HU227522B1 - Environment-friendly process for the synthesis of quaternary amino-steroids and intermediates - Google Patents

Abstract

The present invention relates to 4,4 '- [3a, 17β-bis (acetoxy) -5α-androstane-2β, 16β, -dil] -bis (1,1-dimethylpiperazinium) dibromide of formula (I) (hereinafter pipecuronium). bromide) H and 1- [3a, 17β-bis (acetoxy) -2β- (1-piperidinyl) -5α-androstan-16β-yl] -1-methylpiperidinium bromide of formula (II) (hereinafter called "voruronium bromide") ) lH H

Description

The process according to the invention is as follows:

The starting diacetate derivatives are reacted with the methyl ester of p-toluenesulfonic acid, methyl benzenesulfonic acid, methyl methyl p-nitro or p-bromobenzenesulfonic acid, or methyl methanesulfonic acid or methyl trifluoromethanesulfonic acid. The quaternary ammonium salts of formula (III) or (IV) are reacted with lithium bromide.

PRINTING COPIES

4;

. όά » ^Λ . . .V Φ Α Φ -V „χ φ **; * χ * «φ ^χ / ♦ *.; '.. ·. ······"'

Good

Applicant:

RICHTER Gedeon Chemical Factory Ltd. "Budapest Inventors:

Dr., Zoltán TUBA 40%, Budapest, Sándor MAHŐ 20% Györgyi SZABÓ 20 96, dr, GALIK. George lo%, Aiberdrsm Gábor BALOGH 4%, Budapest.

Internal Priority 200410.07. F 04 02017, Announcement 02.09.2005,

ÍS> 0 $. <> $ Í.O φΧ ν '* * φ X'

Tárgyit the invention (I) Formula _4> ⁴ '(3a47pmisz (acetox.í) ~ 5 ~ an4roszt.án * _2P> Shoot rőbib bis ^ (l ^ 3 Ι »ιοΰΙ'-ρΐρδ £ Γ · ζ & 1ηηι) · 'ύ15χ'θϊ.ΐϊίά (hereinafter pipectronone ~ bromide)

and my image (Π) is 1-pa, 17β-bis (aethoxy) -2 - - (1-piperidinyl) -5α-atrroscutane-16β-β-methyl-piperidinium bronze (a). later on vinylnin bromide)

is an environmentally friendly new process. The invention also includes. procedure (111)

and (IV)

 *

also new intermediates thereof wherein X represents an benzene halonate, or a methane or ethanesulfonate or trifluoromethanesulfonate atom optionally substituted at a para position with a methyl or nitro group or a bromine atom

Plpeknrönlmn-bronhd, vslarnim, is a curare-like, non-depolarizing neuromwtzulcl blocker of compounds of the vecuronium bromide moiety which inhibit the transmission of nerve regions to the striated palate. Their effect can be suspended by antidote, Their outstanding biological property. as a result, both compounds have gained widespread use in the clinic. Their field of application is primarily surgery, where it is used in ischemic narcosis for intestinal narcosis. It is also used in shock therapy and cramps in striated muscles.

The preparation of plpecttronium brondd is described in Hungarian Patent Application No. 165,008, which discloses the synthesis of several synthetic steps starting from 2a, 3aJ.6eöl7a-diepoxy-17-acetoxy-5oo-androstane. Drug Rés), 300% ¾¾ 342-346. article below,

The synthesis of vecuronium bromide is described in U. S. Patent No. 1,434,749 and in Hungarian Patent Specification No. 154,368. A detailed summary is also available in J.Med.Chem., Horse, 1116 (.1973).

The 20 final steps of the known process for the production of pipecnronene brornide and vecuronine m-bnunide are the following:

 φ φφ · «*

ΧΦΦ * * · »»

formula. quaternization of diacetate moieties with methyl ferric acid. in a solution of ether or diethyl ether.

It is known that the above. Methyl brotnide used in quaternizing processes is a highly toxic, colorless, odorless, room-temperature gas-inorganic substance that damages the ozone layer. In view of the property of the latter, the use of ozone-depleting substances in industrial applications is contemplated. <VH, 2,} Korm, sz. It is highly restricted and should be replaced by other non-or less toxic quaternizing mice.

The present invention relates to a novel process wherein the quaternization of the diacetate derivatives of formula (V) and (VI) does not require the use of the methyl bromide reactant. The quenching reaction of methyl ferromide with an 'amine &lt; methylmethyl ester ester &quot;

our surprising and unexpected discovery made it possible for the quaternization of the Yzolfonyl mebl · esterker according to the invention to exchange "solonone ions with chromium ions of the sanlphonate salt ^w of the intermediate of formulas (III) and (IV).

 ***:

^χ χ * \

Φ * Λ φ * Φ * *. . ^{Φ Φ} • * * ΛΦί · 5 áhalában the balance has been shifted to pipekurónium bromide or bromide vekorónium-direction of 99% selectivity using an equilibrium reaction, lítinm-btomid and appropriate selection of reaction parameters.

