Details for Patent: 9,102,627

Title:	Processes for preparing 3-benzazepines
Abstract:	The present invention provides processes and intermediates for the preparation of 3-benzazepines and salts thereof which can be useful as serotonin (5-HT) receptor agonists for the treatment of, for example, central nervous system disorders such as obesity.
Inventor(s):	Wolgast; Beverly L. (San Diego, CA), Gilson, III; Charles A. (San Diego, CA), Aytes; Shelley (San Diego, CA), Estrada; Scott A. (La Jolla, CA), Sengupta; Dipanjan (San Diego, CA), Smith; Brian (San Diego, CA), Rey; Max (Wallisellen, CH), Weigl; Ulrich (Hilzingen, DE)
Assignee:	Arena Pharmaceuticals, Inc. (San Diego, unknown)
Filing Date:	Sep 14, 2012
Application Number:	13/619,788
Claims:	1. A process for preparing a compound of Formula V: ##STR00059## or salt thereof, wherein: R.sup.1 is H or C.sub.1-C.sub.8 alkyl; R.sup.2 is C.sub.1-C.sub.8 alkyl, --CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8 alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), or C.sub.1-C.sub.4 haloalkyl; R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each, independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl, hydroxy, OR.sup.9, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl, NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from C.sub.1-C.sub.8 alkyl, halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R.sup.8a and R.sup.8b are each, independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl, alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl group; R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl; and R.sup.10 and R.sup.11 are each, independently, H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10 and R.sup.11 together with the N atom to which they are attached form a heterocyclic ring; comprising the step of reacting a compound of Formula IX: ##STR00060## or salt thereof, wherein X.sup.2 is halo or SO.sub.2R''; and R'' is C.sub.1-C.sub.8 alkyl, aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4 haloalkoxy, with a cyclizing reagent for a time and under conditions suitable for forming said compound of Formula V. 2. A process according to claim 1, wherein said cyclizing reagent is AlCl.sub.3. 3. A process according to claim 1, wherein the reaction of said compound of Formula IX with said cyclizing reagent is carried out in the presence of 1,2-dichlorobenzene. 4. A process according to claim 1, wherein the reaction of said compound of Formula IX with said cyclizing reagent is carried out at a temperature between 100 and 150.degree. C. 5. A process according to claim 1, wherein X.sup.2 is Cl. 6. A process according to claim 1, wherein X.sup.2 is Br. 7. A process according to claim 1, wherein R.sup.1 is H, R.sup.2 is Me, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is H, R.sup.6 is H, R.sup.8a is H, and R.sup.8b is H. 8. A process according to claim 1, said process further comprising the step of forming said compound of Formula IX or salt thereof by reacting a compound of Formula X: ##STR00061## or salt thereof; with a halogenating/sulfonating reagent for a time and under conditions suitable for forming said compound of Formula IX or salt thereof. 9. A process according to claim 8, wherein said halogenating/sulfonating reagent is SOBr.sub.2 or SOCl.sub.2. 10. A process according to claim 8, wherein the reaction of said compound of Formula X with said halogenating/sulfonating reagent is carried out in the presence of solvent. 11. A process according to claim 10, wherein the reaction of said compound of Formula X with said halogenating/sulfonating reagent is carried out in the presence of solvent comprising dimethylformamide or toluene. 12. A process according to claim 8, said process further comprising the step of reacting a compound of Formula XI: ##STR00062## wherein X.sup.1 is a leaving group, with a compound of the following formula: ##STR00063## or salt thereof, for a time and under conditions suitable for forming said compound of Formula X or salt thereof. 13. A process according to claim 12, wherein X.sup.1 is Br. 14. A process according to claim 12, wherein the reaction of said compound of Formula XI to give said compound of Formula X is carried out at a temperature from about 80 to about 110.degree. C. 15. A process according to claim 8, said process further comprising the step of reacting a compound of Formula XII: ##STR00064## with a further halogenating/sulfonating reagent for a time and under conditions suitable for forming said compound of Formula XI. 16. A process according to claim 15, wherein said further halogenating/sulfonating reagent is PBr.sub.3 or PCl.sub.3. 17. A process according to claim 12, wherein X.sup.1 is Cl. 18. A process according to claim 1, wherein: R.sup.1 is H, R.sup.2 is Me, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is H, R.sup.6 is H, R.sup.8a is H, and R.sup.8b is H; said cyclizing reagent is AlCl.sub.3; the reaction of said compound of Formula IX with said cyclizing reagent is carried out in the presence of 1,2-dichlorobenzene; the reaction of said compound of Formula IX with said cyclizing reagent is carried out at a temperature between 100 and 150.degree. C.; and X.sup.2 is Cl.