SU582768A3 - Method of preparing derivatives of bispiperazineandrostane - Google Patents

Description

(54) THE WAY OF OBTAINING DERIVATIVE BISPIPERASINOUSDROSTANA IS A WATER, corresponding to the general form I, where B is hydrogen; X and H mean those oxo group, are reduced by complex metal hydride, the resulting compound is reacted with a halide - 2 is converted to a quaternary salt or, if necessary, the resulting 3 ° C, P-dihydroxy derivative is acylated in 3. and 17-positions, if necessary, transfer the resulting compound in a known way to the salt of general formula I. The interaction with piperazine is carried out in an aqueous medium, and the reaction time ranges from 35 hours to 5 days. The reaction takes place at 70leOC. At the end of the reaction, the piperazine derivative, applied in excess, is distilled off in vacuo, the residue is triturated with water and the product is decanted. In case piperazine derivatives with a higher boiling point are used. It is advisable to filter the reaction mixture into water and filter the precipitated precipitate. The resulting crude bispieperazine pro- ducts are purified by reprecipitation from acid and alkali or by recrystallization, usually with a combination of both methods. The resulting 2J5, 16 -bispiperazino -HYDROXI-17-OXO-5a (. -Androstane derivatives are reduced with an alkali metal borohydride, for example sodium borohydride, an aluminum alkali metal hydride, for example, lithium aluminum hydride, or with alkoxides of the flashes, or with an alkoxyaluminium alloy, or with an alkali metal, for example, lithium aluminum-aluminum hydride, or using alkoxylimeters, and with the help of alkoxyaluminium-crystals; methoxyethoxylythium, sodium aluminum hydride in a known, from the point of view of reaction, solvent, preferably at room temperature. The resulting product of the reduction is 2,16 j3-bispiperazine-3et, 17-hydroxy-5- "-androstan Under certain conditions, they are acylated as follows: The dioxy derivative is dissolved in pyridine and a solution of acid anhydride or acid chlorohydrin is added with a slight excess. After a reaction time that can be from several minutes to several hours, the acylated product is isolated by pouring in water or by extraction and, if necessary, recrystallized. The acylation is carried out in such a way that 2, 16j9-bispiperazino-3 L. , 17L-dihydroxy-5-androstane derivatives are dissolved in a mixture of glacial acetic acid and acetic anhydride, Lewis acid, preferably zinc chloride, is added in catalytic amounts, and after the reaction time the product is isolated. Quaternary compounds of general form, mouls I, are obtained from free bases by reacting with alkyl halides which contain 1-4 carbon atoms, for example ethyl bromide, propyl bromide, or allyl bromide or benZIL chloride, in an inert solvent, for example methylene chloride, nitro tanne, acetonitrile, nitro-methane, acetonitrile, nitro-methane, acetonitrile, nitro-methane, acetonitrile, nitro-methane, in an inert solvent, for example, methylene chloride, acetonitrile, nitro-methane, or nitroxymethyl chloride. temperature or when heated, usually at the boiling point of the solvent used, at atmospheric pressure, or in a refractory tube under pressure. After distilling off the applied solvent or mixture of solvents, as well as the product used in excess of hapogenide, the product is isolated by trituration with ether or acetone. Example. 100 g of 17-oxo-5 ° C-androst-2-ene are dissolved in 380 ml of freshly distilled isopropenyl acetate and 1 ml of concentrated sulfuric acid in 50 ml of isopropenyl acetate is added to the solution. The reaction mixture is gently and evenly heated to a boil for about 1.5 hours and the acetone formed in this reaction is distilled off continuously. After approximately two-hour distillation, the reaction mixture is cooled to room temperature and poured into 4000 ml of ice-cold water. After many hours, the precipitated precipitate is filtered and thoroughly washed with ice water. The product wet on the filter is dissolved in ether, the solution is washed several times with water and dried over sodium sulfate. After separating the drying agent, the solution is clarified with 250 g of neutral alumina with an activity of L. After stirring for 30 minutes, the adsorine is filtered off and the residue is triturated with 140 ml of methano. The filtered, crystalline, white color of 17-acetoxy-5 "C-anrost-2, 1b-diene is dried to a reduced weight. Yield 92.3 g (80%); , Ш1. 93.94 ° C. 90 g of 17je-acetoxy-5vC-androst2, 16-diene is dissolved in 150 ml of benol and 3000 ml of 2% ether perbenzoic acid is added to the solution. The reaction mixture is left at 5-15 ° C for 24 hours. With the aid of a 5% aqueous solution of atris bisulfate, the peracid is removed, benic acid is removed with ice-cold 5% sodium hydroxide raster. The ether benzene is washed with water to neutralize the reaction, dried over sodium sulfate, and then the solvent is evaporated. The residue is suspended in fir, then filtered and obtained 2 (, 3 I, 1b "c, 17c -diepoxy17-acetoxy-LoC-Androstanum is dried in a vacuum to a constant b. Output 80 g (81%); mp. 182- 184 C.

