Title of Invention	"ENVIRONMENT-FRIEND PROCESS FOR THE SYNTHESIS OF QUATERNARY AMMONIO-STEROIDS".
Abstract	The invention relates to a new, environment-friend process for the synthesis of the known 4,4'-[3α,17β-bis(acetoxy)-5α-androstane- 2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) dibromide of formula (I) (from now on pipecuronium bromide) and 1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane -16β-yl]-1-methyl-piperidinium bromide of formula (II) (from now on vecuronium bromide). Furthermore the invention relates to the new intermediates of formula (III) and formula (IV) of the process, wherein the meaning of X is benzenesulfonate - in given case para-substituted with a methyl or a nitro group or a bromine atom - methanesulfonate, ethanesulfonate or trifluoromethanesulfonate ion.

Title of Invention

"ENVIRONMENT-FRIEND PROCESS FOR THE SYNTHESIS OF QUATERNARY AMMONIO-STEROIDS".

Abstract

The invention relates to a new, environment-friend process for the synthesis of the known 4,4'-[3α,17β-bis(acetoxy)-5α-androstane- 2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) dibromide of formula (I) (from now on pipecuronium bromide) and 1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane -16β-yl]-1-methyl-piperidinium bromide of formula (II) (from now on vecuronium bromide). Furthermore the invention relates to the new intermediates of formula (III) and formula (IV) of the process, wherein the meaning of X is benzenesulfonate - in given case para-substituted with a methyl or a nitro group or a bromine atom - methanesulfonate, ethanesulfonate or trifluoromethanesulfonate ion.

