A Facile Synthesis of 9-(1,3-Dihydroxy-2-propoxymethyl)guanine (Ganciclovir) from Guanosine

Abstract

The potent and selective antiviral drug ganciclovir (6) has been synthesized in two steps via transpurination of fully acetylated guanosine (1) in the presence of 1,3-diacetoxy-2-(acetoxymethoxy)propane (2), followed by deacetylation in aqueous ammonia. The transpurination reaction also provides valuable side products, tetra-O-acetyl-b-D-ribofuranose (5) and the 7-regioisomer of triacetylganciclovir (4); the latter product can be converted to the desired 9-isomer in a thermal 7 ← → 9 isomerization.

Reactions of Transglycosylation in the Nucleoside Chemistry

“…The transpurination approach (route A) can be exemplified here by synthesis of antiviral drugs, acyclovir [18] and ganciclovir [107] (Scheme 20). The acid-catalyzed reaction of tetraacetylguanosine with an excess of pseudosugars (5,67) leads to the formation of diacetyl derivatives of acyclovir (68) or ganciclovir (69), along with the respective 7-regiosiomers (46,70) and tetracetyl--D-ribofuranose (4).…”

A facile synthesis of potent antiherpes drug substance, ganciclovir, 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine, using a new masked glycerol derivative

“…1,2 In view of its substantial commercial importance, several synthetic routes were developed for ganciclovir using guanine, 3,4 acetylguanine, 3 2-amino-6-chloropurine, 3,5 tetraacetylguanosine, 6,7 and diacetylguanine 2 (Figure 1), [8][9][10][11] as the source of guanine moiety. Coupling of one of such guanine derivatives with an appropriately protected, activated glycerol derivative such as 1,3-diacetoxy-2-acetoxymethoxy propane or 1,3-dibenzyloxy-2-acetoxymethoxy propane is the commonly employed strategy to access ganciclovir.…”

A Regioselective Synthesis of Alkyl 2-(Guanin-9-yl)acetates as PNA Building Blocks from 7-(4-Nitrobenzyl)guanine Derivatives

“…peracylated sugars 3 . 9-Alkoxyalkyl-ated products can be obtained in high yields even if an N 9 /N 7 isomeric mixture is formed while the N 7 to N 9 rearrangement takes place upon heating [4][5][6][7][8][9][10] or even at room temperature in DMF 11 .…”

“…Constraining guanine into its lactim form e.g. in the case of 2-amino-6-chloropurine [12][13][14][15][16][17] , 2-amino-6-(arylsulfanyl)purines 18 or O 6 -(N,N-diphenylcarbamoyl) derivatives 19 improves the N 9 /N 7 isomer ratio, but it is not sufficient requirement since the highest yield of N 9 -isomer was around 75% and chromatographic purification could not be avoided in every case, furthermore 2-amino-6-chloropurine is mutagenic and expensive, 2-amino-6-(arylsulfanyl)purines require a strong acidic treatment, the N,N-diphenylcarbamoyl group can be labile 20,21 and this imposes limitations on its applicability. There is a third approach, however, affording exclusively 9-alkylated derivatives.…”

“…13 C NMR (decoupled and J-modulated spin-echo spectra): 20.03, 20.25, 20.39 (3 × CH 3 CO); 28.07 (CH 2 CH=CH 2 ); 35.10 (CH 2 CO); 63.00 (C-5′); 70.28 (C-3′*); 72.16 (C-2′*); 79.83 (C-4′*); 84.56 (C-1′); 115.54 (CH 2 =CH); 120.37 (C-5); 136.73 (CH 2 =CH); 137.74 (C-8); 148.06 (C-2 # ); 148.57 (C-6 # ); 154.65 (C-4); 169.15, 169.35, 169.99 (3 × CH 3 CO); 175.46 (C 4 H 7 CONH). MS (ESI), m/z (rel.%): 492.16 (100) [M + H] + .7-(4-Nitrobenzyl)-N 2 -(pent-4-enoyl)guanine(10)…”