According to the invention, the process of

a) For a solution of the di.acerate slides of formula (V) or (VI) in 2.5 g to 4.0 molar equivalents of p-toluenesulfuric acid methyl tert, benzo-sulfuric acid methyl ester, p-mtro- or p-br-methyl ester, in acetone, acetonitrile, ethyl acetate or benzylsulfonic acid methyl ester, or methane or ethanesulfonic acid meryl ester, the quaternary ammonium derivatives of the general formula (ΠΙ) or (IV) where X is optionally methyl or n-hydroxy in the hoof position;

10. Bromosubstituted benzene sulphonate, or methane or ethanesulfonate ion, is isolated, after which purification and drying is carried out in acetonitrile, while stirring, lithium bromide is added in an amount of from 23 to 5.0 equivalents of the starting material. the precipitated lithium salts formed are by-passed filtered, washed with acetyltyl, the combined filtrates are separated, the precipitated product of formula (I) or (III) is isolated, optionally purified and dried, or la (b) with stirring in an ethanolic solution of 2.5-4.0 molar equivalents of methyl p-toluenesulfonic acid are maintained such that the temperature of the solution is kept below 30 ^U and the mixture is diluted with tetrabidroferal after completion of the reaction to give the quaternary ammonone of formula (III). The derivative - where X is pdolenesulfonalone - - is isolated and, after purification and drying, dissolved in acetonitrile, mixed with 2.5-5.0 equivalents of lialiamide, based on the starting material, to remove the lithium salts formed as a by-product. , washed with acetomtile, the combined filtrates filtered off, the precipitated product of formula (II) is isolated, optionally purified and dried, or

e) To a stirred solution of the diacetate derivative (V) in ethanol is added 2.5 to 4.0 molar equivalents of methyl pdoluobsulfonic acid, so that the temperature of the solution is below 30 ° C.

After completion of the reaction, the reaction mixture is diluted with tetrahydrofuran, the quaternary ammonium derivative of formula (IH) where X- is p-toluenesulfonate-lone is isolated and then purified by purification and drying in ethanol, with stirring. 2.5-5.0 equivalents of lithium ferromide, based on the starting material, and after the reaction is completed, the mixture is diluted with tetrahydrofuran, the precipitated quaternary ammonium derivative of formula (I) is filtered off, washed with tetrahydrofuran and, after drying, dissolved in ethanol After mixing with 2-11.5 equivalents of lununron, then diluting with tetrahydrofuran, the precipitated compound of formula (I) is isolated, washed and dried, or

Λ * «· Φ *

ά) to a solution of the diacetate derivative of formula (V) in acetone, acetonitrile, ethyl acetate or tetrahydrofuran, with stirring, the nitrogen to be quaternized, with from 1.0 to 14 equivalents of trifluoromethylsulfonic acid methyl ester. we give you lo and 35 ^<! Cközöí.t. the resulting ammonia derivative (10), wherein X is a trifluoromethanesulfonate ion and the reaction mixture is diluted with ether, tetrahydrofuran, n-hexane or n-heptane, filtered, and after purification and drying, dissolved in acetone. to the solution is added with stirring 2.5 to 4.0 equivalents of Ht-bromide based on the starting material, the precipitated product of formula (I) is isolated, optionally purified and dried, or

e) 1.0 to 1.1 equivalents of methyl trifluoromethanesulfonic acid methyl ester is added to a solution of the diacetate derivative of formula VI in acetone, ether or tetrahydrofuran at 10 to 35 ° C with stirring for 10 nitrogen atoms quaternized. The reaction is carried out in acetone after diluting the reaction mixture with ether), the ammonia derivative of formula (V), wherein X is trifluoromethanesulfonate ion, is filtered off and, after purification and drying, dissolved in acetone with stirring to the starting material. 2.5-4.0 equivalents of lithium bromide are added, and the precipitated product (11) is isolated, optionally purified and dried, or

f) Formula V or VI. To a solution of the diacetate derivatives in acetone, acetonitrile, ethyl acetate, or tetrahydrofuran, 1.0-1.1 equivalents of trinofluoromethanesulfonic acid methyl ester is added at a temperature between 10 ° C and 35 ° C, with respect to the (Π1) or

A reaction mixture containing 2 to 3 ammonium salts of formula (IV) wherein X is trifluoromethanesulfonate ion based on the quaternary ammonium salts of formula (01) or (IV)

Reaction with 2.5 - 4.0 equivalents of lithium bromide, precipitated. The products of formula (I) or (Π) are isolated, optionally purified and dried, or

g) 2.5 to 4.0 molar equivalents of p-toluenesulfonic acid methyl ether are added to a solution of the diacetate derivative of formula (V) with stirring, so that the temperature of the solution is below 30 T, after stirring, per material

After addition of 2.5 to 5.0 equivalents of lithium bromide, after completion of the reaction, the mixture is diluted with tetrahydrofuran, the quaternary anunion derivative (1) is filtered off, washed with tetrahydrofuran and, after drying, dissolved in ethanol 0.2-0. After stirring with 5 µl equivalents of lmM bromide and diluting with tetrahydrofuran, the precipitated compound of the formula I is isolated, washed and dried.

'-Vww .- k.

$ .89 2 SO: «!.

Χ '*' _φ

The first quatemerisation tear of the above processes is preferably carried out at room temperature. According to method a, preferably 3.0 equivalents of methyl methyl p-toluenesulphonic acid, benzenesulfonic acid methyl ester, p-mtro- or p-bromobenzenesulphonic acid methyl ester or methanesulphonic acid or ethanesulphonic acid methyl ester are used. In the case of methods d), e) and i), the use of more than 1% trifluoromethane sulfomate methyl ester is not preferred.

The ammonium salts of the general formula (10) or (IV) wherein X is an optionally para-position benzene sulphate or methane or ethanesulfonated with methyl or nitro-eopart or bromine atom. Reacting with 4.0 equivalents of lithium bromide net! half.

Formula (Si) or Formula (IV) quaternary ammonium salts, wherein X. "is trifluoromethanesulfonate ion, are preferably reacted with 2.5-4 () equivalents of lithium chromide for a reaction time of from 0.5 to 3.0 hours. The precipitated product is then filtered, washed, dried and optionally purified.

