4-metalated condensed pyrimidines: their preparation and reaction with aldehydes under Barbier-type conditions

[reaction: see text] The organometallic intermediate obtained from halogen-metal exchanges of 4-iodo-6-phenylthieno[2,3-d]pyrimidine under Barbier-type conditions was reacted with aldehydes to form the corresponding alcohols in moderate yields. The reaction involving an organolithium intermediate proceeded only at low temperature, whereas the reaction involving a magnesium ate intermediate also proceeded at room temperature. A crystal structure confirms that the expected constitutional alcohol isomer is formed, where no migration has taken place. The conditions were also suitable for 9-benzyl-6-iodopurine.     

Preconditioned iterative methods for coupled discretizations of fluid flow problems

Computational fluid dynamics, where simulations require largecomputation times, is one of the areas of application of highperformance computing. Schemes such as the SIMPLE (semi-implicitmethod for pressure-linked equations) algorithm are often usedto solve the discrete Navier-Stokes equations. Generally theseschemes take a short time per iteration but require a largenumber of iterations. For simple geometries (or coarser grids)the overall CPU time is small. However, for finer grids or morecomplex geometries the increase in the number of iterationsmay be a drawback and the decoupling of the differential equationsinvolved implies a slow convergence of rotationally dominatedproblems that can be very time consuming for realistic applications.So we analyze here another approach, DIRECTO, that solves theequations in a coupled way. With recent advances in hardwaretechnology and software design, it became possible to solvecoupled Navier-Stokes systems, which are more robust but implyincreasing computational requirements (both in terms of memoryand CPU time). Two approaches are described here (band blockLU factorization and preconditioned GMRES) for the linear solverrequired by the DIRECTO algorithm that solves the fluid flowequations as a coupled system. Comparisons of the effectivenessof incomplete factorization preconditioners applied to the GMRES(generalized minimum residual) method are shown. Some numericalresults are presented showing that it is possible to minimizeconsiderably the CPU time of the coupled approach so that itcan be faster than the decoupled one.     

New Emivirine (MKC-442) Analogues Containing a Tetrahydronaphthalene at C-6 and their Anti-HIV Activity

An 5-ethyl-2-thiouracil derivative with a 6-(tetrahydronaphthalen-1-yl)methyl substituent was synthesized by condensation of thiourea with an adequate β-ketoester which in turn was synthesized in a single step from (tetrahydronaphthalen-1-yl)acetonitrile. The latter starting material was also used to synthesize an analogously substituted tetrahydronaphthalen-1-yl substituted uracil with a locked conformation. Only the non-nucleoside derivatives prepared from the desulfurized substituted 2-thiouracil showed moderate activity against HIV whereas a corresponding non-nucleoside derivative was devoid of activity against HIV.     

Multiple pathways in the synthesis of new annelated analogues of 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (emivirine)

Condensation of 3-(3,5-dimethylphenyl)-2-oxocyclopentanecarboxamide (11) with oxalyl chloride and condensation of ethyl 2-benzylamino-5-methyl-3-phenylcyclopent-1-enecarboxylate (17a) with trimethylsilyl isothiocyanate gave 7-(3,5-dimethylphenyl)-6,7-dihydro-5H-cyclopenta[e][1,3]oxazine-2,4-dione (12) and 1-benzyl-5-methyl-7-phenyl-2-thioxo-1,2,3,5,6,7- hexahydrocyclopentapyrimidin-4-one (18a), respectively. Acid catalyzed ring-closure of 6-(4-methyl-1-phenylpent-3-enyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (26) and radical mediated ring-closure of 1,3-bis(benzyloxymethyl)-5-bromo-6-(1-phenylbut-3-enyl)-1H-pyrimidine-2,4- dione (32a) gave 5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-1H-quinazoline-2,4- dione (28) and 1,3-bis(benzyloxymethyl)-5-methyl-7-phenyl-1,5,6,7- tetrahydrocyclopentapyrimidine-2,4-dione (33), respectively. Annelated emivirine analogues 7-(3,5-dimethylphenyl)-1- ethoxymethyl-1,5,6,7-tetrahydrocyclopentapyrimidine-2,4-dione (4), 1-ethoxymethyl-5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-1H-quinazoline- 2,4-dione (5) and 1-ethoxymethyl-5-methyl-7-phenyl-1,5,6,7- tetrahydrocyclopentapyrimidine-2,4-dione (6) were obtained in few steps from 12, 28 and 18a/33, respectively. These new analogues can be considered as conformationally locaTed analogues of emivirine. However, the compounds 4 6 showed lower activities against HIV-1 than emivirine and it is concluded that the locked conformation disfavours activity against HIV-1.     

New Emivirine (MKC-442) Analogues Containing a Tetrahydronaphthalene at C-6 and their Anti-HIV Activity

Summary. An 5-ethyl-2-thiouracil derivative with a 6-(tetrahydronaphthalen-1-yl)methyl substituent was synthesized by condensation of thiourea with an adequate β-ketoester which in turn was synthesized in a single step from (tetrahydronaphthalen-1-yl)acetonitrile. The latter starting material was also used to synthesize an analogously substituted tetrahydronaphthalen-1-yl substituted uracil with a locked conformation. Only the non-nucleoside derivatives prepared from the desulfurized substituted 2-thiouracil showed moderate activity against HIV whereas a corresponding non-nucleoside derivative was devoid of activity against HIV.