Full Text	The invention relates to a new, environment-friend process for the synthesis of 4,4'- [3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) dibromide of formula (I) (from now on pipecuronium bromide) and 1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium bromide of formula (II) (from now on vecuronium bromide). Furthermore the invention relates to the new intermediates of formula (III) and formula (IV) of the process, wherein the meaning of X- is benzenesulfonate - in given case para- substituted with a methyl or a nitro group or a bromine atom - methanesulfonate, ethanesulfonate or trifluoromethanesulfonate ion. Pipecuronium bromide and vecuronium bromide are known to be curare like, non- depolarizing neuromuscular blocking agents, which inhibit the transmission of the nerve- impulses to the striped muscles. Their effect can be terminated by addition of antidotes. Both compounds have wide clinical application due to their excellent biological effect. Their main application is in the surgery as muscle-relaxants during intubation narcosis. Other applications can be in the shock therapy and in the spasmic disorders of striped muscles. The synthesis of pipecuronium bromide is described in the Hungarian patent No. 165,000, according to which it is a multistep chemical synthesis starting from 2α,3α,16α,17α-diepoxy-17-acetoxy-5α-androstane. An improved synthesis is described in the following publication: Arzneimittel Forschung (Drug Res.) 30(I), 29, 342-346. The synthesis of vecuronim bromide is described in the GB patent No. 1,454,749 and in the Hungarian patent No. 154,368. A detailed summary can also be found in the following publication: J.Med.Chem. 16, 1116(1973). The final step of the known synthesis of pipecuronium bromide and vecuronium bromide is the quaternary ammonium salts formation with methyl bromide in acetone or diethyl ether solution from the diacetate derivatives of formula (V) and formula (VI) respectively. It is known that methyl bromide — used as quaternary ammonium salts forming agent in the above procedures - is a highly toxic, colorless, slightly smelling gas at room temperature, moreover it is an ozone layer damaging compound. Considering its latter feature its industrial use is strictly limited by the Hungarian decree No. 94/2003 (2.07.) referring to ozone layer damaging compounds, therefor it is practical to use an other quaternary ammonium salts forming agent, which is less or not at all toxic. Our invention relates to a new process for the synthesis of quaternary ammonium salts of diacetate derivatives of formula (V) and (VI) without using methyl bromide as reagent. Surprisingly it was found that the "sulfonate" ions of the "sulfonate salt" type intermediates of formula (HI) and (IV) of our invention can be changed for bromide ions - in spite of the fact that generally it is an equilibrium reaction - using lithium bromide as reagent and choosing the appropriate: reaction conditions the equilibrium can be shifted towards the. formation of pipecuronium bromide or vecuronium bromide in 99 % selectivity, therefor the methyl bromide reagent can be replaced by „sulfonyl methyl esters". According to our invention the process is the following: a.) to stirred solutions of the diacetate derivatives of formula (V) or (VI) in acetone, acetonitrile, ethyl acetate or tetrahydrofuran 2.5-4.0 molequivalents of methyl p- toluenesulfonate, methyl benzenesulfonate, methyl p-nitro or p-bromo-benzenesulfonate, or methyl methane or ethanesulfonate is added, the precipitated quaternary ammonio derivatives of formula (III) or (IV) - wherein the meaning of X" is benzenesulfonate, in given case para- substituted with a methyl or a nitro group or a bromine atom, or methanesulfonate or ethanesulfonate ion - are separated, and after an optional purifying and drying, are dissolved in acetonitrile, 2.5-5.0 equivalents of lithium bromide (calculated on the starting material), is added to the stirred solution, the precipitated lithium salts formed as by-products are filtered off, washed with acetonitrile, the combined filtrates are concentrated, the precipitated products of formula (I) or (II) are separated, in given case purified and dried, or b.) to a stirred solution of the diacetate derivative of formula (V) in ethanol, 2.5-4.0 molequivalents of methyl p-toluenesulfonate is added below 30 °C, after the reaction is completed the reaction mixture is diluted with tetrahydrofurane, the precipitated quaternary ammonio derivative of formula (III) - wherein the meaning of X- is p-toluenesulfonate - are separated, and alter an optional purifying and drying, is dissolved in acetonitrile, 2.5-5.0 equivalents of lithium bromide (calculated on the starting material) is added to the stirred solution, the precipitated lithium salts formed as by-products are separated, washed with acetonitrile, the combined filtrates are concentrated, the precipitated product of formula (I) is separated, in given case purified and dried, or c.) to a stirred solution of the diacetate derivative of formula (V) in ethanol, 2.5-4.0 molequivalents; of methyl p-toluenesulfonate is added below 30 °C, after the reaction is completed the reaction mixture is diluted with tetrahydrofurane, the precipitated quaternary ammonio derivative of formula (III) - wherein the meaning of X- is p-toluenesulfonate - are separated, after separating and an optional purifying and drying, is dissolved in ethanol, 2.5-5.0 equivalents of lithium bromide (calculated on the starting material) is added to the stirred solution, after the reaction is completed the reaction mixture is diluted with tetrahydrofuran, the precipitated quaternary ammonio derivative of formula. (I) is separated, washed with, tetrahydrofuran, after drying solved in ethanol, stirred with 0.2-0.5 equivalents of lithium bromide, diluted with tetrahydrofuran, and separated, washed and dried the precipitated compound of formula (I), or d.) to a stirred solution of the diacetate derivative of formula (V) in acetone, acetonitrile, ethyl acetate or tetrahydrofuran 1.0-1.1 equivalents (calculated on nitrogen atoms to be quaternized) of methyl trifluoromethanesulfonate is added at 10-35 °C, the formed quaternary ammonio derivative of formula (III) - wherein the meaning of X- is trifluoromethanesulfonate ion - is precipitated by dilution of the reaction mixture with ether, tetrahydrofuran, n-hexane or n-heptane, and after separating and an optional purifying and drying, is dissolved in acetone, 2.5-4.0 equivalents of lithium bromide (calculated on the starting material) is added to the stirred solution, the precipitated product of formula (I) is separated, in given case purified and dried, or e.) to a stirred solution of the diacetate derivative of formula (VI) in acetone, ether or tetrahydrofuran 1.0-1.1 equivalents (calculated on nitrogen atoms to be quaternized) of methyl trifluoromethanesulfonate is added at 10-35 °C, the precipitated (when the reaction is carried out in acetone after dilution of the reaction mixture with ether) quaternary ammonio derivative of formula (IV) - wherein the meaning of X- is trifluoromethanesulfonate ion- is separated, and after an optional purifying and drying, is dissolved in acetone, 2.5-4.0 equivalents of lithium bromide (calculated on the starting material) is added to the stirred solution, the precipitated product of formula (II) is separated, in given case purified and dried, or f.) to a stirred solution of the diacetate derivatives of formula (V) or formula (VI) in acetone, acetonitrile, ethyl acetate or tetrahydrofuran 1.0-1.1 equivalents (calculated on nitrogen atoms to be quaternized) of methyl trifluoromethanesulfonate is added at 10-35 °C, the reaction mixture containing the quaternary ammonium salts of formula (III) or (IV) - wherein the meaning of X- is trifluoromethanesulfonate ion - is reacted with 2.5-4.0 equivalents of lithium bromide (calculated on the quaternary ammonium salts of formula (HI) or (IV), wherein the meaning of X- is trifluoromethanesulfonate ion), and the precipitated products of formula (I) or (II) are separated, and after an optional purifying dried, or g.) to a stirred solution of the diacetate derivative of formula (V) in ethanol, 2.5-4.0 molequivalents of methyl p-toluenesulfonate is added below 30 °C, after the reaction is completed 2.5-5.0 equivalents of lithium bromide (calculated on the starting material) is added to the stirred solution, after the reaction is completed the reaction mixture is diluted with tetrahydrofuran, the precipitated quaternary ammonio derivative of formula (I) is separated, washed with tetrahydrofuran, after drying solved in ethanol, stirred with 0.2-0.5 equivalents of lithium bromide, diluted with tetrahydrofuran, and separated, washed and dried the precipitated compound of formula (I). The first, quaternizing step of the above processes can preferably carried out at room temperature. In method a) preferably about 3.0 equivalents of methyl p-toluenesulfonate, methyl benzenesulfonate, methyl p-nitro or p-bromo-benzenesulfonate, or methyl methane or ethanesulfonate is used. In method d.), e.) and f.) it is not practical to use more than 10 % excess of methyl trifluoro-methanesulfonate. The quaternary ammonium salts of formula (III) or (IV) - wherein the meaning of X- is benzenesulfonate, in given case para-substituted with a methyl or a nitro group or a bromine atom, methanesulfonate or ethanesulfonate ion are preferably reacted with 4.0 equivalent of lithium bromide in acetonitrile. The quaternary ammonium salts of formula (III) or (IV) - wherein the meaning of X- is trifluoromethanesulfonate ion - are preferably reacted with 2.5-4.0 equivalenta of lithium bromide for 0.5-3.0 h. Then the precipitated product is filtered off, washed, dried and in given case purified. The synthesis of compounds of formula (I) and (II) can be carried out "in one-pot" if methyl trifluoromethanesulfonate is used as reagent. In this case the diacetate derivatives of formula (V) or (VI) are dissolved in acetone, 1.0 equivalent (calculated on nitrogen atoms to be quaternized) of methyl trifluoromethanesulfonate is added to the solution and the mixture is stirred at 15-20 °C until completion of we reaction, preferably for 30 min. After completion of the reaction 2.5-4.0 molequivalents of lithium bromide is added to the reaction mixture and stirring is continued for about 1 h. The precipitated products of formula (I) or (II) are filtered off, then the pipecuroniurn bromide of formula (I) is purified by refluxing in acetone, while the vecuronium bromide of formula (II) by stirring with ether. Another possibility for carrying out the synthesis "in one pot" is given in process g.). The invention is illustrated by the following not limiting examples. Example 1 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,6β-diyl]-bis(1,1-dimethyl-piperazinium) di- (p-toluenesalfonate) To a stirred solution of 20 g (0.035 mol) of 2B,16B-bis(4-methyl-1-piperazinyl)-5α- androstane-3α,17B-diol-diacetate in 500 ml of acetone 19.5 g (0.104 mol) of methyl p- toluenesulfonate was gradually added at such a rate to keep the temperature below 30 °C. The reaction mixture was stirred for 20 h, the precipitated product was filtered off, washed with 2x50 ml of acetone, suspended in 400 ml of acetone and refluxed for 20 min. Then the solid product was filtered off, washed with 2x50 ml of acetone and dried in vacuum to yield 32.0 g of the crude product (melting point: 160-170 °C, decomposition). The crude product was recrystallized from 65 ml of acetonitrile to yield 23.04 g (69.81 %) of the title compound, Melting point: 175-177 °C (decomposition). 1H NMR (500 MHz, DMSO-d6(TMS), δ(ppm)}: 0.74 (3H,s,H-18); 0.98 (3H,s,H-19); 2.03 (3H,s,3-O-CO-CH3); 2.07 (3H,s,17-O-CO-CH3); 2.29 (6H,s, l'-CH3{Tosyl}); 2.45 (1H,m,H-2); 2.78 (8H,m,N-CH2); 3.08 & 3.09 (12H,s & s,N(+)-CH3); 3.17 (1H,m,H-16); 3.27-3.43 (8H,m, N(+)-CH2); 4.72 (1H,d,H-17); 5.14 (1H,m,H-3); 7.11 (4H,m,H-2'&H-6'{Tosyl}); 7.48 (4H,m,H-3' &H-5'{Tosyl}) - Example 2 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyn-bis(1,l-dimethyl-piperazinium) di- methanesulfonate To a stirred solution of 15 g (0.026 mol) of 2β,16β-bis(4-methyl-1-piperazinyl)-5α- androstane-3α,17β-diol-diacetate in 300 ml of acetone 9.0 g (0.08 mol) of methyl methanesulfonate was added at room temperature. The reaction mixture was stirred for 24 h, the precipitated product was filtered off, washed with 2x50 ml of acetone and dried in vacuum to yield 19.83 g of the crude product product. The crude product was dissolved in 100 ml of acetonitrile and 100 ml of acetone was added to the stirred solution. The solid product was filtered off, washed with 2x25 ml of a 1:1 rnixture of acetone and acetonitrile and dried in vacuum to yield 17.3 g (83.3 %) of the title compound. Melting point: 270-272 °C (decomposition).. 