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Tamoxifen (Molecule of the Month for April 2000)

NOLVADEX



It is the trans-isomer of a triphenylethylene derivative of Taxol and is active in the treatment of breast cancer, an oestrogen antagonist. It’s cis isomer has no clinical uses and is not an oestrogen antagonist. Tamoxifen works against the effects of estrogen on these cells (an “anti-estrogen”) slows the growth of cancer cells and prevents original breast cancer from returning. It also has beneficial effects of menopausal estrogen replacement therapy such as lowering of blood cholesterol and slowing of osteoporosis.

Synthesis of tamoxifen Route One – Nonstereospecific synthesis Friedel-craft acylation involving Anisol and Phenylacetic acid. Acylating agent – mixture of PC15/ SnCl4. The ketone formed in 78% yield. Alkylation promoted by treating with Sodium Hydride. It can therefore facilitate an SN2 substitution reaction. The product is alkylated by treatment with 2-(dimethylamino) ethy chloride. The product has a 70% yield The product is treated with PhMgBr to form a tertiary alcohol (G) Dehydration through methanoic anhydride gives the required structure of Tamoxifen with both cis and trans isomers. The isomres of Tamoxifen can be separated by Silica gel thin layer chromatography with benzene.

Route Two – Sterospecific synthesis The phenyl(trimethyl silyl) – acetylene was carbomelated with diethylaluminium chloride – titanocene dichloride reactant to produce a organometallic inrtermediate. This organometallic was then cleaved with N bromosuccinamide to produce the alkene (B) in 85% yield. Palladium – catalysed coupling was used to replace the Br group by a phenyl group. The trimethyl Silyl was replaced by a halogen atom by treating the compound with bromine – sodium methoxide at –78C to produce the vinyl bromide in a yield of 85% the vinyl bromide coupled well with a Zinc organometallic species to produce the ether triaryl olefin in a yield of 84%. The formation if tamoxifenwas achieved by demethylation with sodium ethylthoilate in refluxing dimethyl formamide the the reaction of the phenoxide ion with 2-( dimethylamino) ethyl chloride via a SN2 substitution. This produced a trans isomer in an over all yield of 60% base this produced the stereospecific (Z)- Trans isomer in an overall yield of 60%.

Formal Chemical Name (IUPAC)
(Z)2-[4-(1,2-diphenyl-1-butenyl) phenoxy]-N, N-dimethylethanamine 2-hydroxy-1,2,3-propanetricarboxylate.

Picture of Tamoxifen 3D model

click on the picture of  Tamoxifen above to interact
with the 3D model of the
Tamoxifen structure
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Picture of Tamoxifen

C32H37NO8



Update by Karl Harrison
(Molecule of the Month for April 2000 )

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