The compounds of formulas (1) and (H) are also known as "one pot (" oue-ροΓ ") synthesis; and may be prepared by using, for example, trifluoromethanesulfomic acid methyl quaternizing agent. In this case, the diacetal derivatives of formulas (V) and (VI) are dissolved in acetone by addition of 1 µl of trimethyl methanesulfonylmethyl ester per liter of nitrogen to be quenched and stirring between 15 and 20. until completion of the reaction, preferably for 30 minutes. After the reaction, 2.5-4.0 molar equivalents of Ittinm chromide.

of the reaction mixture and stirring is continued for a further five times. The precipitated formula (I) or (Π)! the products are filtered off, and the pipecuronium bromide of formula (1) is purified by boiling in aetone and the vecuronium bromide of formula (0) is mixed with ether. Another possible way of one-pot synthesis is by. g).

The invention is illustrated by the following examples, which are not intended to limit the invention.

íiífitsí Ífcc íi »$. ií5.n

-8-ί

ΊΟ g (0.035 mol) 2β4όρ · 4? Ϊ́8ζ <4-ϊηοΰνΐψίρδΓ & ζίηίΙ} -5α-8ηώ »§ & ιύη-3α, 1? Β-4ΐοΙ5 diacetate. Dissolve in 500 ml of acetone with stirring and then add 19.5 g (0.104 g) of p-t-toluene-dl-ss-methylteazte to the solution with further vigorous stirring, so that the temperature does not exceed 30 ° C. The reaction mixture is stirred for 20 hours, the precipitate is filtered off, washed twice with 50 ml of acetone and then suspended in 400 ml of acetone and stirred for 20 minutes at reflux temperature. The precipitate is then filtered off, washed twice with 50 ml of ace10 and dried under vacuum. 32.0 g of the title product are obtained (melting point 16-47 ° C, with decomposition), and crude product A is obtained in 65 ml of acetonitrile (23.04 g, <69.81%). Melting point: 1.75177 * € (during decomposition).

0.74 (3H, s, H-18); 0.98 (3H, s, H-19); 2.03 (3H _{f s3-O-CO-CH3);} 2.07 (3H, s, 17-O ~ _CO-CH3); 2.29 (bii, s, r-CR _? {Tosyl.}}; 2.45 (1H, m, H-2); 2.78 <8H, m, N-O _s ); 3.08 & 3.09 (.12H, s & s, N '% CM ₃ );

3.17 αΗ, ητ, Η-Ιόχ 3.27-3.43 <8H, m, N ^ -CBz); 4.72 <1H, d>17); 5.14 (1H, m, H-3); 7.11. <4H, m, H ~ 2 '&H-é'itozii)); 7.48 <4H, m, H-3 '&H-5' (milk) g (0.026 mol) 2H, 4'-bis (4-methyl-1-piperazinyl) -5a-aadn; Dissolve t7β-dicycl · · diacetate in 300 mL of acetone, add methyl methanesulfonic acid methyl ester (9.0 g, <0.08 mol) at room temperature and stir the reaction mixture for 24 hours. The precipitated product was filtered off, washed twice with 50 ml of acetone and dried in vacuo to a bulk yield of 19.83 g of crude product, which was dissolved in 100 ml of acetonitrile, followed by 100 ml of acetone with vigorous stirring. It is washed with a 1: 1 mixture of acetamel pre-triturate and dried under vacuum to constant strength. 17.3 g (83.3%) of the title product are obtained. Melting point: 270-272 ^& C (dec.), »KBUWHSbUBMM

X x y ~ 9 ~

0.75 (3H, s, H-1.8); 0.99 (3H, s, H49); 2.03 (3H, s, 3-O-CO-CiE); 2.08 <3H, s, 17-O-CO-CH? 131 (6H, s, CH ₃ -SO ₂ O ⁰ ); 2.46 (1H, m, H-2); 2.80 (8H, m, N-CH ₂ ); 3.10 & 3.11 <12H, s & s ^ -CHO:

3.18 (1H, m, H-lo); 3.27-3.44 <8 H ₅ m, 4.73 (1H, d, H-17); 5.15 (1H, m, H-3)

2β, Ιόβ-bis (4-methyl-1-piperazimyl) -5α-anα-h oszt-án 3α-3α, 1717β (0.0175 mole) was dissolved in 200 ml of acetone, 5.73 g (0.035). mole) of methyl methoxysulfonic acid is added to the solution at such a rate that the temperature remains between 15 and 20 ° C, and the reaction mixture is then added. stirring at the above temperature for 25 minutes. The reaction mixture was poured into 1000 ml of vigorously stirred diethyl ether, the precipitated product was filtered off, washed twice with 50 ml of a 1: 5 mixture of acetone: diethyl ether and dried under vacuum at a temperature below 40 ° C. 15.0 g (96.7%) of the title product are obtained. m.p. 160-165 ° C (with decomposition).

