Nucleophilic Displacement Reactions of 2-Amino-4-alkylthiopteridines<sup>1-3</sup>

McCormack, John J.; Mautner, Henry G.

doi:10.1021/jo01034a058

Cited by 17 publications

(9 citation statements)

References 2 publications

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“…The reaction of 11 with the chloropyrimidine23 (10) in EtOH containing NaHCOs gave a 44% yield of anomerically pure N2-acetyl-6-(benzylthio)-iV4-(2,3-0-isopropylidene-/3-D-ribofuranosyl)-5-nitro-2,4-pyrimidinediamine (13). An initial attempt to carry out this reaction in the presence of EtsN as the acid acceptor gave a 30% yield of 13 and a 12% yield of the aglycon .…”

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confidence: 99%

Analogs of 8-azaguanosine

Rd¹,

Ja²

1976

J. Med. Chem.

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Two routes for the synthesis of 6-substtituted 8-azaguanosine analogues are described. 2,5,6-Triamino-4(3H)-pyrimidinethione (1) was converted by methylation, nitrosation, and acetylation to -n-acetyl-7-(methylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-5-amine (5). The reaction of 5 with 2,3,5-tri-O-acetyl-D-ribofuranosyl chloride gave a mixture of the 7-, 8-, and 9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-8-azapurines 4a-c which was converted to 8-azaguanosine (7c) and the corresponding 7- and 8-substituted isomers 7a and 7b. 4a-c were also converted with NaOMe to 6-O-methyl-8-azaguanosine (8c) and to the corresponding 7- and 8-substituted isomers 8a and 8b. The preferred route, however, to 6-substituted 8-azaguanosine analogues is an unambigous synthesis through N2-acetyl-6-(benzylthio)-N4-(2,3-O-isopropylidene-beta-D-ribofuranosyl)-5-nitro-2,4-pyrimidinediamine (13), prepared from the reaction of the chloropyrimidine 10 with the aminoribose 11. Catalytic hydrogenation of 13 gave the aminopyrimidine 14, which was converted with nitrous acid to the nucleoside beta-20. Treatment of beta-20 with dilute acid gave 7-(benzylthio)-3-beta-D-ribofuranosyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-5-amine (19). Replacement of the benzylthio group of 19 with various nucleophilic reagents gave 8-aza-6-thioguanosine 17 and analogues 8c, 15, and 16. The thione 17 rearranges in aqueous solution to the thiasiazolopyrimidine 21. The parent [1,2,3]thiadiazolo[5,4-d]pyrimidine-5,7-diamine (24a) was prepared by nitrosation of the triaminopyrimidine (23a). Rearrangement of 24a in the presence of base gave a high yield of the thione 25a which could be rearranged with heat to 24a. Compounds 8a-c, 15-19, 24a, and 25 a were evaluated in the L1210 mouse leukemia screen- Only one compound, 8c, showed high cytotoxicity and borderline L1210 activity resulting from its en,ymatic conversion to 8-azaguanosine.

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confidence: 99%

Analogs of 8-azaguanosine

Rd¹,

Ja²

1976

J. Med. Chem.

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“…2-Acetylamino-4-(benzylthio)-5-nitro-6(lH)-pyrimidinone (3) . A mixture of -toluenethiol (14.0 g, 113 mmol), K2C03 (14.7 g, 106 mmol), DMAC (320 ml), and 2 (24.5 g, 105 mmol) was stirred for 20 hr, then diluted with H20 (11.…”

Section: -Acetylamino-4-chloro-5-nitro-6(lh)-pyrimidinone (2)mentioning

confidence: 99%

“…A solution of the residue in a minimum of water (pH 8) was acidified with 1 N HC1 to pH 2.5. A solution of the resulting precipitate in H20 (25 ml) containing NH4OH (3 drops) was acidified to pH 2.5. The orange precipitate was collected in a refrigerated centrifuge, washed with H20 (pH 2.5), and dried in vacuo (P203): yield 188 mg (58%); Xmax, nm (e X "3) (solvent c), 0.1 N HC1, 300 7.73 (m, 4, C6H4), 7.12 (s, 2, NH2), 8.17 (d, 1, NH), 8.58 (s, 1, 7-CH).…”

