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Title: Researches in pyrimidine chemistry : some potential purine and folic acid antagonists
Author: Spickett, Robert Geoffrey William
Awarding Body: University of London
Current Institution: Royal Holloway, University of London
Date of Award: 1952
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The use of purine and folic acid antagonists in Cancer chemotherapy is reviewed and discussed and the syntheses of some potential purine and folic acid antagonists are recorded. Synthetic methods for the preparation of the pyrimido-(4:5.b)-pyrazine (pteridine) ring system are reviewed with particular reference to the unambiguous synthesis of substituted pteridines. The preparation of 7-amino-6-arylpteridines and 7-hydroxy-6-aryIpteridines by the condensation of 4-amino-5-nitrosopyrinddines with arylacetonitriles and arylacetyl chlorides respectively is reported; thus, providing a new and unambiguous method for the synthesis of these compounds. Pteridines with an amino group in the pyrazine portion of the nucleus have not previously been described. The structure of these compounds is confirmed by their physical and chemical properties. Some of the 7-amino-6-arylpteridine8 have been shown to be antagonists of folic acid when tested microbiologically but none of the compounds tested had any chemotherapeutic effect on the Walker Rat Carcinoma. 2:4:7-Triamino-6-pheryIpteridine is of interest, however, in that it causes hypertrophy of the kidney. The second part of the thesis is concerned with the preparation and reactions of quaternary salts from 2-chloro-5~nitropyrimidines. It is shown that 2:4-dichloro-5-nitropyrimdines react with 2-aminopyridines to yield quaternary salts involving the 2-chloro-qroup of the pyrimidine ring and the cyclic nitrogen atom of the 2-amincpyridine moiety; the 4-chloro group reacts normally with the amino group of 2-aminopyridine. The formation of this type of quaternary salt is a novel reaction in the pyrimidine series and indicates a difference in reactivity between 2- and 4-chloro groups in 2:4-dichloro 5-nitropyrimidaines. Several 2-chloro-5-nitropyrimidines have been shown to form quaternary salts of the above type with 2-aminopyridine and pyridine, but with isoquinoline a different reaction occurs to give 1:2 disubstituted 1:2-dihydro-isoquinolines. The reaction of the quaternary salts formed in the above reaction with ammonia, amines, alcohols and phenols is described and in this way new 2-amino, 2-substituted-amino, alkoxyl and aryloxy-4-(2'-pyridyl)amino-5-nitro pyrimidines have been prepared. The reaction of these quaternary salts with amines and hydroxy compounds is discussed with a view to elucidating the reaction mechanism. By reduction of the 5-nitro group of these derived pyrimidines several substituted 5-aminopyrimidines have been prepared and converted to the corresponding pyrimidotriazoles and dihydropteridines. The former, which are potential purine antagonists, have been tested for chemotherapeutic action on the Walker Rat Carcinoma but are inactive.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Organic Chemistry