Process for preparing benzothiazepines from gamma-aminoalkylbenzenes

1. A process for preparing a 2,3,4,5-aryl-fused tetrahydro[1,4]thiazepine of formula:

which comprises reacting a [2-(acylaminoethyl)thio]arene of formula

with an aldehyde of formula R 4 CHO or an oligomer or polymer thereof, and with an acid, wherein:

Ar is a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring system selected from the group consisting of phenyl, naphthyl, indanyl, tetralinyl, fluorenyl, imidazolyl, indolyl, thiophenyl, benzopyranonyl, thiazolyl, (uranyl, benzofuranyl, benzimidazolyl, quinolinyl, isoquinolinyl and pyrazolyl;

R 1 , R 2 and R 4 are each independently H, (C 1 -C 6 )alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, (C 1 -C 6 )alkyl-aryl, (C 1 -C 6 )alkyl-cycloalkyl, (C 1 -C 6 )alkyl-heterocyclyl or (C 1 -C 6 )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;

R 3 is (C 1 -C 10 )acyl; P(O)R 8 R 9 , C(═O)—R 10 , C(═S)—R 11 , S(═O) 2 R 12 , (CH 2 ) m R 13 , an amine protecting group, OH, (C 1 -C 6 )alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, (C 1 -C 6 )alkyl-aryl, (C 1 -C 6 )alkyl-cycloalkyl, (C 1 -C 6 )alkyl-heterocyclyl or (C 1 -C 6 )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, taken together, R 2 and R 3 form an oxo-substituted nitrogen-containing heterocycle;

wherein, when Ar is phenyl, R 2 and R 3 form an oxo-substituted nitrogen-containing heterocycle;

R 5 is chosen independently in each of its occurrences as H, (C 1 -C 6 )alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, (C 1 -C 6 )alkyl-aryl, (C 1 -C 6 )alkyl-cycloalkyl, (C 1 -C 6 )alkyl-heterocyclyl, (C 1 -C 6 )alkyl-heteroaryl, halogen, acyl, SO 3 , —OR 6 , —SR 6 , —NR 6a R 6b , —N(R 6 )C(═O)OR 7 , N(R 6 )C(═O)R 7 , —C(═O)NR 6a R 6b, —C(═O)OR 6 , —C(═O)R 6 , —OC(═O)R 6 , —NO 2 , —CN, —(C 1 -C 6 )haloalkyl, —O—(C 1 -C 6 )haloalkyl, —N 3 or —P(O)R 6 R 9 , 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;

R 10 and R 11 are each independently H, —OR 14 , —NR 6a R 6b , NHNHR 15 , NHOH, CONH 2 NHR 15 , CO 2 R 15 , CONR 15 , halogen, alkoxy, aryloxy, allyloxy, benzyloxy, substituted benzyloxy, fluoroenylmethoxy, adamantyloxy, (C 1 -C 6 )alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, (C 1 -C 6 )alkyl-aryl, (C 1 -C 6 )alkyl-cycloalkyl, (C 1 -C 6 )alkyl-heterocyclyl or (C 1 -C 6 )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;

R 6 , R 6a , R 6b , R 7 , R 8 , R 9 , R 12 , R 14 , and R 17 are each independently at each of their occurrences H, —OR 15 , —NR 15 R 16 , NHNHR 16 , NHOH, (C 1 -C 6 )alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, (C 1 -C 6 )alkyl-aryl, (C 1 -C 6 )alkyl-cycloalkyl, (C 1 -C 6 )alkyl-heterocyclyl or (C 1 -C 6 )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 R 6a and R 6b , together with the nitrogen to which they are attached, represent a 5, 6, or 7-membered ring nitrogen-containing heterocycle;

R 13 is NH 2 , OH, —SO 2 R 16 , —NHSO 2 R 16 , C(═O)R 17 , NH(C═O)R 17 , —O(C═O)R 17 , or —P(O)R 8 R 9 ; m is an integer from 1-10; and q is zero or an integer from 1-4, provided that when R 5 is —C(═O)R 6 , R 5 is not in an ortho position relative to the sulfur side chain;

R 15 and R 16 are each independently at each of their occurrences H, NHOH, (C 1 -C 6 )alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, (C 1 -C 6 )alkyl-aryl, (C 1 -C 6 )alkyl-cycloalkyl, (C 1 -C 6 )alkyl-heterocyclyl or (C 1 -C 6 )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.

2. The process according to claim 1 , wherein the [2-(acylaminoethyl)thio]arene is first reacted with the aldehyde or an oligomer or polymer thereof and a base to form an [N-hydroxymethyl-2-(acylaminoethyl)thio]arene of formula

and

the [N-hydroxymethyl-2-(acylaminoethyl)thio]arene is then treated with the acid to form the 2,3,4,5-aryl-fused tetrahydro[1,4]thiazepine wherein the acid is a sulfonic acid or a Lewis acid.

3. The process according to claim 2 , wherein the base is an alkali metal hydride, hydroxide or carbonate, pyridine, or a trialkylamine.

4. The process according to claim 3 , wherein the base is NaH, NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , Et 3 N or (iPr) 2 NEt.

5. The process according to claim 1 , wherein the acid is a sulfonic acid or a Lewis acid.

6. The process according to claim 5 , wherein the sulfonic acid is selected from the group consisting of toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, pyridinium p-toluenesulfonate, and trifluoromethanesulfonic acid, and the Lewis acid is selected from the group consisting of boron trifluoride etherate, titanium tetrachloride, aluminum chloride and zinc chloride.

7. The process according to claim 1 , wherein the aldehyde or oligomer or polymer thereof is formaldehyde, paraformaldehyde or 1,3,5-trioxane.