1H NMR {500 MHz, DMSO-d6(TMS), δ(ppm)}: 0.75 (3H,s,H-18); 0.99 (3H,s,H-19); 2.03 (3H,s,3-O-CO-CH3); 2.08 (3H,s,17-O-CO-CH3); 2.31 (6H,s,CH3-SO2O(-)); 2.46 (1H,m,H-2); 2.80 (8H,m,N-CH2); 3.10 & 3.11 (12H,s & s,N(+)- CH3); 3.18 (1H,m, H-16); 3.27-3.44 (8H,m, N(+)-CH2); 4.73 (1H,d,H-17); 5.15 (1H,m,H-3) Example 3 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperaziaium) di- trifluoromethanesolfonate To a stirred solution of 10 g (0.0175 mol) of 2β,16β-bis(4-methyl-1-piperazinyl)-5α- androstane-3α,17β-diol-diacetate in 200 ml of acetone 5.73 g (0.035 mol) of methyl trifluoromethanesulfonate was gradually added at such a rate to keep the temperature between 15-20 °C. The reaction mixture was stirred at this temperature for 25 min, then poured into 1000 ml of stirred diethyl ether, the precipitated product was filtered off, washed with 2x50 ml of a 1:5 mixture of acetone and diethyl ether and dried in vacuum below 40 °C to yield 15.0 g (96.7 %) of the title compound. Melting point: 160-165 °C (decomposition). 1H NMR{500 MHz, DMSO-d6(TMS), δ(ppm)}: 0.75 (3H,s,H-13); 0.99 (3H,s,H-19); 2.03 (3H,s,3-O-CO-CH3); 2.08 (3H,s,17-O-CO-CH3); 2.46 (1H,m,H-2); 2.80 (8H,m,N-CH2); 3.08 & 3.09 (12H,s & s,N(+)-CH3); 3.18 (1H,m,H-16); 3.25-3.42 (8H,m, N(+)-CH2); 4.73 (1H,d,H-17); 5.15 (1H,m,H-3) 19F NMR {471 MHz, DMSO-d6(CCl3F), δ(ppm)}; -77.4 1J19F-13c=322.3 Hz Example 4 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di- trifluoromethanesulfonate To a stirred solution of 10 g (0.0175 mol) of 2β,16β-bis(4-methyl-1-piperazinyl)-5α- androstane-3α,17β-diol-diacetate in 100 ml of acetone 5.7 g (0.034 mol) of methyl trifluoromethanesulfonate was gradually added at such a rate to keep the temperature between 15-20 °C. The reaction mixture was stirred at this temperature for 30 min, then 200 ml of tetrahydrofuran was added and the mixture was stirred for 1 h, The precipitated product was filtered off, washed with 2x20 ml of tetrahydrofuran and dried in vacuum below 40 °C to yield 14.25 g (90.76 %) of the title compound. Melting point: 168-170 °C (decomposition). Example 5 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di- trifluoromethanesulfonate To a stirred solution of 10 g (0.0175 mol) of 2β,16β-bis(4-methyl-1-piperazinyl)-5α- androstane-3α,17β-diol-diacetate in 200 ml of acetone 6 g (0.0365 mol) of methyl trifluoromethanesulfonate was added in 10 min at 20-25 °C. The reaction mixture was stirred at this temperature for 25 min, then 100 ml of hexane was added and the inixture was stirred for 1 h. The precipitated product was filtered off, washed with 2x25 ml of hexane and dried in vacuum below 40 °C to yield 15.8 g (98.75 %) of the title compound. Melting point: 167-170 °C (decomposition). Example 6 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di- trifluoromethatnesulfonate To a stirred solution of 10 g (0.0175 mol) of 2(3,16(3-bis(4-methyl-1-piperazinyl)-5α- androstane-3α,17β-diol-diacetate in 200 ml of acetone 6 g (0.0365 mol) of methyl trifluoromethanesulfonate was added in 10 min at 18-21 °C. The reaction mixture was stirred at this temperature for 30 min, then 100 ml of n-heptane was added and the mixture was stirred for 2 h. The precipitated product was filtered off, washed with 2x20 ml of n-heptane and dried in vacuum below 40 °C to yield 15.8 g (98.75 %) of the title compound. Melting point: 167-170 °C (decomposition). Example 7 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethy-piperazinium) di- benzenesulfonate To a stirred solution of 2.5 g (0.0043 mol) of 2β,16β-bis(4-methyl-1-piperazinyl)-5α- androstane-3α,17β-diol-diacetate in 50 ml of acetone 2.275 g (0.013 mol) of methyl benzenesulfonate was added and the reaction mixture was stirred at room temperature for 24 h. The precipitated product was filtered off, washed with 2x25 ml of acetone and dried in vacuum. The so obtained 3.1 g of crude product was suspended in 50 ml of acetone and refluxed for 20 min. Then the solid product was filtered off, washed with 2x10 ml of acetone and dried in vacuum to yield. 2.57 g (64.25 %) of the title compound. Melting point: 172-175 °C (decomposition). 1H NMR (500 MHz, DMSO-d6(TMS), δ(ppm)}: 0.74 (3H,s,H-18); 0.98 (3H,s,H-19); 2.03 (3H,s,3-O-CO-CH3); 2.07 (3H,s,17-OCO-CH3); 2.45 (1H,m,H-2); 2.79 (8H,m,N-CH2); 3.09 (12H,s,N(+)-CH3); 3.18 (1H,m,H-16); 3.25-3.42 (8H,m, N(+)-CH2); 4.73 (1H,d,H-17); 5.14 (lHtm,H-3); 7.61 (4H,m,H-2' & H-6'{Ph-SO2O(- )}); 7.30 (2H,m,H-4'{Ph-SO2O(-)}); 7.31 (4H,m,H-3' & H-5' [PH-SO2O(-)}) Example 8 1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium trifluoromethanesulfonate To a stirred solution of 5 g (0.0092 mol) of 2β,16β-bis(l-piperidinyl)-5α-androstane- 3α,17β-diol-diacetate in 75 ml of diethyl ether 1.52 g (0.0092 mol) of methyl trifluoromethanesulfonate was added at 15-20 °C. The reaction mixture was stirred at this temperature for 20 min, then the precipitated product was filtered off, washed with 2x20 ml of diethyl ether and dried. The so obtained 6.5 g crude product was purified by stirring in 50 nil of diethyl ether in order to remove traces of the starting material to yield 6.0 g (92 %) of the title compound. Melting point: 217-219 °C (decomposition). 1H NMR (500 MHz, DMSO-d6(TMS), δ(ppm)): 0.76 (3H,s,H-18); 0.98 (3H,s,H-19); 2.00 (3H,s,3-O-CO-CH3); 2.18 (3H,s,17-O-CO-CH3); 2.26 (1H,m,H-2); 2.41 (4H,m,N-CH2); 3.12 (3H,s,N(+)-CH3); 3.26-3.49 (4H,m,. N(+)-CH2); 4.22 (1H,m,H-16); 5.14 (1H,d,H-17); 5.17 (1H,m,H-3) 19F NMR {471 MHz, DMSO-d6(CCl3F), δ(ppm)}: -77.4 1J19F-13C=322.4 Hz Example 9 1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium p-toluenesulfonate To a stirred solution of 6 g (0.011 mol) of 2β,16β-bis(l-piperidinyl)-5α-androstane- 3αβ,17β-diol-diacetate in 150 ml of acetone 9 g (0.048 mol) of met hyl p-toluenesulfonate was added at room temperature. The reaction mixture was stirred for 72 h, the precipitated product was filtered off, washed with 2x20 ml of acetone and dried. The so obtained 5 g crude product was suspended in 50 ml of acetone and refluxed for 20 min. Then the solid product was filtered off, washed with 2x15 ml of acetone and dried in vacuum to yield 4.5 g (55.9 %) of the title compound. Melting point: 240-245 °C (decomposition). 1H NMR {500 MHz. DMSO-d6(TMS), δ(ppm)}: 0.74 (3H,s,H-18); 0.98 (3H,S,H-19); 2.01 (3H,s,3-O-CO-CH3); 2.17 (3H,s,17-O-CO-CH3); 2.25 (1H,m,H-2); 2.29 (3H,s, 1'-CH3{Tosyl}); 2.41 (4H,m,N-CH2); 3.11 (3H,s,N(+)-CH3); 3.24-3.47 (4H,m, N(+)-CH2); 4.24 (1H,m,H-16); 5.12 (1H,d,H-17); 5.17 (1H,m,H-3); 7.11 (4H,m,H-2'&H-6'{Tosyl}); 7.49 (4H,m,H-3' & H-5'{Tosyl}) Example 10 1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium methanesulfonate The title compound was obtained according to the method described in Example 9 using 2β,16β-bis(l-piperidinyl)-5α-androstane-3α,17β-diol-diacetate and methyl methanesulfonate as starting materials. Yield 20 %. Melting point: 260-263 °C (decomposition). 1H NMR {500 MHz, DMSO-d6(TMS), δ(ppm)}: 0.76 (3H,s,H-18); 0.98 (3H,s,H-19); 2.01 (3H,s,3-O-CO-CH3); 2.18 (3H,s,17-O-CO-CH3); 2.25 (1H,m,H-2); 2.30 (3H,s,CH3-SO2O(-)); 2.41 (4H,m,N-CH2); 3.12 (3H,s,N(+)-CH3); 3.30- 3.49 (4H,m, N(+)-CH2); 4.26 (1H,m,H-16); 5.14 (1H,d,H-17); 5.17 (1H,m,H-3) Example 11 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) dibromide To a stirred solution of 5 g (0.0052 mol) of 4,4'-[3α,17β-bis(acetoxy)-5α-androstane- 2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di-(p-toluenesulfonate) in 80 ml of acetonitrile 1.85 g (0.021 mol) of lithium bromide was added at room temperature. The precipitation of lithium p-toluenesulfonate formed as a by-product started immediately. After stirring for 1 h the precipitated by-product was filtered off and washed with 3x20 ml of acetonitrile. The combined filtrates were concentrated to a volume of 50 ml in vacuum below 40 °C and this residue was added to 300 ml of stirred acetone. The so obtained mixture was stirred for 30 min, the precipitated product was filtered off, suspended in 50 ml of acetone and refluxed for 20 min. The product was filtered off, washed with 2x15 ml of acetone and dried in vacuum, to yield 3.3 g (81.3 %) of the title compound. Melting point: 275-278 °C (decomposition). 1H NMR {500 MHz, DMSO-d6(TMS), δ(ppm)}: 0.75 (3H,s,H-18); 0.99 (3H,s,H-19); 2.04 (3H,s,3-O-CO-CH3); 2.09 (3H,s,17-O-CO-CH3); 2.47 (1H,m,H-2); 2.81 (8H,m,N-CH2); 3.138 & 3.141 (12H,s & s,N(+)-CH3); 3.19 (1H,m,H- 16); 3.27-3.46 (8H,m, N(+)-CH2); 4.73 (1H,d,H-17); 5.15 (1H,m,H-3) Example 12 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) dibromide To a stirred solution of 2.5 g (0.0052 mol) of 4,4'-[3α,17β-bis(acetoxy)-5α- anarostane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di-methanesulfonate in 50 ml of acetonitrile 1.1 g (0.012 mol) of lithium bromide was added at room temperature. The precipitation of lithium methanesulfonate formed as a by-product started immediately. After stirring for 2 h the precipitated lithium salt was filtered off and washed with 2x30 ml of acetonitrile. The combined filtrates were added to 150 ml of stirred acetone, the so obtained mixture was stirred, for 30 min, the precipitated product was filtered off, washed with 2x10 ml of acetonitrile and dried in vacuum to yield 2.2 g (91.6 %) of the title compound. Melting point: 270-272 °C (decomposition). Example 13 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyn-bis(1,1-dimethyl-piperazinium) dibromide To a stirred solution of 5 g (0.0054 mol) of 4,4'-[3α,17β-bis(acetoxy)-5α-androstane- 2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di-(trifluormethane-sulfonate) in 200 ml of acetone 1.889 g (0.021 mol) of lithium bromide was added at room temperature. After stirring for 30 min the precipitated product was filtered off, washed with 2x30 ml of acetone, suspended in 40 ml of acetone and refluxed for 20 min. Then the product was filtered off, washed with 2x20 ml of acetone and dried in vacuum to yield 3.76 g (88 %) of the title compound. Melting point: 270-272 °C (decomposition). Example 14 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) dibromide To a stirred solution of 2 g (0.002 mol) of 4,4'-[3α,17β-bis(acetoxy)-5α-androstane- 2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di-benzenesulfonate in 32 ml of acetonitrile 0.76 g (0.008 mol) of lithium bromide was added at room temperature. After stirring for 2 h the precipitated lithium benzenesulfonate formed as a by-product was filtered off and washed with 2x10 ml of acetonitrile. The combined filtrates were concentrated to a volume of 15 ml ' in vacuum below 40 °C and this residue was added to 150 ml of stirred acetone. The so obtained mixture was stirred for 1 h, the precipitated product was filtered off, washed with . 2x20 ml of acetone, suspended in 30 ml of acetone and refluxed for 20 min. Then the product was filtered off, washed with acetone and dried in vacuum to yield 1.35 g (81.3 %) of the title compound. Melting point: 275-278 °C (decomposition). Example 15 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(14-dimethyl-piperazinium) dibromide To a stirred solution of 2 g (0.0034 mol) of 2B,16B-bis(4-methyl-1-piperazinyl)-5α- androstane-3α,17β-diol-diacetate in 60 ml of acetone 1.13 g (0.0068 mol) of methyl trifluoromemanesulfonate was gradually added at such a rate to keep the temperature below 20 °C. The reaction mixture was stirred for 30 min, then 1.13 g (0.012 mol) of lithium bromide was added and stirring was continued for 1 h. The precipitated product was filtered off, washed with 2x20 ml of acetone, suspended in 25 ml of acetone and refluxed for 20 min. Then the solid product was filtered off, washed with 2x20 ml of acetone and dried in vacuum to yield 2.5 g (93.9 %) of the title compound. Melting point: 269-272 °C (decomposition). Example 16 1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium bromide To a stirred solution of 2 g (0.0028 mol) of 1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)- 5α-androstane-16β-yl]-1-methyl-piperidinium trifluormethane-sulfonate in 20 ml of acetone 0.98 g (0.0112 mol) of lithium bromide was added. After stirring for 30 min the reaction . mixture was diluted with 20 ml of diethyl ether, the precipitated product was filtered off, washed with a. 1:1 mixture of acetone and diethyl ether (2x20 ml) and dried in vacuum to yield 1.6 g (88.9 %) of the title compound. Melting point: 230-239 °C (decomposition). 