Section: Methylmentioning

confidence: 99%

Synthesis of N10-methyl-4-thiofolic acid and related compounds

Rd¹,

Temple²,

Jl³

et al. 1975

J. Med. Chem.

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Compound 21 (N10-methyl-4-thiofolic acid) and related compounds were prepared as potential inhibitors of the cofactor forms of tetrahydrofolate. The preparation of 2-acetylamino-4-(benzylthio)-6-chloro-5-nitropyrimidine (4) provided an intermediate that was allowed to react with methyl p-[(3-aminoacetonyl)methylamino]benzoate oxime (16). The oxime function of the resulting 6-substituted aminopyrimidine 6 was hydrolyzed to give the corresponding acetonylaminopyrimidine 7, which on reductive cyclization gave methyl p-[[[2-amino-4-(benzylthio)-7,8-dihydro-6-pteridinyl]methyl]methylamino]benzoate (9). This dihydropteridine was oxidized with potassium permanganate, and the product was treated successively with sodium hydrosulfide to replace the benzylthio group and with aqueous sodium hydroxide to hydrolyze the ester function to give p-[[(2-amino-3,4-dihydro-4-thioxo-6-pteridinyl)methyl]methylamino]benzoic acid (N10-methyl-4-thiopteroic acid, 12). Another route to 12 involved the interaction of 2,5-diamino-4,6-dichloropyrimidine (15) with 16 to give methyl p-[[(2-amino-4-chloro-7,8-dihydro-6-pteridinyl)methyl]methylamino]benzoate (13). Displacement of the chloro group of 13 with sodium hydrosulfide followed by the simultaneous air oxidation of the dihydropteridine ring and saponification of the ester group gave 12. After protection of the 2-amino and 4-thioxo moieties of 12, the resulting intermediate benzoic acid was coupled with diethyl L-glutamate. The product of this reaction was deblocked to give 21. Methylation of 21 gave the corresponding 4-(methylthio) derivative 22, which on reaction with hydrazine gave the 4-hydrazino analog 23 of methotrexate. Reduction of 12 and 21 with sodium hydrosulfite gave the dihydropteridines 24 and 25, respectively. The title compound was an excellent inhibitor of the growth of Streptococcus faecium ATCC 8043. However, this and related compounds were ineffective inhibitors of dihydrofolic reductase and showed no significant activity in either the KB cell culture screen or against L1210 leukemia cells in mice.

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“…5-Nitro-2-furyl Phenyl Ketone O-Acetyloxime (14). A mixture of 71 g (0.30 mol) of 10, 61 ml (0.60 mol) of AC2O, and 700 ml of p-dioxane was heated under reflux for 19 hr.…”

Section: Table Imentioning

confidence: 99%

Synthesis of 7H-pyrimido [4,5-b] [1,4] thiazines related to 7,8-dihydropteridines of biological importance

Kim¹,

Mautner²

1974

J. Med. Chem.

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Nucleophilic Displacement Reactions of 2-Amino-4-alkylthiopteridines^1-3

Cited by 17 publications

References 2 publications

Analogs of 8-azaguanosine

Analogs of 8-azaguanosine

Synthesis of N10-methyl-4-thiofolic acid and related compounds

Synthesis of 7H-pyrimido [4,5-b] [1,4] thiazines related to 7,8-dihydropteridines of biological importance

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Nucleophilic Displacement Reactions of 2-Amino-4-alkylthiopteridines1-3

Cited by 17 publications

References 2 publications

Analogs of 8-azaguanosine

Analogs of 8-azaguanosine

Synthesis of N10-methyl-4-thiofolic acid and related compounds

Synthesis of 7H-pyrimido [4,5-b] [1,4] thiazines related to 7,8-dihydropteridines of biological importance

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Nucleophilic Displacement Reactions of 2-Amino-4-alkylthiopteridines^1-3