Process for preparing benzothiazepines from gamma-aminoalkylbenzenes

A process for preparing a 2,3,4,5-tetrahydro[1,4]benzothiazepine of formula:

• which comprises reacting a [2-(acylaminoethyl)thio]arene of formula
• with an aldehyde of formula R4CHO or an oligomer or polymer thereof, and with an acid, wherein:
• Ar is phenyl;
• R1, R2 and R4 are each independently H, (C1-C6)alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, (C1-C6)alkyl-aryl, (C1-C6)alkyl-cycloalkyl, (C1-C6)alkyl-heterocyclyl or (C1-C6)alkyl-heteroaryl, each of the aryl, cycloalkyl, heterocyclyl and heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of halogen, alkyl, alkoxyl, nitro, cyano and haloalkyl;
• R3 is (C1-C10)acyl;
• P(O)R8R9, C(═O)—R10, C(═S)—R11, S(═O)2R12, (CH2)mR13, an amine protecting group, OH, (C1-C6)alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, (C1-C6) alkyl-aryl, (C1-C6)alkyl-cycloalkyl,(C1-C6)alkyl-heterocyclyl or (C1-C6)alkyl-heteroaryl, each of the aryl, cycloalkyl, heterocyclyl and heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of halogen, alkyl, alkoxyl, nitro, cyano and haloalkyl;
• R5 is chosen independently in each of its occurrences as H, (C1-C6) alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, (C1-C6)alkyl-aryl, (C1-C6)alkyl-cycloalkyl, (C1-C6)alkyl-heterocyclyl, (C1-C6)alkyl-heteroaryl, halogen, acyl, SO3, —OR6, —SR6, —NR6aR6b, —N(R6)C(═O)OR7, N(R6)C(═O)R7, —C(═O)NR6aR6b, —C(═O)OR6, —C(═O)R6, —OC(═O)R6, —NO2, —CN, —(C1-C6)haloalkyl, —O—(C1-C6)haloalkyl, —N3 or —P(O)R8R9, each of the aryl, cycloalkyl, heterocyclyl and heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of halogen, alkyl, alkoxyl, nitro, cyano and haloalkyl;
• R10and R11 are each independently H, —OR14, —NR6aR6b, NHNHR15, NHOH, CONH2NHR15, CO2R15, CONR15, halogen, alkoxy, aryloxy, allyloxy, benzyloxy, substituted benzyloxy, fluoroenylmethoxy, adamantyloxy, (C1-C6)alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, (C1-C6)alkyl-aryl, (C1-C6)alkyl-cycloalkyl, (C1-C6)alkyl-heterocyclyl or (C1-C6)alkyl-heteroaryl, each of the aryl, cycloalkyl, heterocyclyl and heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of halogen, alkyl, alkoxyl, nitro, cyano and haloalkyl;
• R6, R6a, R6b, R7, R8, R9, R12, R14 and R17 are each independently at each of their occurrences H, —OR15, —NR15R16, NHNHR16, NHOH, (C1-C6)alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, (C1-C6)alkyl-aryl, (C1-C6)alkyl-cycloalkyl, (C1-C6)alkyl-heterocyclyl or (C1-C6)alkyl-heteroaryl, each of the aryl, cycloalkyl, heterocyclyl and heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of halogen, alkyl, alkoxyl, nitro, cyano and haloalkyl, or R6a and R6b, together with the nitrogen to which they are attached, represent a 5, 6, or 7-membered ring nitrogen-containing heterocycle;
• R15 and R16 are each independently at each of their occurrences H, NHOH, (C1-C6)alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, (C1-C6)alkyl-aryl, (C1-C6)alkyl-cycloalkyl, (C1-C6)alkyl-heterocyclyl or (C1-C)alkyl-heteroaryl, each of the aryl, cycloalkyl, heterocyclyl and heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of halogen, alkyl, alkoxyl, nitro, cyano and haloalkyl;
• R13 is NH2, OH, —SO2R16, —NHSO2R16, C(═O)R17, NH(C═O)R17, —O(C═O)R17, or —P(O)R8R9;
• m is an integer from 1-10;
• and q is zero or an integer from 1-4, provided that when R5 is —C(═O)R6, R5 is not in an ortho position relative to the sulfur side chain.