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    • 专利摘要:
    Novel quaternary ammonium salts of certain phenylpropylamines and phenylbutylamines are disclosed. They are useful drugs for treating arrhythmia and prolonging the action potential of cardiac muscle. They are prepared by reacting a tertiary amine with an alkyl salt.
    公开号:SU745360A3
    申请号:SU782705793
    申请日:1978-12-19
    公开日:1980-06-30
    发明作者:Барнет Моллой Брайан；Ирвин Стейнберг Митчел
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR PRODUCING PENYLALKYLAMINE DERIVATIVES The invention relates to the method of (Production of new derivatives of phenylalkylamine, which have physiologic activity and can be used in medicine. In medical practice, use of salt (0-bromobenzyl) -ethyl dimethylammonium 1 was found. the described derivatives have a number of side effects, which limits their pE) name. The aim of the invention is to expand the arsenal of means of action on a living organism. According to the invention, a method is described for the preparation of quaternary ammonium salts of phenylalkylamine of the general formula b- / (CHz) n-cU (U XAI 5 p 1 or 2; 25 RJ. - hydrogen or alkyl C - g JR - hydrogen or alkyl Cj; Rj - alkyl C 1.4 or phenylalkyl C 1-4;. „R is alkyl; L1: it’s legs i. I | than, 2, alk Rg but drank these R – alkyl C 1-10 / or Rd and R5 together with the adjacent atom nitrogen form a heterocyclic ring with 4-7 carbon atoms; R.- independently hydrogen, hydroxy halide, nitro, alkoxy C, or alkyl Ci-3, provided that at least one of B or RY is hydrogen and the other is different .- from nitrogru p; 1, then R5 is alkyl; X is an anion. The method according to the invention consists of the reaction of the three-way arylamine NRgR9R | 0 de Rg, R9 JO is one of 5 and /. at Rji-iRg- / y-CHz- ( CHz) nC pp. 7 X, where R is Rg, R, R or selected above .In these formulas, Rj is hydrogen or C -2 IS is precisely methyl, ethyl, is hydrogen or alkyl C. d, and names methyl, ethyl , isopropyl or about R - alkyl C1-4 for example methyl, l, propyl, butyL or isopropyl,
     & i SMSVilf
    4 ,,. ,,, i .., ,, -, .-, -.
    phenylalkyl Cj. j; 4 phenylmethyl, phenylethyl, 3-phenylpropyl, 4-phenylbutyl, or phenylisopropyl 1-alkyl 1-8 include methyl, ethyl, propyl, butyl, isopentyl, 2-methylbuty, 2-methylpentyl, 1-Oylpentyl, goptil, octyl , isooctyl and t. P. ; Rj alkyl C 1-10, for example methyl, ethyl ,.  pentyl, isohexyl, 2-ethylheptyl, heptyl, 3-methylheptyl, 1,2-dimethylheptyl, 1,2-dimethyloctyl, 1,1-dimethylheptyl, nonyl, decyl and the alkyl groups related to them; if p.  1 and R and Ry are different from nitro, then R5 is C 6-10 alkyl. In addition, R and R are alkyl groups, together with the nitrogen atom to which they are attached, can form a heterocyclic ring with 4-7 carbon atoms. .  Examples of such ring systems include pyrrolidine, piperidine, hexahydroazepine, and octagus droazepine.   hydrogen, hydroxy halo, alkoxy C, 2 nitro or alkyl C. 2 Typical halides are fluorine, chlorine and bromine.  Examples of alkoxy C are methoxyl, ethoxy and isopropyl.  Alkyl with i-a - methyl, ethyl and propyl.  As X, an anion can be introduced, which together with the ammonium cation forms a therapeutically acceptable c & l. Anions such as chloride, bromide, sulfonate, p -toluenesulfonate, meta sulfonate, p-bromophenylsulfonate, frsfat, carbonate, are usually used oxalate, succinate citrate, benoate, acetate, etc. P.  The best and most commonly used anion is bromide.  .  . .  , Usually, M, M-dialkyl-3-phenylpropylamine or N, N-dialkyl-4-phenylbutylamine is reacted with an almost equimolar amount or with an excess of alkylating reagent, for example, alkyl halide alkyl sulfate, alkyl tosylate and the like. P.  In particular, it is possible to react the disubstituted propyl or butyl 1 min of the formula.     .  .    -.  -.     R - (JHz- (CHz) n- | -w with alkyl radicals with a reagent of the formula RS-X, in a solvent, for example, diethyl ether.  Quaternary ammonium salts of Bbj, obtained according to any of the decree methods, are distinguished by high crisis.  Usually, if a tertiary amine and al: is reacting with a kilirut reagent, the salt falls out of solution and is filtered off.  The salt obtained is easily purified by the organic method, for example, by recrystallization from this; common organic solvents, such as ethyl acetate, acetone, methanol, benzene, etc. P.  In the preparation of the quaternary ammonium salts according to the invention, it is possible to carry out the reaction of a tertiary amine with phenylpropyl or phenylbutyl derivatives, in which in the 1-position it is easily eliminating a group, for example, chlorine, bromine, methanesulfonyl, p -toluenesulfonyl, azide, and so on. P.  