SU438262A1 - Method for preparing 16,17-substituted 5-bromo-6 fluoro-21-acetoxypregnanone-20 - Google Patents

Description

The invention relates to the field of producing new compounds - 16, 17-substituted 5a-bromo-6p-fluoro-21 - acetoxypregnanone - 20, used as Intermediates in the synthesis of fluorinated corticosteroids.

A known method for producing such type of compounds includes bromination of 3-substituted D-pregnenol-3p-ones-20, replacement of the halogen by an acetoxy group and addition of bromine and fluorine on A-double bond. However, with such a sequence of reactions, the known method includes additional stages, for example, the regeneration of the D-double bond undergoing reservation in the 21-brominated process, nor.

The proposed method allows to eliminate the disadvantages of the known method.

Applying the known bromination reaction of € 21 and selectively replacing 21 bromine with an acetoxy group to 16, 17-substituted 5a-bromo-6p - fluoropreganol-3p - one - 20, it was proposed to obtain new compounds that are not described in the literature and are important intermediate products. in the synthesis of physiologically active compounds.

In accordance with the invention, a method is described for the preparation of 16, 17-substituted babrom-6p-fluoro-21-acetoc. Of S. impregnanone-20 of general formula I

C-HjOAr SOL --K, B,

Yo

Vg

where Ri R2 is hydroxy or methyl groups, or R, and R2 form together an epoxy group;

RS is a hydrogen atom, and R is a hydrogen atom or an acetyl group, consisting in that a compound of the general formula II

eNz.

for,

rrVJCCJ

Mrr

25

where R, Ri, Ro, and Ra are as defined above, brominated in a solvent in the presence of hydrogen halide, and in the resulting 5,21-dibromo-6-fluoro derivative, bromine at 21 is selectively replaced by acetoxy with an alkali metal acetate or triethylammonium; an organic solvent, and the desired product is isolated by known techniques.

According to the proposed method, bromination is carried out with approximately 1 mol of bromine in a solution of an organic solvent, for example chloride (methylene or ethyl alcohol, in the presence of alcohol saturated with hydrogen chloride, or ethyl acetate with hydrogen bromide. The duration of the Process depends on the temperature of the reaction solution, For example, broiling at 20-25 ° C ends after 20-30 minutes, at 10-15 minutes. The substitution of 21-bromine for acetoxy-grinna is carried out by the action of potassium acetate. in acetone at boiling point and and action-triethyl mmoni acetate at a temperature of 20 ° C and below.

Example 1. To a suspension of 3.1 g of 5a-bromo6 | 3-fluoropregnantriol-3, 8, 16a, 17a-one-20 in 31 ml of methylene chloride was added 1.5 ml of a solution of HCl in methanol and a few drops of bromine. The reaction mass is heated to 25 ° C and the rest of the bromine is added dropwise. At the same time, the temperature of the reaction mass rises to - | -32 ° C. After 15 minutes, the solution becomes clear and discolored, then the dibromide precipitates out. The reaction mass is cooled to -5 ° C, the precipitated precipitate is filtered off, washed with bicarbonate solution and water until neutral. 2.4 g of 5a, 21-dibromo-6 | 3 are obtained - fluoropregnantriol-Zr, 16a, 17a-one-20; m.p. 165-167 ° C (decomposition); , 8 ° (0.5% CHCU), Rt 0.68 (Silufol, hexane-ethyl acetate 1: 1). The mother liquor is neutralized with bicarbonate solution, the organic layer is separated, washed with thiosulfate, water until neutral, dried with sodium sulfate. The solvent is evaporated, the residue is crystallized from methanol. A total of 1.1 g of 5a, 21-dibromo-p-fluoropregnantrio, l-3p, 16a, 17a-one-20; m.p. 163-164 ° C. The overall yield is 96%.

iOo The IR spectrum obtained dibromide is completely identical to the sample isolated by bromination of 20-carbethoxy hydrazone 5 abrom-6 | 3-fluoropregnantriol-3p, 16a, 17a-one-20.

