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Details for Patent: 5,614,639

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Details for Patent: 5,614,639

Title: Process for preparing 2-substituted benzo[b]thiophene compounds and intermediates thereof
Abstract:The present invention provides processes for preparing 2-substituted benzo[b]thiophene compounds, some of which are useful as intermediates for preparing pharmaceutically-active compounds and others which are useful, inter alia, for the treatment of osteoporosis in postmenopausal women.
Inventor(s): Hauser; Kenneth L. (Greencastle, IN), Palkowitz; Alan D. (Carmel, IN), Sall; Daniel J. (Greenwood, IN), Thrasher; Kenneth J. (Indianapolis, IN)
Assignee: Eli Lilly and Company (Indianapolis, IN)
Filing Date:Mar 31, 1995
Application Number:08/415,014
Claims:1. A process for preparing a compound of formula I ##STR23## comprising a) forming a 2-position boronic acid derivative of a compound of formula II ##STR24## b) coupling the reaction product from step a), a compound of formula III ##STR25## with a compound of formula IV ##STR26## wherein R.sup.1 is --H, --OH, or OR.sup.3, in which R.sup.3 is a hydroxy protecting group;

R.sup.2 is --H, --OH, or OR.sup.4, in which R.sup.4 is a hydroxy protecting group; and

X is bromo, iodo, or triflate.

2. A process according to claim 1 wherein R.sup.1 is --OR.sup.3 and R.sup.2 is --OR.sup.4, and R.sup.3 and R.sup.4 each are C.sub.1 -C.sub.4 alkyl.

3. A process according to claim 2 wherein R.sup.3 and R.sup.4 each are methyl.

4. A process according to claim 3 wherein X is iodo.

5. A process according to claim 4 wherein steps a) and b) are carried out in the same vessel.

6. A process according to claim 1 wherein steps a) and b) are carried out in the same vessel.

7. A process for preparing a compound of formula I ##STR27## comprising a) selectively brominating, iodinating or triflating a compound of formula II ##STR28## to provide a compound of formula V ##STR29## b) coupling said formula V compound with a compound of formula VI ##STR30## wherein R.sup.1 is --H, --OH, or OR.sup.3, in which R.sup.3 is a hydroxy protecting group;

R.sup.2 is --H, --OH, or OR.sup.4, in which R.sup.4 is a hydroxy protecting group; and

X is bromo, iodo, or triflate.

8. A process according to claim 7 wherein R.sup.1 is OR.sup.3 and R.sup.2 is OR.sup.4, and R.sup.3 and R.sup.4 each are C.sub.1 -C.sub.4 alkyl.

9. A process according to claim 8 wherein R.sup.3 and R.sup.4 each are methyl.

10. A process according to claim 9 wherein X is iodo.

11. A process according to claim 10 wherein steps a) and b) are carried out in the same vessel.

12. A process according to claim 7 wherein steps a) and b) are carried out in the same vessel.

13. A process for preparing a compound of formula VII ##STR31## comprising steps a) and b) according to claim 1, and further comprising c) acylating a compound of formula I with a compound of formula VIII ##STR32## wherein R.sup.1 is --H, --OH, or OR.sup.3, in which R.sup.3 is a hydroxy protecting group;

R.sup.2 is --H, --OH, or OR.sup.4, in which R.sup.4 is a hydroxy protecting group;

R.sup.5 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino;

R.sup.6 is bromo, chloro, iodo, or an activating ester group; and

n is 2 or 3;

d) optionally removing the R.sup.3 and/or R.sup.4 hydroxy protecting groups; and

e) optionally forming a pharmaceutically acceptable salt of said formula VII compound.

14. A process according to claim 13 wherein R.sup.1 and R.sup.2 of said formula VII compound each are --OH.

15. A process according to claim 14 wherein n is 2 and R.sup.5 is 1-piperidinyl.

16. A process according to claim 15 wherein said pharmaceutically acceptable salt is the hydrochloride salt.

17. A process according to claim 16 wherein R.sup.6 is bromo or chloro.

18. A process for preparing a compound of formula VII ##STR33## comprising steps a) and b) according to claim 7, and further comprising c) acylating a compound of formula I with a compound of formula VIII ##STR34## wherein R.sup.1 is --H, --OH, or OR.sup.3, in which R.sup.3 is a hydroxy protecting group;

R.sup.2 is --H, --OH, or OR.sup.4, in which R.sup.4 is a hydroxy protecting group;

R.sup.5 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino;

R.sup.6 is bromo, chloro, iodo, or an activating ester group; and

n is 2 or 3;

d) optionally removing the R.sup.3 and/or R.sup.4 hydroxy protecting groups; and

e) optionally forming a pharmaceutically acceptable salt of said formula VII compound.

19. A process according to claim 18 wherein R.sup.1 and R.sup.2 of said formula VII compound each are --OH.

20. A process according to claim 19 wherein n is 2 and R.sup.5 is 1-piperidinyl.

21. A process according to claim 20 wherein said pharmaceutically acceptable salt is the hydrochloride salt.

22. A process according to claim 21 wherein R.sup.6 is bromo or chloro.

23. A process for preparing a compound of formula I ##STR35## comprising: coupling a compound of formula III ##STR36## with a compound of formula IV ##STR37## wherein R.sup.1 is --H, --OH, or OR.sup.3, in which R.sup.3 is a hydroxy protecting group;

R.sup.2 is --H, --OH, or OR.sup.4, in which R.sup.4 is a hydroxy protecting group; and

X is bromo, iodo, or triflate.

24. A process for preparing a compound of formula I ##STR38## comprising: coupling a compound of formula V ##STR39## with a compound of formula VI ##STR40## wherein R.sup.1 is --H, --OH, or OR.sup.3, in which R.sup.3 is a hydroxy protecting group;

R.sup.2 is --H, --OH, or OR.sup.4, in which R.sup.4 is a hydroxy protecting group; and

X is bromo, iodo, or triflate.

25. A process for preparing a compound of formula VII ##STR41## comprising: the process according to claim 1, and further comprising acylating a compound of formula I with a compound of formula VIII ##STR42## wherein R.sup.1 is --H, --OH, or OR.sup.3, in which R.sup.3 is a hydroxy protecting group;

R.sup.2 is --H, --OH, or OR.sup.4, in which R.sup.4 is a hydroxy protecting group;

R.sup.5 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino;

R.sup.6 is bromo, chloro, iodo, or an activating ester group; and

n is 2 or 3;

optionally removing the R.sup.3 and/or R.sup.4 hydroxy protecting groups; and

optionally forming a pharmaceutically acceptable salt of said formula VII compound.
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