198481-33-3

Pale Beige Solid

Bazedoxifene Acetate is a nonsteroidal selective estrogen receptor modulator (SERM). Bazedoxifene Acetate is used as an antiosteoporotic.

bazedoxifene, a novel selective estrogen receptor modulator (serm), has been developed to have favorable effects on bone and the lipid profile while minimizing stimulation of uterine or breast tissues. two large phase iii

Bazedoxifene is a third generation nonsteroidal selective estrogen receptor modulator (SERM), used clinically to treat postmenopausal osteoporosis. Bazedoxifene binds to estrogen receptor-α with IC50 = 26 nM, similar to that of raloxifene, but lower affinity than 17-β estradiol. Bazedoxifene did not stimulate proliferation of MCF-7 cells, instead inhibited 17β -estradiol-induced proliferation with IC50 = 0.19 nM, exhibiting a desirable profile of agonist/antagonist activity.

The selective estrogen receptor modulator bazedoxifene acetate was approved in Spain for the treatment of osteoporosis in postmenopausal women. The drug was discovered by Wyeth (now Pfizer) and licensed to Almirall. Clinical trials with bazedoxifene along with conjugated estrogens demonstrated significant improvement in bone mineral density and prevented bone loss in postmenopausal women without osteoporosis. It also reduces fracture risks among women with postmenopausal osteroporosis.

Among many syntheses reported for this drug, the most recent process scale synthesis (multi-kg scale) is highlighted and involves the union of azepane ether 9 and indole 12. 4-Hydroxybenzyl alcohol (6) was converted in two steps to chloride 9 (the Scheme). The reaction of 6 with 2-chloroethyl azepane hydrochloride (7) in a biphasic mixture of sodium hydroxide and toluene in the presence of tetrabutylammonium bromide (TBAB) gave the desired intermediate alcohol 8 in 61% yield. Treatment of 8 with thionyl chloride (SOCl2) gave the requisite chloride 9 in 61% yield. The reaction of 2-bromopropiophenone (10) with an excess of 4-benzyloxy aniline hydrochloride (11) in the presence of triethylamine (TEA) in N,N-dimethylformamide (DMF) at elevated temperatures resulted in indole 12 in 65% yield. Alkylation of 12 with benzylchloride 9 in the presence of sodium hydride (NaH) afforded N-alkylated compound 13. The benzyl ether functionalities from compound 13 were removed via hydrogenolysis and subsequently subjected to acidic conditions, providing diol 14 as the hydrochloride salt in 91% yield. The hydrochloride was then exchanged for the acetate via free base preparation with 5% sodium bicarbonate or triethylamine, followed by treatment with acetic acid giving bazedoxifene acetate (II) in 73¨C85% yield.

This potent and selective estrogen receptor modulator, or SERM (FW = 530.65 g/mol; CAS 198481-33-3; Solubility: 00 mM in DMSO), also named 1-[[4-[2- (hexahydro-1H-azepin-1-yl) ethoxy]phenyl]methyl]-2- (4- hydroxyphenyl) -3-methyl-1H-indol-5-ol, selectivity targets the extrogen receptor ERα (IC50 = 26 nM), with weaker action against ERβ (IC50 = 99 nM), inhibiting 17β-estradiol-induced proliferation of MCF-7 cells. Bazedoxifene represents a promising new treatment for osteoporosis, one with a potential for less uterine and vasomotor effects than selective estrogen receptor modulators now used clinically.