8. The process according to claim 1 , wherein R 3 is acetyl, benzoyl, toluoyl, benzyloxycarbonyl, t-butoxycarbonyl, acryloyl, oxalyl or —C(═O)NR 6a R 6b , wherein R 6a and R 6b are each independently hydrogen, (C 1 -C 6 )alkyl, aryl, heterocyclyl, heteroaryl, (C 1 -C 6 )alkylaryl, (C 1 -C 6 )alkylheterocyclyl, or (C 1 -C 6 )alkylheteroaryl, or taken together, NR 6a R 6b represents a 5, 6, or 7-membered ring nitrogen-containing heterocycle.

9. The process according to claim 1 , wherein:

R 5 is (C 1 -C 6 )alkyl, halogen, —OR 6 , —SR 6 , —NO 2 , —CN, —(C 1 -C 4 )haloalkyl or —O—(C 1 -C 4 )haloalkyl; and R 6 is H or (C 1 -C 6 )alkyl.

10. The process according to claim 1 ,

which comprises treating a [2-(acylaminoethyl)thio]arene of formula

with an aldehyde of formula R 4 CHO or an oligomer or polymer thereof, and an acid to produce a compound of formula

wherein R 3a is (C 1 -C 10 )acyl of formula —C(═C)—R 18 an amine protecting group, wherein R 18 is H, (C 1 -C 6 )alkyl, (C 1 -C 5 )alkoxy, allyloxy, benzyloxy, substituted benzyloxy, fluorenylmethoxy or adamantyloxy.

11. The process according to claim 10 , which further comprises cleaving R 3a to produce a 4-unsubstituted 2,3,4,5-aryl-fused tetrahydro[1,4]thiazepine of formula

12. The process according to claim 11 , which further comprises reacting the 4-unsubstituted 2,3,4,5-aryl-fused tetrahydro[1,4]thiazepine with R 3 X to produce a compound of formula

wherein

R 3 is (C 1 -C 10 )acyl; P(O)R 8 R 9 , C(═O)—R 10 , C(═S)—R 11 , S(═O) 2 R 12 , (CH 2 ) m R 13 , an amine protecting group, OH, (C 1 -C 6 )alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, (C 1 -C 6 )alkyl-aryl, (C 1 -C 6 )alkyl-cycloalkyl, (C 1 -C 6 )alkyl-heterocyclyl or (C 1 -C 6 )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, taken together, R 2 and R 3 form an oxo-substituted nitrogen-containing heterocycle; and

X is halogen, (C 1 -C 10 )acyloxy, or an activated ester residue.

13. The process according to claim 11 , which further comprises reacting the 4-unsubstituted-2,3,4,5-aryl-fused tetrahydro[1,4]thiazepine with a compound of formula X—CH 2 —COOR′ wherein X is a halogen and R′ is (C 1 -C 6 )alkyl to form an ester compound of formula:

and hydrolyzing the ester to form a compound of formula:

14. The process according to claim 10 , wherein R 3a is t-butoxycarbonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl or fluorenylmethoxycarbonyl.

15. The process according to claim 12 , wherein R 3 X is an acid chloride, an acid anhydride, an activated ester, a chloroformate or a carbamic chloride.

16. The process according to claim 10 , wherein the method further comprises treating a compound of formula

wherein R 3a is —C(═O)—R 13 wherein R 18 is (C 1 -C 4 )alkoxy, allyloxy, benzyloxy, substituted benzyloxy, fluorenylmethoxy or adamantyloxy, with an amine of formula HNR 6a R 6b , wherein R 6a and R 6b are each independently hydrogen, (C 1 -C 6 )alkyl, aryl, heterocyclyl, heteroaryl, (C 1 -C 6 )alkylaryl, (C 1 -C 6 )alkylheterocyclyl, or (C 1 -C 6 )alkylheteroaryl, or taken together, NR 6a R 6b represents a 5, 6, or 7-membered ring nitrogen-containing heterocycle, to form a compound of formula:

17. The process according to claim 1 , which further comprises preparing the [2-(acylaminoethyl)thio]arene by reacting a compound of formula

with a compound of formula

to provide a compound of formula

optionally in the presence of a base followed by reaction with a compound of formula R 3 X, wherein LG is a leaving group for nucleophilic displacement by thiol and X is a leaving group for nucleophilic displacement by an amine.

18. The process according to claim 17 , wherein LG is a halogen or a sulfonate, the base is an alkali metal hydride, hydroxide or carbonate, pyridine or a trialkylamine and R 3 X is an acid chloride, an acid anhydride, an activated ester, a chloroformate or a carbamic chloride; wherein the sulfonate is selected from the group consisting of methanesulfonate, toluenesulfonate, benzenesulfonate, trifluoromethanesulfonate, nitrophenylsulfonate and bromophenylsulfonate, and wherein the halogen is selected from the group consisting of chloro, iodo and bromo.

19. The process according to claim 1 , wherein the [2-(acylaminoethyl)thio]arene is prepared by;

reacting a compound of formula

with a compound of formula

optionally in the presence of a base, wherein LG is a leaving group for nucleophilic displacement by a thiol.

20. The process according to claim 19 , wherein LG is a halogen or a sulfonate and the base is an alkali metal hydride, hydroxide or carbonate, pyridine or a trialkylamine, wherein the sulfonate is selected from the group consisting of methanesulfonate, toluenesulfonate, benzenesulfonate, trifluoromethanesulfonate, nitrophenylsulfonate and bromophenylsulfonate, and wherein the halogen is selected from the group consisting of chloro, iodo and bromo.

21. The process according to claim 1 , wherein Ar is phenyl and R 2 and R 3 form a pyrrolidone, oxazolidinone or piperidinone.

22. The process according to claim 1 , wherein R 1 , R 2 and R 4 are hydrogen.