1H NMR (500 MHz, DMSO-d6(TMS), δ(ppm)}: 0.76 (3H,s,H-18); 0.98 (3H,s,H-19); 2.01 (3H,s,3-O-CO-CH3); 2.19 (3H,s,17-O-CO-CH3); 2.25 (1H,m,H-2); 2.41 (4H,m,N-CH2); 3.14 (3H,s,N(+)-CH3); 3.26-3.50 (4H,m, N(+)-CH2); 4.35 (1H,m,H-16); 5.14 (1H,d,H-17); 5.16 (1H,m,H-3) Example 17 1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium bromide To a stirred solution of 2 g (0.0027 rnol) of l-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)- 5α-androstane-16β-yl]-1-methyl-piperidinium p-toluenesulfonate in 32 ml of acetonitrile 0.95 g (0.01 mol) of lithium bromide was added. After stirring for 1 h the precipitated lithium p- tolenesulfonate formed as a by-product was filtered off and washed with. 2x20 ml of acetonitrile. The combined filtrates were evaporated below 40 °C and 60 ml of diethyl ether was added to the residue. The precipitated product was filtered off, washed with a 1:2 mixture of acetonitrile and diethyl ether and dried in vacuum to yield 1.53 g (87.47 %) of the title compound. Melting point: 228-230 °C (decomposition). Example 18 4,4,-[3α,17β-bis-(acetyloxy)-5α-androstane-26,16[3-diyll-bis(1,1-dimethylpiperazinium) di-(p-toluenesnlfonate) To a stirred solution of 20 g (0.035 mol) of 3α,17β-bis(acetyloxy)-2β,16β-bis(4- methyl-1-piper,azinyl)-5α-androstane in 100 ml ethanol, 19.5 g (0.104 mol) of methyl-(p- toluenesulfonate) was gradually added at such a rate to keep the temperature below 30 °C. The reaction mixture was stirred for 3 hrs., then was diluted with 500 ml tetrahydrofurane and 3 hrs. strirring the solid material was filtered off, washed with 2x50 ml tetrahydrofurane, dried in vacuum to yield 31 g of crude product which was recrystallized in acetonitrile to yield 26 g (78.7 %) of the title compound. Melting point: 175-177 °C. Example 19 4,4'-[3α,17β-bis-(acetyloxy)-5α-androstane-2β,16β-diyl]bis(1,1-dimethylpiperazinium) dibromide To a stirred solution of 10 g (0.0104 mol) of 4,4'-[3α,17β-bis-(acetyloxy)-5α- androstane-2β,16β-diyl]-bis(1,1-dimethylpiperazirrium) di-(p-toluenesulfonate) in 50 ml of ethanol, 3.7 g of lithium bromide was added at room temperature. The reaction mixture was stirred for 4 hrs., then diluted with 200 ml of tetrahydrofurane and after 3 hrs. the precipitated . product was filtered off washed twice with 20 ml of tetrahydrofurane, dried in vacuum. The 7.2 g of crude product was dissolved in 36 ml of ethanol, 0.36 g lithium bromide was added and the solution stirred for 2 hrs., then diluted with 150 ml of tetrahydrofurane. The product was filtered off, washed twice with 20 ml of tetrahydrofurane and dried in vacuum. The obtained title compound was suspended in 60 ml of acetone and refluxed for 20 rhin. The product was filtered off and dried in vacuum. Yield: 6.7 g (83 %), melting point: 265-269 °C (decomp.). Example 20 4,4'-[3α,17β-bis-(acetyloxy)-5α-androstane-2β,16β-diyl-bis(1,1-dimethylpiperazinium) dibromide To a stirred solution of 20 g (0.035 mol) of 3α,17β-bis(acetyloxy)-2β,16β-bis(4- methyl-1-piperazinyl)-5α-androstane in 100 ml ethanol, 19,5 g (0.104 mol) of methyl-(p- toluenesulfonate) was gradually added at such a rate to keep me temperature below 30°C. The reaction mixture was stirred for 3 hrs., 10.96 g (0.116 mol) of lithium bromide was added at room temperature and stirred for 2 hrs, then diluted with 600 ml of tetrahydrofurane and stirred another 4 hrs. The precipitated product was filtered off, washed twice with 40 ml of tetrahydrofurane, dried in vacuum to yield 30 g of the product, which was solved in 80 ml of ethanol, 1.3 g lithium bromide was added stirred for 1 far., then diluted with 250 ml of tetrahydrofurane and the precipitated product was fdtered off, washed with 2x40 ml of tetrahydrofurane, dried in vacuum. The crude product was suspended in 130 ml of acetone and refluxed for 20 min, the solid product was filtered off, washed with 2x50 ml of acetone and dried in vacuum. Yield: 27.5 g (83 %), melting point: 265-269 °C (decomp.): WE CLAIM : 1. The quaternary ammonio derivatives of formula (III) wherein the meaning of X- is a benzenesulfonate - in given case para-substituted with a methyl or a nitro group or a bromine atom - or a methanesulfonate, an ethanesulfonate or a trifluoromethanesulfonate ion. 2. The compounds of formula (III) as claimed in claim 1 consist of: 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di-(p- toluenesulfonate), 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di- methanesulfonate, 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di- benzenesulfonate, 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di- trifluoromethanesulfonate. 3. The quaternary ammonio derivatives of formula (IV) wherein the meaning of X- is a benzenesulfonate - in given case para-substituted with a methyl or a nitro group or a bromine atom — or a methanesulfonate, an ethanesulfonate or a trifluoromethanesulfonate ion. 4. The compounds of formula (IV) as claimed in claim 3 consist of: 1-[3α,17β-bis(acetoxy)-2(3-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium trifiuoromethanesulfonate, 1-[3α, 17β-bis(acetoxy)-2β-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium p- toluenesulfonate, 1-[3α, 17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium methanesulfonate. 5. An environment-friend process for the synthesis of 4,4'-[3α,17β-bis(acetoxy)-5α- androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) dibromide of formula (I) and 1-[3α, 17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium bromide of formula (II) characterized by a.) adding 2.5-4.0 molequivalents of methyl p-toluenesulfonate, methyl benzenesulfonate, methyl p-nitro or p-bromo-benzenesulfonate, or methyl methane or ethanesulfonate to the stirred solutions of the diacetate derivatives of formula (V) or (VI) in acetone, acetonitrile, ethyl acetate or tetrahydrofuran, separating the precipitated quaternary ammonio derivatives of formula (III) or (IV) - wherein the meaning of X- is a benzenesulfonate, in given case para-substituted with a methyl or a nitro group or a bromine atom, or a methanesulfonate or an ethanesulfonate ion-, and after an optional purifying and drying, dissolving the above obtained quaternary ammonio derivatives of formula (III) or (IV) in acetonitrile, adding 2.5-5.0 equivalents of lithium bromide (calculated on the starting material) to the stirred solution, separating and washing the precipitated lithium salts formed as by-products with acetonitrile, combining and concentrating the filtrates and separating and drying after an optionally purifying the precipitated products of formula (I) or (II), or b.) adding 2.5-4.0 molequivalents of methyl p-toluenesulfonate to a stirred solution of the diacetate derivative of formula (V) in ethanol, below 30 °C, diluting the reaction mixture after the reaction is completed with tetrahydrofurane, separating the precipitated quaternary ammonio derivative of formula (III) - wherein the meaning of X- is p-toluenesulfonate -, adding 2.5-5.0 equivalents of lithium bromide (calculated on the starting material) to the stirred solution in acetonitrile of the separated quaternary ammonio derivative of formula (III) - wherein the meaning of X- is p-toluenesulfonate - , separating and washing with acetonitrile the precipitated lithium salts formed as by-products, concentrating the combined mother liquor and washing liquids, and separating and drying after an optionally purifying the precipitated product of formula (I), or c.) adding 2.5-4.0 molequivalents of methyl p-toluenesulfonate to a stirred solution of the diacetate derivative of formula (V) in ethanol, below 30 °C, diluting the reaction mixture after the reaction is completed with tetrahydrofurane, separating the precipitated quaternary ammonio derivative of formula (III) - wherein the meaning of X- is p-toluenesulfonate -, adding 2.5-5.0 equivalents of lithium bromide (calculated on the starting material) to the stirred solution in ethanol of the separated quaternary ammonio derivative of formula (III) - wherein the meaning of X- is p-toluenesulfonate - , after the reaction completed diluting the reaction mixture with tetrahydrofuran, separating and washing with tetrahydrofuran the precipitated product of formula (I), dissolving them in ethanol, giving 0.2-0.5 equivalents of lithium bromide to the solution, diluting with tetrahydrofuran, and separating and drying after an optionally purifying the precipitated product of formula (I), or d.) adding 1.0-1.1 equivalents (calculated on nitrogen atoms to be quaternized) of methyl trifluoromethanesulfonate to a stirred solution of the diacetate derivative of formula (V) in acetone, acetonitrile, ethyl acetate or tetrahydrofuran at 10-35 °C, diluting the reaction mixture with ether, tetrahydrofuran, n-hexane or n-heptane and separating the precipitated formed quaternary ammonio derivative of formula (III) - wherein the meaning of X- is trifluoromethanesulfonate ion - after an optional purifying and drying, dissolving the obtained quaternary ammonio derivative of formula (III) - wherein the meaning of X- is trifluoromethanesulfonate ion - in acetone, adding 2.5-4.0 equivalents of lithium bromide (calculated on the starting material) to the stirred solution, and drying after an optionally purifying the precipitated product of formula (I), or e.) adding 1.0-1.1 equivalents (calculated on nitrogen atoms to be quaternized) of methyl trifluoromethanesulfonate to a stirred solution of the diacetate derivative of formula (VI) in acetone, ether or tetrahydrofuran at 10-35 °C, separating the precipitated (when the reaction is carried out in acetone after diluting of the reaction mixture with ether) quaternary ammonio derivative of formula (IV) - wherein the meaning of X- is trifluoromethanesulfonate ion -, and after an optional purifying and drying dissolving the quaternary ammonio derivative of formula (IV) - wherein the meaning of X- is trifluoromethanesulfonate ion - in acetone, adding 2.5-4.0 equivalents of lithium bromide (calculated on the starting material) to the stirred solution drying after an optionally purifying the precipitated product of formula (II), or f.) adding 1.0-1.1 equivalents (calculated on nitrogen atoms to be quaternized) of methyl trifluoromethanesulfonate to a stirred solution of the diacetate derivatives of formula (V) or formula (VI) in acetone, acetonitrile, ethyl acetate or tetrahydrofuran at 10-35 °C, reacting the reaction mixture containing the quaternary ammonium salts of formula (III) or (IV) - wherein the meaning of X- is trifluoromethanesulfonate ion - with 2.5-4.0 equivalents of lithium bromide (calculated on the quaternary ammonium salts of formula (III) or (IV), wherein the meaning of X- is trifluoromethanesulfonate ion), and after an optional purifying drying the separated precipitated products of formula (I) or (II), or g.) adding 2.5-4.0 molequivalents of methyl p-toluenesulfonate to a stirred solution of the diacetate derivative of formula (V) in ethanol below 30 °C, subsequently, after the reaction is completed, adding 2.5-5.0 equivalents of lithium bromide (calculated on the starting material) to the stirred solution, then after the reaction is completed, diluting the reaction mixture with tetrahydrofuran, after the precipitation is completed, separating the precipitated quaternary ammonio derivative of formula (I), washing with tetrahydrofuran, after drying disolving in ethanol, stirring the solution with 0.2-0.5 equivalents of lithium bromide, diluting with tetrahydrofuran, and separating, washing and drying the precipitated compound of formula (I). 6. Process d) for the synthesis of 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β- diyl]-bis(1,1-dimethyl-piperazinium) dibromide of formula (I) as claimed in claim 5, wherein by reacting the reaction mixture containing the quaternary ammonium salt of formula (III) - wherein the meaning of X- is trifluoromethanesulfonate ion - with lithium bromide without isolating the quaternary ammonium salt of formula (III). 7. Process e) for the synthesis of 1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α- androstane-16β-yl]-1-methyl-piperidinium bromide of formula (II) as claimed in claim 5, wherein by reacting the reaction mixture containing the quaternary ammonium salt of formula (IV) - wherein the meaning of X- is trifluoromethanesulfonate ion - with lithium bromide without isolating the quaternary ammonium salt of formula (IV). The invention relates to a new, environment-friend process for the synthesis of the known 4,4'-[3α,17β-bis(acetoxy)-5α-androstane- 2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) dibromide of formula (I) (from now on pipecuronium bromide) and 1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane -16β-yl]-1-methyl-piperidinium bromide of formula (II) (from now on vecuronium bromide). Furthermore the invention relates to the new intermediates of formula (III) and formula (IV) of the process, wherein the meaning of X is benzenesulfonate - in given case para-substituted with a methyl or a nitro group or a bromine atom - methanesulfonate, ethanesulfonate or trifluoromethanesulfonate ion.

