CarbaMic acid, N-3H-iMidazo[4,5-c]pyridin-4-yl-, 1,1-diMethylethyl ester synthesis

Yield:934816-43-0 96%

Reaction Conditions:

Stage #1: 4-(N₆,N₆-di-tert-butyloxycarbonylamino)-1-tert-butyloxycarbonyl-imidazo[4,5-c]pyridinewith sodium methylate in tetrahydrofuran;methanol at 0; for 0.166667 h;
Stage #2: with hydrogenchloride;water in tetrahydrofuran;methanol; pH=9;

Steps:

2

"Starting material was recovered in 98%. ^bIt was difficult to separate a desired product from remaining 7The 3 -deaza-tetrazolopurine (19) was converted to the 3-deazaadenine (13) by hydrogenolysis, followed by protection of the amino groups with di-tert-butyl dicarbonate [(BoC)₂O] afforded tris-JV-Boc-3-deazaadenine (14) in 94 % yield. Tris-N-Boc-3- deazaadenine (14) was transformed into λ^-Boc-S-deazaadenine (15a) with NaOMe in THF in 96% yield.^15a The removal of N₉-BoC group of 14 with 1.0 M NaHCO₃ in THF gave N⁶, N⁶- diBoc-3-deazaadenine (15b) in 92% yield.^15bWith protected 3-deazaadenine derivatives (15a and 15b) in hand, Mitsunobu reaction of 5 with 15a or 15b was carefully investigated in the presence of triphenyl phosphme (Ph₃P), diisopropyl azodicarboxylate (DIAD) and THF. The coupling reaction of N^-Boc-S- deazaadenine (15a) with 5 provided a mixture of Νg-and Ν₇-isomers (16a:17a = 1:4) in 83% yield. In (15b), however, the selectivity toward the Ng- isomer (17b) over the N₇-isomer (16b) increased to 10:lin 88% yield, The major product 17b was easily separated from the reaction mixture by silica-gel column chromatography. The removal of Boc, trityl and isopropylidenyl groups of 17b by methanolic HCl gave 3- deazaneplanocin A (2) in 65% overall yield from 6-chloro-3-deazaadenine (14) (7 steps). The regioselectivity of 15b toward the N9-position in the Mitsunobu reaction was enhanced to 5- and 2.5-fold compared with those of 5 and 15a, respectively. Thus, iV^Λ^-diBoc-S- deazaadenine (15b) was successfully applied to the preparative scale synthesis of 3- deazaneplanocin A (2) in 65% overall yield from 7.; To a solution of compound 14 (2.40 g, 5.52 mmol) in 200 mL of THF, 2.60 mL of NaOMe (12.0 mmol, 25 wt% in MEOH) was added at 0 °C. After 10 min, the basic solution was treated with 1.0 N HCl to get pH 9. The resulting solution was treated with MgSO4 and filtered. The filtrate was concentrated and purified on silica gel pad (CH₂Cl₂ to CH₂Cl₂:Me0H 20:1 v/v) to give compound 15a (1.25 g, 5.32 mmol) in 96% yield. ¹H-NMR (CDCl₃, 500 MHz) δ 11.92 (br, IH), 11.10 (br, IH), 8.12 (d, J = 6.0 Hz, IH), 8.15 (s, IH), 7.48 (d, J = 6.0 Hz, IH), 1.59 (s, 9H); ¹³C-NMR (CDCl₃, 125 MHz) δ 154.23, 150.73, 142.39, 139.43, 139.32, 120.01, 110.59, 82.05, 28.35; HRMS (ES) calcd for C₁₁H₁₄N₄O₂ (M+H⁺) 235.1195, found 235.1168.

References:

WO2007/47793,2007,A2 Location in patent:Page/Page column 37-38; 91