7//- benzothiazepines

1 Pyrrolo[l,2]thiazepines. Hydroxy lactam 280a (n — m — 1), upon treatment with neat TFA at room temperature gives a 20 1 mixture of benzothiazepines 283 and 284 in overall 94% yield. In contrast, 280b (n — 2,m — 0) produces 

The alternate route starting from 293 provides the target compound in improved 58% yield. 

Preliminary acetylation of thiol 294 followed by a displacement step, using 2 equiv. of MeONa or NaH in DMF/benzene, gives tricycle 295 in 25% yield (Equation (34) (1996T7745)). 

2 Pyrrolo-benzothiazepines with other fusion modes. Thiazepine with fused pyrrole ring 250b can be prepared by condensing ortho-amino thiophenol with pyrrole carbaldehyde 249 in moderate yield (Equation (31), Section 3.1.1.4 

Pyrrolo[3,4-c][l,5]-benzothiazepin-3-ones 300 are available from ketoester 299 by a three-step sequence which includes hydrolysis and decarboxylation, aldol condensation and cyclization with o-aminothiophenol (Equation (35) (1993CE773)). 

Sulphur extrusion occurs when 2-phenyl-4-methylthiobenzo[6]-l,4-thiazepine (21) is refluxed in propan-2-ol containing morpholine. Formation of the product (23) is accounted for by the sequence (21) (22) - (23) 

A series of 5-dialkylaminoethyl-benzo-l,5-thiazepin-4-ones (36) has been obtained by reaction of the known benzo-l,5-thiazepin-4-ones (35) with dialkylaminoethyl chlorides and sodium hydride in dioxan or, better, DMSO. The acetoxy-compounds (37) are converted by standard procedures into benzo-l,5-thiazepine derivatives such as (38) and (39). 

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The cyclization of l-dialkylaminobut-l-en-3-ynes with l-amino-2-mercapto-benzene occurs with the same ease (0°C, EtaO, 20 min), the yieldof2-dialkylamino-4-methyl-5//-1,5-dihydro-1,5-benzothiazepines (107) reaching 87 and 91% (85USSRP1130565 88ZOR88). 

The high yields of the end products and the absence of other reliable synthetic routes to 1,5-benzothiazepine, 1,4-dithiepin, and 1,5-dithiocin derivatives of the above structures (85KGS1443) make these cyclizations attractive from the preparative point of view. 

Chemical Name cis-(-t)-3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxy-phenyl)-1,5-benzothiazepin-4(5H)-one hydrochloride... 

The action of 2-(bromomethyl)benzoyl bromide on thioamides results in the formation of 2,4-benzothiazepin-5(l/7)-ones l.47... 

Benzothiazepin-5(4/7)-one (2) is obtained by the thermal ring closure of the thiosalicylamide derivative l.49... 

Cyclodehydration of S-(carboxymethyl)thiosalicylamide (3) with acetic anhydride gives 1,4-benzothiazepine-3,5(2.fif,4//)-dione (4).50... 

The benzothiazepinone 2 is converted into the Ar-methyl derivative 5 by treating its sodium salt with iodomethane and into 5-methoxy-l,4-benzothiazepine (6) with trimethyloxonium tet-rafluoroborate. Compound 6 gives the S-methyl salt 7 on methylation with iodomethanc/sil-ver(I) tetrafluoroborate.49... 

Treatment of a solution of the benzothiazepinedione 1 with ethanolic potassium hydroxide gives the potassium salt, which reacts with iodomethane (3 mol equiv) in a sealed tube at 100°C for three hours to give the (V-methyl derivative, 4-methyl-1,4-benzothiazepine-3,5(2//,4/7)-dione (2a).50 The (V-ethyl derivative 2b is prepared similarly.50... 

Methoxy-l,4-benzothiazepine (3) extrudes sulfur when heated in boiling heptane to yield 1-methoxyisoquinoline the salt 4 is converted into the hydrotetrafluoroborate of l-methoxy-4-(methylsulfanyl)isoquinoline on thermolysis (see Houben-Weyl, Vol.E7a, p678).+y... 

Of simple 1,5-benzothiazepines, only the 2-unsubstituted or 2-phenyl-substituted 4-methoxy-1,5-benzothiazepines are known. X-ray crystallography of the phenyl compound shows that the seven-membered ring exists in a boat form.51... 

For the oxidation of 1,5-benzothiazepines to give the corresponding A-monoxidcs, see Houben-Weyl, Vol.Ell, p714. 

The 1,5-benzothiazepin-4(5//)-ones 2 undergo 0-methylation on treatment with trimethyl-oxonium tetrafluoroborate to give 4-methoxy-l, 5-benzothiazepines 7 a56 and 7b.51... 

Verapamil is a phenylalkylamine which blocks L-type Ca2+ channels in a use-dependent manner. The drug binds to the inactivated state of the channel. Diltiazem is a benzothiazepine derivative with a profile of action most similar to that of verapamil. 

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