Process for preparing benzothiazepines from gamma-aminoalkylbenzenes

1. 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 R 4 CHO or an oligomer or polymer thereof, and with an acid, wherein:

Ar is phenyl;

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;

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 8 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 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)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 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.

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

the [N-hydroxymethyl-2-(acylaminoethyl)thio]arene is then treated with the acid to form the 2,3,4,5-tetrahydro[1,4]benzothiazepine 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 an 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)N(R 19 ) 2 , wherein each R 19 is 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, N(R 19 ) 2 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, aryl, heterocyclyl, heteroaryl, 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 , wherein

q is 0 or 1; R 1 , R 2 and R 4 are hydrogen;

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

R 5 is H, (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,

R 6 is H or (C 1 -C 6 )alkyl; and the process further comprises converting a compound of formula

to an oxalate compound of formula

wherein M is H, ammonium, an alkali metal or an alkaline earth metal.

11. The process according to claim 10 , wherein the conversion step comprises

cleaving the R 3 group to provide a 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine of formula:

acylating 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine with an oxalate ester; and

hydrolyzing the ester.

12. The process according to claim 11 , wherein the hydrolysis step comprises treating the ester with a base of an alkali metal hydride, hydroxide or carbonate, pyridine, or a trialkylamine and, optionally when M is H, acidifying.

13. The process according to claim 12 , 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.

14. The process according to claim 11 , which further comprises converting the oxalate compound wherein M is H into a salt thereof, wherein M is a cation selected from Na + , Mg ++ , Ca ++ and ammonium.

15. The process according to claim 11 , wherein q is 1 and R 5 is OCH 3 at position 7 of the benzothiazepine ring, and the compound has the formula

wherein M is hydrogen, ammonium, an alkali metal or an alkaline earth metal.

16. The process according to claim 15 , for specifically preparing a compound of the formula

wherein the [2-(acylaminoethyl)thio]arene has the formula

the aldehyde is paraformaldehyde and the acid is toluenesulfonic acid or hydrochloric acid and the reaction provides a CBZ-protected benzothiazepine of formula

and the method further comprises:

cleaving carbobenzyloxy group with acid to provide 7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine;

acylating the 7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine with methyl chlorooxalate;

hydrolyzing the methyl ester with aqueous base;

acidifying to form the acid compound; and

optionally converting the acid compound to a compound of formula

wherein M is ammonium, an alkali metal or an alkaline earth metal.

17. The process according to claim 1 , wherein R 3 is R 3a , and the 2,3,4,5-tetrahydro[1,4]benzothiazepine is prepared by

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(═O)—R 18 or an amine protecting group, wherein R 18 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, allyloxy, benzyloxy, substituted benzyloxy, fluorenylmethoxy or adamantyloxy.

18. The process according to claim 17 , which further comprises cleaving R 3a to produce a 4-unsubstituted-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine of formula

19. The process according to claim 18 , which further comprises acylating the 4-unsubstituted-2,3,4,5-tetrahydrobenzo[f][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; and

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

20. The process according to claim 18 , which further comprises reacting the 4-unsubstituted-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine to with a compound of formula X—CH2—COOR′ wherein X is a halogen and R′ is an alkyl to form an ester compound of formula:

and hydrolyzing the ester to form a compound of formula:

21. The process according to claim 17 , wherein R 3a is t-butoxycarbonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl or fluorenylmethoxycarbonyl.

22. The process according to claim 17 , wherein the method further comprises treating a compound of formula

wherein R 3a is —C(═O)—R 18 wherein R 18 is (C 1 -C 4 )alkoxy, allyloxy, benzyloxy, substituted benzyloxy, fluorenylmethoxy or adamantyloxy, with an amine of formula HN(R 19 ) 2 , wherein each R 19 is 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, N(R 19 ) 2 represents a 5, 6, or 7-membered ring nitrogen-containing heterocycle, to form a compound of formula:

23. The process according to claim 17 , wherein the [2-(acylaminoethyl)thio]arene compound has the formula

and is reacted with

(i) the formaldehyde and an acid to form a protected benzothiazepine of the formula:

or

(ii) the formaldehyde and a base to form an [N-hydroxymethyl-2-(acylaminoethl)thio]benzene of formula;

and

the [N-hydroxymethyl-2-(acylaminoethl)thio]benzene is further reacted with an acid to provide a protected benzothiazepine of the formula

wherein:

R 3a is (C 1 -C 10 )acyl of formula —C(═O)—R 18 or an amine protecting group;

R 5a is H, (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;

R 6 is H or (C 1 -C 6 )alkyl; and

R 18 is H, (C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy, allyloxy, benzyloxy, substituted benzyloxy, fluorenylmethoxy or adamantyloxy.

24. The process according to claim 23 , further comprising the step of cleaving the R 3a group to obtain a compound of formula

25. The process according to claim 24 , further comprising the step of acylating the 4-unsubstituted 2,3,4,5-tetrahydrobenzo[f][1,4]benzothiazeine with R 3 X to obtain 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; and

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

26. The process according to claim 23 , which further comprises converting

to

wherein M is H, ammonium, an alkali metal or an alkaline earth metal.

27. The process according to claim 26 , wherein:

the converting is accomplished by cleaving the R 3a group to provide a 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine, acylating the 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine with an oxalate ester, and hydrolyzing the ester; and/or

the hydrolysis step comprises treating the ester with a base and, optionally, when M is H, acidifying, wherein the base is an alkali metal hydride, hydroxide or carbonate, pyridine, or a trialkylamine, and optionally converting the resulting product wherein M is H into a salt thereof, wherein M is a cation.

28. 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.

29. The process according to claim 28 , 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, tri fluoromethanesulfonate, nitrophenylsulfonate and bromophenylsulfonate, and wherein the halogen is selected from the group consisting of chloro, iodo and bromo.

30. 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.

31. The process according to claim 30 , 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.

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

33. The process according to claim 19 , wherein R 3 X is an acid chloride, an acid anhydride, an activated ester, a chloroformate or a carbamic chloride.