1,2,6-Thiadiazine 1,1-dioxides synthesis

In the oxathiolane area, a paper from Wellcome Laboratories describes work done there on the preparation of 3-thiacytosine and related compounds, whilst a synthesis of 3TC involving an enantioselective enzymic hydrolysis has been reported. The difluorophosphonate analogue 200 of FTC has been made as a racemate with other diastereomers, and 1,2,6-thiadiazine dioxide analogues of 3TC have been reported. A full account has appeared concerning the synthesis of regioisomeric systems such as 201 (see Vol.28, p.297). ... 

Synthesis and structural studies of new 3-alkylamino-pyrido[43-e][l,2,4]thiadiazine 1,1-dioxides have been reported <99T5419>. 

The synthesis of this ring system by condensation of 3,4,5-triamino-l,2,6-thiadiazine-l,1-dioxide with formic acid equivalents to give the fused imidazole ring dates back to the review by Montgomery and Secrist <1984GHEC(5)607>. This methodology was extended to cyclocondensation reactions of 3,4,5-triamino-l,2,6-thiadia-zine-1,1-dioxide with electrophiles such as methyl chloroformate and carbon disulfide to yield 6-oxo 98 and 6-thioxo 99 derivatives of 4-aminoimidazo[4,5-d-l,2,6-thiadiazine-2,2-dioxide respectively (Scheme 72) <1999BMC1617>. 

Fusion has also been employed in the synthesis of 3-cyclopentylpyrido[4,3- ]thiadiazine 1,1-dioxide 226 from the corresponding amide 225 (Scheme 33) <1996JME937>. 

Pyrazino[2,3-c][l,2,6]thiadiazines are 2-thiapteridines, and their 2,2-dioxide derivatives (276) have been used in the preparation of 7-folic acid analogues (279). The latter had no biological activity, however. In the synthesis, the 7-methyl group of derivatives (276) is first brominated with pyridinium... 

The amidine 61 when treated with alkylsulfonyl chlorides forms the intermediate thiazoline diazadiene 62 which cyclises to give the thiazolo[3,2-6]-l,2,4-thiadiazine-l,1-dioxide 63 in moderate yield. This is the first synthesis of this class of compound <02TL4099>... 

The 1,2,6-thiadiazines 571 are prepared from the -diketones 569 and sulfamide 570 in high yields (Scheme 257) <1965M216>. An efficient synthesis of iV-aryl-l,2,6-thiadiazine 1,1-dioxides 573 is based on the cyclization of 3-chloropropyl phenylsulfamide 572 using potassium carbonate in dimethyl sulfoxide (Scheme 258) <2003TL5483, 2003T6051, CHEC-III(9.07.9)385>. 

A superior synthesis of 3-amino-4-alkyl- and 3-amino-4-aryl-4//-l,2,4-benzothiadiazine 1,1-dioxides (135), involving the amino-dechlorination of chloro compounds (130 R = alkyl or aryl) with aqueous ammonia in chloroform has been reported <86S864> yields are excellent (86-94%). It has been shown that l,5-diphenyl-6-bromo-lA 2,4-thiadiazine 1-oxide (136) (see Section 6.14.6.3.3) undergoes metal exchange with butyllithium and, on quenching the mixture with ethyl chloro-formate, the 6-ethoxycarbonyl derivative (137) is obtained in moderate yield (31%). Displacement... 

Substituted 2 f-l,2,4-benzothiadiazin-3(4//)-one 1,1-dioxides are available by a one-pot intramolecular Friedel-Crafts reaction involving the action of chlorosulfonyl isocyanate on a secondary aromatic amine in the presence of aluminum chloride <85IJC(B)1295>. Chlorosulfonyl isocyanate is also employed in the synthesis of oxazolo- and thiazolo[2,3-z(][l,2,4]-thiadiazin-3(2//)-ones (196 X = O and S) from 2-ethyloxazolines (195 X = O) and 2-ethylthiazolines (195 X = S) respectively (Scheme 33) <93SC121>. 

The scope of the reaction was probed by extending the reaction to the synthesis of six-membered cyclic sulphamides. The reaction of 367 with acetamidine gave 1,2,4,6-thiatriazinone-1,1-dioxides 371 (equation 121) in yields of 20%. Fragmentation of the intermediates prior to cyclization is considered to account for the low yields. Modest yields of the pyridothiatriazinone 372 were obtained by condensation of aminopyridine with 367 (equation 122). Aminotriazoles when reacted with 367 yielded the triazolothiatriazinones 373 (equation 123). The reaction of 2-amino-3-ethoxycarbonyl 4,5,6,7-tetrahydro-l-benzothiophen (374) with isopropyl sulphamoyl chloride gives the iV-(isopropyl)-iV -(3-ethoxycarbonyl-4,5,6,7-tetrahydro-l-benzothiophene)sulphamide (375)369. Cyclization of 375 with 5% sodium hydroxide leads to the formation of the cyclic sulphamide 3-isopropyl-4-oxo-3,4,5,6,7,8-hexahydro-1H [ 1 ] -benzothieno [2,3-d] -2,1,3-thiadiazin-2,2-dioxide (376) in 42% yield. Decarboxylation of 375 also occurs in the reaction with the formation of iV-(isopropyl)-iV -(4,5,6,7-tetrahydro-l-benzothiophene)sulphamide 377... 

Two new nucleosides of cyclic sulphamides (392 and 393) have been reported by Vorbruggen and co workers374. The synthesis involves reaction (equation 128) of the 1,2,6-thiadiazine-1,1-dioxide (394) with l-0-acetyl-2,3,5-tri-0-benzoyl-/ -D-ribofuranose (395) the intermediate nucleoside (396) is debenzylated to give 3-amino-6-(2,3,5-tri-0-benzoyl-/ -D-ribofuranosyl)-6//-1,2,6-thiadiazine-1,1 -dioxide (392). 3,6-Dihydro-3 -oxo-6-(/ -D-ribofuranosyl)-2//-1,2,6-thiadiazine-1,1 -dioxide (393) is prepared in a similar manner. 

There are several methods available for the synthesis of 1,2,6-thiadiazine 1,1-dioxides. A common method is a two-step procedure condensing a /3-amino ketone or ester with sulfamyl chloride (prepared from chlorosulfonyl isocyanate and water in tetrahydrofuran) followed by cyclization with potassium hydroxide or preferably with sodium methoxide. The synthesis works with substituted sulfamyl chlorides and with CSI (Section 9.07.9.1.1). A solid-phase variant of this reaction was effected. 

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