Full Text

The invention relates to a new, environment-friend process for the synthesis of 4,4'-
[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) dibromide
of formula (I) (from now on pipecuronium bromide)

and 1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium
bromide of formula (II) (from now on vecuronium bromide).

Furthermore the invention relates to the new intermediates of formula (III)

and formula (IV)

of the process, wherein the meaning of X- is benzenesulfonate - in given case para-
substituted with a methyl or a nitro group or a bromine atom - methanesulfonate,
ethanesulfonate or trifluoromethanesulfonate ion.
Pipecuronium bromide and vecuronium bromide are known to be curare like, non-
depolarizing neuromuscular blocking agents, which inhibit the transmission of the nerve-
impulses to the striped muscles. Their effect can be terminated by addition of antidotes. Both
compounds have wide clinical application due to their excellent biological effect. Their main
application is in the surgery as muscle-relaxants during intubation narcosis. Other applications
can be in the shock therapy and in the spasmic disorders of striped muscles.
The synthesis of pipecuronium bromide is described in the Hungarian patent No.
165,000, according to which it is a multistep chemical synthesis starting from
2α,3α,16α,17α-diepoxy-17-acetoxy-5α-androstane. An improved synthesis is described in
the following publication: Arzneimittel Forschung (Drug Res.) 30(I), 29, 342-346.
The synthesis of vecuronim bromide is described in the GB patent No. 1,454,749 and
in the Hungarian patent No. 154,368. A detailed summary can also be found in the following
publication: J.Med.Chem. 16, 1116(1973).
The final step of the known synthesis of pipecuronium bromide and vecuronium
bromide is the quaternary ammonium salts formation with methyl bromide in acetone or
diethyl ether solution from the diacetate derivatives of formula (V)

and formula (VI)

respectively.
It is known that methyl bromide — used as quaternary ammonium salts forming agent
in the above procedures - is a highly toxic, colorless, slightly smelling gas at room
temperature, moreover it is an ozone layer damaging compound. Considering its latter feature
its industrial use is strictly limited by the Hungarian decree No. 94/2003 (2.07.) referring to
ozone layer damaging compounds, therefor it is practical to use an other quaternary
ammonium salts forming agent, which is less or not at all toxic.
Our invention relates to a new process for the synthesis of quaternary ammonium salts
of diacetate derivatives of formula (V) and (VI) without using methyl bromide as reagent.
Surprisingly it was found that the "sulfonate" ions of the "sulfonate salt" type intermediates of
formula (HI) and (IV) of our invention can be changed for bromide ions - in spite of the fact
that generally it is an equilibrium reaction - using lithium bromide as reagent and choosing
the appropriate: reaction conditions the equilibrium can be shifted towards the. formation of

pipecuronium bromide or vecuronium bromide in 99 % selectivity, therefor the methyl
bromide reagent can be replaced by „sulfonyl methyl esters".
According to our invention the process is the following:
a.) to stirred solutions of the diacetate derivatives of formula (V) or (VI) in acetone,
acetonitrile, ethyl acetate or tetrahydrofuran 2.5-4.0 molequivalents of methyl p-
toluenesulfonate, methyl benzenesulfonate, methyl p-nitro or p-bromo-benzenesulfonate, or
methyl methane or ethanesulfonate is added, the precipitated quaternary ammonio derivatives
of formula (III) or (IV) - wherein the meaning of X" is benzenesulfonate, in given case para-
substituted with a methyl or a nitro group or a bromine atom, or methanesulfonate or
ethanesulfonate ion - are separated,
and after an optional purifying and drying, are dissolved in acetonitrile, 2.5-5.0
equivalents of lithium bromide (calculated on the starting material), is added to the stirred
solution, the precipitated lithium salts formed as by-products are filtered off, washed with
acetonitrile, the combined filtrates are concentrated, the precipitated products of formula (I) or
(II) are separated, in given case purified and dried, or
b.) to a stirred solution of the diacetate derivative of formula (V) in ethanol, 2.5-4.0
molequivalents of methyl p-toluenesulfonate is added below 30 °C, after the reaction is
completed the reaction mixture is diluted with tetrahydrofurane, the precipitated quaternary
ammonio derivative of formula (III) - wherein the meaning of X- is p-toluenesulfonate - are
separated,
and alter an optional purifying and drying, is dissolved in acetonitrile, 2.5-5.0
equivalents of lithium bromide (calculated on the starting material) is added to the stirred
solution, the precipitated lithium salts formed as by-products are separated, washed with
acetonitrile, the combined filtrates are concentrated, the precipitated product of formula (I) is
separated, in given case purified and dried, or
c.) to a stirred solution of the diacetate derivative of formula (V) in ethanol, 2.5-4.0
molequivalents; of methyl p-toluenesulfonate is added below 30 °C, after the reaction is
completed the reaction mixture is diluted with tetrahydrofurane, the precipitated quaternary
ammonio derivative of formula (III) - wherein the meaning of X- is p-toluenesulfonate - are
separated,

after separating and an optional purifying and drying, is dissolved in ethanol, 2.5-5.0
equivalents of lithium bromide (calculated on the starting material) is added to the stirred
solution,
after the reaction is completed the reaction mixture is diluted with tetrahydrofuran, the
precipitated quaternary ammonio derivative of formula. (I) is separated, washed with,
tetrahydrofuran, after drying solved in ethanol, stirred with 0.2-0.5 equivalents of lithium
bromide, diluted with tetrahydrofuran, and separated, washed and dried the precipitated
compound of formula (I), or
d.) to a stirred solution of the diacetate derivative of formula (V) in acetone,
acetonitrile, ethyl acetate or tetrahydrofuran 1.0-1.1 equivalents (calculated on nitrogen atoms
to be quaternized) of methyl trifluoromethanesulfonate is added at 10-35 °C,
the formed quaternary ammonio derivative of formula (III) - wherein the meaning of
X- is trifluoromethanesulfonate ion - is precipitated by dilution of the reaction mixture with
ether, tetrahydrofuran, n-hexane or n-heptane, and
after separating and an optional purifying and drying, is dissolved in acetone, 2.5-4.0
equivalents of lithium bromide (calculated on the starting material) is added to the stirred
solution, the precipitated product of formula (I) is separated, in given case purified and dried,
or
e.) to a stirred solution of the diacetate derivative of formula (VI) in acetone, ether or
tetrahydrofuran 1.0-1.1 equivalents (calculated on nitrogen atoms to be quaternized) of methyl
trifluoromethanesulfonate is added at 10-35 °C,
the precipitated (when the reaction is carried out in acetone after dilution of the
reaction mixture with ether) quaternary ammonio derivative of formula (IV) - wherein the
meaning of X- is trifluoromethanesulfonate ion- is separated, and
after an optional purifying and drying, is dissolved in acetone, 2.5-4.0 equivalents of
lithium bromide (calculated on the starting material) is added to the stirred solution, the
precipitated product of formula (II) is separated, in given case purified and dried, or
f.) to a stirred solution of the diacetate derivatives of formula (V) or formula (VI) in
acetone, acetonitrile, ethyl acetate or tetrahydrofuran 1.0-1.1 equivalents (calculated on
nitrogen atoms to be quaternized) of methyl trifluoromethanesulfonate is added at 10-35 °C,

the reaction mixture containing the quaternary ammonium salts of formula (III) or
(IV) - wherein the meaning of X- is trifluoromethanesulfonate ion - is reacted with 2.5-4.0
equivalents of lithium bromide (calculated on the quaternary ammonium salts of formula (HI)
or (IV), wherein the meaning of X- is trifluoromethanesulfonate ion), and
the precipitated products of formula (I) or (II) are separated, and after an optional
purifying dried, or
g.) to a stirred solution of the diacetate derivative of formula (V) in ethanol, 2.5-4.0
molequivalents of methyl p-toluenesulfonate is added below 30 °C,
after the reaction is completed 2.5-5.0 equivalents of lithium bromide (calculated on
the starting material) is added to the stirred solution,
after the reaction is completed the reaction mixture is diluted with tetrahydrofuran, the
precipitated quaternary ammonio derivative of formula (I) is separated, washed with
tetrahydrofuran, after drying solved in ethanol, stirred with 0.2-0.5 equivalents of lithium
bromide, diluted with tetrahydrofuran, and separated, washed and dried the precipitated
compound of formula (I).
The first, quaternizing step of the above processes can preferably carried out at room
temperature. In method a) preferably about 3.0 equivalents of methyl p-toluenesulfonate,
methyl benzenesulfonate, methyl p-nitro or p-bromo-benzenesulfonate, or methyl methane or
ethanesulfonate is used. In method d.), e.) and f.) it is not practical to use more than 10 %
excess of methyl trifluoro-methanesulfonate.
The quaternary ammonium salts of formula (III) or (IV) - wherein the meaning of X-
is benzenesulfonate, in given case para-substituted with a methyl or a nitro group or a
bromine atom, methanesulfonate or ethanesulfonate ion are preferably reacted with 4.0
equivalent of lithium bromide in acetonitrile.
The quaternary ammonium salts of formula (III) or (IV) - wherein the meaning of X-
is trifluoromethanesulfonate ion - are preferably reacted with 2.5-4.0 equivalenta of lithium
bromide for 0.5-3.0 h. Then the precipitated product is filtered off, washed, dried and in given
case purified.
The synthesis of compounds of formula (I) and (II) can be carried out "in one-pot" if
methyl trifluoromethanesulfonate is used as reagent. In this case the diacetate derivatives of
formula (V) or (VI) are dissolved in acetone, 1.0 equivalent (calculated on nitrogen atoms to

be quaternized) of methyl trifluoromethanesulfonate is added to the solution and the mixture
is stirred at 15-20 °C until completion of we reaction, preferably for 30 min. After completion
of the reaction 2.5-4.0 molequivalents of lithium bromide is added to the reaction mixture and
stirring is continued for about 1 h. The precipitated products of formula (I) or (II) are filtered
off, then the pipecuroniurn bromide of formula (I) is purified by refluxing in acetone, while
the vecuronium bromide of formula (II) by stirring with ether. Another possibility for carrying
out the synthesis "in one pot" is given in process g.).
The invention is illustrated by the following not limiting examples.

Example 1
4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,6β-diyl]-bis(1,1-dimethyl-piperazinium) di-
(p-toluenesalfonate)
To a stirred solution of 20 g (0.035 mol) of 2B,16B-bis(4-methyl-1-piperazinyl)-5α-
androstane-3α,17B-diol-diacetate in 500 ml of acetone 19.5 g (0.104 mol) of methyl p-
toluenesulfonate was gradually added at such a rate to keep the temperature below 30 °C. The
reaction mixture was stirred for 20 h, the precipitated product was filtered off, washed with
2x50 ml of acetone, suspended in 400 ml of acetone and refluxed for 20 min. Then the solid
product was filtered off, washed with 2x50 ml of acetone and dried in vacuum to yield 32.0 g
of the crude product (melting point: 160-170 °C, decomposition). The crude product was
recrystallized from 65 ml of acetonitrile to yield 23.04 g (69.81 %) of the title compound,
Melting point: 175-177 °C (decomposition).
1H NMR (500 MHz, DMSO-d6(TMS), δ(ppm)}:
0.74 (3H,s,H-18); 0.98 (3H,s,H-19); 2.03 (3H,s,3-O-CO-CH3); 2.07 (3H,s,17-O-CO-CH3);
2.29 (6H,s, l'-CH3{Tosyl}); 2.45 (1H,m,H-2); 2.78 (8H,m,N-CH2); 3.08 & 3.09 (12H,s &
s,N(+)-CH3); 3.17 (1H,m,H-16); 3.27-3.43 (8H,m, N(+)-CH2); 4.72 (1H,d,H-17); 5.14
(1H,m,H-3); 7.11 (4H,m,H-2'&H-6'{Tosyl}); 7.48 (4H,m,H-3' &H-5'{Tosyl}) -
Example 2
4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyn-bis(1,l-dimethyl-piperazinium) di-
methanesulfonate
To a stirred solution of 15 g (0.026 mol) of 2β,16β-bis(4-methyl-1-piperazinyl)-5α-
androstane-3α,17β-diol-diacetate in 300 ml of acetone 9.0 g (0.08 mol) of methyl
methanesulfonate was added at room temperature. The reaction mixture was stirred for 24 h,
the precipitated product was filtered off, washed with 2x50 ml of acetone and dried in vacuum
to yield 19.83 g of the crude product product. The crude product was dissolved in 100 ml of
acetonitrile and 100 ml of acetone was added to the stirred solution. The solid product was
filtered off, washed with 2x25 ml of a 1:1 rnixture of acetone and acetonitrile and dried in
vacuum to yield 17.3 g (83.3 %) of the title compound. Melting point: 270-272 °C
(decomposition)..
1H NMR {500 MHz, DMSO-d6(TMS), δ(ppm)}:

