Sulindac synthesis

Fluormated agents such as flurbiprofen (II), flunisal(i2), diflunisal (13), and sulindac (14), acting as prostaglandin synthesis mhibitors, have been available for some time [5] The recent introduction of flunoxaprafen (15), a lipoxygenase inhibitor, is notable It reportedly produces considerably less severe gastric disturbance [75]... 

Pd/P(t-Bu)., in the presence of Cy2NMe, is an unusually mild and versatile catalyst for Heck reactions of aryl chlorides (Tables 1 and 2) (as well as for room-temperature reactions of aryl bromides).21 22 23 Example A, the coupling of chlorobenzene with butyl methacrylate, illustrates the application of this method to the stereoselective synthesis of a trisubstituted olefin a-methylcinnamic acid derivatives are an important family of compounds that possess biological activity (e.g., hypolipidemic24 and antibiotic25) and serve as intermediates in the synthesis of pharmaceuticals (e.g., Sulindac, a non-steroidal anti-inflammatory drug26). Example B, the coupling of 4-chlorobenzonitrile with styrene, demonstrates that Pd/P(t-Bu). can catalyze the Heck reaction of activated aryl chlorides at room temperature. 

Synthesis (Tull et al. (Merck Co.), 1975 1976) Friedel-Crafts reaction of fluorobenzene and a-bromoisobutyryl bromide gives 5-fluoro-2-methylindan-1-one, which is treated with 4-methylthiobenzylmagnesium chloride to yield 5-fluoro-2-methyl-1-(4-methylthiobenzyl)indene. Condensation with glyoxylic acid in the presence of N-benzyltrimethyl ammonium hydroxide (Triton B) gives 3-carboxy methylene-5-fluoro-2-methyl-1 -(4-methylthio-ben-zyl) indene, which is isomerized in acid to 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)indene-3-acetic acid. Oxidation with hydrogen peroxide affords sulindac. 

This methodology has been successfully applied to the asymmetric synthesis of (R)- and (S)-sulindac (90-92% ee), which is a chiral sulfoxide marketed as an antiinflammatory drug (Scheme 3.54) [165],... 

NSAIDs inhibit prostaglandin synthesis, and in so doing can reduce GFR in susceptible patients, including those with cirrhosis. A number of renal complications can occur, including acute renal failure. All NSAIDs have been associated with nephrotoxicity. There is a small amount of data suggesting that renal effects are less likely to occur with sulindac, but studies relate to short-term therapy only, and there have been case reports of acute renal failure developing in high-risk patients [4,27,35]. 

The antihypertensive effect of beta-blockers can be impaired by the concurrent administration of some nonsteroidal anti-inflammatory drugs (NSAIDs), possibly because of inhibition of the synthesis of renal vasodilator prostaglandins. This interaction is probably common to all beta-blockers, but may not occur with aU NSAIDs for example, sulindac appears to affect blood pressure less than indometacin (405-407). 

Antihypertensive drugs Indometacin Reduction in hypotensive effect, probably related to impaired prostaglandin synthesis (causing salt and water retention) and vascular prostaglandin synthesis (causing vasoconstriction) Avoid all NSAIDs in treated hypertensive patients if possible if not, use sulindac preferentially may need additional antihypertensive therapy... 

The ability of sulindac to inhibit prostaglandin synthesis and impair renal function has been confirmed in a different high-risk group, namely patients with hepatic cirrhosis and ascites [82]. We have also identified the development of profound acute kidney injury in risk prone patients who received sulindac for several days to weeks. Collectively, these studies suggest caution in accepting any NSAID as being "renal sparing". 

Sedor JR, Williams SL, Chremos AN et al. Effects of sulindac and indomethacin on renal prostaglandin synthesis. Clinical Pharmacology Therapeutics 1984 36 85-91. 

Mistry CD, Lote CJ, Currie WJ et al. Effects of sulindac on renal function and prostaglandin synthesis in patients with moderate chronic renal insufficiency. Clinical Science 1986 70 501-505. 

Barreiro EJ, Lima MEF. The synthesis and antiinflammatory properties of a new sulindac analogue synthesized from natural safrole. J Pharmaceut Sci 1992 81 1219—22. 

Various NSAIDs, such as ibuprofen, indomethacin, ketoprofen, phenylbutazone, piroxicam, and oxyphenbutazone, can decrease renal creatinine and lithium clearance by their common inhibitory action on prostaglandin synthesis. Aspirin (acetylsalicylic acid) and sulindac have not been found to increase lithium plasma steady-state concentrations. ... 

Sulindac was introduced in the United States in 1978 by Merck as a result of chemical studies designed to produce an analogue without the side effects commonly associated with the use of indomethacin, particularly Gl irritation. It achieved wide popularity, and it remains one of the more widely used NSAIDs. Its synthesis also was reported by Shen et al. (50). Sulindac is a pro-drug and is converted to a metabolite that appears to inhibit the cyclooxygenase system approximately eight-fold as effectively as aspirin. In anti-inflammatory and antipyretic assays, it is only about half as potent as indomethacin but is equipotent in analgetic assays. 

The use of NSAID in patients with essential and renovascular hypertension is complicated largely because of negative interaction with other drug therapy. An important exception to this observation may be sulindac, a NSAID with the putative unique property of inhibiting only extrarenal PG synthesis However, the selective nature of sulindac s inhibition of PG synthesis has been disputed Sulindac potentiates, rather than antagonizes, the antihypertensive effect of thiazides in patients with essential hypertension. However, there are case reports of nephrotic syndrome, sometimes associated with acute interstitial nephritis, related to sulindac therapy. ... 

Synthesis of Sulindac Sulindac 23 is a nonsteroidal anti-inflammatory drug mainly used in the treatment of pain, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and acute gouty arthritis. More recently, it attracted also the attention of the scientists for its anticancer effects. It used to be sold in its racemic form, but its enantiopure preparation was known since 2001. The... 

The application of the Bolm catalytic system to the synthesis of sulindac 23 via asymmetric sulfoxidation of 24 led to a comparable stereoselectivity of the enantioenriched sulfoxide 25 product compared with the synthesis proposed... 

SCHEME 48.12. Fe(III)-catalyzed asymmetric sulfoxidation step for the synthesis of sulindac 23 application of Schiff base chiral ligand 26 and carboxylate additive 27. 

Maguire R, Papot S, Ford A, Touhey S, O Connor R, Clynes M. Enantioselective synthesis of sulindac. Synlett 2001 41. ... 

Korte A, Legros J, Bolm C. Asymmetric synthesis of sulindac by iron-catalyzed sulfoxidation. Synlett 2004 2397-2399. 

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