Total synthesis of lasofoxifene and nafoxidine

ABSTRACT An intramolecular reductive coupling process of diketone with low-valent titanium species to form a dihydronapthalene skeleton was an important step in the synthesis of nafoxidine (1) and lasofoxifene (2). Diketone 6 was prepared in a convenient, three-step sequence starting from 3-methoxy benzaldehyde in good yields. GRAPHICAL ABSTRACT

Lasofoxifene was tested also for the prevention of osteoporosis and for the treatment of vaginal atrophy. [1] Both 1 and 2 were also studied for their anti-breast-cancer [2] properties. Osteoporosis is one of the most common disorders in elderly subjects and represents a major public health problem, affecting up to 50% of postmenopausal women and 20% of men older than 50 years. Lasofoxifene 0.5 mg/day significantly increased bone mineral density (BMD) and decreased bone turnover compared to a placebo.
After lasofoxifene showed promise for osteoporosis, a few improved methods were reported and patented. All protocols for the generation of lasofoxifene 2 utilized nafoxidine 1 or its derivatives as a precursor. Lednicer et al. [3] reported a method for the synthesis of 1 via the dehydration of the tertiary alcohol obtained from the Grignard reaction of 6-methoxy-2-phenyl-1-tetralone with appropriate reagent. Cameron et al. [4] at Pfizer used the methodology of Suzuki reaction to add aromatic nucleus at the 2-position to 1-aryl-2bromo-3,4-dihydronaphthalene with phenyl bromide. Chiu [5] at Pfizer also showed an alternative route to 1 and 2 via the intermolecular reductive coupling process of a diketone using a titanium species to form the desired nucleus. Isamu et al. [6] prepared 1 and 2 via a three-component coupling process of 4-pivaloyloxy benzaldehyde, cinnamoyl trimethyl silane, and anisole in the presence of HfCl 4 to give a coupling product, which on routine transformations gave 1. Other researchers [7] used palladium chemistry to prepare 2-aryl-6-methoxy-1-tetralone from bromo benzene and 6-methoxy-1-tetralone, and another team [8] also started with 6-methoxy-1-tetralone and did a Grignard reaction with 1-[2-(4-bromophenoxy)ethyl)] pyrrolidine, followed by bromination and Suzuki reaction with phenyl boronic acid to give 1.

Results and discussion
Our synthetic strategy for nafoxidine 1 and lasofoxifene 2 is described in Scheme 1. Compared to the reported methods, our methodology is simple and practical. In this methodology, the first step is a known aldol condensation between 3-methoxy benzaldehyde 3 and acetophenone to give compound chalcone [9] 4. Compound 4 on hydrogenation gave 3-(3-methoxyphenyl)-1-phenyl propane-1-one [9] 5. Compound 5 on Friedel-Crafts benzoylation with 4-(2-chloro ethoxy)benzoyl chloride [10] 8 gave compound 6a and a cyclized product 6. Both compounds can be separated on column chromatography, but we found it better to separate them after the titanium chloride reaction. The crude mixture 6 and 6a were subjected to reductive cyclization with titanium trichloride and Zn-Cu couple [5] reaction to give a mixture of 6 and 7. The diaryl dihydronaphthalene compound 7 was separated. Compound 7 was reacted with pyrrolidine to give compound [4] 1 in an overall yield of 26%.
Compound 1 is converted to lasofoxifene 2 in a reported way and was compared with the reported material [4] (Scheme 2).
In conclusion we have reported a practical and simple total synthesis of nafoxidine and lasofoxifene.

Materials and instruments
Most of the reagents used in this work were obtained from commercial suppliers and were of laboratory-reagent or analytical-reagent (LR/AR) grade. Solvents were purified before use by standard procedures. Melting points were determined using open capillary tubes on a Polmon melting-point apparatus (model 96) and are uncorrected. 1 H (400 MHz) and 13 C (100 MHz) NMR spectra were recorded by using a Bruker 400 spectrometer with tetramethylsilane (TMS) as an internal standard. Infrared (IR) spectra were recorded on a Perkin-Elmer Spectrum 100 FTIR spectrophotometer as KBr pellets or with the neat products. Mass spectra were recorded on an API 2000 LCMS/MS Applied Bio Systems MDS Sciex spectrometer. Microanalysis was performed on a Perkin-Elmer 240CHN elemental analyzer. Analytical thin-layer chromatography (TLC) was conducted on E-Merck 60F254 aluminium-packed plates of silica gel (0.2 mm). Developed plates were visualized by using ultraviolet (UV) light or in an iodine chamber. Highperformance liquid chromatography (HPLC) was performed by using a Shimadzu 2010 instrument.  {3-[4-(2-chloro-ethoxy)-phenyl]-6-methoxy-1H-inden-2-yl}-phenylmethanone (6) and 3-{2-[4-(2-chloro-ethoxy)
For conformation of the product, 2 g of crude product was purified quickly using column chromatography.
The first compound on elution with 10% ethyl acetate in hexane gave a cyclization product whose structure 6 was confirmed on the basis of spectral data.