Thiazin 2-chloro

CN 6-Chloro-4-hydroxy-2-methyl-A-2-pyridinyl-2//-thieno[2,3-e]-l,2-thiazine-3-carboxamide 1,1-dioxide... 

Benzyl-9-phenyl-3,4-dihydro-27/,677-pyrimido[6,l-A [l,3]thiazine-6,8-(7//)-dione was prepared from 3-benzyl-6-chloro-l-(3-chloropropyl)-5-phenylpyrimidine-2,4-(17/,3//)-dione and NaSH hydrate in DMF in 27% yield <1995W035296>. 

The reaction of tetrahydro-l,3-thiazine-2-thione and diethyl 2-chloro-malonate in the presence of triethylamine in boiling methylene chloride for 1.5 hr gave tetrahydro-1,3-thiazin-2-ylidenemalonate (508) in 33% yield via 507 through Eschenmoser sulfur elimination, together with traces of the mesoionic derivative (509) [77JCS(P 1) 1107]. In a similar reaction, diethyl 2-bromomalonate afforded the mesoionic compound (509) in 80% yield. Tetrahydro-l,3-thiazin-2-ylidenemalonate (508) was also obtained in 42% yield from 509 by irradiation in the presence of tributylphosphine in ethanol for 15 hr under argon [77JCS(P1)1107]. 

Dialkyl and isopropylidene malonates were reacted with 2-chloro-l,3-thiazinium chlorides (1686) in methylene chloride in the presence of triethylamine to give (1,3-thiazin-2-ylidene)malonates (1687) in 5-13% yields (89AP593, 89GEP3803783). 

L-Perhydro-l,4-thiazine-3-carboxylic acid 1-oxide is a natural AA found in some red and brown algae. It was synthesized from L-cystine in several steps. The heterocyclic ring was prepared by cyclization of 5-(2-chloro- or bromoethyl)-L-Cys in the presence of triethylamine. Perhydro-l,4-thiazine-3-carboxylic acid was then oxidized with H2O2/ACOH to give the sulfoxide (64JOC2203). Cystine also reacted with ethyl a-bromopropionate in liquid ammonia to give 5-oxoperhydro-l,4-thiazine-3-carboxylic acid [76JCS(P2)203],... 

The reaction mode depends mainly on the choice of the base and reaction conditions, but route B is usually more common. Thus, tetrahydro-l,4-thiazine derivative 157 the structure of which was proved by X-ray crystal structure analysis (Fig. 7) [22b] was obtained in the reaction of the chloro ester 1-Me with 2-aminoethanethiol (156) using K2CO3 or EtgN as a base in 43 and 20% yield, respectively (Scheme 49) [22b, 26]. In the latter case, the secondary amino group in the primary tetrahydrothiazine product 157 underwent Michael addition to a second molecule of 1-Me to give 2-[r-(spirocyclopropanetetrahydrothiazinyl) cyclopropyl]-2-chloroacetate 158 (14% yield). When KOH in the presence of di-benzo-18-crown-6 was employed, however, the seven-membered heterocycles 155 (42%) and 159 (48%) were obtained upon reaction of 1-Me with 1,3-pro-panedithiol and 2-aminoethanethiol, respectively (Scheme 49) [26]. 

