5-Aminothieno pyrimidine

With a similar approach, Dave and Shah have developed a simple, fast, solvent-free and high-yielding, variant of the Gould-Jacob type synthesis of thieno[3,2-e]pyrimido[l,2-c]pyrimidines. In this example the conventional condensation between 4-aminothieno-2,3-dyrimidines and diethyl ethoxymethylenemalonate via acyclic intermediates (usually performed in 5-6 h) was compared with a solvent-free single-step microwave procedure (7-10 min) applying a multimode microwave oven (BPL 700T, Mumbai, India) [7], Scheme 6. 

Aminothieno[2,3-c/]pyrimidines (339) are available from 2-amino-3-cyanothiophenes (Scheme 96) (67JOC2376). Treatment of these compounds with excess triethyl orthoformate... 

Approach G involves the successive formation of the N(3)-C(4) and C(2)-N(3) bonds of the pyrimidine ring during cascade heterocyclization. Such transformations can be exemplified by condensation of substituted 2-alkoxycarbonyl-3-(R2-car-bonyl)aminothieno[2,3-6]pyridines 95 with primary amines or hydrazine giving rise to fused pyrimidin-4(3A)-ones 96 (1993PH26, 1997KGS847). In the case of R4 = EtO, the reaction gives pyrimidine-2,4-dione derivatives 97 as the final products (1993PH95). 

Starting from 2-amino-3-cyano-4,5-dihydrothiophenes 60 the derived 2-benzamido derivatives 61 were treated with cyclohexylamine, morpholine, piperidine, or pyrrolidine to yield the respective 5,6-dihydro-2-phenyl 4-substituted aminothieno[2,3-d]pyrimidines 62a-d (83CPB401). In the presence of tin(IV) chloride, benzamides 61 reacted with acetic (or propionic) anhydride to give the corresponding 3-acetyl(or propionyl)thieno[2,3-[Pg.206]

Heating 4-chloropyrimidine-5-carbonitriles 87 or 93 and alkyl 2-mercap-toacetates in ethanol containing base gave directly 5-aminothieno[2,3-d]-pyrimidines 89 (88JHC959, 88KGS1559 89JPR893, 89JPR957) or 94... 

Similar cyclocondensations between 4-thioxopyrimidine-5-carbonitriles 113 or 115 and alkylating agents provided a large number of 5-aminothieno[2,3-d]pyrimidines 114 or 116. 2-Phenyl-6-methylpyrimidines... 

Substituted aminothieno[3,2-d]pyrimidines 247 were obtained from o-aminocarbonitriles 246 by a four-step reaction sequence as described for the corresponding thieno[3,2-<7]pyrimidine isomer 59 (91EUP452002). 

Several 5-aminothieno[3,4-d]pyrimidine-2,4-diones 358 showed phosphodiesterase inhibitory activity superior to that of theophylline (90MI9 91MI3). 

If 4-aminothieno[2,3- ]pyrimidines are desired, the simplest approach is to use a 3-cyano-thiophene as precursor. Formamide or triethylorthoformate are commonly used to convert the amine (270 R1 = H) into the thienopyrimidine (271 R1 = H) (Equation (94)) <88JPR585>. The use of formic acid has been reported to give the 4-oxo compound instead <92MI 707-04). Guanidine reacts with the thiophene (270 R1 = H) to give only a 24% yield of product (271 R1 = NH2) <90HCA797>. 

Treatment of 7-cyanothieno[3,2-d]oxazin-4-ones 125 with primary amines yielded the corresponding 4-aminothieno[3,4-d]pyrimidines 126 [90EGP(D)282011], Condensation of 4-cyano-3-ethoxymethylenethio-phenes 127 with ammonium acetate also gave 126 (R = R = H) (82S1056). 

Cyclization of 5-cyano-6-methylpyrimidine-2,4(l//,3H)-diones 136 with elemental sulfur generated the corresponding 5-aminothieno[3,4-d]-pyrimidine-2,4(l//,3//)-diones 137 (90MI1 91MI2). Similarly, cyclization of 5-cyanopyrimidine-4(3H)-thiones 138 with sulfur afforded the 5-amino-4-thioxo derivative 139 (90LA1215). 

Brough PA, Barril X, Borgognoni J et al (2009) Combining hit identification strategies fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone. J Med Chem 52 4794—4809... 

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