0.75 (3H, s, H48); 0.99 (3H, s, H-19); 2.03 (3H, s _t 3 -O-CO-CH ₃ ): 2.08 (3H, s, 17-O-C 6 -C ₅ -Cl ₃ ); 2.46 (1H, m>2); 2.80 (8H, m, H € H _a); 3.08 fe 3.09 (12H, s fe sX ^ -CH.0; 3.18 <1H, m, H-16); 3.25 · 3.42 (SH, m, N 2 -CH 2); 4.73 (1H, 0.11-17); 5.15 (1H, m, H-3)

-77.4 ¹ Wbc ~ 322.3 Hz

g (0.0175 mole) of 2β, 16β-Μ§ζ (4 ~ ηι © ί0-1-ρίρ0Γαζη.ΰΙ) -5α- »τ) .0Γθδζ10η′-3α, 17β · 4ίοί2S is dissolved in 100 µl of acetone with stirring, Trifluoromethanesulfonic acid methyl ester (5.7 g, 0.034 mol) was added dropwise to the solution at a temperature between 15 and 20 ° C and stirring was continued for 30 minutes while maintaining the above temperature. Tetrahydrofuran (200 mL) was added to the reaction mixture, and after stirring for one hour, the precipitated product was filtered off, washed twice with 5 mL of tetrahydrofuran and dried in vacuo to dryness at 40 C to afford 14.25 g (90.70%) of the title compound. Melting point:

168-170 ° C (with decomposition).

SMAS.

* ♦ ΦΦΦ * φ χ. «Φ φφ ** * Φ * Χ Φ * X Φ * * φφφ · **

Φ φ φ X * Φ Λ * Φ> ί »φ XX φφ *> ^ΑΑ

(Trlilmír »ajetáí8gmlfonáO

10 g (0.0175 mole) of 2p, 1bp-bis (4-methyl-1-piperazinyl) -5tx-andrestane-8tx, 17H-diol acetal are dissolved in 2 g of acetone with stirring and then at 20-25 ° C for 10 minutes. 6 g (0.0305 mol) of trifluoromethanesulfonic acid methyl silicone are added dropwise to the solution and stirred at the same temperature for a further 25 minutes. Thereafter, 100 ml of n-hexane were added to the teakcholate and the precipitated solution was stirred for an additional hour, then the precipitated product was filtered off, washed twice with 25 ml of n-hexane, and dried under vacuum at a temperature below 40 ° C. 15.8 g (98.75%) of the title product are obtained. M.p. 107-170 ° C (with decomposition).

g (0.0175 mole) of 2β, 6β-β-bis (4-methyl-1-piperazinyl) -5α-α ”-bosol” 3 x Πβ-diol hectate was dissolved in 200 mL of aetone with stirring and then 18-21 ° C. To a temperature of C, 6 g (0.0365 moles) of tinphenormethane-sulfonic acid m.c. is added dropwise over 10 minutes. Stirring was continued for 30 minutes while maintaining the fend temperature. This was followed by adding 100 ml of n20 heptane to the reaction mixture and stirring for two more hours. The precipitated product was filtered off, washed twice with 20 ml of n-heptámnd and finally vacuum dried at a temperature below 40 ⁰ C tömegáilandőságig to give title product (15.8 g, 98.75% yield). Melting point: 167-170 (with decomposition).

2.5 g (0.0043 mole) of 2β, 16β ~ όί8ζ (4 ~ ηι © Η1-1νρ1ρβΓ8Ζίηί1) -5α-8η4Γθδζΐ4η-3α, 17β '· ό1ον are dissolved in 50 µl of acetone with stirring, then 2.275 g (0, 0.13 mol) of a benzylsulfonic acid methyl ester are added and the mixture is stirred at room temperature for an additional 24 hours. The precipitated product is then filtered off, washed twice with 25 ml of acetone and dried under vacuum to constant weight. The crude product (3.1 g) was suspended in acetone (50 ml); and stirred at reflux temperature for 20 minutes, then the filter is filtered, washed twice with 100 ml of alum, dried in vacuo to a constant consistency. 2.57 g (64.25%) of dm are obtained. Melting point. ·. 172-175 ° C (with decomposition).

0.74 (3H, s, H ~ 18); 0.98 (3H, s, H -19); 2.03 (3H, s, 3-O-CO-CH ₃ ); 2.07 (3H, s, _{17-O-CG-CH3);} 2.45 (1H, m, H-2); 2.79 (8H, m>X%); 3.09 (12H, s> ^O- CH 3); 3.18 (1H, m, H-16); 3.25-3.42 (8H, m, N 1 -C%); 4.73 (W, H-17); 5.14 (1H, m, H-3); 7.61 (4H, m, H-2 '&H-6' {Ph-SO ^{2 O} }}; 7.30 <2H, m, H-4 '(Ph-SO 2 O ^G 1); 7.31 <4H , m, H ~ 3 '&H-5' {Pfa ~ SO ^{2 O} 1) g (0.0092 mole) 2 ?, 16? -bis (? 1-piperidinyl) ~ 5 (? -androstane-3? x, 17? -diol diacetate). 75 ml diedléierben dissolved with stirring and. at a temperature between 15-20 ^° C, trifluoromethane sulfonic acid, their methyl (1.52 g, 0.0092 mol) was added, the stirring was continued at the same temperature. for 20 minutes, then the precipitated product was filtered off, washed with diethyl ether (2 x 20 mL), dried to give crude product (6.5 g), which was stirred in diethyl ether (50 mL) to remove the trace starting material (6.0 g, 92%). mp 217-219 ° C (with decomposition), m.p.

0.76 (3H, s, B-18); 0.98 (3B, 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, m35f-CH ₂ ); 3.12 (SH (N, -) - (CH3); 3.26-3.49 (4H, m, N ₂ -Ce ₂ ); 4.22 (1H, m, B); 5.14 (MM-17); 5.17 <.ttU \ tt-3)

-77.4 ⁵ L _3W . _13CS? 322.4 Hz

SS3S.O5J2.

g (0.011 mol) of 2β, 16β-bis (1-piperidinyl) -5α-androstane-3α-17β-diol diethyl acetate is dissolved in 150 ml of acetone with stirring and then 9 g (0.048 mol) of p30 toluenesulfomic acid methyl ester is added at room temperature. to the solution. The stirring. After 72 hours, the precipitated product is filtered off, washed twice with 20 ml of acetone and dried in vacuo.

