Synthesis of 2,4‐diamino‐9H‐indeno[2,1‐d]pyrimidines

Abstract

As part of a search for new antifolic, antimalarial, and antitumor agents, a series of 2,4-diamino-9H-indeno[2,1d]pyrimidines was prepared by condensation of guanidine with substituted 2-alkoxy-3-cyano-lKindenes. Base-catalyzed cyclization of 1,2-bis(cyanomethyl)benzenes afforded 2-amino-3-cyano-lH-indenes, which were converted into 3-cyano-2-methoxy-Uindenes by acid hydrolysis and treatment of the resultant 1-cyano-2-indanones with diazomethane. Alternatively, 2-amino-3-cyano-M-indenes could be transformed directly into 2-ethoxy-3-cyano-M-indenes by reaction with ethanol and sulfuric acid. The 2,4diamino-9H-indeno[2,1-d]pyrimidines represent a new type of planar, tricyclic pyrimethamine analog, in which free rotation of the phenyl and pyrimidine rings is prevented by means of a methylene bridge.As part of a larger chemical and biological program involving polycyclic 2,4-diaminopyrimidines (2), we recently reported the synthesis (3-5) and growth-inhibitory properties (6) of 1,3-diaminobenzolf ]quinazolines (I, X = -CH=CH-) and 1,3-diamino-5,6-dihydrobenzolflquinazolines (I, X = -CH2CH2-). These tricyclic systems are of considerable interest as structural analogs of pyrimethamine (11), a well-known antifolic agent which has been used clinically for a number of years in the treatment of malaria (7). Additional interest in these analogs was provided by the experimental antitumor activity reported for the closely related 2,4diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine (111) (8). I 11 R = CH,, R = 4'43 111 R' = H, R = 3', 4'-C1,

Synthesis of Indeno[1,2‐d]pyrimidin‐5‐Ones and Their Fluorescence in Solid State

“…The reaction of 3a with guanidine carbonate (2a) was carried out by direct heating using a hot plate (reaction temperature: 300°C) to obtain 2, 5-diamino-1,3,4,6tetraazafluoranthene (6) in 43% yield. Compound 6 could also be synthesized from 2a and 2-(aminomethylsulfanyl) methyleneindan-1,3-dione (5), which was obtained by the reaction of 1 with 28% ammonia (4a) under methanol reflux (yield: 49%). Furthermore, compound 6 could be easily prepared by reacting 1 with 2a (yield: 37%) (Scheme 1).…”

“…2-(Amino-methylsulfanyl)methyleneindan-1,3-dione (5). A mixture of 2.50 g (10.0 mmol) of 1 and 50 ml of methanol, and 10 ml of ammonia solution (28%) (4a) was refluxed for 10 min.…”

The Risk of Recrystallization: Changes to the Toxicity and Morphology of Pyrimethamine

“…More recently, de Villiers et al described newly discovered toxic solvatomorphs of rifampicin which may have resulted as a consequence of contaminated organic solvents being used during manufacturing (14). Pyrimethamine and some of its derivatives are purified by recrystallization with alcohol (15)(16)(17)(18). Recrystallization is a technique employed universally to alter the solid state chemistry of an API (19,20).…”

Quinazolines. VII. Synthesis of 1,3‐Diamino‐5,6‐dihydrobenzo[f]quinazolines

“…The parent member of the 1,3-diamino-5,6-dihydro-benzoIf]quinazoline series (6, R = H) was first described in 1962 as the product of the fusion reaction between 2-tetralone and cyanoguanidine (Equation 1) (8), and its angular rather than linear structure was later established conclusively through an alternate synthesis from guanidine and l-cyano-3,4dihydro-2-methoxynaphthalene (9,lO). The intermediate cyano enol ether was prepared from 1-(2-cyanoethy1)-2-cyanomethylbenzeneuia Thorpe-Ziegler cyclization, acid hydrolysis, and 0-alkylation with diazomethane, a strategy employed concurrently to convert 1,2bis(cyanomethy1) benzenes into 2,4-diamino-9H-indeno- [2,1-d]pyrimidines (6). In the work described here, a series of alkyl-, chloro-, and methoxy-substituted 1,3diamino-5,6-dihydrobenzolf]quinazolines (6a-6r) was synthesized v i a the cyanoguanidine fusion method, which was judged to be preparatively more attractive than the guanidinetcyano enol ether approach.…”