Triazolo thiazine

Quantitation of the oral bronehodilator 2,5-diethyl-7-(tetrahydro-l,4-thiazin-4-yl)-l,2,4-triazolo[l,5-c]pyrimidine (R-836) (195) in plasma and urine of humans and experimental animals utilized reversed-phase HPLC and UV deteetion (88MI1). 

Basic hydrolysis of the [l,2,4]triazolo[5,l-3][l,3]thiazine derivative 77 was described to yield triazole-thione 78, the reaction proceeding in 59% yield <2005ZOR1092>. Related partially saturated triazolothiazines 79 were also subjected to ring-opening reaction aqueous hydrolysis afforded the acid 80 <2004KGS1256>, whereas reaction of 79 with hydrazine hydrate yielded the acid hydrazine 81 <2004ZOR260>. Both transformations took place in high yields. 

Several new cyclizations to [l,2,4]triazolo[3,4-A [l,3]thiazines have been published recently, and these are summarized in Scheme 40. In all the four cases shown here, the thiazine ring is partially saturated. 

A general route to [l,2,4]triazolo[3,2-A][l,3]thiazines was discovered by Britsun etal. <2001ZOR1102, 2004KGS1256, 2004ZOR260>. In these publications, reaction of triazole thiones 332 with various substituted acrylic chlorides was reported to yield a series of ring-closed products 333 with the substituent of the reagent in the six-membered ring at the position adjacent to the sulfur atom. 

Novel ring opening reactions of the 1,3-thiazinone moiety of triazolo[5,l- ][l,3]thiazines (13) have been studied Britsun et al. <2005CHE1334>. The experienced transformations are reminiscent of formation of 81 from 79 (Section 11.16.5.1.1). In the frame of this research activity, ring contraction of the thiazine moiety to a thiazole was also observed by the same team <2005CHE782>. 

A variety of N,S-bis(nucleophiles) react with unsaturated 5(47/)-oxazolones to produce triazolo-l,3-thiazin -ones 570 and 1,3-thiazin-4-ones 572. Mechanistically, Michael addition of the bis(nucleophile) to 569 and 571 followed by ring opening with concomitant cyclization leads to the observed products. 

The chemistry of l,2,4-triazolo[4,3-a]pyrimidines is covered in the first installment of a general treatment of 1,2,4-triazolopyrimidines (isostears of purines) by Professor M. A. E. Shaban and Dr. A. E. A. Morgaan (Alexandria University, Egypt). The final installment of Dr. I. Hermecz s (CHINOIN Ltd., Hungary) five-part-series on pyrido-oxazines, -diazines, and -thiazines comprises Chapter 4 of the present volume and covers ben-zologs of pyrido[l,2,-a]pyrimidines. Parts I through IV appeared in Volumes 69-72 of our series. 

The thiazine dithiones also react with hydrazine, hydroxylamine, semi-carbazide, and thiosemicarbazide. Hydrazine gives 3-aminopyrimidine-2,4-dithiones (214) (Scheme 87) [80JCR(S)148]. Thiosemicarbazide reacts in the same way as diamines to give [l,2,4]triazolo[l,5-a]pyrimidines (215) (Scheme 88). 

At 20 °C 4-amino-5-aminomethyl-3-benzyl-l,2,3-triazole (408) gives with CS2 the dithiocarbamate (409), which upon heating affords the novel heterocyclic system 1,2,3-triazolo[4,5-d][l,3]thiazine (410) (and not the expected 8-azapurine) <8oag319, 80aG(E)310,... 

Finally, 96 (and its 2-methyl analog), when heated in pyridine with carbon disulfide and triethylamine (bath at 115°C, 6 h), yielded 95% of 7- and 8-methyl-1,6-dihydro-8-azapurine-2-thione. Derivatives of a new ring system were produced instead of azapurines when the 3-methyl and 3-benzyl analogs of 96 were treated similarly, giving 3-alkyl-3,7-dihydro-3//-1,2,3-triazolo[4,5-[Pg.169]

A derivative of a hitherto unknown nucleus was produced when 4-amino-5-aminomethyl-3-methyltriazole was refluxed with carbon disulfide and triethylamine in pyridine, which yielded 3-methyl-3,7-dihydro-l,2,3-triazolo-[4,5-d][l,3]thiazine-5-thione (98) (3 hr, 53%) the 3-benzyl analog was made similarly (63%) [80JCS(P1)2009]. Cyclization of 4-anilino-5-ethoxycarbonyltriazole with polyphosphoric acid produced 1 f/-triazolo-[4,5-h]quinol-4-one (99) [80EUP(A)2562]. Similarly, ring closure of 4-(2-pyridylamino)triazole-5-carboxylic acid (or its esters) gave l//-pyrido-[l,2-a]-l,2,3-triazolo[4,5-d]pyrimidin-4-one (100) (77GEP2757929). 4-Amino-5-formyl-3-methyltriazole and pentane-2,4-dione, set aside in 20% sulfuric acid, yielded 3,5-dimethyl-3//-l,2,3-triazolo [4,5-6] pyridin-6-yl... 

Condensation of anthranilic acid with various ort/zo-esters and reaction of semicarbazides, gave 2-substituted benzoxazin-4-ones and also by the reaction of hydrazones with aryl-/alkyl-ureas and by salicylaldehyde or 2-hydroxyacetophenones with 4-aryl-/alkyl-semicarbazides. Hydrolysis of o-aminoesters and subsequent treatment with phosgene gave 40. Fused oxazine with bridge head nitrogen 41 and triazolo[3,4-Z>]thiazines 42 were also prepared . The 2,3-dihydrobenzoxazine 43, thiomorpholines 44 and phenothiazines 45 were prepared. ... 

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