ΦΦΧΦ ** thus yielding 5 g of crude product. It is suspended in 50 ml of acetone and stirred at reflux for 20 minutes, then the product is filtered off, washed twice with 1.5 ml of acetone and dried under vacuum to constant weight. 4.5 g (55.9%) of the title product are obtained. Mp 240245 ° C (with decomposition).

SHWR.jSW MHz. PMSO-dfffMS), Sp _B m) i;

0.74 (3H, s, B-18); 0.98 (3H, s, H-19); 2.01 <3H> s, 3-O-C0 ~ _CH3); 2.17 (3H, s, 17-O-CO-CH ₃ ); £ 25 (1H, m, H ~ 2); 2.29 (3H, s,? 2.41 (4H, npN-C%); 3.11 (3H,? N °? CH ₃ ); 3.24-3,47 (4H, m, 0Η ~ ^Ν ω _2}, 4.24 <R, m, H4ő); 5.12 (W, H-17); 5.17 (1H, m, H-3); 7.11 (4H, m, H-2 '& H ~ 6' {tosyl} X 7.49 (4H, m, H-3 '&H'S'ltozyl))

Ilkáikig

The title product was prepared according to Example 9 from 2β _> 16β-0ί5ζ (1-ρ1ροή41η13) -5α-3η. <Ϊ́Γθχζη1η-3 (Χ, .17β41ο1) and methanesulfomimethyl ester; Yield: 20.0%; 260-263 ° C (decomposition by hand).

0.76 (3H, s, H-18); 0.98 (3H, s, H49); 2.01 (3H, s, 3-O-CO-CH _s ); 2.18 (3H, s, 17-O-CO-CH ₃ ); 2.25 (1H, m, H-2); 2.30 (3H, s, CH ₃ - xSO ₂ O ⁶⁾ ); 2.41 (4H, m, G-GH2); 3.12 <3H, s> N * ^: 4CH3>; 3.30-3.49 (4H, m, N 1 -CH 2); 4.26 (1H, m>16); 5.14 (1H, d, H47): 5.17 (1H, m, H4)

IkioisM g (0.0052 mol) of 4,4'-η 4 -4,4-bis (acetoxy) -5 δ-8-androstane-2β, 1,6β-dodbis (1,4-dinethyldipiperazinium) di- (p-toluenesulfonate) in 80 ml. lithium bromide (1.85 g, 0.021 mol) was added at room temperature. The by-product lithium (p-toluenesulfonyl) precipitates immediately. After stirring for an additional hour, the precipitate was filtered off, washed with acetonitrile (3 x 20 ml). The combined filtrates were concentrated in vacuo to 50 ml under vacuum at 40 ° C and the residue was stirred with 300 ml of acctcnb.cz under vigorous stirring. added. The resulting mixture was stirred for an additional thirty minutes, then the precipitated product was filtered, slurried in 50 ml of acetone and heated to reflux for 20 minutes.

ÍS0S.8SJ2.

ΧΦΦ φφφ Φ <ΦΦ * ΦΦ · **

Φ V * * φ Φ Φ. X φ φ φ φ * * * φφ ΦΦ ΧΦ **

The product was filtered off, washed with acetone (2 x 15 mL), and dried under vacuum to constant weight to give 3.3 g (81.8%) of the title product. Melting point: 275-278 ° C (with decomposition).

0.75 (3H, sJc18); 0.99 (3H, s, H-1.9); 2.04 (3H, s, 3-O-CO-CH ₅₎ l 7.09 (3H, s, _{17-O-C0-CH's),} 2,4? 5 (1H, m, H-2); 2.81 (δH, .m, N-CH _s ); 3.138 & 3441 (L2H, s & s, H · M%> 3.19 3,273,46 (8H, m, N ^C * M7H _2); 4.73 (lH, d, H-7);! 545 ( H, m, H-3)

You IEA &

2.5 g (0.0052 mole) of 44 ^<(3a ^ _í l BBZ (acetyloxy) -5o-androstan-'2 ^, Í6p ~ <alkyl] -bAz (l4dímetil-pi ^? Razínimn) -dimetánsznlfónátot 50 ml lithium 4-romide (1.1 g, 0.012 mol) was added at room temperature. The lithium methanesulfonate formed as a by-product immediately began to precipitate. The precipitated reaction mixture was stirred for an additional two hours and the precipitated lithium salt was filtered off. Wash twice with 30 mL of acetonitrile Add the iS combined filtrates to 150 mL of your steel with vigorous stirring, filter the resulting product, wash with 2 x 10 mL of acetonitrile, and dry under vacuum to give 2.2 g (91.6). m.p. 270272 ° C (with decomposition).

(g <0.0054 mole) 4 ·, 4 (3 <χ, 1? β'Μ $ ζ (8θθΙοχί) -5α-'8η0Γθ8ζΐύη-2β, 10β-0 «Ι] · 'Μ8ζ (1,1'- Dissolve (trinuot - sniffin) in 200 ml of steel and add 1.889 g (0.02.1 mole) of lmd bromide to the solution with vigorous stirring at room temperature and continue for thirty minutes. The precipitated product is filtered off, washed twice with 30 ml of acetone, then suspended in 40 ml of acetone and stirred vigorously at reflux for 20 minutes, and the product is filtered off, washed twice with 20 ml of acetone in vacuo and dried to give 3.76 g. (88%), m.p. 270272 ° C (with decomposition).

