6- Chloro-9 purine preparation

Deoxy-5 -fluoroadenosine (911) and the analogs 910, 912, 913 were prepared by coupling of 5-deoxy-5-fluoro-D-ribofuranose and 6-chloro-purine. 2, 5 -Dideoxy-5 -fluoroadenosine (914) was prepared through a displacement reaction of the corresponding 5 -0-tosyl precursor with fluoride (BU4NF in DMF). The carbocyclic nucleosides 915 and 916 have been prepared and their antiviral activities evaluated. 

Pyrimido-fused purines can be prepared by intramolecular cyclization of A -(3-hydroxypropyl)guanines, a reaction similar to that of Equation (202). This cyclization can be achieved either via the mesylate <1997JME3248> or (presumably) by conversion of the hydroxyl substituent to chloro (Equation 204) <2001CPB188, 2002JME3440>. 

Dichloro-9-[2-benzoyloxyethoxymethyl]purine was prepared as a key intermediate, which upon selective substitution of the 6-chloro group by ammonia followed by deamination and then displacement of the 2-chloro group gave 9-(2-hydroxyethoxymethyl)guanine. The use of the same synthetic procedure led to a variety of analogs. Of these ACV was found to... 

A series of 2-amino-6-fluoro-9-(13-dihydroxy-2-propoxymethyl)purine mono and diesters has been synthesized, as potential prodrugs of ganciclovir, from 2-amino-6-chloro-9-(13-dihydroxy-2-propoxymethyl)purine <99JMC324>. 2-Amino-6-atylsulfanylpurines 78 can easily be prepared from guanine (77) in what is essentially a one-pot reaction <99T5239>. 

Adenosine analogues where the furanose ring was replaced with alternative dihydro- and tetrahydrofurans were prepared from 6-chloro-9-(4-methylenetetrahydrofuran-3-yl)-9/7-purine <2002T4865>. Of particular interest was the transformation of the exocyclic alkene on the THF ring first by dihydroxylation, then elimination to yield (4-(6-aminopurin-9-yl)-2,5-dihydrofuran-3-yl)methanol after amination of the purine ring at C-6. This A-alkenylpurine was reduced (Pd/C, H2, 25 psi, 73% yield) to provide the tetrahydrofuran-3-yl derivative. 

To expand the diversity of their libraries Brill et al.16 also modified various heterocycles by alkylation, acylation, or metal-mediated coupling reaction prior to resin capture. A remaining chloro substituent was still available for nucleophilic displacement or a palladium-mediated coupling reaction with anilines, phenols, and boronic acids on solid phase [see Fig. 10 for the preparation of purine derivative (62)]. 

Chemicals. The surfactants used in this work were obtained from Sigma Chemical Co. and mobile phases were prepared using distilled and deionized water. The purines were obtained from B-L Biochemicals and Merck Chemicals. The buffers and the other test solutes were obtained from Fisher Scientific. The amines were derivatized with 7-chloro-4-nitrobenzo-2,1,3-oxadizaole (NBD-C1) from Regis Chemicals using a procedure supplied by the manufacturer. 

Related selenoxopurines have been prepared by replacement of the 6-amino group in selected purines. Thus 9-(/3-D-ribofuranosyl)-6-selenoxo-l,6-dihydropurine (371) was conveniently prepared (56% yield) from adenosine in aqueous pyridine with hydrogen selenide over 5 days at 65 °C. In a similar manner 2-aminoadenosine furnished 6-selenoguanosine (21%) (B-78MI40903, p. 673,75CC319,75JHC493). The latter compound may also be obtained (58% yield) from 2-amino-6-chloro-9-(2,3,5-tri-0-acetyl-/3-D-ribofuranosyl)purine and sodium hydrogen selenide. The method adopted for the preparation of selenoxo derivatives depends on the relative availability of the appropriate chloro or aminopurine. 

Chloro-9-(/3-D-ribofuranosyl)purine has similarly been prepared from inosine (63JOC945) by chlorination of 6-thioinosine (63MI40903) or, perhaps most successfully, by reaction of 2, 3, 5 -tri-0-acetylinosine with (chloromethylene)dimethylammonium chloride when yields of 70% are produced (B-78MI40903, p. 611). The latter reagent is obtained from phosgene and DMF in chloroform solution . 

Aminopurines are generally synthesized by the nucleophilic displacement of chloro or methyl-sulfanyl substituents by ammonia or amines (Section 7.1.1.3.4.1.). However, the Traube cyclization is also a useful method. Thus, adenine is prepared by the condensation of pyrimidine-4,5,6-triaminc with formamide under reflux.The same method can also be employed for the preparation of purine-2,6-diaminc (1) (Table 20). 

Todo-substituted purines are of comparatively minor importance. They can be prepared from the chloro derivative and hydriodic acid or, rarely, by direct iodination, for example, the formation of 8-iodocaffeine from caffeine and iodine at 150 C for bhours. ... 

The 2 -deoxythioguanosine 13 is prepared from 2-acetamido-6-chloro-9-[2-deoxy-3,5-di-d)-(4-toluoyl)-/ -D-ribofuranosyl]purine by replacement of the chlorine and removal of the toluoyl groups in one step with methanolic sodium methoxide saturated with hydrogen sulfide. ... 

A mixture of 6-chloro-9-(2,3,5-tri-0-acetyI-)3-D-ribofuranosyl)purin-2-amine (0.293 g, 0.685 mmol), anhyd, distilled pentyl nitrite (1.53 mL, 11.4 mmol), and dry CCL (30 niL) was heated at reflux temperature under Nj for 24 h. The solvent was then removed and the resulting residue taken Up in CH,Cl2 (3 mL) and chromatographed (preparative layer silica gel plates, developed twice with i-PrOH/CH CL, 1 50). Elution of the only significant band Rf = 0.29) with MeOH/CH CIj gives, after crystallization (EtOH), colorless needles yield 0.2 g (66%) rap 139 -t4t°C. 

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