Tamoxifen (Tamoxifen Citrate)

text by Charlotte Wilson Magdalen College Oxford

images by Karl Harrison

Trade name-NOLVADEX@

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

It is the trans-isomer of a triphenylethylene derivative 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.

Beneficial effects

The beneficial effects of menopausal estrogen replacement therapy such as lowering of blood cholesterol and slowing of osteoporosis.

Side-effects

• hot flushes and vaginal discharge.
• irregular menstrual periods, dizziness, headaches, fatigue, loss of appetite, nausea and/or vomiting, vaginal dryness or bleeding, irritation of the skin around the vagina.
• An increase in the number of blood clots, particularly in women who are receiving anticancer drugs along with tamoxifen.
• A more than doubled risk of developing uterine cancer.  Symptoms – Abnormal vaginal bleeding and lower abdominal (pelvic) pain.
• Increased risk of developing cataracts and other eye problems such as corneal scarring or retinal changes.
• Tamoxifen has been known to cause liver cancer in rats but so far not in humans, however, it can cause life threatening liver toxicities.
• One study suggested there is a possible increase in cancers of the digestive tract.
• Tamoxifen makes premenopausal women more fertile, but the use of tamoxifen incurs fetal harm.

Manufacturers Information (manufactured by Astrazeneca)

NOLVADEX®(tamoxifen citrate) Tablets, a nonsteroidal antiestrogen are for oral administration. NOLVADEX Tablets are available as: 10 mg Tablets. Each tablet contains 15.2 mg of tamoxifen citrate which is equivalent to 10 mg of tamoxifen. 20 mg Tablets. Each tablet contains 30.4 mg of tamoxifen citrate which is equivalent to 20 mg of tamoxifen. Inactive Ingredients: carboxymethylcellulose calcium, magnesium stearate, mannitol and starch.

Synthesis of tamoxifen

Route One – Nonstereospecific synthesis

1. Friedel-craft acylation involving Anisol and Phenylacetic acid.  Acylating agent – mixture of PC1₅/ SnC_l4.  The ketone formed in 78% yield.
2. Alkylation promoted by treating with Sodium Hydride.  It can therefore facilitate an SN₂ substitution reaction.
3. The product is alkylated by treatment with 2-(dimethylamino) ethy chloride.  The product has a 70% yield
4. The product is treated with PhMgBr to form a tertiary alcohol (G)
5. Dehydration through methanoic anhydride gives the required structure of Tamoxifen with both cis and trans isomers.
6. The isomres of Tamoxifen can be separated by Silica gel thin layer chromatography with benzene.

Route Two – Sterospecific synthesis

1. The phenyl(trimethyl silyl) – acetylene was carbomelated with diethylaluminium chloride – titanocene dichloride reactant to produce a organometallic inrtermediate.
2. This organometallic was then cleaved with N bromosuccinamide to produce the alkene (B) in 85% yield.
3. Palladium – catalysed coupling was used to replace the Br group by a phenyl group.
4. 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%
5. the vinyl bromide coupled well with a Zinc organometallic species to produce the ether triaryl olefin in a yield of 84%.
6. 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.
7. 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%.