3ö ψν ΦΦΧΦ φ φ * φ *

Φ X Φ

Χ * Φφ *. *

dlbromhi

ϊ.0 g (0.002 mole) of 4,4 ^'- {3 <x, Í7p ~ bis (the ^<: ethoxy) ~ 5-androsZtáa 2P4ÖP-diyl> during bis (14 "dimetll.píperaztoiumj-dibenzolazulfönátot 32 ml of acetonitrile were stirred After stirring at room temperature, 0.76 g (0, (X) 8 moles) of lithium bromide was added to the solution and stirring was continued for another two hours. The precipitated lithium benzobenzylbnate by-product was filtered off, washed twice with 1 ml of acetonitrile. The combined hairs were evaporated in vacuo to a volume of 15 ml at a temperature below 48 ° C, and the residue was added to 150 ml of acetone with vigorous stirring and stirred for an additional hour. The precipitated product was filtered, washed twice with 28 ml of acetone and suspended in 30 ml of acetone. After stirring vigorously at reflux for 20 minutes, the product is filtered off, washed with acetone and dried under vacuum to a constant weight to give 1.35 g (81.3%) of the title compound. Mp 275-278 ° C (dec. and in the meantime).

g (0, 0034 moles) of '2β, 16β-bis (4-mer 1-pipexazazmh) -5β-androstane-3β, 10β-8β-diacetate are dissolved in 60 ml of acetone and then with vigorous stirring. 1.0 g (0.0068 mole) of methyl trienoromethanesulfonic acid methyl ester was added at a rate such that the temperature was kept below 20 * C. The reaction mixture was stirred for 30 minutes, followed by 1.13 g (8.812 moles) of lithium bromide. The precipitated product is filtered off, washed twice with 20 ml of acetone, then suspended in 25 ml of acetone and stirred vigorously at reflux for 20 minutes. The solid product is then filtered off and washed twice with 20 ml of acetone each time. Drying under vacuum to constant weight gave 2.5 g (93.9%) of the title compound, mp 269-272 ° C (with decomposition).

bromide g (8, (8128 moles) i- [30,10-bis (aethoxy) -2p (1-piperidinyl) -5α-androstan-16p-yl] methylpiperidine: trihydromethylsulfonate Dissolve in 28 ml of acetone and add 8.98 g (8,0112 moles) of lithium bromide to the solution with vigorous stirring, followed by a further thirty Si.

Continue for -1.5 minutes. The reaction mixture was diluted with diethyl ether (20 mL), the precipitated product filtered off and washed twice with 20 mL of a 1: 1 mixture of acetomethyl ether and dried under vacuum to constant volume. . 1.6 g of product (88.0%} of the title compound Melting point: 230 239 ^S C (dec).

0.76 <3HaH-IS>; 0.98 (3x, s, H-19); 2.01 C3H, s, 3-O-CO-CHS): 2.10 (3íks, 17-O ~ _CO-CH3); 2.25 (1H, m, M ~ 2); 2.41 (4H, m, N-CH ₂ ); 3.14 (311, §, Ν ^ω ·· € Η · .Ο; 3.26–3.50 (4H, m, 4.35

5.14 <1H, d ₍ B-17); 5.16 (tH, m, H ~ 3)

g (0.0027 g) 1- (3α, 17ββ-bis (aethoxy) -2β-Cl-pipendinyl) -5α-androstane-16β-ylmethyl-piperaldehyde - (p-toinolsulfonate) was dissolved in 32 ml aoetonitrile and with stirring, 0.95 g (0.01 mmol) of Ktuum bronze was added to the solution. Stirring was continued for an additional hour, after which the precipitated lithium (p-toluenesulfonate) product was filtered off and washed twice with 20 ml of acetor. The combined filtrates were evaporated at a temperature below 40 ° C and 60 ml of dielyl ether were added to the residue, which was filtered off and washed with acetone / diethyl ether (1: 2) to dryness under vacuum to give 1.53 g (87.47%). M.p .: 228-230 ° C (with decomposition).

g (0.035 mol) of 3a, 17β-bis (aoethoxy) -2β, 6β-bbz0-tneoyl-1-piperazolyl) -5β-andthoslane was dissolved in 100 ml of ethanol with stirring, followed by 19.5 g (0.104 g) of p. -toluolszulfoasav25 metiiészten added at such a rate that the temperature remains below 30 C, ^e. After stirring for 3 h, the reaction mixture was diluted with 500 mL of tenahydmurane and after stirring for a further 3 h, the precipitated solid was silied, washed twice with 50 mL of tetrabydrohnane and dried in vacuo to constant weight. The resulting crude product (31 g) was recrystallized from ethanone to give the title compound (26 g, 78.7%). Melting point: 175-177 ° C.

2SCS.S9.O.

