Raloxifene synthesis

Benzothiophenes have always been of interest for medicinal chemistry and can be found in a number of marketed drugs such as Sertaconazole (Gineder-mofix), Zileuton (Leutrol) and Raloxifene (Evista). The classical synthesis of benzo thiophenes starts from thiophenols, reacting with bromoacetaldehyde dimethyl acetal, followed by cycUzation using strong acid. An alternative and more convenient route was also described starting from benzaldehydes which... 

Fig. 7.3. Osteoclastogenesis after estrogen deficiency. Estrogen deprivation leads to an increase in the synthesis of RANKL for stromal/OB cells of the BM. This increase in the expression of RANKL leads to an increase in OCS. Estrogen deficiency also induces the synthesis and secretion of cytokines, such as IL-6 and M-CSF, that increase the number of preosteoclasts in the BM, and thus increases OCS. Nonetheless, certain cells of the immune system, such as monocytes and T-cells, intervene in the process when the supply of estrogens fails. These cells secrete IL-1 and TNF-a that are powerful inductors of OCS. When estrogens or agonists of estrogen receptors like raloxifene are administered, the synthesis and secretion of many of the mentioned cytokines diminish and the synthesis and liberation of OPG and TGF-/S are stimulated. These molecules inhibit OCS by inhibiting the RANKL/RANK signal pathway and by promoting osteoclast apoptosis...

In the pharmaceutical synthesis industry, piperidine is used in some drugs such as budipine (antiparkinsonian drug), raloxifene (used in the prevention of osteoporosis), minoxidil (an oral drug to treat high blood pressure). Minoxidil has the interesting side effect of hair growth and reverses hair loss. A two percent minoxidil solution can be used to treat this condition. 

There are two main types of internal standards. The first ones are stable isotope labeled (SIL) internal standards. They are compounds in which several atoms in the analytes are replaced by their respective stable isotopes, such as deuterium (2H, D or d), 13C, 15N, or 170. Labeling with the first three isotopes are most common, particularly labeling with deuterium (due to less difficulty in synthesis and therefore less expensive). For examples, raloxifene-d4-6-glucuronide was used as the internal standard for the determination of raloxifene-6-glucuronide [5] and 1, 2, 3, 4-13C4 estrone (PCJEl) was used as the internal standard for estrone (El) [6], The usage of stable isotope labeled internal standards in quantitative LC-MS or GC-MS analysis is often termed as isotope dilution mass spectrometry (IDMS) [7],... 

The first reported synthesis of the raloxifene scaffold was based on the coupling of carboxylic acid fragment 12 with benzothiophene nucleus 13. The main carbon-carbon bond formation was thus achieved via nucleophilic attach of the benzothiophene through its C(3) position on the activated carbonyl of 12. The final step in the synthesis was the cleavage of both methyl ethers to unmask the requisite hydroxyls.48,49... 

Development of just-described SNAr approach to introduce the requisite hydroxyethylpiperidine moiety late in the synthesis provided not only a rapid approach to raloxifene (1) but also a versatile entry into additional analog scaffolds 29.54 Thus advanced known intermediate 13 was acylated under standard conditions to provide key SNAr substrates 28, which reacted with a the series of 0,S and N anion nucleophiles to generate the adducts 29. Cleavage of both methyl ethers in 28 followed by application of the SNAr methodology provided raloxifene (1) in overall 70% yield. 

Shinde PS, Shinde SS, Renge AS et al (2009) An efficient synthesis of raloxifene in ionic liquid a green approach. Lett Org Chem 6 8-10... 

I The clinical uses of anastrozole (decreases estrogen synthesis), danazol (decreases ovarian steroid j synthesis), domiphene (decreases feedback inhibition), and the selective estrogen-receptor modulators j tamoxifen and raloxifene are considered. 

The Friedel-Crafts acylation reaction at the C3 position of a substituted benzothiophene was shown to be a key C-C bond forming step in the synthesis of raloxifene, as first reported in 1984 and illustrated below. ... 

In pursuit of additional derivatives, Eli Lilly scientists sought to synthesize constrained analogues of raloxifene. The synthesis of these analogues used a unique method of constructing the benzothiophene ring system through an acid-promoted dehydrative carbocationic cyclization of the hydroxythioacetamide using methanesulfonic acid as illustrated below. 

The synthesis of raloxifene (Evista) is one such example. Raloxifene is currently approved for use as a therapy to treat and prevent osteoporosis. Researchers at Eli Lilly published the first synthesis and biological evaluation of LYl56758, which would later be named raloxifene, in 1984. ... 

The synthesis of raloxifene began with the construction of the benzothiophene core structure by acid-promoted cyclization and rearrangement as discussed previously. ... 

Queiroz employed BINAP or XantPhos as hgands in the synthesis of benzo[b]thiophenes [199). One of the most important drugs based on this structural motif is raloxifene, which is used in the treatment of osteoporosis, and potentially also for Alzheimer s disease. 

It has been shown that, in the reactions of phenoxides with 4-nitrophenyl triflate (9) in DMF, nucleophilic attack occurs at the sulfur centre (path a) however, with 2,4-dinitrophenyl triflate, attack is switched to the carbon centre (path b). Oxydehalogena-tion reactions of l-halo-2-methylsulfonylbenzenes with amino alcohol nucleophiles have been used in the synthesis of thiotomoxetine, and reactions of 2-dialkylamino-1-ethoxides with 3-aroyl-2-arylbenzothiophenes have been used in the synthesis of raloxifene. Other reports involve the methoxydehalogenation reactions of 6-halo-1,2-acenaphthylene derivatives " and nucleophilic attack on a phenylacetic mustard. ... 

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