Claims for Patent: 5,731,327

Summary for Patent: 5,731,327

Title:	Synthesis of 3- 4-(2-aminoethoxy)benzoyl!-2-aryl-6-hydroxybenzo b!thiophenes
Abstract:	The present invention is directed to chemical processes for preparing 2-aryl-6-hydroxy-3- 4-(2-aminoethoxy)benzoyl!benzo b!-thiophenes. The present invention is also directed to crystalline solvates and a non-solvated crystalline form of 6-hydroxy-2-(4-hydroxyphenyl)-3- 4-(2-piperidinoethoxy)benzoyl!-benzo b!thiophene hydrochloride, as well as processes for their preparation.
Inventor(s):	Wayne Douglas Luke
Assignee:	Eli Lilly and Co
Application Number:	US08/467,485
Patent Claims:	1. Non-solvated crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3- 4-(2-piperidinoethoxy)benzoyl!benzo b!thiophene hydrochloride, having substantially the following X-ray diffraction pattern obtained with copper radiation: ______________________________________ d-line spacing I/I.sub.o (Angstroms) (×100) ______________________________________ 13.3864 71.31 9.3598 33.16 8.4625 2.08 7.3888 7.57 6.9907 5.80 6.6346 51.04 6.1717 29.57 5.9975 5.67 5.9135 9.87 5.6467 38.47 5.4773 10.54 5.2994 4.74 4.8680 4.03 4.7910 5.98 4.6614 57.50 4.5052 5.75 4.3701 9.03 4.2516 69.99 4.2059 57.64 4.1740 65.07 4.0819 12.44 3.9673 22.53 3.9318 100.00 3.8775 9.07 3.7096 33.38 3.6561 21.65 3.5576 3.36 3.5037 7.97 3.4522 18.02 3.4138 4.65 3.2738 10.23 3.1857 8.90 3.1333 6.24 3.0831 9.43 3.0025 12.13 2.9437 4.96 2.8642 7.70 2.7904 11.95 2.7246 3.05 2.6652 3.32 2.5882 7.30 ______________________________________ 2. The crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3- 4-(2-piperidinoethoxy)benzoyl!benzo b!thiophene hydrochloride of claim 1 wherein the amount of 6-hydroxy-2-(4-hydroxyphenyl)-3- 4-(2-Piperidinoethoxy)benzoyl!benzo b!thiophene hydrochloride present is at least 95% by weight. 3. A process for preparing non-solvated crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3- 4-(2-piperidinoethoxy)benzoyl!-benzo b!thiophene hydrochloride comprising(a) reacting a solvated form of 6-hydroxy-2-(4-hydroxyphenyl)-3- 4-(2-piperidinoethoxy)benzoyl!benzo b!thiophene hydrochloride in methanol or in a mixture of methanol and water with about one equivalent of base, (b) extracting the solution from step (a) with an aliphatic hydrocarbon solvent, (c) adding about one equivalent of hydrochloric acid to the methanolic solution from step (b), and (d) isolating the crystalline compound. 4. The process of claim 3 wherein the aliphatic hydrocarbon solvent is hexane or heptane. 5. The process of claim 3 wherein the base is sodium hydroxide. 6. The process of claim 3 wherein the hydrochloric acid is a 2 N aqueous solution. 7. A process for preparing non-solvated crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3- 4-(2-piperidinoethoxy)benzoyl!-benzo b!thiophene hydrochloride comprising(a) reacting a solvated form of 6-hydroxy-2-(4-hydroxyphenyl)-3- 4-(2-piperidinoethoxy)benzoyl!benzo b!thiophene hydrochloride in methanol or in a mixture of methanol and water with about one equivalent of base, and (b) adding about one equivalent of hydrochloric acid to the methanolic solution from step (a), and (c) isolating the crystalline compound. 8. The process of claim 7 wherein the base is sodium hydroxide. 9. The process of claim 7 wherein the hydrochloric acid is a 2 N aqueous solution. 10. Crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3- 4-(2-piperidinoethoxy)benzoyl!benzo b!thiophene hydrochloride when prepared by the process of claim 3. 11. Crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3- 4-(2-piperidinoethoxy)benzoyl!benzo b!thiophene hydrochloride when prepared by the process of claim 7. 12. A pharmaceutical formulation comprising the crystalline compound of any one of claims 3-4 and one or more pharmaceutically-acceptable carriers, diluents, or excipients.