20 g of 2 ° C, 3 et, 16, 17.-diepoxy-I7ji-acetoxy-5 o.-androstane is dissolved in a mixture of 100 ml of N-methyl piperazine and 30 ml of water. The reaction mixture was kept under nitrogen atmosphere for 70 hours at.

After this time has elapsed, the excess N-methyl piperazine is evaporated in vacuo. The residue is rubbed with acetone, filtered and washed with ice-cold acetone. The resulting crude product is boiled for two minutes in a double amount of acetone and then cooled again to. White crystals of 2 g of 16 -bis- (4-methyl-1-piperazino) -3 I-hydro-SI-17-OXO-5-androstane are filtered off and dried in vacuo to a constant weight. Yield 19 g (63%); m.p. 195-197 C.

Calculated,%: C, 66.6 H, 10.3; NU, 7

SgdN5O02 1h Nao.

Found,%; C, 66.4; H 10.5; N 10.5 Example 2. 20 g 2ot, 3eC, l6 «, 17 °. -diapoxy-17-acetoxy-5 "-androstane is dissolved in a mixture of 80 ml of α-hydroxyethylpiperazine and 20 ml of water. The reaction mixture is heated at a temperature of 120 ° C for 70 hours under a nitrogen atmosphere, during the course of the reaction, the excess reaction time the α-hydroxyethylpiperazine is distilled off. The residue is triturated with acetone, filtered and lavied with ice-cooled acetone. The resulting crude product is mixed with a double amount of acetone, and then a white crystalline 2, 16-bis- (4-hydroxyethyl-1-piperazinyl) -HL-HYDROXY-17-OXO-5 ot-androstac is filtered off and dried in a vacuum to constant this weight. Yield 16.9 g (50.3%); m.p. 168

170- C.

Calc,% g 63.9; H 10.0; K9, .6

YHCHOTSM., 2HGDaid,% s With 63.6 N 9.7; N9.6.

Example 3, 10.6 g of 2, 16-bis- (4-methyl-1-piperazinyl) -3 I-hydroxy-17-oxo-5-androstane is dissolved in a mixture of 50 ml of tetrahydrofuran, 50 ml and 50 ml of methanol. To the solution at room temperature, with vigorous and vigorous stirring for about 20 minutes, add 9 g of sodium borohydride in 20 ml of water. The reaction mixture is stirred for another 20 minutes and then the solvent is distilled off in vacuo at room temperature. The residue is dissolved in a tenfold amount of chloroform and

the solution is thoroughly washed first with a 2% sodium hydroxide solution, then with water. The solution is dried over sodium sulfate and chloroform is distilled off. The residue is dissolved in three times the amount of acetone and kept at the boil for several minutes. From the newly cooled solution, 2 O-bis- (4-methyl-1-piperazinyl) -3 et, 17-dihydroxy-5-o is filtered off. -androstan and dried in vacuo to constant weight. Yield 9.3 g (91%) -; m.p. 244246 0.

Calculated,% g C 68.7; H 10.67, K 10.0

C gHjrzOaN.

Found,%; C ba, 4; H 10.70; N10,8

Example4. 10g2, 16-bis- (4-hydroxyethyl-1-piperazinyl) -3-hydroxy-17-oxo-5 ° C-androstane is dissolved in a mixture of 50 ml of tetrahydrofuran and 40 ml of methanol. 9 g of sodium borohydride in 20 ml of water are added to the solution at room temperature and with vigorous stirring for about 20 minutes. The reaction mixture is stirred for a further 20 minutes and thereafter the solvent is distilled off in vacuo at room temperature. The residue is dissolved in a tenfold amount of chloroform and the solution is washed with a 2% sodium hydroxide solution, then with water. The solution is dried over sulfate and chloroform is distilled off. The residue is dissolved in three times the amount of acetone and kept for several minutes at the boil. After cooling to OC, white crystalline 2 iil6 -bis- (4-hydroxyethyl 1-1-piperazinyl) -3 ot, 17 - dihydroxy-5 X-androstan is filtered off and dried under vacuum to constant weight. The yield of 8.2 g (82%); m.p. 204206 С,

Calculated% s C H 10.2; N9.5

SmNvbO Kts-2NaO.

Found,%: C 63.7; H 10.0; N 9.7.

Example 5. 5, and 2, 16-bis- (4-methyl-1-piperazinyl) -Zo (., 17J1 -dihydroxy-5 ° C-androstane) are dissolved in a mixture of 20 ml of acetic anhydride and i5 ml of glacial acetic acid and the solution is mixed with 0.5 g of gsh chloride. The reaction mixture is stirred at room temperature for 3 hours and then poured into 250 ml of ice water. The solution is carefully alkalized at 0 ° C (pH 9-10), the precipitate is filtered and washed with cold water. The product, which has a slightly ointment-like consistency, dissolves in ether. The solution is dried on After the filtering, the ether is distilled off, the residue is triturated with petroleum ether and the white flaky 2JI, 16-bis- (4-methyl-1-piperazinyl) -ZoF is filtered off. 17 -diacetoxy-5 ° C -androstane. The product is dried in vacuo to constant weight. Yield 5 g (71%.