The 6//-l,3-thiazin-6-iminium hydroperchlorate salts 78-81 give interesting products when treated with nucleophiles <2003H(60)2273>. Hydrolysis of 6-imino-6//-l,3-thiazine hydroperchlorate 78 affords (2Z,4Z)-2-cyano-5-hydroxy-5-phenyM-azapenta-2,4-dienethioamide 82 in excellent yield, while treatment with morpholine gives 2-(morpholinomethylene)malononitrile 83 and thiobenzamide. The 5-(ethoxycarbonyl) -(methylthio)-2-aryl-6/7-l,3-thiazin-6-iminium salts 79 and 80 react with hydroxide or morpholine to afford ethyl 4-(methylthio)-2-aryl-6-thioxo-l,6-dihydropyrimidine-5-carboxylates 84 and 85. In the case of the 4-chloro analogue 80, the (Z)-ethyl 2-(5-(4-chlorophenyl)-37/-l,2,4-dithiazol-3-ylidene)-2-cyanoacetate 87 is also formed for the reaction with sodium hydroxide. The 1,2,4-dithiazoles 86 and 87 can be obtained as the sole product when 79 and 80 are treated with sodium acetate in DMSO. Benzoxazine 88 is isolated when the iminium salt 81 is treated with morpholine or triethylamine. Nitrile 89 is formed as a ( /Z)-mixture when 6-imino-67/-l,3-thiazine hydroperchlorate 79 is reacted with triethylamine and iodomethane in methanol <2003H(60)2273>. 

Thiazin-4-ones 236 are obtained when 2-chloro-2-(T(Timinomethylthio)cyclopropyl)acetates 235 are reacted with titanium tetraisopropoxide in dichloromethane <2001EJ03025>. The yield is dependent on the group attached to C-2 and observed diastereoselectivities are poor. Representative examples are shown in (Scheme 29). Interestingly, thiazolines 237 are formed under basic conditions. 

The acetamido alkenethiolate (416), generated by the reductive cleavage of 2,3-dihydro-l,4-thiazin-2-one (415) in liquid ammonia (cf. p. 625), reacted with l-chloro-3-bromopropane in a two-stage process to give (417). 

Chloro-4-hydroxy-2-methyl-1,1 -dioxo-1,2-dihydro-1 l6-thieno[2,3 e][1,2]thiazine-3-carboxylic acid pyridin-2-ylamide, 6-chloro-4-hydroxy-2-methyl-/V-(2-pyridyl)-2H-thieno[2,3-e]-1,2-thiazine-3-carbox-amide-1,1-dioxide, CnH,oC N30AS2, Mr 371.81, mp 225-230 °C (decomp.)... 

A six-membered nitrogen-sulfur heterocycle, namely, a 2,3-dihydro-2-imino-4//-benzo[e thiazin-4-one, is produced on reaction of methyl 2-chloro-3,5-dinitrobenzoatc with thiourea in basic medium 373 furthermore, a tetrahydrospirobenzothiazine 213 is formed in addition to its hexahydrospiroquinazoline analog on interaction of cyclohexanone with thiourea in hydrochloric acid.329... 

Reaction of 4-phenyl-6-chloro-2(lH)-pyridone and 3-aminopropanethiol on heating in ethylene glycol at 190-200°C afforded 8-phenyl 2,3, 4,6-tetrahydropyrido[2,l-6][l,3]thiazin-6-one (79CPB1207). 2,3,4,6,7,116-Hexahydro[l,3]thiazino[2,3-a]isoquinolin-4-ones (204) were obtained in the reactions of 3,4-dihydroisoquinolines and 3-mercaptopropionic acid in the presence of p-toluenesulfonic acid (69FRP155211 87MI1). 

Although 2-//-l,2-oxazines are unstable, the 1,3-isomers are quite well known. The 1,4-oxazines are relatively uncommon and unexplored. Aspects of the halogenation of oxazines and thiazines have been summarized (84MI14). Much more is known about the sulfur analogues, especially the benz derivatives of 1,4-thiazine (see Part 3). When perfluorinated 1-chloro-1,2-thiazine was heated with potassium fluoride, the chlorine was replaced by fluorine (92CB581). 

C yHlyClN2 100643-71-8) see Loratadine (4.V)-6-chloro-3,4-dihydro-2//-thieno[3,2-c]-l,2-thiazin-4-ol 1,1-dioxide... 

Pyrazolo[3,4-J][l,3]thiazin-4-ones and isoxazolo[5,4-J][l,3]thiazin-4-ones are produced by the reaction of 4-chloro-6-oxo-l,3-thiazin-5-al with hydrazine and hydroxylamine <84KGS1328). 

