Tetrazole, 5-methyl-, reaction with

Aminosodium salt and acylated with 1 H-tetrazole-1 -acetyl chloride. The acetoxy group is then displaced by reaction with 5-methyl-1,3-4-thi-adiazole-2-thiol in buffer solution. The product acid is converted to the sodium salt by NaHCOa. 

Compound 145 on lithiation <1999SM(102)987> and subsequent reaction with carbon dioxide afforded compound 146. Sandmeyer reaction of 2-bromodi thieno[3,2-A2, 3 -with copper(l)cyanide in hot iV-methyl pyrrolidine (NMP) gave the corresponding nitrile 148 which was then converted to the tetrazole 149 with a mixture of sodium azide and ammonium chloride in NMP in low overall yield (Scheme 14) <2001JMC1625>. 

The seemingly complex imidazolone (78-3) is in fact obtained in a single step by reaction of the amino-ester (78-1) with the iminoether (78-2) derived from capro-nitrile. The relatively acidic proton on the heterocyclic ring is next removed by reaction with sodium hydride. This anion is then alkylated with the same biphenyl-methyl bromide (77-2) that was used to prepare losartan to afford (78-4). The nitrile group is in this case converted to the tetrazole by means of tributyltin azide, a reagent that involves milder conditions than the traditional acidic medium used to generate hydrazoic acid. Thus, treatment of (78-4) with the tin reagent affords irbesartan (75-5) [82]. 

The epioxazoline is successively treated with chlorine, sodium iodide, cuprous oxide and boron trifluoride to produce the exomethylene compound (V). Methoxylation using chlorine with a methoxide followed by reaction with 1-methyl-lH-tetrazole-5-thiol and partial de-blocking using phosphorous pentachloride converts exomethylene (V) into the nucleus (VI). Acylation of the nucleus with an appropriately blocked side-chain (VII) followed by final de-blocking using aluminum chloride gives moxalactam acid (VIII). 

Alkylation of N-unsubstituted tetrazoles with diazomethane. N-Unsubstituted tetrazoles 24 react with diazomethane providing isomeric 1- and 2-methyltetrazoles 215 and 216 in a ratio close to that observed in alkylation of the respective tetrazolates with dimethyl sulfate or methyl iodide (Equation 23) <2000H(53)1421>. A possible reason for this similarity is that a (fast) proton transfer from the heterocyclic NH-acid (cf. Section 6.07.5.3.2) to diazomethane occurs in the first stage. Then, in the rate-limiting stage, the resulting tetrazolate anion reacts with the protonated diazomethane. Unfortunately, a detailed study of this reaction presents experimental difficulties since the determination of diazomethane concentration in solutions is always troublesome. 

Because of the deactivated ir-deficient nature of the ring, nucleophilic attack can readily occur on tetrazoles. Nucleophilic replacement of halogens at the C-5 position has been widely used for the synthesis of disubstituted tetrazoles, e.g. (56). Kinetic studies of the reaction between 5-bromo-l-methyltetrazole and the 2-methyl isomer with piperidine have shown the 1-methyl compound to be considerably more reactive. Comparison of these kinetics with similar reactions for a series of azoles has suggested that two to three deactivating doubly bound nitrogens (—N=) are required to overcome the electron release from one pyrrole-type nitrogen atom in these systems <67JCS(B)64l>. 

A number of reactions of 6-azidotetrazolo[l,5-6]pyridazine (63CPB348) have been reported and include (i) reduction to (266), (ii) substitution by alkoxide and hydroxide to (267) and (268), (iii) reaction with secondary amines (76JOC3152) to form (269) and (270) in a thermal process involving imines and (iv) interaction with ethyl acrylate to give the 1 2 adduct (271) (74MI41501). Since 6-azidotetrazolo[l,5-6]pyridazine can also, potentially, form a second fused tetrazole, the equilibrium between 7-methyl- and 8-methyl-6-azidotetrazolo[l,5-6]pyridazine (Scheme 21) has been studied (74MI41501). 

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