RU2012148092A - TRIPHENYLPHOSPHONIUM SALTS OF LUPANE TRITERPENOIDS, METHOD FOR PRODUCING AND APPLICATION AS ANTITUMOR SUBSTANCES - Google Patents

Abstract

1. Triphenylphosphonium salts of betulinic acid of the formula 1, 20,29-dihydrobetulinic acid of the formula 2 and 20,29-dihydro-3-epi-betulinic acid of the formula 3, general formula 4-12: 2. The method for producing compounds 4-12 of claim 1, comprising the following steps: a) get betulonic acid 41 by oxidizing betulin under the action of Jones reagent in acetone; b) get betulinic acid 1 by reducing betulonic acid 41 NaBH in a solvent mixture CHCl: MeOH = 1: 1 followed by transformation of acid 1 into methyl ester 1a under the influence of CHN in EtO, then acetylated to compound 39; c) get betulonate 36 and dihydrobetulonates 13 and 14 from betulonic acid 41 by its transformation into acid 42 by hydrogenation, synthesis of esters 43-45, their subsequent ally o alkylation to compounds 13, 14 and 36 under the influence of CM (SiMe), EtB and allyl bromide in dimethoxyethane; d) stereoselectively reduce betulonates 13, 14 and 36 under the influence of NaBH-modified CeCl · 7HO to give 3β-OH epimers, betulin 36a and dihydrobetulin acids 15, 16; dihydrobetulonate 13 is stereoselectively reduced to 3α-OH epimer 17 under the action of lithium tri-sec-butyl borohydride (L-selectride); 3β- and 3α-epimers of alcohols 15-17, 36a are acetylated into ethers 18-20, 37; e) hydroborated compounds 15, 17-20, 37 and 39 followed by oxidation of organoboron compounds to alcohols 21-25, 38, 39a under the action of 30% HO and an aqueous solution of NaOH; f) alcohols 21, 22, 25, 38, 39a are iodinated with crystalline iodine in the presence of imidazole and triphenylphosphine; g) bromides 32-34 are obtained from alcohols 23-25 in two stages via intermediate mesylates 29-31 by the interaction of alcohols with methanesulfonyl chloride in the presence of pyridine and DMAP, followed by the interaction of mesylates 29-31 with LiBr in acetone; h)

Claims (7)

1. Triphenylphosphonium salts of betulinic acid of the formula 1, 20,29-dihydrobetulinic acid of the formula 2 and 20,29-dihydro-3-epi-betulinic acid of the formula 3, general formula 4-12:

2. The method of obtaining compounds 4-12 of claim 1, comprising the following stages: a) get betulonic acid 41 by oxidation of betulin by the action of Jones reagent in acetone; b) betulinic acid 1 is prepared by reducing betulonic acid 41 NaBH ₄ in a solvent mixture of CHCl ₃ : MeOH = 1: 1, followed by transformation of acid 1 into methyl ether 1a under the influence of CH ₂ N ₂ in Et ₂ O, then acetylated to compound 39; c) betulonate 36 and dihydrobetulonates 13 and 14 are prepared from betulonic acid 41 by its transformation into acid 42 by hydrogenation, synthesis of esters 43-45, their subsequent allylic alkylation to compounds 13, 14 and 36 under the influence of CM (SiMe ₃ ) ₂ , Et ₃ B and allyl bromide in dimethoxyethane; d) stereoselectively reduce betulonates 13, 14 and 36 under the influence of NaBH ₄ modified CeCl ₃ · 7H ₂ O to give 3β-OH epimers, betulinic 36a and dihydrobetulinic acids 15, 16; dihydrobetulonate 13 is stereoselectively reduced to 3α-OH epimer 17 under the action of lithium tri-sec-butyl borohydride (L-selectride); 3β- and 3α-epimers of alcohols 15-17, 36a are acetylated into ethers 18-20, 37; e) hydroborate compounds 15, 17-20, 37 and 39, followed by oxidation of the organoboron compounds to alcohols 21-25, 38, 39a under the influence of 30% H ₂ O ₂ and an aqueous solution of NaOH; f) alcohols 21, 22, 25, 38, 39a are iodinated with crystalline iodine in the presence of imidazole and triphenylphosphine; g) receive bromides 32-34 from alcohols 23-25 in two stages through intermediate mesylates 29-31 by reacting alcohols with methanesulfonyl chloride in the presence of pyridine and DMAP, followed by reacting mesylates 29-31 with LiBr in acetone; h) receive bromide 40 by reacting betulininate 39 with N-bromosuccinimide (NBS) in CCl ₄ in the presence or absence of AIBN; i) bromide 34 is subjected to hydrogenolysis in the presence of a 10% Pd / C catalyst to give compound 35; j) the halides are reacted with an excess of triphenylphosphine by boiling in solvents to give salts 4-12. 3. The method according to claim 2, in which the preparation of compound 39 is carried out by acetylation of betulinic acid methyl ester 1a with Ac ₂ O in pyridine or AcCl in THF in the presence of pyridine and 4-dimethylaminopyridine (DMAP). 4. The method according to claim 2, in which the preparation of compounds 18-20, 37 is carried out by acetylation of alcohols 15-17 and 36a with Ac ₂ O in pyridine or AcCl in THF in the presence of pyridine and DMAP. 5. The method according to claim 2, in which the production of alcohols 21-25, 38 and 39a is carried out by hydroboration of compounds 15, 17-20, 37 and 39 under the action of the complex BH ₃ · THF or dimethyl sulfide-borane complex in THF. 6. The method according to claim 2, in which the preparation of triphenylphosphonium salts 4-12 is carried out by reacting lupane terpenoid halides with an excess of triphenylphosphine while boiling in toluene or acetonitrile for 16-48 hours in an argon atmosphere. 7. The use of phosphonium salts of lupane triterpenoids 4-12 as antitumor substances.