0.75 (3H,s,H-18); 0.99 (3H,s,H-19); 2.03 (3H,s,3-O-CO-CH3); 2.08 (3H,s,17-O-CO-CH3);
2.31 (6H,s,CH3-SO2O(-)); 2.46 (1H,m,H-2); 2.80 (8H,m,N-CH2); 3.10 & 3.11 (12H,s & s,N(+)-
CH3); 3.18 (1H,m, H-16); 3.27-3.44 (8H,m, N(+)-CH2); 4.73 (1H,d,H-17); 5.15 (1H,m,H-3)
Example 3
4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperaziaium) di-
trifluoromethanesolfonate
To a stirred solution of 10 g (0.0175 mol) of 2β,16β-bis(4-methyl-1-piperazinyl)-5α-
androstane-3α,17β-diol-diacetate in 200 ml of acetone 5.73 g (0.035 mol) of methyl
trifluoromethanesulfonate was gradually added at such a rate to keep the temperature between
15-20 °C. The reaction mixture was stirred at this temperature for 25 min, then poured into
1000 ml of stirred diethyl ether, the precipitated product was filtered off, washed with 2x50
ml of a 1:5 mixture of acetone and diethyl ether and dried in vacuum below 40 °C to yield
15.0 g (96.7 %) of the title compound. Melting point: 160-165 °C (decomposition).
1H NMR{500 MHz, DMSO-d6(TMS), δ(ppm)}:
0.75 (3H,s,H-13); 0.99 (3H,s,H-19); 2.03 (3H,s,3-O-CO-CH3); 2.08 (3H,s,17-O-CO-CH3);
2.46 (1H,m,H-2); 2.80 (8H,m,N-CH2); 3.08 & 3.09 (12H,s & s,N(+)-CH3); 3.18 (1H,m,H-16);
3.25-3.42 (8H,m, N(+)-CH2); 4.73 (1H,d,H-17); 5.15 (1H,m,H-3)
19F NMR {471 MHz, DMSO-d6(CCl3F), δ(ppm)};
-77.4 1J19F-13c=322.3 Hz
Example 4
4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di-
trifluoromethanesulfonate
To a stirred solution of 10 g (0.0175 mol) of 2β,16β-bis(4-methyl-1-piperazinyl)-5α-
androstane-3α,17β-diol-diacetate in 100 ml of acetone 5.7 g (0.034 mol) of methyl
trifluoromethanesulfonate was gradually added at such a rate to keep the temperature between
15-20 °C. The reaction mixture was stirred at this temperature for 30 min, then 200 ml of
tetrahydrofuran was added and the mixture was stirred for 1 h, The precipitated product was
filtered off, washed with 2x20 ml of tetrahydrofuran and dried in vacuum below 40 °C to
yield 14.25 g (90.76 %) of the title compound. Melting point: 168-170 °C (decomposition).

Example 5
4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di-
trifluoromethanesulfonate
To a stirred solution of 10 g (0.0175 mol) of 2β,16β-bis(4-methyl-1-piperazinyl)-5α-
androstane-3α,17β-diol-diacetate in 200 ml of acetone 6 g (0.0365 mol) of methyl
trifluoromethanesulfonate was added in 10 min at 20-25 °C. The reaction mixture was stirred
at this temperature for 25 min, then 100 ml of hexane was added and the inixture was stirred
for 1 h. The precipitated product was filtered off, washed with 2x25 ml of hexane and dried in
vacuum below 40 °C to yield 15.8 g (98.75 %) of the title compound. Melting point: 167-170
°C (decomposition).
Example 6
4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di-
trifluoromethatnesulfonate
To a stirred solution of 10 g (0.0175 mol) of 2(3,16(3-bis(4-methyl-1-piperazinyl)-5α-
androstane-3α,17β-diol-diacetate in 200 ml of acetone 6 g (0.0365 mol) of methyl
trifluoromethanesulfonate was added in 10 min at 18-21 °C. The reaction mixture was stirred
at this temperature for 30 min, then 100 ml of n-heptane was added and the mixture was
stirred for 2 h. The precipitated product was filtered off, washed with 2x20 ml of n-heptane
and dried in vacuum below 40 °C to yield 15.8 g (98.75 %) of the title compound. Melting
point: 167-170 °C (decomposition).
Example 7
4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethy-piperazinium) di-
benzenesulfonate
To a stirred solution of 2.5 g (0.0043 mol) of 2β,16β-bis(4-methyl-1-piperazinyl)-5α-
androstane-3α,17β-diol-diacetate in 50 ml of acetone 2.275 g (0.013 mol) of methyl
benzenesulfonate was added and the reaction mixture was stirred at room temperature for 24
h. The precipitated product was filtered off, washed with 2x25 ml of acetone and dried in
vacuum. The so obtained 3.1 g of crude product was suspended in 50 ml of acetone and
refluxed for 20 min. Then the solid product was filtered off, washed with 2x10 ml of acetone

and dried in vacuum to yield. 2.57 g (64.25 %) of the title compound. Melting point: 172-175
°C (decomposition).
1H NMR (500 MHz, DMSO-d6(TMS), δ(ppm)}:
0.74 (3H,s,H-18); 0.98 (3H,s,H-19); 2.03 (3H,s,3-O-CO-CH3); 2.07 (3H,s,17-OCO-CH3);
2.45 (1H,m,H-2); 2.79 (8H,m,N-CH2); 3.09 (12H,s,N(+)-CH3); 3.18 (1H,m,H-16); 3.25-3.42
(8H,m, N(+)-CH2); 4.73 (1H,d,H-17); 5.14 (lHtm,H-3); 7.61 (4H,m,H-2' & H-6'{Ph-SO2O(-
)}); 7.30 (2H,m,H-4'{Ph-SO2O(-)}); 7.31 (4H,m,H-3' & H-5' [PH-SO2O(-)})
Example 8
1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium
trifluoromethanesulfonate
To a stirred solution of 5 g (0.0092 mol) of 2β,16β-bis(l-piperidinyl)-5α-androstane-
3α,17β-diol-diacetate in 75 ml of diethyl ether 1.52 g (0.0092 mol) of methyl
trifluoromethanesulfonate was added at 15-20 °C. The reaction mixture was stirred at this
temperature for 20 min, then the precipitated product was filtered off, washed with 2x20 ml of
diethyl ether and dried. The so obtained 6.5 g crude product was purified by stirring in 50 nil
of diethyl ether in order to remove traces of the starting material to yield 6.0 g (92 %) of the
title compound. Melting point: 217-219 °C (decomposition).
1H NMR (500 MHz, DMSO-d6(TMS), δ(ppm)):
0.76 (3H,s,H-18); 0.98 (3H,s,H-19); 2.00 (3H,s,3-O-CO-CH3); 2.18 (3H,s,17-O-CO-CH3);
2.26 (1H,m,H-2); 2.41 (4H,m,N-CH2); 3.12 (3H,s,N(+)-CH3); 3.26-3.49 (4H,m,. N(+)-CH2);
4.22 (1H,m,H-16); 5.14 (1H,d,H-17); 5.17 (1H,m,H-3)
19F NMR {471 MHz, DMSO-d6(CCl3F), δ(ppm)}:
-77.4 1J19F-13C=322.4 Hz
Example 9
1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium
p-toluenesulfonate
To a stirred solution of 6 g (0.011 mol) of 2β,16β-bis(l-piperidinyl)-5α-androstane-
3αβ,17β-diol-diacetate in 150 ml of acetone 9 g (0.048 mol) of met hyl p-toluenesulfonate was
added at room temperature. The reaction mixture was stirred for 72 h, the precipitated product
was filtered off, washed with 2x20 ml of acetone and dried. The so obtained 5 g crude product

was suspended in 50 ml of acetone and refluxed for 20 min. Then the solid product was
filtered off, washed with 2x15 ml of acetone and dried in vacuum to yield 4.5 g (55.9 %) of
the title compound. Melting point: 240-245 °C (decomposition).
1H NMR {500 MHz. DMSO-d6(TMS), δ(ppm)}:
0.74 (3H,s,H-18); 0.98 (3H,S,H-19); 2.01 (3H,s,3-O-CO-CH3); 2.17 (3H,s,17-O-CO-CH3);
2.25 (1H,m,H-2); 2.29 (3H,s, 1'-CH3{Tosyl}); 2.41 (4H,m,N-CH2); 3.11 (3H,s,N(+)-CH3);
3.24-3.47 (4H,m, N(+)-CH2); 4.24 (1H,m,H-16); 5.12 (1H,d,H-17); 5.17 (1H,m,H-3); 7.11
(4H,m,H-2'&H-6'{Tosyl}); 7.49 (4H,m,H-3' & H-5'{Tosyl})
Example 10
1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium
methanesulfonate
The title compound was obtained according to the method described in Example 9
using 2β,16β-bis(l-piperidinyl)-5α-androstane-3α,17β-diol-diacetate and methyl
methanesulfonate as starting materials. Yield 20 %. Melting point: 260-263 °C
(decomposition).
1H NMR {500 MHz, DMSO-d6(TMS), δ(ppm)}:
0.76 (3H,s,H-18); 0.98 (3H,s,H-19); 2.01 (3H,s,3-O-CO-CH3); 2.18 (3H,s,17-O-CO-CH3);
2.25 (1H,m,H-2); 2.30 (3H,s,CH3-SO2O(-)); 2.41 (4H,m,N-CH2); 3.12 (3H,s,N(+)-CH3); 3.30-
3.49 (4H,m, N(+)-CH2); 4.26 (1H,m,H-16); 5.14 (1H,d,H-17); 5.17 (1H,m,H-3)
Example 11
4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium)
dibromide
To a stirred solution of 5 g (0.0052 mol) of 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-
2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di-(p-toluenesulfonate) in 80 ml of acetonitrile
1.85 g (0.021 mol) of lithium bromide was added at room temperature. The precipitation of
lithium p-toluenesulfonate formed as a by-product started immediately. After stirring for 1 h
the precipitated by-product was filtered off and washed with 3x20 ml of acetonitrile. The
combined filtrates were concentrated to a volume of 50 ml in vacuum below 40 °C and this
residue was added to 300 ml of stirred acetone. The so obtained mixture was stirred for 30
min, the precipitated product was filtered off, suspended in 50 ml of acetone and refluxed for

