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Warfarin and Acenocoumarol

52 1

New Efficient Catalysts in the Synthesis of Warfarin and Acenocoumarol


Neue wirksame Katalysatoren fur die Synthese von Warfarin und Acenocumarol Ivo C. Ivanov, Ilia Manolov*,and Liliana A. Alexandrova
Institute of Pharmacologyand Pharmacy, Bulgarian Medical Academy, Dunav 2, BG-1000 Sofia, Bulgaria Received January 2 1.1990 In the preparation of the anticoagulants warfarin (3a) and its 4-substituted derivatives (e.g. acenocoumarol, 3b) by Michael addition of 4-hydroxycoumarin(1) to the corresponding 4-aryl-3-buten-2-ones(2). ammonialV2), aliphatic or acromatic a m i n e ~ ~ .~ ~y ), ridine~.~ quinoline3), .~, alkali phosphate^^'^^'. sodium acetate or citrate3, borax3 and alkali alkoxides6) have been used as catalysts till now.

We found out that by accomplishing this reaction in aqueous medium either alkali fluorides (KF, NaF) or quarternary ammonium salts (phase-transfer catalysts) can be applied as highly efficient catalysts (Table 1). For comparison of the reaction times the addition process was carried out also without any catalyst (entries 1 and 12) and in the presence or triethylamine or trisodium phosphate (entries 10 and 11) being the most recommended catalysts in the literature. Accomplished in pyridiae or in glacial acetic acid in the presence of sodium acetate the reaction gave dark-coloured by-products and the purification of the products was complicated. Diluted sulfuric acid inhibited or stopped this reaction. The following general conclusions can be drawn from the experimental data presented in Table 1. First, for the preparation of warfarin (3a) the phase-transfer catalysts in optimum concentration of 5 mol per cent are more suitable. The yield of 3a is not essentially influenced by the nature of the quartemary salt. The use of these catalysts reduces the reaction time to about 5 % while the use of KF reduces it only to about 50 % (entry 9). Even more, the catalysed processes give markedly higher yields of 3a. Second, the alkali fluorides in a concentration of 5 mol per cent are more useful for the preparation of acenocoumarol (3b). There is practically no difference in the effects of the salts used in entries 13 and 16. Alkali fluorides reduce the reation time to 33 9% while triethylbenzylammonium chloride (entry 17) shortens it to about 50 %. The simultaneous application of both catalysts (entry 18) does not
PH

enhance the catalytic effect, and the product isolated in these trials is of low quality. High yields are achieved when using the catalysts described above - nearly 80 % for triethylbenzylamrnoniurn chloride in 3a (entry 3) and for NaF in 3b (entry 16). The reaction mixture remains pale-coloured till the end of the process and the corresponding product can be isolated easily in a rather pure state. The Michael addition occurs by refluxing in a heterogeneous mixture, since 4-hydroxycoumarin (1) is soluble in hot water and the unsaturated ketone 2 is a melt. Obviously, fluoride ions act as a week basic catalyst with good solubility in the org. phase lo). However, complementary studies should be undertaken for a reasonable explanation of the catalytic effect of quartemary ammonium salts in the absence of any base (in contrast to the numerous examples in
lit.
)).

Experimental Part
M.p.: Btichi 510 apparatus (Switzerland), uncorrected. - TLC: Al-foils Kieselgel 60 FZ4. Merck (FRG), developed by cyclohexane-chlorofomacetic acid (10104, vol. parts), detection: UV 254 nm. - The reaction time is determined by TLC monitoring (till exhaustion of the starting 1). General procedure Water (160 ml) and the corresponding catalyst (Table 1) are added under stirring to a mixture of equimolar amounts (50 mmol each) of Chydroxycoumarin (1) and unsaturated ketone 2a or b. Then the mixture is refluxed under vigorous stirring for a period shown in Table 1. The product is filtered, triturated and washed successively with hot water (3 x 100 ml) and, after cooling, with ether (2 x 50 ml). If necessary, the product can be recrystallized from glacial acetic acid or ethyl acetate. The yields are given in Table 1.

Arch. Pharm. (Weinheim)323,521-522(1990)

OVCH VerlagsgesellschaftmbH, D-6940 Weinheim, 1990 0365-~6233/90/0808-521$3.50 + .25/0

522
Table 1 : Influence of some catalysts on the synthesis of 3a, b
Entry No.
1 2 3 4 5 6 7 8 9 10 11 12

Ivanov, Manolov. and Alexandrova

Product
3a

Catalyst (amount) Without catalyst5) Triethylbenzylammonium chloride (2.5 rnol %) Triethylbenzylammonium chloride (5 mol %) Triethylbenzylammoniun chloride (10 rnol %) Tetrabuty lammonium chloride (5 mol %) Benzyltributylammonium chloride (5 rnol %) Tetraoctylammonium bromide (5 mol %) Aliquat 336 (5 mol %) KF (5 mol %) Triethylamine*3) (7.7 mol %) Na$O:8) (6 rnol %) Without catalyst KF (5 mol %) KF (10 rnol %) NaF (15 mol %) NaF (5 rnol %) Triethylbenzylammonium chloride (5 mol %) KF (5 rnol %) + triethylbenzylammonium chloride (5 mol %)

Duration, h
42

Yield.
%

M.p.,OCb)
160-161 155-158 155-158 155-158 150-154 156-159 155-157 158-160 158-162 159-161 159-161
C)

46 66

2
2 3 2 3 2 20 3 10 6

83
84 77

83
75 68 71 67 57 78 77

3b

13
14 15

2
2 2 2 3

C)
C)
C) C)

16
17

83 75 79 88

C)

18

92

157-180 coloured

Notes: a) Yield of isolated product without recrystallization, TLC homogeneous. The m.p. corresponds to the product obtained with the given yield. c, The tipical m.p. of the crude acenocoumml is in the rahge 192-196OC (lit.*): m.p. 196-199OC).
b ,

References
1

2 3 4 5 6

D.F. Starr and K.K. Haber, US Pat. 2 666 064 (1954); C.A. 49,380h (1955). H.G. Krey, DDR Pat. 15092 (1958); C.A. 54.3458de (1960). C.G. Joshi and J.L.Bose, Indian J. Technol. 10,461 (1972). J.D. Rizzo and P.J. Davis, J. Pharm. Sci. 78, 183 (1989). M. Ikawa, M.A. Stahmann, and K.P. Link, J. Am. Chem. SOC.66,902 (1944); US Pat. 2 427 578 (1947): C.A. 42, P603h (1948). W . Stoll and F. Litvan, US Pat. 2 648 682 (1953). Geigy AG, Basel; C.A. 49, P 2522fg (1955).

S. Lacobescu and T. Gostea, Fr. Pat. 1 271 976 (1962); C.A. 56. 15488g(1962). 8 P. Spiess and W. Spiess, Brit. Pat. 734 142 (1955); C.A. 50, 7143a (1956). 9 K. Knoevenagel, D.O.S. 948 507 (1956). C.F. Spiess & Sohn and Norddeutsche Affinerie; C.A. 53.2258 g (1959). 10 R. Curci, M. Fiorentino, L. Troisi, J.O. Edwards, and R.H. Pater, J. O r g .Chem. 45,4758 (1980). 11 E.V. Dehmlow and S.S. Dehmlow, Phase Transfer Catalysis, 2nd Ed., Verlag Chemie, Weinheim, 1983. 12 The Merck Index, 10th Ed., p. 29, Rahway, USA, 1983. [KPh528]

Arch. Pharm. (Weinheim) 323,521-522 (1990)