Calculated,%: C 69.2; H 9.7; N9.7

SzaN vOmMts.

Found,% C 69.0; H 9.8; N10.0 EXAMPLE 6: 4.5 g 2, 16 -bis - (4-hydroxyethyl-1-piperazinyl) -3, 17 -dihydroxy-5o4. g-androstane is dissolved in a mixture of 25 ml of acetic anhydride and 5 ml of glacial acetic acid and 0.5 g of qi chloride (1kg) is added to the reaction mixture and the mixture is stirred at room temperature for 4 hours and then poured into 250 ml of ice water. The solution is carefully alkalized at RT (pH 9-10), the precipitate is filtered and washed with thoroughly cold water. The crude is obtained; the product is diluted in ether, the solution is dried with sodium sulfate and after filtering the drying agent is mixed with five times the amountsilica gel After filtering off the adsorbent, the ether is distilled. and dried in vacuo to constant weight. Yield 4.4 g (81%).

Calculated,%: C 65.3; H 8.9; N7.8

«Aeronautical

Found,% C 65.2; H 8.7; N7.8.

Example7. 2g, 16-bis {4-methyl-1-piperazinyl) -3 D, 17-diacetoxy-5o (.androstane) is dissolved in 15 ml of acetonitrile and 6 MP of gsillilbromide is added to the solution. The reaction mixture is boiled for 2 hours, then cooled to room temperature and mixed with ether. The precipitated 2, diacetoxy-5 "4 -androstanedibromide is filtered off and the npoNM is mixed with a mixture consisting of acetonitrile and ether in a ratio of 1: 3. The product is dried in a vacuum to constant weight. Yield 2.5 g (86%).

Calculated,%: C 55.0; H 8.2; Vg18,6

jgHeeOdN, Yr. Found:% C 54.7; H 8.4 Bg18, b. PRI me R 8.0.35 g of 2D, 16-bis- (4-methyl-1-piperazinyl) -ZoC, 17-diacetoxy-5- "-androstane is dissolved in 5 ml acetonitrile and 2 ml of benzyl chloride was added to the solution. The reaction mixture is boiled and mixed with ether. Fallen 2, 16 -bis- (4-methyl-4-benzyl-1-piperaeinil) -ZoC. 17-diacetoxy-5 ° C androstanedichloride 5 is filtered and washed with ether. The product is recrystallized from ethanol-ether. The output of 0.48 g (96%) so pl. 180-182 C.

Calculated,%: C 65.6; H 8.6; B1 8.2

10С27 Н70 ОчКцСеа 2.Н20.

Found,% C 65.4; H 8.3; , 0, Example9. 4g2, 16ji-bis- (4-methyl-1-piperazinyl) -3 4., 17 Ji-diacetoxy-5H-androstane is dissolved in a mixture of 40 ml of methylene chloride and 20 ml of nitromethane and 9 ml of methyl bromide is added to the solution. The reaction mixture is allowed to stand at room temperature in a refractory tube for two days. Formed as a by-product in an amount of a few percent and the trimethobromide-derivative released from the reaction mixture is filtered off. The solution is diluted with ether, the precipitated f, 16f - (4-dimethyl-1-piperazinyl) -C, 17-diacetoxy-5 "4-androstan-dibromide is filtered off and recrystallized from a mixture of 0 methylene chloride-ether. Yield 4.5 g (81%); m.p. 252-254С.

Calculated,%: C 52.6; H 8.2; Vg20,0,

C3sH6iO, Ki, brj-2H20.

5 Found: C, 52.4; H 8.0; , 7.

Example 10: O, 6 g of 2, 16-bis- (4-methyl-1-piperazinyl) -3-hydroxy-17-oxo-5 ° C-androstane is dissolved at the boil in 20 ml of acetonitrile and 3 ml of allyl bromide. The reaction mixture was boiled for 2 hours, then a white precipitated crystalline 2fl, I6fi-bis- (4-methyl-4-allyl-1-pi5 perazinyl) -3e4. hydroxy-17-oxo-5. -androstanedibromide is filtered off, washed thoroughly with acetonitrile and then dried. Yield 0.7 g (80%) m.p. 258-260 S.

Calculated,%: C54.9; H8.3;

Wg2r, 9.

Claims (1)

one. }. Jr-lartft f if. RosbtxHranz ,, F. SondKaCtner, b. syntKests of fln-droiteronej. Qrij. dKaTn: i955, 20,542.