SU1766259A3 - Method of obtaining griseolic acid derivatives - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R1 and R2 are H, OH or halogen; R3 and R4 are carbamoyl or carboxyl which may be protected; A is formula II-IV (X and Y are OH which may be protected substituted OH, etc.; Z is H or OH which may be protected; W, together with N, forms N-oxide, lower alkyloxy, etc.] and salt thereof. EXAMPLE:Griseolic acid-N<1>-oxide dimethyl ester. USE:A cardiovascular agent, antithrombotic agent, ameliorant for cerebral function, diuretic agent, agent for cranial nerves, smooth muscle relaxant and remedy for cancer. PREPARATION:Dimethyl griseolate expressed by formula V is suspended in methanol, and m-chloroperbenzoic acid is added and reacted therewith at room temperature to afford the aimed compound (exemplified compound) expressed by formula I (R1 and R2 are OH; R3 and R4 are carboxy protected with methyl; A is formula IV (W is N-oxide).

Description

The invention relates to heterocyclic compounds, in particular, derivatives of griseolic acid, which is the source for the synthesis of biologically active derivatives of griseolic acid. The goal is a way to get new intermediates. Synthesis is carried out by the alkylation of dimethylgrizeole-M-ox-nth p. -Nitrobenzyl bromide, myl and benz and lromide in 3 d e of an organic acid, such as dimethylformamide. in the presence of a base, triztilamine at room temperature.

The invention relates to a method for producing new derivatives of griseolic acid, which can be used as starting materials in the synthesis of biologically active derivatives of griseolic acid.

The purpose of the invention is a method of obtaining new derivatives of griseolic acid, which can be used in the synthesis of derivatives of griseolic acid, which have valuable pharmacological properties.

This goal is achieved by a method of obtaining derivatives of griseolic acid of the overall Formula ί

where E is Cd-Sshalkyl Etsbenzyl or nitrobenzyl, which consists in the fact. that the compound of general formula I

ΝΚ, τ

χλ /

Nn

/ ° \> - </

Oh oh

M 01

>

where K has the indicated meanings, subjecting XI "to interaction with a compound of the general formula ΙΗ

I ι x

where Hz has the indicated values, in the amide of an organic acid in the presence of a base.

NOSS

KOOSH ^Χ ° ^{Ζ he} he

3

1766259

four

Example 1. Dimethylgreezeolate-оксид ^ oxide.

8.14 g of dimethylgreezolate are suspended in methanol. 6.90 g of meta-chloroporbenzoic acid are added, and the mixture is stirred at room temperature for 24 hours. Then the solvent is distilled off under reduced pressure. When the solvent is almost distilled off, 300 ml of diethyl ether are added and the resulting clots in the solution are ground with a spatula until they disappear, the mixture is filtered, and the resulting filtrate is washed with 100 ml of diethyl ether, evaporated and dried to obtain 7.81 g of a white powdery substance. This powder is dissolved in 200 ml of methanol and 300 ml of methylene chloride with heating, and then the solvent is distilled off under reduced pressure to a volume of 50 ml. The resulting crystals are filtered off to obtain 6.31 g of the title compound as white powdery crystals.

NMR spectrum [CO2 / r5O], ό ppm. 3.68 (ЗН. Singlet), 3.78 (32Н, singlet), 4.60 (1H, doublet, = 5.0 Hz), 4.67 (1H, singlet), 6.15 (1 K, doublet , ΰ = 2.2 Hz), 5.90 (1 N, doublet of doublets, = 2.2 and 5.0 Hz), 6.53 (1 H, singlet). 8.53 (1 H, singlet), 8.72 (1 H, singlet).

Example 2. Dimethyl-M ^1- para-nitrsbenzyloxygryseolate,

35 ml of dimethylformamide is added to 1.48 g of dimethylgreezeolate-A-oxide. 2.2 / g para-nitrobenzyl bromide and an equal amount of triethylamine, and the resulting mixture was stirred at room temperature overnight. The solvent is distilled off under reduced pressure, and the residue is crystallized by adding diethyl ether. The mixture is then filtered and the residue is dissolved in a mixture of ethyl acetate and 10% by weight of sodium bicarbonate solution. The separated organic layer was washed with water, dried with anhydrous magnesium sulphate. the solvent is filtered off and the residue is then purified on a chromatographic column with silica gel, eluting with methylene chloride. containing 3% (v / v) methanol, 1.5 g of the title compound are obtained.

NMR spectrum (SEZ / GZO), ЗО. ppm: 3.653.73 (together with MN, each singlet), 4.56 (1.N. doublet, = 5.0 Hz), 4.63 (1H, singlet), 5.7 7 (1 N , doublet, = 2.2 Hz), 5.45 (2H, singlet) 5.87 (1H, doublet of doublets, 3 = 2.2 and 5.0 Hz). 6.41 (1 H, singlet), 7.6-8.43 (6H. Multiplet).

Example 3. Diyatil-HH -benzyloxygriseslate.

5.35 g of dimetplgreseolate-NG-oxide, /, 5 ml of benzidbrsmide and an equal amount of triethylamine are left overnight in 90 ml of dimethylformamide at room temperature. Then, the resulting mixture is treated in the same manner as described in Example 2. The resulting solution is poured into 1 liter of hexane, and 0.5 liter of distilose ether with stirring. The obtained powdery substance is filtered, and as a result, 5.4 g of this is obtained and the title of the compound as an crude product.

NMR spectrum (SOZ / ZZO). d. ppm 3.33, 3.71 (together with ZN, each singlet) 4.54 (1K, doublet. 3 = 5.0! t) 4.68 (Ή-U single g), 5.1 (1H. doublet, 3 = 2.2 Gtsu. 5.33 (2H, singlet). 5.83 (1H. Doublet of doublets. 3 "2 2 and 5.0 Hz). 6.46 (1 N. singlet), 7.3-7.? (5N. Cartoon and payment), 8 , 32 and 8.39 (together 1H. Each singlet).

Formula a isobrot -, ν ·. about

The method of obtaining derivatives of griseol acid of the General formula

Claims (1)

% ΰΰ3. / 0% OZOO - -'yoZOZ oud! 7 - C at Sl - sfil: R / - races ;, aly geneugsaneil. dtl d h ay u and y with I ham. that the compound of the general formula FOU "F. Ρ.ΟΟΓ 'Α 0% where C has the specified values are subjected to interaction with the compound m about b esch f f ρ m y g, s SUKH where P- has the indicated meanings. - halogen in amide yergeni'-eschsy ksch. moons _and u-odpeutts eii base.