Pyrrolo thiazepines

Pyrrolo-thiazepine 236 was obtained by connecting the a-carbon of the pyrrole moiety with the carbonyl group of 237 using phosphorus pentachloride in anhydrous dichloromethane (Equation 20) <2003MOL678>. A similar procedure was followed by Campiani et al. <1997EJM241>. Petrova et al. reported the synthesis of the related imidazothiazepine by polyphosphoric acid-mediated cyclization <2003SC4355>. 

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... 

Intramolecular electrophilic cyclization of methyl selenoate gives only a 12% yield of benzo[/]pyrrolo[2,l- ][l,3]thiazepin-9(10H)-one 285, while cyclization of an acetate derivative under a variety of the conditions failed (Scheme 61 (1998JMC3763)). An alternate route from pyrrole ketones 286 by oxidation and TFAA induced cyclization proved to be advantageous providing a 40% yield of 285. 

Pyrrolo[l,2]thiazepine 68 (R = Ph X = S) can be obtained from the corresponding acid 67 via an intramolecular Fiiedel-Crafts acylation (Scheme 14, Section 2.1.1.5 (1997EJM241, 1996JMC2672, 1994JMC4100, 1994JMC1427)). 

I.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... 

Similarly, methylation of pyrrolo-benzothiazepines 172 (Scheme 34, Section 2.3.1 (1994MI283)) and 307 (Scheme 66, Section 3.3.1.2 (2005FES385)) with methyl iodide in acetone in the presence of potassium carbonate proceeds regioselectively and produces N-methyl pyrrole derivatives as sole products. Methylation on the thiazepine ring nitrogen requires stronger base, i.e. potassium ferf-butoxide, to give dimethyl 174 and 311, respectively. 

Hydroxy and 0x0 groups and other O-linked groups. Treatment of the potassium enolate of the pyrrolo-benzazepine and benzoxepine ketones 68 with the A7,A7-diethylcarbamyl chloride gives carbamates 69 (Scheme 14, Section 2.1.1.5 (2002JMC4276)). A similar modification has been reported for a benzopyrro-lo[l,2]thiazepine (1997EJM241). 

As is the case with other five-membered rings condensed to 1,5-benzo-thiazepines, pyrrolo derivatives have received intensive study and several synthetic routes have appeared. Although it would be possible to obtain several pyrrolo-l,5-benzothiazepines, only two types of fusion have been reported. 

Compound 425, prepared from pyrrole according to a similar method described in the literature <1975MI43>, was hydrolyzed to give the corresponding acid 426, which was cyclized by treatment with PPA at 80 °C (Equation 102) <2000TL6605>. These sequential reactions produced two products. X-ray crystal analysis has shown that the major one is 2-methyl-3,4-dihydro-2//-pyrrolo[2,3y ][l,2]thiazepin-5(6//)-one 1,1-dioxide 427, and the minor one is 2-methyl-3,4-dihydro-27/-pyrrolo[3,4 ][l,2]thiazepin-5(7//)-one 1,1-dioxide 428. No amount of the 2-sulfonyl derivative 429 was detected. 

Dihydropyrrolo[2,l-6]thieno[3,2-/][l,3]thiazepin-4-one 34 as an intermediate for the synthesis of 4-(4-methylpiperazino)pyrrolo[2,l-i>]thieno[3,2-/ [l, 3]thiazepine 35 - a potential antipsychotic agent - was obtained from 2-[2-(thien-2-ylsulfanyl)-l//-l-pyrrolyl]acetic acid 33 by cyclisation onto the p-position of the thiophene ring using either exposure of the acid to phosphorus pentoxide (method A) or (method B) conversion to acid chloride followed by the addition of tin (IV) chloride (Scheme 35) [55],... 

The control of blood pressure by inhibition of angiotensin-converting enzyme is of great interest to clinicians since the method offers a useful treatment for sufferers of hypertension. Relatively few compounds having this ability are available to the medical profession. Kim has described the synthesis and pharmacological action of pyrrolo[2,l-c][l,4]thiazepins and results appear promising. The diastereomer (393) was shown to have activity equivalent to that of the widely prescribed antihypertensive, Captopril. 

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