Xfrfr * fr .frfrfr frfr ** frfrfrfr fr x »· * * ** ** φ * fr v fr« * fr * frfrfrfr * x frfr «* ** g (0.0104 mole) 4.4 * -í3a, 17β-Bis (methoxy) -5α-alpha-2-pyridyl-his (t, idylmethyl-piperazole) -di-C-toluenesulfonate is dissolved in 50 ml of ethanol with stirring, followed by 3.7 g at room temperature. Lithium bromide was added, the reaction mixture was stirred for 4 hours, then diluted with 200 ml of tetralodrofuran, and after a further 3 hours, the precipitated product was filtered, washed twice with 20 ml of tetrahydrofuran and dried under vacuum to constant weight. Dissolve in 36 ml of ethanol and give 0.36 g of lithium bimetidotate. to it, for 2 hours. The precipitated product was filtered off, washed twice with 20 ml of tetralidofluorobutane and dried in vacuo to a constant volume. The product thus obtained is slurried in 1 ml aetone and refluxed for 20 minutes. The product was filtered and dried under vacuum to constant weight to give 6.7 g (83%) of the title compound, mp 265-269 ° C (with decomposition).

dibremld g (0.035 mol) 3a, 17β-bis (aethoxy) -2,000, bis-bis (4-methyl-1-piperazinyl) -5a-dimethestrestane was dissolved with stirring. In 100 ml of ethanol. then (0.104 mol) of p-toluolszulfonsavmedlésztert 19.5 g was added at such a rate that the temperature remained below 30 ° C ^5. After stirring for 3 hours, lithium bronze (10.06 g, 0.116 mol) was added at room temperature, stirred for 2 hours, then diluted with 600 N tetralofluorofuran and stirred for an additional 4 hours. The precipitated product was filtered, twice with 40 mL of tetrofluoric acid. wash, dry under vacuum to constant weight. 30 g of product are obtained, which is dissolved in 80 ml of ethanol, 1.3 g of lithium bromide is added, stirred for one hour, diluted with 250 ml of tetrahydrofuran, filtered, washed twice with 40 ml of tetrahydrofuran and dried in vacuo to a residue. The crude product is .130 mL in aetone. slurry, boil for 20 min, filter the solid, wash with 2 x 50 mL acetone and dry under vacuum to constant weight to give the title product (27.5 g, 83%); 265-269 ° C (with decomposition).

25öS. ( ». 1I.

Claims (6)

