Synthesis of Betulin Bromobenzoate, Dicinnamate, and Disuccinate in Melts of the Corresponding Acids
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SYNTHESIS OF BETULIN BROMOBENZOATE, DICINNAMATE, AND DISUCCINATE IN MELTS OF THE CORRESPONDING ACIDS
V. A. Levdansky,1 A. A. Kondrasenko,1 A. V. Levdansky,1 and B. N. Kuznetsov1,2*
Esters of betulin (1) containing bioactive aromatic and aliphatic carboxylic acids are interesting as hepatoprotectors and anti-inflammatory, antiulcer, and immunomodulating agents [1, 2]. Betulin 3,28-disuccinate and 3,28-dicinnamate were shown to possess hepatoprotective activity and to inhibit influenza virus [3–5]. The well-known method for preparing betulin 3,28-disuccinate consists of acylation of 1 by succinic anhydride in anhydrous Py for 15 h. The 3,28-dicinnamate is obtained by treating 1 with cinnamic acid chloride in a mixture of anhydrous Py and Bu3N for 4 h [3]. Acylation of 1 by succinic anhydride in CH2Cl2 in the presence of imidazole for 12 h was disclosed in a patent [4]. The biological activity of several esters of 1 was studied [6]. The results showed that betulin 28-cinnamate was obtained in 92% yield by reacting cinnamic acid with 1 in the presence of SOCl2 at 40°C for 2 h and in 21% yield by reacting cinnamic acid chloride with 1 in anhydrous Py in the presence of 4-dimethylaminopyridine at 40°C for 2 h. The above methods for preparing esters of 1 require the use of toxic and costly reagents and long reaction times. Therefore, the search for and development of new and economical methods for synthesizing esters of 1 are still challenging. The goal of the research was to develop synthetic methods for betulin 28-p-bromobenzoate, 3,28-dicinnamate, and 3,28-disuccinate via esterification of 1 in melts of p-bromobenzoic, cinnamic, and succinic acids. The preparation of betulin dibenzoate and diphthalate via fusion of 1 with benzoic and phthalic acids was reported [7]. In continuation of efforts on the synthesis of esters of 1, esterification in melts of p-bromobenzoic, cinnamic, and succinic acids at 220–255°C to produce betulin 28-p-bromobenzoate (2a), 3,28-dicinnamate (2b), and 3,28-disuccinate (2c) was studied. 29 20
30
26
1
CH2 OH
28
26
25
17
a, b, c
CH2OR2
9
15 7
4
19
22 13 17
10
HO
30
19
12 25
29
3
27
27
R1 O 24
23
24
1
23
2a-c
a: R1 = H, R2 = pBrC6H4CO; b: R1 = R2 = C6H5CH=CHCO; c: R1 = R2 = HOOC(CH2)2CO a. pBrC6H4COOH, 250–255°C; b. C6H5CH=CHCOOH, 240–250°C; c. HOOC(CH2)2COOH, 220–230°C
The structures of the obtained esters of 1 were established by IR and NMR spectroscopy and comparison of the obtained data and with the literature on analogous compounds [2–5]. The IR spectrum of 2a, in contrast with that of 1, showed a C=O absorption band at 1679 cm–1. The PMR spectrum of 2a contained resonances for aromatic-ring protons at 7.94–7.97 and 7.66–7.69 ppm. The 13C NMR spectrum of 2a had resonances for 37 C atoms, which corresponded to the formula C37H53BrO3.
1) Institute of Chemistry and Chemical Technology, Siberian Branch, Russian Academy of Sciences, 50-24 Akademgorodok, Krasnoyarsk, 660036, e-mail: [email protected]; 2) Siberian Federal University, 79 Prosp. Svobodnyi, Krasnoyarsk, 66
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