20 min. The product was filtered off, washed with 2x15 ml of acetone and dried in vacuum, to
yield 3.3 g (81.3 %) of the title compound. Melting point: 275-278 °C (decomposition).
1H NMR {500 MHz, DMSO-d6(TMS), δ(ppm)}:
0.75 (3H,s,H-18); 0.99 (3H,s,H-19); 2.04 (3H,s,3-O-CO-CH3); 2.09 (3H,s,17-O-CO-CH3);
2.47 (1H,m,H-2); 2.81 (8H,m,N-CH2); 3.138 & 3.141 (12H,s & s,N(+)-CH3); 3.19 (1H,m,H-
16); 3.27-3.46 (8H,m, N(+)-CH2); 4.73 (1H,d,H-17); 5.15 (1H,m,H-3)
Example 12
4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium)
dibromide
To a stirred solution of 2.5 g (0.0052 mol) of 4,4'-[3α,17β-bis(acetoxy)-5α-
anarostane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di-methanesulfonate in 50 ml of
acetonitrile 1.1 g (0.012 mol) of lithium bromide was added at room temperature. The
precipitation of lithium methanesulfonate formed as a by-product started immediately. After
stirring for 2 h the precipitated lithium salt was filtered off and washed with 2x30 ml of
acetonitrile. The combined filtrates were added to 150 ml of stirred acetone, the so obtained
mixture was stirred, for 30 min, the precipitated product was filtered off, washed with 2x10 ml
of acetonitrile and dried in vacuum to yield 2.2 g (91.6 %) of the title compound. Melting
point: 270-272 °C (decomposition).
Example 13
4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyn-bis(1,1-dimethyl-piperazinium)
dibromide
To a stirred solution of 5 g (0.0054 mol) of 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-
2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di-(trifluormethane-sulfonate) in 200 ml of
acetone 1.889 g (0.021 mol) of lithium bromide was added at room temperature. After stirring
for 30 min the precipitated product was filtered off, washed with 2x30 ml of acetone,
suspended in 40 ml of acetone and refluxed for 20 min. Then the product was filtered off,
washed with 2x20 ml of acetone and dried in vacuum to yield 3.76 g (88 %) of the title
compound. Melting point: 270-272 °C (decomposition).

Example 14
4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium)
dibromide
To a stirred solution of 2 g (0.002 mol) of 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-
2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di-benzenesulfonate in 32 ml of acetonitrile 0.76
g (0.008 mol) of lithium bromide was added at room temperature. After stirring for 2 h the
precipitated lithium benzenesulfonate formed as a by-product was filtered off and washed
with 2x10 ml of acetonitrile. The combined filtrates were concentrated to a volume of 15 ml '
in vacuum below 40 °C and this residue was added to 150 ml of stirred acetone. The so
obtained mixture was stirred for 1 h, the precipitated product was filtered off, washed with .
2x20 ml of acetone, suspended in 30 ml of acetone and refluxed for 20 min. Then the product
was filtered off, washed with acetone and dried in vacuum to yield 1.35 g (81.3 %) of the title
compound. Melting point: 275-278 °C (decomposition).
Example 15
4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(14-dimethyl-piperazinium)
dibromide
To a stirred solution of 2 g (0.0034 mol) of 2B,16B-bis(4-methyl-1-piperazinyl)-5α-
androstane-3α,17β-diol-diacetate in 60 ml of acetone 1.13 g (0.0068 mol) of methyl
trifluoromemanesulfonate was gradually added at such a rate to keep the temperature below
20 °C. The reaction mixture was stirred for 30 min, then 1.13 g (0.012 mol) of lithium
bromide was added and stirring was continued for 1 h. The precipitated product was filtered
off, washed with 2x20 ml of acetone, suspended in 25 ml of acetone and refluxed for 20 min.
Then the solid product was filtered off, washed with 2x20 ml of acetone and dried in vacuum
to yield 2.5 g (93.9 %) of the title compound. Melting point: 269-272 °C (decomposition).
Example 16
1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium
bromide
To a stirred solution of 2 g (0.0028 mol) of 1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-
5α-androstane-16β-yl]-1-methyl-piperidinium trifluormethane-sulfonate in 20 ml of acetone
0.98 g (0.0112 mol) of lithium bromide was added. After stirring for 30 min the reaction .

mixture was diluted with 20 ml of diethyl ether, the precipitated product was filtered off,
washed with a. 1:1 mixture of acetone and diethyl ether (2x20 ml) and dried in vacuum to
yield 1.6 g (88.9 %) of the title compound. Melting point: 230-239 °C (decomposition).
1H NMR (500 MHz, DMSO-d6(TMS), δ(ppm)}:
0.76 (3H,s,H-18); 0.98 (3H,s,H-19); 2.01 (3H,s,3-O-CO-CH3); 2.19 (3H,s,17-O-CO-CH3);
2.25 (1H,m,H-2); 2.41 (4H,m,N-CH2); 3.14 (3H,s,N(+)-CH3); 3.26-3.50 (4H,m, N(+)-CH2);
4.35 (1H,m,H-16); 5.14 (1H,d,H-17); 5.16 (1H,m,H-3)
Example 17
1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium
bromide
To a stirred solution of 2 g (0.0027 rnol) of l-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-
5α-androstane-16β-yl]-1-methyl-piperidinium p-toluenesulfonate in 32 ml of acetonitrile 0.95
g (0.01 mol) of lithium bromide was added. After stirring for 1 h the precipitated lithium p-
tolenesulfonate formed as a by-product was filtered off and washed with. 2x20 ml of
acetonitrile. The combined filtrates were evaporated below 40 °C and 60 ml of diethyl ether
was added to the residue. The precipitated product was filtered off, washed with a 1:2 mixture
of acetonitrile and diethyl ether and dried in vacuum to yield 1.53 g (87.47 %) of the title
compound. Melting point: 228-230 °C (decomposition).
Example 18
4,4,-[3α,17β-bis-(acetyloxy)-5α-androstane-26,16[3-diyll-bis(1,1-dimethylpiperazinium)
di-(p-toluenesnlfonate)
To a stirred solution of 20 g (0.035 mol) of 3α,17β-bis(acetyloxy)-2β,16β-bis(4-
methyl-1-piper,azinyl)-5α-androstane in 100 ml ethanol, 19.5 g (0.104 mol) of methyl-(p-
toluenesulfonate) was gradually added at such a rate to keep the temperature below 30 °C.
The reaction mixture was stirred for 3 hrs., then was diluted with 500 ml tetrahydrofurane and
3 hrs. strirring the solid material was filtered off, washed with 2x50 ml tetrahydrofurane,
dried in vacuum to yield 31 g of crude product which was recrystallized in acetonitrile to
yield 26 g (78.7 %) of the title compound. Melting point: 175-177 °C.

Example 19
4,4'-[3α,17β-bis-(acetyloxy)-5α-androstane-2β,16β-diyl]bis(1,1-dimethylpiperazinium)
dibromide
To a stirred solution of 10 g (0.0104 mol) of 4,4'-[3α,17β-bis-(acetyloxy)-5α-
androstane-2β,16β-diyl]-bis(1,1-dimethylpiperazirrium) di-(p-toluenesulfonate) in 50 ml of
ethanol, 3.7 g of lithium bromide was added at room temperature. The reaction mixture was
stirred for 4 hrs., then diluted with 200 ml of tetrahydrofurane and after 3 hrs. the precipitated
. product was filtered off washed twice with 20 ml of tetrahydrofurane, dried in vacuum. The
7.2 g of crude product was dissolved in 36 ml of ethanol, 0.36 g lithium bromide was added
and the solution stirred for 2 hrs., then diluted with 150 ml of tetrahydrofurane. The product
was filtered off, washed twice with 20 ml of tetrahydrofurane and dried in vacuum. The
obtained title compound was suspended in 60 ml of acetone and refluxed for 20 rhin. The
product was filtered off and dried in vacuum. Yield: 6.7 g (83 %), melting point: 265-269 °C
(decomp.).
Example 20
4,4'-[3α,17β-bis-(acetyloxy)-5α-androstane-2β,16β-diyl-bis(1,1-dimethylpiperazinium)
dibromide
To a stirred solution of 20 g (0.035 mol) of 3α,17β-bis(acetyloxy)-2β,16β-bis(4-
methyl-1-piperazinyl)-5α-androstane in 100 ml ethanol, 19,5 g (0.104 mol) of methyl-(p-
toluenesulfonate) was gradually added at such a rate to keep me temperature below 30°C. The
reaction mixture was stirred for 3 hrs., 10.96 g (0.116 mol) of lithium bromide was added at
room temperature and stirred for 2 hrs, then diluted with 600 ml of tetrahydrofurane and
stirred another 4 hrs. The precipitated product was filtered off, washed twice with 40 ml of
tetrahydrofurane, dried in vacuum to yield 30 g of the product, which was solved in 80 ml of
ethanol, 1.3 g lithium bromide was added stirred for 1 far., then diluted with 250 ml of
tetrahydrofurane and the precipitated product was fdtered off, washed with 2x40 ml of
tetrahydrofurane, dried in vacuum. The crude product was suspended in 130 ml of acetone
and refluxed for 20 min, the solid product was filtered off, washed with 2x50 ml of acetone
and dried in vacuum. Yield: 27.5 g (83 %), melting point: 265-269 °C (decomp.):

WE CLAIM :
1. The quaternary ammonio derivatives of formula (III)

wherein the meaning of X- is a benzenesulfonate - in given case para-substituted with a
methyl or a nitro group or a bromine atom - or a methanesulfonate, an ethanesulfonate or a
trifluoromethanesulfonate ion.
2. The compounds of formula (III) as claimed in claim 1 consist of:
4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di-(p-
toluenesulfonate),
4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di-
methanesulfonate,
4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di-
benzenesulfonate,
4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) di-
trifluoromethanesulfonate.
3. The quaternary ammonio derivatives of formula (IV)

wherein the meaning of X- is a benzenesulfonate - in given case para-substituted with a
methyl or a nitro group or a bromine atom — or a methanesulfonate, an ethanesulfonate or a
trifluoromethanesulfonate ion.
4. The compounds of formula (IV) as claimed in claim 3 consist of:
1-[3α,17β-bis(acetoxy)-2(3-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium
trifiuoromethanesulfonate,
1-[3α, 17β-bis(acetoxy)-2β-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium p-
toluenesulfonate,
1-[3α, 17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium
methanesulfonate.
5. An environment-friend process for the synthesis of 4,4'-[3α,17β-bis(acetoxy)-5α-
androstane-2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) dibromide of formula (I)

and 1-[3α, 17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane-16β-yl]-1-methyl-piperidinium
bromide of formula (II)

characterized by

a.) adding 2.5-4.0 molequivalents of methyl p-toluenesulfonate, methyl
benzenesulfonate, methyl p-nitro or p-bromo-benzenesulfonate, or methyl methane or
ethanesulfonate to the stirred solutions of the diacetate derivatives of formula (V)
or (VI)
in acetone, acetonitrile, ethyl acetate or tetrahydrofuran,
separating the precipitated quaternary ammonio derivatives of formula (III)

or (IV)

