Synthesis of thiolated oligonucleotides without a capping step

A process for preparing an oligonucleotide comprising

• a) reacting the compound of Formula (I):
• with the compound of Formula (II):
• to form a compound of Formula (III):
• and
• b) sulfurizing the compound of Formula (III) with a sulfurization agent to form a compound of Formula (IV):
• and from unreacted compound of Formula (I) forms a compound of Formula (V):
• wherein
• each R1 and R11 are independently a nucleobase, wherein the NH2 of the nucleobase, if present, is protected by an amine protecting group;
• each R2 and R12 are independently selected from the group consisting of H, halo, and C1-6alkoxy optionally substituted with C1-6alkoxy;
• R3 is a solid support;
• Y is absent, a nucleotide, or an oligonucleotide comprising 2 to 50 nucleotides;
• each R4 is H;
• each R14 is H;
• R15 is a hydroxy protecting group;
• R16 is CH2CH2CN;
• R17a and R17b are independently C1-6alkyl;
• wherein the sulfurization agent is (i) 3-amino-1,2,4-dithiazole-5-thione (XH or ADTT);
• (ii) phenylacetyl disulfide (PADS);
• (iii) 3-(dimethylamino-methylidene)amino)-3H-1,2,4-dithiazole (DDTT);
• or (iv) 3H-1,2-benzodithiol-3-one 1,1-dioxide;
• wherein RS is —C(SH)(═N)—CN;
• —C(═O)CH2C6H5;
• —C(═S)NHC(═S)N═CHN(CH3)2;
• or
• wherein the sulfurization agent is reacted for a sufficient amount of time to substantially completely convert unreacted compound of Formula (I) to the compound of Formula (V) and to convert the compound of Formula (III) to Formula (IV);
• wherein a sufficient amount of sulfurization agent is added to substantially completely convert unreacted compound of Formula (I) to Formula (V) and to convert the compound of Formula (III) to Formula (IV);
• and
• wherein the compounds of Formulas (I), (II), (III), (IV), and (V) are optionally in the form of a pharmaceutically acceptable salt;
• provided that sulfurization step (b) is not followed by a capping step.