The reaction of 2-chloro-3-(7V-substituted amino)pyrazines (233) with thioglycolates gives 2,3-dihydro-4-substituted-(4//)-pyrazino[2,3-6][ 1,4]thiazin-3-ones (234) <71JAP32670, 74JAP(K)49041397> with analgesic properties (Equation (34)). 

Another method for preparing pyrimido[4,5-/>][ 1,4]thiazines is to reflux 2,5-diamino-4-hydroxy-6-thiolpyrimidine (257) in ethanol with 7V-(3-chloro-2-oxopropyl)-/>-toluenesulfonamide (258) and NaHC03 <90GEP3919214>. The resulting pyrimido[4,5-fe][l,4]thiazines (259) are antimalarials (Equation (37)). 

In the reactions of 4-chloro and 4-tosyloxy-2-methylpyrimidine-5-carboxylic acids (280) with thioureas (281) derivatives of 2,3-dihydro-1 -methylpyrimido[5,4-e][l, 3]thiazines (282) have been obtained (Equation (44)) <89MI 719-06). 

Cyclisation of 5-benzylsulfonyl-3-chloro-4-methoxycarbonylaminoisothiazole (18) using an excess of NaOMe in DMF gave 3-methoxy-5-oxo-6-phenyl-5,6-dihydro-4//-isothiazolo[5,4-f>]-1,4-thiazine 7,7-dioxide 19, which was the first representative of a new heterocyclic ring system. Compound 18 was prepared in good yield (81%) by the reaction of 17 with PhI(OAc)2 in methanol <02RCB187>. 

Chloro-2-[4-[4-(2H-benzimidazo-2-oxo-l-yl)piperidin-l-yl]butyl]-2H-thieno[3,2-e]-l,2-thiazine 1,1-dioxide hydrochloride, (V), and related 5HT7 receptor agonists prepared by May (5) were effective in the treatment of circadian rhythm disorders. 

A-Acylation is, of course, rendered more difficult by the presence of substituents in positions 1 and 9, owing to steric effects. Massie and Kadaba observed that 1-substituted derivatives may be acetylated with acetic anhydride in pyridine, but the use of anhydrous solvents throughout the synthesis and purification is required, since the products are very readily hydrolyzed. 1-Chloro-lO-acetylpheno-thiazine, for example, loses its acyl group even on pouring the reaction mixture into water. Isopropenyl acetate has been recommended by the same authors as an acetylating agent which is able to overcome the steric hindrance in 1-substituted phenothiazines. 

H-1,4-Thiazine 6-(4-Chloro-phenyl)-3-formyl- E9a, 433 ( — R2NH -> Imin)... 

SYNS AMINAZIN MONOHYDROCHLORIDE AMPLIACTIL MONOHYDROCHLORIDE CHLORACTIL CHLORAZIN 2-CHLORO-10-(3-DIMETHYLAMINOPROPYL) PHENOTHLAZINE MONOHYDROCHLORIDE D CHLOROPROMAZINE MONOHYDROCHLORIDE CPZ 10-(3-DIMETHYLAMINOPROPYL)-2-CHLOROPHENO-THIAZINE MONOHYDROCHLORIDE HEBANIL HIBANIL HIBERNAL HYBERNAL KLOR-PROMAN KLORPROMEX LARGACTIL MONOHYDROCHLORIDE LARGAKTYL MEGAPHEN NCI-CO5210 NEURAZINE NORCOZINE PHENOTHIAZINE HYDROCHLORIDE... 

Diels -Alder reactions are widely applicable because of their versatility in building up six-mem-bered ring systems. For example. [4 + 2]-cycloaddition reactions of halogcnatcd thiazyls and 2-chloro-1,l,3.4,4-pentafluorobuta-l,3-dicne (7) furnish the corresponding 124,2-thiazines 8.63... 

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