- wherein the meaning of X- is a benzenesulfonate, in given case para-substituted
with a methyl or a nitro group or a bromine atom, or a methanesulfonate or an ethanesulfonate
ion-,
and after an optional purifying and drying, dissolving the above obtained quaternary
ammonio derivatives of formula (III) or (IV) in acetonitrile, adding 2.5-5.0 equivalents of
lithium bromide (calculated on the starting material) to the stirred solution, separating and
washing the precipitated lithium salts formed as by-products with acetonitrile, combining and
concentrating the filtrates and separating and drying after an optionally purifying the
precipitated products of formula (I) or (II), or
b.) adding 2.5-4.0 molequivalents of methyl p-toluenesulfonate to a stirred solution of
the diacetate derivative of formula (V) in ethanol, below 30 °C, diluting the reaction mixture
after the reaction is completed with tetrahydrofurane, separating the precipitated quaternary
ammonio derivative of formula (III) - wherein the meaning of X- is p-toluenesulfonate -,
adding 2.5-5.0 equivalents of lithium bromide (calculated on the starting material) to
the stirred solution in acetonitrile of the separated quaternary ammonio derivative of formula
(III) - wherein the meaning of X- is p-toluenesulfonate - , separating and washing with
acetonitrile the precipitated lithium salts formed as by-products, concentrating the combined
mother liquor and washing liquids, and separating and drying after an optionally purifying the
precipitated product of formula (I), or
c.) adding 2.5-4.0 molequivalents of methyl p-toluenesulfonate to a stirred solution of
the diacetate derivative of formula (V) in ethanol, below 30 °C, diluting the reaction mixture

after the reaction is completed with tetrahydrofurane, separating the precipitated quaternary
ammonio derivative of formula (III) - wherein the meaning of X- is p-toluenesulfonate -,
adding 2.5-5.0 equivalents of lithium bromide (calculated on the starting material) to
the stirred solution in ethanol of the separated quaternary ammonio derivative of formula (III)
- wherein the meaning of X- is p-toluenesulfonate - , after the reaction completed diluting
the reaction mixture with tetrahydrofuran, separating and washing with tetrahydrofuran the
precipitated product of formula (I), dissolving them in ethanol, giving 0.2-0.5 equivalents of
lithium bromide to the solution, diluting with tetrahydrofuran, and separating and drying after
an optionally purifying the precipitated product of formula (I), or
d.) adding 1.0-1.1 equivalents (calculated on nitrogen atoms to be quaternized) of
methyl trifluoromethanesulfonate to a stirred solution of the diacetate derivative of formula
(V) in acetone, acetonitrile, ethyl acetate or tetrahydrofuran at 10-35 °C,
diluting the reaction mixture with ether, tetrahydrofuran, n-hexane or n-heptane and
separating the precipitated formed quaternary ammonio derivative of formula (III) - wherein
the meaning of X- is trifluoromethanesulfonate ion -
after an optional purifying and drying, dissolving the obtained quaternary ammonio
derivative of formula (III) - wherein the meaning of X- is trifluoromethanesulfonate ion - in
acetone, adding 2.5-4.0 equivalents of lithium bromide (calculated on the starting material) to
the stirred solution, and drying after an optionally purifying the precipitated product of
formula (I), or
e.) adding 1.0-1.1 equivalents (calculated on nitrogen atoms to be quaternized) of
methyl trifluoromethanesulfonate to a stirred solution of the diacetate derivative of formula
(VI) in acetone, ether or tetrahydrofuran at 10-35 °C,
separating the precipitated (when the reaction is carried out in acetone after diluting of
the reaction mixture with ether) quaternary ammonio derivative of formula (IV) - wherein the
meaning of X- is trifluoromethanesulfonate ion -, and
after an optional purifying and drying dissolving the quaternary ammonio derivative of
formula (IV) - wherein the meaning of X- is trifluoromethanesulfonate ion - in acetone,
adding 2.5-4.0 equivalents of lithium bromide (calculated on the starting material) to the
stirred solution drying after an optionally purifying the precipitated product of formula (II), or

f.) adding 1.0-1.1 equivalents (calculated on nitrogen atoms to be quaternized) of
methyl trifluoromethanesulfonate to a stirred solution of the diacetate derivatives of formula
(V) or formula (VI) in acetone, acetonitrile, ethyl acetate or tetrahydrofuran at 10-35 °C,
reacting the reaction mixture containing the quaternary ammonium salts of formula
(III) or (IV) - wherein the meaning of X- is trifluoromethanesulfonate ion - with 2.5-4.0
equivalents of lithium bromide (calculated on the quaternary ammonium salts of formula (III)
or (IV), wherein the meaning of X- is trifluoromethanesulfonate ion),
and after an optional purifying drying the separated precipitated products of formula
(I) or (II), or
g.) adding 2.5-4.0 molequivalents of methyl p-toluenesulfonate to a stirred solution of
the diacetate derivative of formula (V) in ethanol below 30 °C,
subsequently, after the reaction is completed, adding 2.5-5.0 equivalents of lithium
bromide (calculated on the starting material) to the stirred solution,
then after the reaction is completed, diluting the reaction mixture with tetrahydrofuran,
after the precipitation is completed, separating the precipitated quaternary ammonio derivative
of formula (I), washing with tetrahydrofuran, after drying disolving in ethanol, stirring the
solution with 0.2-0.5 equivalents of lithium bromide, diluting with tetrahydrofuran, and
separating, washing and drying the precipitated compound of formula (I).
6. Process d) for the synthesis of 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-2β,16β-
diyl]-bis(1,1-dimethyl-piperazinium) dibromide of formula (I) as claimed in claim 5, wherein
by reacting the reaction mixture containing the quaternary ammonium salt of formula (III) -
wherein the meaning of X- is trifluoromethanesulfonate ion - with lithium bromide without
isolating the quaternary ammonium salt of formula (III).
7. Process e) for the synthesis of 1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-
androstane-16β-yl]-1-methyl-piperidinium bromide of formula (II) as claimed in claim 5,
wherein by reacting the reaction mixture containing the quaternary ammonium salt of formula
(IV) - wherein the meaning of X- is trifluoromethanesulfonate ion - with lithium bromide
without isolating the quaternary ammonium salt of formula (IV).

The invention relates to a new,
environment-friend process for the synthesis of the
known 4,4'-[3α,17β-bis(acetoxy)-5α-androstane-
2β,16β-diyl]-bis(1,1-dimethyl-piperazinium) dibromide
of formula (I) (from now on pipecuronium bromide)
and 1-[3α,17β-bis(acetoxy)-2β-(1-piperidinyl)-5α-androstane
-16β-yl]-1-methyl-piperidinium bromide of
formula (II) (from now on vecuronium bromide).
Furthermore the invention relates to the new intermediates
of formula (III) and formula (IV) of the process, wherein
the meaning of X is benzenesulfonate - in given case
para-substituted with a methyl or a nitro group or a
bromine atom - methanesulfonate, ethanesulfonate or
trifluoromethanesulfonate ion.

Documents:

00891-kolnp-2007-assignment-1.1.pdf

00891-kolnp-2007-correspondence-1.1.pdf

0891-kolnp-2007-abstract.pdf

0891-kolnp-2007-assignment.pdf

0891-kolnp-2007-claims.pdf

0891-kolnp-2007-correspondence others.pdf

0891-kolnp-2007-description (complete).pdf

0891-kolnp-2007-form1.pdf

0891-kolnp-2007-form3.pdf

0891-kolnp-2007-form5.pdf

0891-kolnp-2007-international publication.pdf

0891-kolnp-2007-international search authority report.pdf

0891-kolnp-2007-pct others.pdf

0891-kolnp-2007-priority document.pdf

891-KOLNP-2007-(10-02-2012)-CORRESPONDENCE.pdf

891-KOLNP-2007-ABSTRACT.pdf

891-KOLNP-2007-AMANDED CLAIMS.pdf

891-KOLNP-2007-ASSIGNMENT.pdf

891-KOLNP-2007-CORRESPONDENCE.pdf

891-KOLNP-2007-DESCRIPTION (COMPLETE).pdf

891-KOLNP-2007-EXAMINATION REPORT REPLY RECIEVED.pdf

891-KOLNP-2007-EXAMINATION REPORT.pdf

891-KOLNP-2007-FORM 1.pdf

891-KOLNP-2007-FORM 18-1.1.pdf

891-kolnp-2007-form 18.pdf

891-KOLNP-2007-FORM 2.pdf

891-KOLNP-2007-FORM 3-1.1.pdf

891-KOLNP-2007-FORM 3.pdf

891-KOLNP-2007-FORM 5.pdf

891-KOLNP-2007-GPA.pdf

891-KOLNP-2007-GRANTED-ABSTRACT.pdf

891-KOLNP-2007-GRANTED-CLAIMS.pdf

891-KOLNP-2007-GRANTED-DESCRIPTION (COMPLETE).pdf

891-KOLNP-2007-GRANTED-FORM 1.pdf

891-KOLNP-2007-GRANTED-FORM 2.pdf

891-KOLNP-2007-GRANTED-SPECIFICATION.pdf

891-KOLNP-2007-MISCLLENIOUS.pdf

891-KOLNP-2007-OTHERS-1.1.pdf

891-KOLNP-2007-OTHERS.pdf

891-KOLNP-2007-PETITION UNDER RULE 137-1.1.pdf

891-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf

abstract-00891-kolnp-2007.jpg

« Previous Patent

Next Patent »

Patent Number

251667

Indian Patent Application Number

891/KOLNP/2007

PG Journal Number

13/2012

Publication Date

30-Mar-2012

Grant Date

27-Mar-2012

Date of Filing

13-Mar-2007

Name of Patentee

RICHTER GEDEON VEGYÉSZETI GYÁR RT.

Applicant Address

GYÖMRÓI UT 19-21, H-1103, BUDAPEST

Inventors:

#	Inventor's Name	Inventor's Address
1	TUBA, ZOLTAN	BOGAR U.20/B, H-1022, BUDAPEST
2	SZABO, GYORGYI	KATONA JOZSEF U. 10/A, H-1137, BUDAPEST.
3	GALIK, GYORGYI	PESTI UT 185, H-2730, ALBERTIRSA.
4	BALOGH, GABOR	KORPONA U. 14, H-1183, BUDAPEST.
5	MAHO, SANDOR	RIM U.20, H-1183, BUDAPEST.

PCT International Classification Number

C07J 43/00

PCT International Application Number

PCT/HU2005/000104

PCT International Filing date

2005-09-15

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	P0402017	2004-10-07	Hungary
2	P0500817	2005-09-02	Hungary