IR (cc-1): 3440 (OD), 1720 (CO), 1455 1240, 1050, 1010. Nuclear Magnetic Resonance Spectrum (CDClg-f + SOZOO; b, MD): 0.664 (18СНз); 1.236 (7-3.5 Hz, doublet 19-CH3); 4.31 (quartet, AV system 21-CHgBr); 4.3 (H-3); 4.56 and 5.07 (/ -49 Hz, H-6); 4.92 (H-16).

1.8 g of technical 5a, 21-dibromo-6p-fluoropregnantriol-3 (3, 16a, 17a-one-20 is dissolved in 45 ml of acetone, 0.9 g of potassium acetate is added and boiled for 40 minutes. cooled, potassium acetate is filtered off, the acetone is evaporated in vacuo, ether is added to the residue, the precipitate is filtered off, 215-acetate 5a-bromo-6p is obtained fluoropregna, netrol-3p, 16a, 17a, 21-one-20; mp 178 , 5 - 180.5 ° С (decomposition, from acetone), 6 °

(0.5% CH € 1h).

IR spectrum (hedgehog): 3428 (OH), 1751 (OAc), 1715 (CO), 1460, 1380, 1050.1010.

Nuclear Magnetic Resonance Spectrum (СОСЬ, б, М.Д.): 0.63 (18-СНз); 1.16 (~ -3.5 Hz, doublet 19-CH3);

2D (COCHS); 4.2 (H-3); 4.3 and 5.1 (/ -49 Hz, (); 4.85 and 4.94 (CH2-21).

Found,%: C 54.00; H 6.74; .Br 15.79.

СгзНз ВГРОб.

Calculated,%: C 54.46; H 6.78; Vg 15.81.

21-Acetate 5a - bromo - 6 | 3 - fluorine - 16a, 17a isopropylidenedioxypregnandiol -Gp, 21-one20, obtained by reaction with acetone in the presence of perchloric acid; m.p. C (decomposition); -6.5 ° (0.6%

CHCla).

NK-spectrum (CS-1): 3520 (OH), 1740, 1240 (OAc), 1725 (CO).

NMR spectrum (COCl 3, b, ppm): 0.60 (18-СНз); 1.17 (doublet, 19-CH3); 1.15 and 1.43

C (CH3) 2.1 (COCH3); 4.3 (H-3), 4.36 and 5.18 (H-6); 4.9 (H-il6); 4.82 and 4.94 (SNg-21).

Literary data: so pl. 201.5-202 ° C; (0.8% CHCIa).

Example 2. To a solution of 5 g of 5a-bromo-6rfluoro-16a, 17a-oxycapregnenolone in 100 ml of methylene chloride was added 3 ml of a 12% solution of HCl in methanol and then a solution of 0.7 L1L of bromine in 10 ml of methylene chloride over 10 min. After decolouration after 20 minutes, the reaction mass is poured into bicarbonate solution, the organic layer is separated, washed with sodium thiosulfate solution and water until neutral, dried with anhydrous sodium sulfate, and the solvent is evaporated. The residue is crystallized with ether, cooled, filtered. 5.25 g of 5a, 21-dibromo-6p-fluoro-16a, 17-oxidopregnanol-3p-one is obtained | 20. Yield 88.9%;

1PL 170-171 ° C (decomposition); a C-46 ° (0.5% chloroform); Rf 0.72 (hexane-ethyl acetate 1: 1).

IR spectrum (0.4% in SNRC, cm): 3600 (OH), iI710 (CO).

NMR spectrum (CDCla, b, ppm): 1.03 (18-СНз); 1.23 doublet 19-CH3); 3.77 (H-16); 3.88 (); 4.31 (H-3); 5.01 and 4.52 (/ -49 Hz, H-6).

Found,%: C 48.92; H 5.77; Br 31.60.

C21 "2 Br2ROz.

(Calculated,%: C 49.61; H, 5.75; Br, 31.49; 2.2 g of 5.21-dibromo-6p-fluoro-16a; 17a-oxo-oxidophenanol-3p-one-20 is dissolved in 20 ml of acetone, add 1 g of potassium acetate and boil

30 minutes, then the reaction mass is cooled, the precipitate of potassium acetate is filtered off. The acetone filtrate is evaporated in a vacuum, ether is added to the residue, and the precipitate is filtered off. 1.71 g (82%) of 21-acetate-5a-bromo-6p-fluoro-16a are obtained, 17 - oxide-prenane diol