1. The general imagery of (Η!) Ch _s f M ΦΦΦΦ ΦΦΦ Φ * *** (CA) 5 quaternary ammonium derivatives wherein X is a benzoalsalibate, or methane or cyanosoltbaate ·· or trifluoromethanesulfonate substituted in a para position with a methyl or nitro group or with a bromine atom 2. One of the following compounds of formula (131) according to claim 1: Κ) 4,4 ^γ - | 3α, .17β-Β1.8ζ (η <χ4οχί) -5α-δηί1τοδ'Ζίΰη ~ 2β _> 16β-0ϋ1ρ0ΐδ2 (1,1'-dimethyl-piperazirmmyl-di-Cptoino). 4 _sec 4 ^! '(3a, 7 (i-bis (acetoxy) -5'-x') tdrosdilatate-2, 3, 6, 6-dbtlhls (tert-dimethyl-1-pipetazinium) -dimethanesulfinate, 4,4 ^, - [3 '_> .t7p-bis (aeethoxy) -5,6-8η4Γ0 $ ζ · ίΰη-2β _> 16β-ΰϋ1} -0Ιδ2 (1 _> 1 ~ 4ίηΐ8ΐί1-ρΙρ0τηζίπΗηη) 15 dibenzenesulfonate, 4 ₅ 4 ^! 430,1? Δ · -01§ζ (ηοοξοχ1) '· 5α ·· ηηαχο8ζΐ2η' · 2βΚδβ-41ΰ1 · 5Κζ (1 J -dimethyl-plperazmittml-di (trifluoromethane - methane s ztd yarn), 3. The t-10ixWSae of formula OV) WS.883 & quaternary armnone derivatives wherein X is a benzene sulfonate or methane or ethanesulfonate or trifluoromethanesulfonate substituted at a para position with a metal or nitro group or a bomatomate; A compound of formula (IV) according to claim 3 which is one of the following; 1- (3- (Χ »Πβ-Μ§ζ (δοοίοχΙ)" 2β- (1-ριρ © π <Ι1 «ί1) -5α- ώΌ82 ^ ^ η-1όβ ·· 11] -1-ιηδΐΠ ~ ρφ6τί41ηίηηϊ- ( ΐτιβ "οτmetánsznlfonát) H3mM? Pbtas (ethylene} -2- (1-piperidinyl) -4,5-androstane-t-1 H -methyl-piperidinuro ~ (p10 toluenesulfonate). <RTI ID = 0.0> IJlotlJ-bis-acetyloxySp-tripiperyl-lO-O </RTI> andandrose-l-l-tneyclplinidinyl] methanesulfonate. S. An environmentally friendly process is the use of 4 _> 4 ^, ·· [3α, 17β-1 «δζ (8θ« ΐοχί) -5α- & η0Γθδζΐάη2.p _> end-dull4sis (rildimethyl-pipew; mlinn) dibromide of formula (I) and ( 0) Formula 1-13α _> 1.7β-0ί8ζ (3θ «4οχ1) -2β" (1-ρ1ρηηύ1η11) ·· 5α ·· ·ηΰΓθ & ζ (άπ-1δβ · 'ίΙρ1-ίη © ι piperidlninm-brondd) so »that BUJofe.ífcc φ * * * «« ♦ Ο Φ *** ΦΦΦ * φφ or formula. to a solution of the dlacetate derivatives in acetone, ethyl acetate, ethyl acetate or tetrahydrofuran, with stirring, 2.5-4.0 molar equivalents of p-toluenesulfonic acid methyl ester, benzenesulphonic acid methyl ester, p-sitro or p-butylbenzenesulfonic acid methyl, ethanesulfomic acid methyl ester is added, the precipitated (Hl) Or (IV): quatemer arnmdninm numerical tables of the general formula <WS, «K s> s. <s>.; S, where X is a given case. denotes benzo substituted benzoyl lonate, or methyl or nitrous sulphate in the fatty position, and then, after purification and drying, dissolved in acetomifil; (l), 2.5 to 5.0 equivalents of the starting lithium chloride are added to the starting material, while stirring, the precipitated lithium formed is dried, washed with acetonitrile, and the combined filtrates are separated, and the precipitated product (1) or (II) is isolated. , optionally purified and dried, or, in a stirred hand, 2.5 to 4.0 molar equivalents of p-toluenesulfuric acid in a stirred bed of ethanol solution of the diacetate derivative of formula (V) is added to maintain the temperature of the solution below 30 X 3. the mixture is diluted with tetrahydrofuran, the quaternary anunionium derivative of general formula (01) is isolated, where X is p-toluenesulfonate, and after purification and drying, dissolved in acetonitrile with stirring; In addition, 2.5 to 5.0 equivalents of IKI-chromide are added to the starting material, the precipitated lithium salts formed are by-passed filtered, washed with ethylene, the combined filtrates are evaporated, the product of formula (1) is isolated, optionally purified and dried. , obsession e) adding to the ethanolic solution of the diaethate derivative of formula (V) with stirring, 2.5-4.0 molar equivalents of methyl p-tosyl sulfonic acid, so that the temperature of the solution is below 30 ° C. After completion of the reaction, the reaction mixture is diluted with Liquid Trichloromethane, the quaternary ammonium derivative (01) where X is p-toluenesulphonate is isolated and, after purification and drying, dissolved in ethanol, with stirring, to the starting material. 2.5-5 () equivalents of Ikiamchromide are added and the thimble end titanium is diluted with tetrhydroforan to yield the quaternary ammonone derivative of formula (1) «ίΚϊίϊ.ίίΟί 2S3öjSS> "! -21k-gray with tetzahldrofuran. washed, dissolved in ethanol, dried over ethanol, mixed with 0.2-0.5 equivalents of lithium hrenude based on the starting material, diluted with tetrahydrofuran, and the coffees are isolated, washed and dried, or d) the diacetate derivative of imageine (V) is acetone, acetyltril, ethyl acetate or 5 of tetrahydrofuran, with stirring, based on the nitrogen atoms to be quaternized 1.0-1.1 eq. Of trifluoromethanesulfonic acid methyl ester is added at 10 and 35 ° C to form the ammonium derivative of formula (III) wherein X is trifluoromethanesulfonate ion in ether, tetrahydrofuran, n-hexane or n. -beptane diluted, filtered, and after purification and drying, if necessary, dissolved in acetone with stirring. 2.5 to 4.0 equivalents of lithium bromide per 10 starting materials are isolated, and the precipitated product is isolated, optionally purified and dried, or e) 1.0 to 1.1 equivalents of methyl trifluoromethanesulfonic acid methyl ester is added to a solution of the diacetate derivative of formula VI in acetone, ether or tetrahydrofuran at 10 to 35 ° C, based on the atoms to be quaternized, if the reaction is carried out in acetone. after completion of diluting the reaction mixture with ether), the ammonium derivative of formula (IV), wherein X is a fluorophenyl styronate ion, is filtered off, and after purification and drying, it is dissolved in acetone with stirring for 2.5-4% of the starting material. 0 equivalents of lithium bromide are added, the precipitated product of formula (Π) is isolated, optionally purified and dried, or (R) To a solution of the diacetate derivatives (V) or (VIII) in acetone, acetonitrile, ethyl acetate or tetrahydrofuran is added with stirring 1.0-1.1 equivalents of methyl trifluoromethanesulfonic acid methyl ester at 35 ° C. C, a reaction mixture containing a large amount of ammonium of formula (111) or (IV) where X is a trifluoromethanesulfonate ion to the quaternary ammonium salts of formula (Si) or (IV) wherein X is a trifluoromethanesulfonate ion by reaction with 2.5-4.0 equivalents of lyrinm-bmnnd, the precipitated products of formula (I) or (Π) are isolated, optionally purified and dried, or g) To a stirred solution of the diacetate derivative of formula (V) in ethanol is added 2.5-4 molar equivalents of p-toluenesulfonic acid methyl ester under stirring so that the temperature of the solution is below 30 ° C. After completion of the reaction, the solution is allowed to remain in solution, based on the starting material, with stirring 2.5-5.0 equivalents of lithium bromide are added and the reaction is quenched with tetrahydrofuran to precipitate. The quaternary ammonium derivative (1) is filtered off. SSJiöKMSöC 2S9S.Ö8.lg. washed with tetrahydroforan, dissolved in ethanol after plowing, mixed with 0.24) of lithium bronchodolate (starting material), diluted with potassium tetroxide, the precipitated compound of formula (I) was isolated, washed and dried. She. Process d) according to claim _{5 for the preparation of} 4- [4- (3x, n? -Bis (acetoxy) -5? 5) α-androstane-2?, 10? -Dull-bis (1,1,4-methyl-piperazine-dimethyl-dibromide). , characterized in that after completion of the quatemerisation reaction, the resulting reaction mixture containing a quatemeric ammonium derivative of formula (ΠΪ) wherein X is trifluoromethanesulfonate ion is reacted without isolation of the quatemeric anunizedunion derivative (ΠΪ). . 10 7, Process (e) according to claim 5, for the preparation of 1- [3tx, nisbis (acetoxy) -2,5- (1-piperidinyl) -5a-androstatope-3-yl-1-neryl-p-parparidyloum bromide of formula (II). , characterized in that after completion of the quaternization reaction, the reaction mixture containing the quaternary amine amine derivative represented by general formula (IV) - wherein X7 is methylmorphosulfonamone - is reacted without isolation of the quaternary ammonium amide derivative (IV). . lííium bromide