Entry 1 and two) with a rather minor difference in between the three PTCEntry 1

Entry 1 and two) with a rather minor difference in between the three PTC
Entry 1 and two) with a rather minor distinction among the three PTC agents attempted (Table two). As TBABr was working effectively for N3 alkylation and further screens confirmed its efficiency (Supplementary Tables S1 and S2), this catalyst was selected for the larger scale reaction. Additionally, further screens had been performed to figure out appropriate amounts of base and methyl 2-bromoacetate (Supplementary Table S1). Unique bases (K2 CO3 and K3 PO4 ) have been also compared and revealed that the alkylation reaction final results in the least quantity of impurities when it really is performed in Heptane or acetonitrile (MeCN) within the presence of K2 CO3 . To confirm these outcomes, more screenings (Supplementary Tables S1 and S2) were performed, which showed that a reaction in heptane was cleaner compared to MeCN (Supplementary Figures S2 and S3). On the other hand, upon a transfer of conditions to a larger scale, solubility became an issue (5 vol of heptane was employed in test reactions (Table 2, entries six and 11)), which did not look an issue at the time. Nevertheless, bigger amounts of compound 2 took longer occasions to dissolve in five vol of heptane as well as the alkylation product 3 is usually poorly soluble within this solvent. To overcome this difficulty, we chose to carry out the reaction within a DCM/heptane mixture (this test reaction was completed before larger scale (Table two, entry 14)). Finally, immediately after the series of screens, 5 vol DCM/heptane (1:4 (v/v)), 4 equiv. of K2 CO3 and 0.05 equiv. of TBABr have been selected for the bigger scale of MeU 2 -OH alkylation. The level of K2 CO3 was enhanced for precisely the same explanation as for N3 alkylation. Nonetheless, the scaling-up of a PTC reaction utilizing strong base can from time to time develop into difficult. The grinding effect from the magnet in smaller sized scale PTC reactions is extra pronounced and therefore fresh particle surface is constantly exposed. We observed that the PTC alkylation on a bigger scale did not visit completion soon after stirring at ambient GNE-371 web temperature for 66 h in comparison to the small-scale reaction which was completed right after 36 h (Table 2, entry 14).Molecules 2021, 26,five ofThe extra added amounts of K2 CO3 , TBABr and methyl 2-bromocetate facilitated the reaction to go to completion. At this point, a one-pot three-step synthesis followed. The reaction sequence began with selective PSB-603 site opening of your 5 position of compound 3 employing TFA in THF:water (5:1, v/v).Table two. Screen for suitable situations for 2′-OH alkylation of 5-methyl uridine intermediate.No. Methyl 2Bromoacetate 1.2 equiv. 1.two equiv. 1.two equiv. two equiv. 2 equiv. two equiv. two equiv. 2 equiv. two equiv. two equiv. two equiv. two equiv. 2 equiv. 2 equiv. Solvent, five Vol MeCN MeCN MeCN MeCN Toluene Heptane DCM DMF MeCN Toluene Heptane DCM DMF Base K2 CO3 , two equiv. K2 CO3 , 2 equiv. K2 CO3 , two equiv. K2 CO3 , 2 equiv. K2 CO3 , two equiv. K2 CO3 , 2 equiv. K2 CO3 , two equiv. K2 CO3 , two equiv. K3 PO4 , two equiv. K3 PO4 , 2 equiv. K3 PO4 , 2 equiv. K3 PO4 , two equiv. K3 PO4 , two equiv. (PTC) Catalyst MeNOct3 Cl, 0.2 equiv. Oct4 NBr, 0.two equiv. Oct4 NBr, 0.2 equiv. Oct4 NBr, 0.2 equiv. Oct4 NBr, 0.2 equiv. Oct4 NBr, 0.2 equiv. Oct4 NBr, 0.two equiv. Oct4 NBr, 0.two equiv. Oct4 NBr, 0.2 equiv. Oct4 NBr, 0.2 equiv. Oct4 NBr, 0.2 equiv. Oct4 NBr, 0.two equiv. TBABr, 0.05 equiv. HPLC Area , Conver., RT, 1h 7 Solution trace 8 15 Solution trace five Product trace 7 51 4 9 5 9 Solution trace HPLC Location , Conver., RT, Overnight 50 16 54 86 11 51 22 76 83 18 50 37 32 76 (93 immediately after 36 h)1. two. three. four. 5. six. 7. 8. 9. ten. 11. 12. 13. 1.