【药物名称】Tifenazoxide, NN-414
化学结构式(Chemical Structure):
参考文献No.44022
标题:Fused 1,2,4-thiadiazine derivs., their preparation and use
作者:Hansen, J.B.; Nielsen, F.E. (Novo Nordisk A/S)
来源:EP 1140945; US 6329367; WO 0037474
合成路线图解说明:

The known dichloro thienothiadiazine (I) was condensed with 1-methylcyclopropylamine (II) to produce the target 3-amino thienothiadiazine.

参考文献No.49559
标题:Novel process
作者:Nielsen, F.E.; Ebdrup, S. (Novo Nordisk A/S)
来源:WO 0102410
合成路线图解说明:

By cyclization of O-methylvalerolactam (I) with 3-(4-o-tolyl-1-piperazinyl) propionic acid hydrazide (II) in refluxing xylene, followed by a treatment with ethanolic HCl.

合成路线图解说明:

Acylation of (1-methylcyclopropyl)guanidine (IV) with 3-bromo-5-chlorothiophene-2-sulfonyl chloride (III) under Schotten-Baumann conditions afforded the sulfonyl guanidine (V). This was cyclized to the desired thienothiadiazine upon treatment with Cs2CO3 and Cu2O in boiling butanol.

合成路线图解说明:

In a closely related method, guanidine (IV) was sulfonylated with 3,5-dichlorothiophene-2-sulfonyl chloride (VI), and the resultant sulfonylguanidine (VII) was then cyclized in the presence of Cs2CO3 and Cu2O as above.

合成路线图解说明:

In a different method, (1-methylcyclopropyl)guanidine (I) is acylated by 3-bromo-5-chlorothiophene-2-sulfonyl chloride (II) to produce the sulfonyl guanidine (III). Intramolecular cyclization of (III) in the presence of Cu2O and Cs2CO3 leads to the title thienothiadiazine derivative. Similarly, acylation of guanidine (I) with 3,5-dichlorothiophene-2-sulfonyl chloride (IV) provides sulfonyl guanidine (V), which is then cyclized in the presence of Cu2O and Cs2CO3.

合成路线图解说明:

In an alternative method, sulfonylation of N-isopropylguanidine (V) with 2,5-dichlorothiophene-3-sulfonyl chloride (IV) produced the sulfonyl guanidine (VI). This was then cyclized to the title compound by treatment with copper bronze and potassium carbonate in boiling DMF.

参考文献No.56712
标题:A new process for preparing fused 1,2,4-thiadiazine derivs.
作者:Nielsen, F.E.; Kornoe, H.T.; Rasmussen, K.G. (Novo Nordisk A/S)
来源:WO 0250085
合成路线图解说明:

In a closely related method, guanidine (IV) was sulfonylated with 3,5-dichlorothiophene-2-sulfonyl chloride (VI), and the resultant sulfonylguanidine (VII) was then cyclized in the presence of Cs2CO3 and Cu2O as above.

合成路线图解说明:

A related strategy was based in the lithiation of either sulfonylguanidines (V) or (VII) with BuLi, followed by treatment with trimethyl borate to afford the intermediate methyl boronate (VIII) which upon acidic quenching led to the boronic acid (IX). Cyclization of (IX) to the title bicyclic derivative was then accomplished by treatment with cupric acetate in pyridine.

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