Tamoxifen reactions

Several Grignard reactions are used on an industrial scale in drug synthesis.95 The syntheses of both tamoxifen and droloxifene, which are estrogen antagonists used in treatment of breast cancer and osteoporosis, respectively, involve Grignard addition... 

Scheme 11.4 shows some other representative Friedel-Crafts acylation reactions. Entries 1 and 2 show typical Friedel-Crafts acylation reactions using A1C13. Entries 3 and 4 are similar, but include some functionality in the acylating reagents. Entry 5 involves formation of a mixed trifluoroacetic anhydride, followed by acylation in 85% H3PO4. The reaction was conducted on a kilogram scale and provides a starting material for the synthesis of tamoxifen. Entry 6 illustrates the use of bismuth triflate as... 

Acolbifene is also metabolized to a QM (Scheme 10.10)64 formed by oxidation at the C-17 methyl group. This QM is considerably more reactive compared to the tamoxifen quinone methide, which indicates that the acolbifene quinone methide is an electrophile of intermediate stability (Table 10.2). In addition, the acolbifene QM was determined to react with deoxynucleosides, with one of the major adducts resulting from reaction with the exocyclic amino group of adenine.64... 

Recently, Larock and coworkers used a domino Heck/Suzuki process for the synthesis of a multitude of tamoxifen analogues [48] (Scheme 6/1.20). In their approach, these authors used a three-component coupling reaction of readily available aryl iodides, internal alkynes and aryl boronic acids to give the expected tetrasubsti-tuted olefins in good yields. As an example, treatment of a mixture of phenyliodide, the alkyne 6/1-78 and phenylboronic acid with catalytic amounts of PdCl2(PhCN)2 gave 6/1-79 in 90% yield. In this process, substituted aryl iodides and heteroaromatic boronic acids may also be employed. It can be assumed that, after Pd°-cata-lyzed oxidative addition of the aryl iodide, a ds-carbopalladation of the internal alkyne takes place to form a vinylic palladium intermediate. This then reacts with the ate complex of the aryl boronic acid in a transmetalation, followed by a reductive elimination. 

The enzyme is the principal participant in N-demethylation reactions where the substrate is a tertiary amine. The list of substrates includes erythromycin, ethylmor-phine, lidocaine, diltiazem, tamoxifen, toremifene, verapamil, cocaine, amiodarone, alfentanil and terfenadine. Carbon atoms in the allylic and benzylic positions, such as those present in quinidine, steroids and cyclosporin A, are also particularly prone to oxidation by CYP3A4, a range of substrates is illustrated in Figure 7.10. 

Another application of this chemistry is the asymmetric synthesis of the cyclopropane analog 25 of the breast cancer treatment agent tamoxifen 26 (Scheme 14.2) [53]. The Rh2(S-DOSP)4-catalyzed reaction of phenyldiazoacetate 3 with diarylethylene 23 at... 

An alternative way of making tamoxifen is the direct interaction in the Grignard reaction of the a-ethyldeoxybenzoin and the 4-(2-dimethylaminoethoxy)phenyhnagnesium bromide, and further dehydration of the resulting carbinol (28.2.9) followed by subsequent separation of the mixture of E and Z isomers [49-56]. 

The most frequent adverse reactions to tamoxifen include hot flushes, nausea, and vomiting. The incidence of endometrial cancer shows a twofold increase in women on longterm treatment with tamoxifen. 

Nausea, vomiting, and hot flashes may accompany tamoxifen administration. Tamoxifen may cause a transient flare of tumor growth and increased pain due to bone metastases. These reactions are thought to be due to an initial estrogenic action of this drug. Mild or tran-... 

A variant on the sequence in which the third aromatic ring is introduced by reaction of the ketone in chloroethyl ether (9-4) with the hthio reagent from 1-4-di-iodobenzene leads in several steps to iodoxifene (9-5) [10]. 4-Hydroxy-tamoxifen, in which a hydroxyl group has been introduced on one of the benzene rings, comprises one of the principal metabolites of the drug. The unnatural meta isomer of... 

Reports of adverse reactions to raloxifene should be considered alongside those reported for tamoxifen and other anti-estrogens. However, earlier reports have pointed to a considerable increase in thromboembolism, as has some recent large-scale work (3), and it would be premature to draw final conclusions about the conditions in which it can safely be used. 

An important synergistic reaction between radiation-related pulmonary fibrosis and tamoxifen has been described in 196 women followed for a minimum of 5 years, with a relative risk of 2.0 (39). However, others have shown that tamoxifen did not increase the pulmonary toxicity of agents such as carmustine and dacarbazine (40). 

In a prospective study even in low doses (for example 10 mg/day or lower) tamoxifen caused ocular toxicity if given for a sufficiently long period most of the changes were reversible but they justify very close monitoring (44). A related compound, MER-29 (triparanol), causes cataract and has various other adverse reactions in common with tamoxifen. 

Tamoxifen has several adverse effects on the skin, including edema, flushing, rashes, hyperhidrosis, urticaria, alopecia, and hypertrichosis. Radiation recall dermatitis, a severe painful inflammatory skin reaction in sites that have previously been exposed to ionized radiation, can occur in patients taking tamoxifen (59). In one case the tamoxifen was withdrawn and the skin healed spontaneously in 7 weeks (60). Toremifene, a tamoxifen analogue, was well tolerated during 18 months of continuous treatment no signs of radiation recall developed. 

Fan, P. W., Bolton, J. L. Bioactivation of Tamoxifen to Metabolite E Quinone Methide Reaction with Glutathione and DNA. Drug Metab. Disp. 2001, 29, 891-896. 

Top S, Dauer B, Vaissermann J, Jaouen G (1997) Facile route to ferrocifen, 1-[4-(2-dimethy-laminoethoxy)]-l(phenyl-2-ferrocenyl-but-l-ene), first organometallic analogue of tamoxifen, by the McMurry reaction. J Organomet Chem 541 355-361... 

Tamoxifen 352, a non-steroidal anti-estrogen, employed for treatment of breast tumors which are estrogen receptor positive488, has been labelled with 131l489 for imaging and detection of breast tumors (equation 224). The reaction of diazonium salts (355, tetraphenylb-orate and 2-naphthalenesulphonate) with equimolar aqueous sodium iodide without catalysts or in the presence of Cu catalysts gave 353 in 6-10% yield only489. 

Give a mechanism for the elimination reaction in the formation of tamoxifen from p. 489 and comment on the fact that it gives a mixture of cis and trans alkenes. 

A 70-year-old woman with a history of mastectomy developed syncope which lasted a few seconds. She had taken tamoxifen 10 mg bd for 10 years and had no history of allergic reactions. Doppler ultrasound showed aortic stenosis and coronary angiography was performed using 150 ml of iopromide (a non-ionic contrast medium, iodine 370 mg/ml). She had visual hallucinations (spiders on the wall, moving curtains) 30 minutes after the injection of iopromide. The symptoms resolved 72 hours later without any specific treatment. Neurological and psychiatric examinations were normal, as were brain MRI and Doppler ultrasound of the carotid and vertebral arteries. 

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