Chloroacetonitrile → HCID 86673651, compound

Participants

Reaction Steps

An alternative method for the preparation of the N-tert-butyloxycarbonyl protected compounds of formula 4, wherein R3 is a tetrazol-5-yl ring substituted by R4, R4 has the above-mentioned meanings and R5 is unsubstituted phenyl is shown in reaction scheme 2. According to reaction scheme 2 the heterocyclic group R3 is not introduced via reaction with a compound of formula 5 as shown in reaction scheme 1, but is build up in a multi-step procedure. In a first step tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (Experimental part—Example B50) is reacted with chloroacetonitrile in an appropriate solvent such as chloroform, tetrahydrofuran, acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide in the presence of a base such as potassium carbonate, sodium carbonate, diisopropylethylamine or triethylamine preferably at elevated temperature preferably at 100° C. to yield tert-butyl 4-[1-(cyanomethyl)-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (Experimental part—Example B14a). Transformation of the cyano group of tert-butyl 4-[1-(cyanomethyl)-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate to the corresponding tetrazole moiety (tert-butyl 4-[2,4-dioxo-6-phenyl-1-(1H-tetrazol-5-ylmethyl)-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate and tert-butyl 4-[2,4-dioxo-6-phenyl-1-(2H-tetrazol-5-ylmethyl)-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate; Experimental Part—Example 14b) can be accomplished by conversion with sodium azide in the presence of triethyl ammonium chloride in a suitable solvent such as for example N,N-dimethylformamide at elevated temperature preferably at 100° C. In a subsequent reaction step the tautomeric compounds tert-butyl 4-[2,4-dioxo-6-phenyl-1-(1H-tetrazol-5-ylmethyl)-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate and tert-butyl 4-[2,4-dioxo-6-phenyl-1-(2H-tetrazol-5-ylmethyl)-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate are alkylated with a compound of formula 6, wherein R4 has the above-mentioned meanings and LG stands for a suitable leaving group, such as for example a halide, preferably chlorine or bromine, or a mesyl or tosyl group in the presence of a base such as for example lithium hydride, sodium hydride or potassium carbonate, sodium carbonate, diisopropylethylamine, triethylamine in an appropriate solvent such as for example N,N-dimethylformamide or dimethyl sulfoxide at elevated temperature, preferably at 40° C. to yield tert-butyl 4-{1-[(2-(R4)-2H-tetrazol-5-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate and 4-{1-[(1-(R4)-1H-tetrazol-5-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate.

Provenance & Evidence