The Prototype Compound for the Oral Anticoagulants Rodney C. Hayward School of Pharmacy, C.I.T., Private Bag. Trentham P.O., New Zealand The coumarin anticoagulants provide illustrative, carhanion-mediated, bond-forming reactions and interesting target heterocycles for the undergraduate laboratory. The storv of the introduction of the title bishvdroxvcoumarin ( ~ i & m a r o l ,USP) (Ia, Fig. 1)into t h e r a p e u k s is"a particularly interesting one ( I ) . Dicumarol was established (2) as the cause of the hemorrhagic sweet clover disease' in cattle fed spoiled hay made from the sweet clovers, Melilotus alba or M. officinalis. This compound provided the leading structure for the familv of oral anticoarmlants shown in Firmre 1.A series of similarly icidic 1,3-indaidiones has been foind to constitute an additional class of anticoapulants. Dicumarol was usefully introdiced into medicine ( 4 ) to lower blood coagulability in, for example, the treatment and prophylaxis of thromhoemholic disorders in veins and, to a lesser extent, arteries. However, a slow onset of action and an idiosyncratic \,ariation i n adsorption and metahdism made ~licumarula less-than-idwldrux. Of the many aniil~r~ues rrg., structures Ic-e) ultimatelv svithesized. themost useful has been racemic warfarin2 (fc) as its sodium salt (6). The high activity of warfarin as an anticoagulant caused it to be originally proposed for rodent control. I t became the world's most useful rodenticide. Pivotal to an open-ended synthetic laboratory schedule on the coumarin anticoaaulants3 was a facile svnthesis of 4hgdroxyroumilrm (lb,. 'l'he published itr;iteglt,i in ~ h iarea i fall rouchlv into twocutwc,ries: r I I rondens3tir,n o f a ~ h m d with a derivative of malonic acid (7), and (2) a carbanionmediated condensation effected in a phenolic ester or ketone (8).From the latter group, we have fbund that condensation of o-hydroxyacetophenone with diethyl carhonate in the presence of sodium hydride as a base (8d) to be a n easily manipulated and high-yield reaction. The reaction could conceivably proceed by either a 0-keto ester or alternatively via the O-acyl derivative: cyclization will afford the same product. Dicumarol was simply prepared by condensation of the 4-hydroxycoumarin with aqueous formaldehyde solution (Fig. 2) (2). 4-Hydroxycoumarin and its derivatives have many of the chemical properties of P-keto esters. The reactions develop in a straightforward way from ethyl acetoacetate.
'
The administration of vitamin K can reverse the dicumarol-induced hypoprothrombinemia. Anticoagulants such as the coumarin derivatives are indirect in action, depressing the hepatic vitamin-Kdepencsnt biosynthesis of prothrombin and other clotting facton. See, for example, ref. 13). Warfarln is an acronym for the paten1 holder W~sconsmA "mnl Researcn Foundat on, plus tne sufflxderaved from coumarrn (5) For example; warfarin can be synthesized by a Michael addition of the bhydroxycoumarin enolate anion to (&bphenyl-3-buten-2-one (benzalacetone). Purified for procedure see ref. (9). The sodium hvdride was used as a 50% disoersion as ~,~~~~ in oil and ~~~such is an easy-to& powerf-I oase. Safety in using sodium hydride must be emphasized. Provioed ihal norma care is ta*en and all apparatus is dry, use of an neR atmosphere for we gh~ngtne dispers~on or for the subsequent reaction is not necessary. Any dispersion adhering to spatulas, etc., can be safely destroyed by submerging them in absolute ethanol. ~
(Dieurnarol, USP) "
(Ib) R = -H (Warfarin,USP) (Phenproeournan, USP) (A'cetoeournarol)
(le) R = -CH(Ph)CH2COCHI
(Id) R = -CH(Ph)CH1CH, (Id R =-CH(P-NO~P~)CH~COCH~
(IIb) R = -Ph (Ile) R = -CH,CH(Ph)=
(Phenindione. USP) (Diphenadione. USP)
Figure 1. Structuralfamilies of the oral anticoagulants
Figure 2. Reaction pathway prcducing Dicumarol.
Experimental Procedure 4-Hydroxycoumarin (Ib) A solution of o-hydroxyacetophenone (0.022 mole) and diethyl carbonate (0.055 mole)' (Fumehood) in dry toluene (30 ml) is added dropwise over 20 min to a stirred suspension of sodium hydride (0.033 mole)5in dry toluene (30 ml) held in anoil hath maintained at 110°C. The ethanol farmed during the reaction is removed by distillation. When all the ethanol has been removed, the thick mixture is allowed to cool and is extracted with water. The aqueous layer and washings are combined, treated with a little charcoal, filtered, and the chilled filtrate acidified by the dropwise addition of hydrochloric acid to precipitate the product. The product is filtered off,washed with cold water and sucked as dry as possible. It is recrystallized from 50% aqueous ethanol to give the product in 90-91% yield (two crops) as needles, m.p. 213-214T (ref. 10):m.p. 213-214°C). 3.3'-Methylene bis(4-hydroxycoumarin) (la) 4-Hydroxycoumarin (1.0 g) is dissolved in hailing water (300ml). The solution is allowed to coal to 70°C and 40%aqueous formaldehyde solution (10 ml) (Fumehood) quickly added with stirring. The mixture is then chilled, the crude product filteredoff and washed well with water, dried and recrystallized from cyclohexanone/toluene a3 prisms, 0.89g (85.8%),m.p. 292-295-C (ref. 11): m.p. 287-293T). Volume 61
Number 1 January 1984
87
Literature Cited Link, K. P.. Circulation, 19.97 11959);Harwy Lac*. Sen, 39,162 (194M4). Stahmann,M.A., Huebner,C.F.,sndLink,K.P., J. B i d Chem., 138.513 (1941). Silverman, R. B., J. Amer Chem Soc., 103,3910 (1981). Butt, H.R, Allen, E. V., and Bollman, J. L., Mayo Ciinic Pmc.. 16,388 11941). Ikawa,M.,Stahmann.M.A..and Link,K.P., J. Amsr Chem. Soc, 66,902 (1944). (6)O'Reilly, R. A,. in "The Phmscologieal Basis afTherspeutic%," 6th ed.,Gilman, A. G.. Gaadman. L. S..and Gilman, A. (Editors),Macmillan, Nev Yark, 1980. ( I ) Ziegler, E., and Junek, H.. Monorsh. Chrm., 66,29 11955): Mentmr, C., Vexcier, P., Besudet, C.. and Ville. A:,Bull. Soc. Chim. fi.,460 (1957): Shsh,V. % h e , J. L..
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Journal of Chemical Education
and Shah, R. C., J. O w Chem., 25 677 11960): Gorden, J. F.,Hayes, N. F., and Thornson, R H., J. Chem. Soc., 3315 11956). (8) (a) Pauly. H.,andLockemann, K.,Cham. Bar. 48.26 (1915); 1b)Boyd, J.,Robertson, A , and Whalley, W. B., J. Chem. So% 174 11946): I d Dickenson, H.,U.S. Patent 2,449,162 (1948); Chem. Ahtr.. 43. 694. Id) Ahhott Laboratories British Patent 705,316 (1954): Chem. Ahrr.. 50.1088d. (9) vo.81, A. 1,:'ATedbaokof Practical o*mia Chemistty:.4th ed., Longman, Ine.,Nw York, 1918, p. 372. (10) "CRC HandbookofChemi3tryand Phyairn," 58th Ed., CRC Press 1911-78. (11) '"The Marek Inder,"9fh ed.,Merek & Co., Rahway, NJ, 1916.
