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It will be recalled that both epinephrine and norepinephrine are pressor agents, that is, they cause an increase in blood pressure. It would therefore be expected that antagonists to these endogenous pressor amines might have a useful effect on hypertension. One approach to this problem consists in the preparation of compounds that interfere with biosynthesis of these amines by the administration of false substrates* that would be unable to go through the final steps of biogenesis. A crucial step in the biosynthetic scheme for formation of norepinephrine consists in the decarboxylation of DOPA (dihydroxyphenylalanine, 75) to dopamine (76). (Side chain hydroxylation completes the scheme.) Substitution at the carbon adjacent the carboxyl group should hinder this reaction. Reaction of the substituted phenyl-acetone (77) with ammonium chloride and potassium cyanide affords the corresponding a-aminonitrile (78). The L isomer is then separated from the racemate by means of the camphorsulfonic acid salt. (The unwanted d isomer can then be subjected to basic hydrolysis to give back starting ketone that can be then recycled.) Treatment of the l isomer with concentrated sulfuric acid at the same time effects hydrolysis of the nitrile to the acid and cleavage of the remaining methyl ether. There is thus obtained methyldopa (79).21 While this drug has in fact found considerable use as an antihypertensive agent, there is evidence to indicate that the mechanism of action may be considerably more Involved than a simple block of pressor amine synthesis.
The thyroid gland, located in the base of the neck, exerts ;i key role on growth and metabolism. In contrast with that of some of the other endocrine glands, this control is effected Ihrough a pair of relatively simple molecules, thyroxine, and its close congener, triiodothyronine. Cases of thyroid deficiency (hypothyroidism) are common enough to warrant the production
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of these hormones commercially. In contrast to the steroid hormones, thyroxine and its analogs have few, if any, applications beyond replacement therapy. Since the structure of the hormone is constant among most mammals, crude extracts of thyroid glands from slaughterhouses constitute an important form of drug for treatment of deficiencies. The pure hormones are used in medicine as well; these in turn are obtained both by total synthesis and purification of extracts from animal sources.
One published synthesis starts by the formation of the ben-zenesulfonate of phenol, 77. This compound, it should be noted, is particularly suited for nucleophilic aromatic substitution, since the benzenesulfonate is activated by the ortho nitro, as well as the para carbonyl group. In fact, treatment of 77 with the anion from the monomethyl ether of hydroquinone gives the di-phenyl ether (79). Azlactones such as 80 have proven of great utility in synthesis, since the parent amino acid is cyclized into a form that masks both the amino and carboxyl groups. The reactivity of the methylene group is enhanced by the adjacent imine. Condensation of the aldehyde group of 79 with 80 by means of sodium acetate and acetic anhydride affords 81. When the condensation product is exposed to sodium methoxide, this reagent attacks the carbonyl group of the azlactone; the ring is thus opened to form the ester enamide (82). Reduction of this product with Raney nickel selectively reduces the aromatic nitro group to the corresponding amine (83). This amine is then transformed to an iodo group by diazotization and treatment of the diazonium salt with iodine-sodium iodide. Catalytic hydrogenation over platinum reduces the enamine double bond; hydrolysis of this ester-amide gives the amino acid (86). The aromatic methyl ether in the remote ring is then cleaved by means of hydroiodic acid (80) to afford the key diodo intermediate (87). The L form of this amino acid is isolated by optical resolution for further elaboration to the thyroid hormones. In the course of synthetic work on the thyroid hormones, a series of specialized reactions have been developed for the direct introduction of iodine ortho to phenolic groups. Thus, treatment of the diiodo compound with either the sodium salt of W-iodo-p-toluenesulfonamide or a mixture of iodine and sodium iodide in aqueous dimethylamine affords ¿-triiodothyronine,22 which goes by the generic name of liothyro-nine (88). This compound, interestingly, is more active as av thyroid hormone than thyroxine itself. Treatment of intermediate (87) with an excess of one of the iodinating reagents gives levo-thyroxine (89).22 Preparation of the diiodo derivative from the D form of the intermediate, 87, gives dextrothyroxine, a compound with much reduced thyroid activity that has been used for the treatment of elevated cholesterol levels.
II I
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REFERENCES
1. J. S. Nicholson and S. S. Adams, U. S. Patent 3,228,831 (1966).
2. S. S. Adams, J. Bemard, J. S. Nicholson, and A. B. Biancafort, U. S. Patent 3,755,427 (1973).
3. I. T. Harrison, B. Lewis, P. Nelson, W. Rooks, A. Roszkowski, A. Tomalonis, and J. H. Fried, J. Med. ehem., 13, 203 (1970).
5. A. Horeau and J. Jacques, Compt. Rend., 224, 862 (1947).
8. H. Martin and F. Hafliger, U. S. Patent 2,404,588 (1946).
9. Anon., British Patent 753,799 (1956).
10. V. Petrow, 0. Stephenson, and A. M. Wild, U. S. Patent 2,885,404 (1959).
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12. H. E. Zaugg and B. W. Horrom, J. Amer. Chem. Soc., 72, 3004
13. H. G. Kolloff, J. H. Hunter, E. H. Woodruff, and R. B. Moffett, J. Amer. Chem. Soc., 70, 3862 (1948).
15. Anon., British Patent 940,540 (1963).
16. F. F. Blicke and C. E. Maxwell, J. Amer. Chem. Soc., 64, 428 (1942) .
17. N. Brock, E. Kuhas, and D. Lorenz, Arzneimittel Forsch., 2, 165 (1952).
18. H. Najer, P. Chabrier, and R. Guidicelli, Bull. Soc. Chim. (Fr.), 335 (1958).
19. P. A. J. Janssen, J. Amer. Chem. Soc., 76, 6192 (1959).
20. M. A. Spielman, A. 0. Geiszier, and W. J. Close, J. Amer. Chem. Soc., 70, 4189 (1948).
21. D. Reinhold, R. A. Firestone, W. A. Gaines, J. Chemerda, and M. Sletzinger, J. Org. Chem., 33, 1209 (1968).
22. H. Nahm and W. Siedel, Chem. Ber., 96, 1 (1963).
CHAPTER 7
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