Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen bonded directly to ring carbon of the purine ring...
Patent
1996-03-07
1998-05-26
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen bonded directly to ring carbon of the purine ring...
544251, C07D47318
Patent
active
057567379
DESCRIPTION:
BRIEF SUMMARY
This application is based on International Application No. PCT/EP94/00308, filed on Feb. 3, 1994 and published as International Publication No. WO 95/07281 on Mar. 16, 1995.
BACKGROUND OF THE INVENTION
The present invention relates to a novel, improved process for the preparation of 9-(2-hydroxy)-ethoxymethyl-guanine, of formula (I) ##STR1##
The preparation of compound (I), known as "acyclovir" and widely used in therapy as an antiviral, was described for example in Belgian Patent 833,006 starting from guanine, which is first subjected to trimethylsilylation at the three 2-amino, 6 and 9 positions. The resulting silylated intermediate is then treated with 2-benzoyloxyethoxymethyl chloride, to form (after deprotection of the N.sup.2 and N.sup.6 positions) 9-(2-benzoyloxy)ethoxymethyl-guanine, from which acyclovir is recovered by ammonolysis in methanol. The process involves the use of a very strong excess of the silylating agent, with obvious problems as far as costs and wastes are concerned, moreover it leads to a product which is remarkably impure for the presence of the 7-substituted isomer in unacceptable amounts in view of the pharmaceutical use.
British Patent 1.567.671 discloses another process, in which the protection of the amino group at the 2- position is carried out by acylation; the patent claims, as acylating groups, acetyl, propionyl, butyryl and benzoyl, even though the only described case is the one of N.sup.2,9-diacetylguanine, which is reacted with 2-oxa-1,4-diacetoxybutane to give N.sup.2 -acetyl-9-(2-acetoxy)ethoxymethyl-guanine, which is hydrolysed to yield finally acyclovir, in yields which could be satisfactory if only remarkable amounts (up to 13%) of the 7-isomer did not form, which--besides forming to the detriment of the desired product--involves further expensive purification steps.
U.S. Pat. No. 4,146,671 provides a method for the preparation of guanine derivatives, including acyclovir, by reacting a diacylated guanine with a diester of 2-oxa-or 2-thiabutanediol and subsequent hydrolysis.
EP 0 532 878 describes the preparation of acyclovir starting from guanosine and a diester of 2-oxa-butanediol and acetic anhydride, followed by hydrolysis. The desired product is obtained together with the 7-isomer, which is to be converted into the desired 9-isomer.
SUMMARY OF THE INVENTION
Now it has surprisingly been found that acyclovir can be obtained in high yields, substantially preventing the undesired 7-isomer to form, by carrying out the alkylation of the 9- position of the purine ring with 2-oxa-1,4-diacetoxybutane on N.sup.2 -formylguanine. The latter compound is described in literature (Shapiro, Biochemistry, 8, 231-245 (1969)). According to this author, N.sup.2 -formylguanine can be obtained by treatment of the glyoxal-guanine adduct with sodium periodate and/or periodic acid. The process is reproducible in high yields, although N.sup.2 -formylguanine can be obtained, according to the process of the invention, also through other ways.
DESCRIPTION OF PREFERRED EMBODIMENTS
N.sup.2 -formylguanine may also be obtained by the following: hydrogen peroxide or lead tetraacetate; solvents such as dimethylformamide or dimethylsulfoxide, optionally in the presence of dicyclohexylcarbodiimide; solvents such as dimethylformamide, dimethylsulfoxide, hexamethyl-phosphoric triamide or formic acid.
Whichever operative procedure to prepare N.sup.2 -formylguanine is followed, the subsequent reaction of said compound with 2-oxa-1,4-diacetoxybutane leads, in yields above 90% (and, more significantly, with formation of only traces of the 7-isomer) to N.sup.2 -formyl-9-(2-acetoxy)ethoxymethyl-guanine, which is finally deacylated either in a single step, with aqueous alkali, or is first deformylated in acid medium and finally deacetylated by alkali hydrolysis. The following scheme summarizes the process according to the invention. ##STR2##
In said scheme R is hydrogen, C.sub.1 -C.sub.4 alkyl or phenyl. The diol product (2) can be recovered in high yields suspending guanine (1) in H.sub.2 O, add
REFERENCES:
patent: 4146715 (1979-03-01), Schaeffer
patent: 4816447 (1989-03-01), Ashton
Shapiro, Biochemistry 8, 238(1969).
Frare Giovanni
Piccoli Gianfranco
Pucci Sabina
Turchetta Stefano
Berch Mark L.
Recordati S.A. Chemical and Pharmaceutical Company
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