Pyrrolopyrimidine formation

Treatment of fervenulin 4-oxide 1 with 1.5 equivalents of DMAD in toluene at 95°C for 3 hours resulted in the formation of the pyrrolopyrimidine 2 in 62% yield. It was suspected that water in the solvent was participating in the formation of 2. Evidence in support of this hypothesis was obtained by carrying out the reaction in anhydrous toluene. The product obtained (56%) was the pyrrolopyrimidine 3. Unexpectedly, use of ethanol as the solvent gave the pyrrolopyrimidine 4 in 34% yield, together with 29% of recovered starting material. 

The hydrazone of a 5-formylpyrimidine (114) when treated with sodium hydride and then heated to 150°C also results in formation of a pyrrolopyrimidine (115) (Equation (36)) <89H(29)1993>. In a related reaction, treatment of 2,4-diamino-6(l//)-oxopyrimidine (116) with methyl chloro-formylacetate gives both the pyrrolopyrimidine (117), and the furopyrimidine (118) (Equation (37)) <89JCS(Pl)2375>. The latter can be converted into pyrrolopyrimidine products. Pyrrolopyrimidines with 5-amino substituents can be prepared from 5-cyanopyrimidines utilizing similar chemistry <88LA633>. 

The use of pyrimidines as precursors for pyrrolo[3,4-rf]pyrimidines is the most common synthetic approach. 6-Phenyl-7-(substituted)amino-pyrrolo[3,4-ii]pyrimidine-2,4(l//,3//)-diones (164) are readily obtained from the reaction of 5-formylpyrimidines (163) with arylamines (Equation (54)) <89BCJ3043>. Formation of the Schiff base, followed by cyclization, is the proposed pathway. A more traditional approach is found in the conversion of the cyanoester (165), via the amide, to the corresponding pyrrolopyrimidine (166) (Equation (55)) (88LA643). 

The reaction of dimethyl acetylenedicarboxylate with the thiazolo-pyrimidine 1-oxide (183) resulted in the formation of the pyrimidothiazine (184). The latter compound underwent thermal ring-contraction to the pyrrolopyrimidine (185) (Scheme 85). ... 

MO-LCAO-MNDO method allowed calculation of proton affinities and dipole moment <90Mi 8ii-02>. A MINDO/1 calculation on the ylide (13) predicted more ready addition of DMAD to position 6 than to position 2, thus rationalizing the proportion of pyrrolopyrimidines (14) and (15) formed in cycloaddition (Equation (1)) <86H(24)3473> (see also 8.11.9.2.2). In partly reduced systems, Molecular Orbital Package (MOPAC) heats of formation of pyrrolizine derivatives from pyrrolooxazinone (16) and alkynes <92JA593>, and deprotonation preference in pyrrolopyrazinedione (17) were calculated <79JA1885>. 

Reproducible conversion to a pharmaceutically acceptable pure salt proved not to be trivial in the present case. In fact, despite their obvious structural similarities, all of the compounds studied in this series required the development of their own salt formation procedure. They all required different conditions for salt generation due to the propensity of the pyrrolopyrimidines to retain solvents and moisture, in addition to solubility concerns. We finally settled on treatment with two equivalents of HCi in a mixed solvent system of 9 1 ethyl acetate methanol. This choice of solvent mixture allowed for the warm dissolution and polishing of the sparingly soluble free base and a high recovery of >99% pure solvent-free final product. The overall chemical sequence to produce PNU-101033E in the forward sense is shown in Scheme 3. 

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