential coupling cycles including at least one coupling of a dinucleotide dimer subunit to a free 3’-terminal group of a growing chain. The oligonucleotides include at least two nucleoside subunits joined by a N3'→P5' phosphoramidate linkage. The method may include the steps of (a) deprotecting the protected 3' amino group of a terminal nucleoside attached to a solid phase support, said deprotecting forming a free 3' amino group； (b) contacting the free 3' amino group with a 3'-protected amino-dinucleotide-5'-phosphoramidite dimer in the presence of a nucleophilic catalyst to form an internucleoside N3'→P5' phosphoramidite linkage； and (c) oxidizing (e.g., sulfurizing) the linkage. The compositions produced by the subject methods may include a reduced amount of one or more (N-x) oligonucleotide products. Also provided are pharmaceutical compositions including the subject oligonucleotide compositions.本揭露內容提供一種經由連續偶合循環來製備寡核苷酸之固相方法，該等循環包括至少一次二核苷酸二聚物次單元偶合於增長鏈之游離3'-末端基團。寡核苷酸包括至少兩個藉由N3'→P5'磷醯胺酯鍵聯接合之核苷次單元。該方法可包括以下步驟：(a)使連接於固相支撐物之末端核苷之經保護3'胺基脫保護，該脫保護形成游離3'胺基；(b)使該游離3'胺基與3'-經保護胺基-二核苷酸-5'-亞磷醯胺酯二聚物在親核催化劑存在下接觸以形成核苷間N3'→P5'亞磷醯胺酯鍵聯；以及(c)使該鍵聯氧化(例如硫化)。藉由標的方法產生之組合物可包括降低量之一或多種(N-x)寡核苷酸產物。亦提供包括標的寡核苷酸組合物之醫藥組合物。