In this method, a tertiary amine is reacted, for example methylethyloctylamine, with an equimolar amount of a phenylpropyl derivative, for example 3- (3-bromophenyl) propyl chloride or a phenylbutyl derivative, for example 4- (4-methoxyphenyl) butyl bromide.  Such condensation is usually carried out in an inert solvent, for example diethyl. ohm ether or benzene, or the reaction can be carried out without them.  Condensation usually ends in, for 1-10 days, if it is carried out at 50-200 ° C.  The product is a quaternary ammonium salt, and is usually crystalline and is isolated if desired by filtration and recrystallization.  Example 1  N-Nonyl-4-phenylbutylamine.  A solution of 30 g of 4-phenylbutyl chloride and 77 g of nonylamine was heated at 100 s for 48 h.  The reaction mixture was cooled, added to 5 l of water.  Then water solution: rational. the mixture was alkalinized 5 n.  sodium hydroxide solution.  The aqueous alkaline solution was extracted with a few drops, several times with diethyl ether, the extracts were combined, the solvent was distilled off in vacuum and an oil was obtained, it was distilled and 30.2 g of N- (nonyl) -4-phenylbutylamine were obtained.  Example 2  N-Hanil-N-4-phenylbutylamine.  To a cold {5®c) solution of 28.2 ml of 90% aqueous ant formic acid. The slots were added in portions over 10 minutes to a solution of 30.2 g of N-nonyl-4-phenylbutylamine and 27 ml of 37% aqueous formaldehyde.  The reaction mixture was stirred and heated at 12 hours.  Then the mixture was cooled to acidified with 90 ml of 4 n.  HC, acidic solution evaporated to. 20 ml, then the mixture was diluted with water and the acidic solution was washed with diethyl ether, basified with 5N. caustic soda.  The aqueous solution was extracted 3 times with 100 ml of diethyl ether.  The ether extracts were combined, washed with water and dried.  Distillation of the solvent in vacuo gave 30.16 g of product as an oil.  This oil was distilled and 24.99 g of H-nonyl-M-methyl-4-feiyl-4-phenylbutylamine were obtained; . t. kip  124-127 ° С 0.01 (mm Hg Art. ).  PRI im p 3.  (-Nrnil-Mme. til-4-fbnylbutyl1 they are oceanic.  To the permeate solution 24.99 g N-.  -nonyl-N-methyl-4-phenylbutylamine in about 300 ml of isopropyl alcohol was added per one portion of 7.8 g of oxalic acid in 120 ml of isopropyl alcohol.  The product crystallized out of solution, it was filtered and 23.9 g of M-nonyl-M-methyl-4-phenylbutylammonium oxalate, t, were obtained. square  118-120 ° C: Calculated for dl, C 69, H 9.83J N 3.69.  .  Found,%: C 69.819, H 9.60; N 3.89.  Example 4  N, M-Dimethyl-M-but nyl-4-phenylbutylammonium.  7 g of M-nonyl-M-metsh1-4-phenylbutyl ammonium oxalate suspended in diethyl ether and reacted with 5 N.  caustic soda.  The organic layer was separated, the solvent was distilled off and obtained. 5.3 g of M-nonyl-M-methyl-4-phenylbutylamine.  This compound was dissolved in 150 ml of diethyl ether and stirred at 25 ° C in a flask, dried with a calcium sulfate drying tube.  The ether solution was saturated with gaseous methyl bromide and the mixture was stored at room temperature for 48 hours.  The resulting precipitate was filtered and recrystallized from 50 ml of ethyl acetate and 80 ml of cyclohexanone.  The crystalline product was filtered, dried in a desiccator and obtained 2. , 27 g of N, N-dimethyl-M-nonyl-4-phenylbutylammonium bromide; t. square  59-61c.  Calculated,%: C 65.61} H 9.6; N 3.64, - Br 20.78.  C2I HsgBrN.  Found,%: C 65.94; H 9.82; N 3.68; Вг 20,55.  Examples 5-24.  By the reaction of a tertiary amine with alkyl bromide, the following compounds were obtained according to the method of Example 4.  N, N-Diheptyl-Y-methyl-4-phenylbuty ammonium bromide; square  84-8bS  Calculated for C25H4bBgM,%: C 68.1 H 10.52; N ЗД8; Br 18.14.  Found,%: C 67.88; H 10.56, N 3.27; Вг 18,01.  N, M-Dimethyl-N-octyl-4-phenylbutyl ammonium bromide; t. square  47-50 ° C. .   Calculated for Cgo HC, BrN%.  C, 64.8 H, 9.80; N 3.78; Br 21.57.  . Found,% C 64.67; H 9.51, N 3.56; Br 21.49.   N, L-Dihexyl-N-methyl-4-phenylbuty: ammonium bromide; t. square  65-67 0.  Calculated for C23H42BN /% sC, 66.9 N, 10.26; N 3.4Q; Br 19.37.  Found,%: C 66.73; H 10.11; N 3.36, Br 19.45.  N, M-Dipentil-M-methyl-4-phenylbutylammonium bromide; t. square  61-bz C ;.  Calculated for C2i, HrBnH,%: C 65.6 H 9.96; N 3.64; Br 20.78.  Found: С 65,32; H 9.87, N 3.57; Wg 21.00.  N, N-Dimethyl-N-isopropyl-4-phenylbutylammonium bromide; t. square  162-164c.  Calculated for C, 5 H feBrN,%: C 60.00; 8.73; N 4.66; Br 26.61.  Found,%: C 59.85; H 8.48; 4.51; Br 26.71.  N, N-Dimethyl-M-propyl-4-phenylbummonium bromide; t. square  93-95 ° C.  Calculated for Cjg N2bVgM,%: C 60, OO; 8.73; N 4.66; Br 26.61.  Found,%: C 59.73, H 8.45, N 4.40, 26.59.  N, N-Dimethyl-N-pentil-4-phenylbutylammonium bromide; t.  square . 76-78 C.  Calculated for C) -,%: C 62.19, 9.21; -N 4.27; Br 24.34.  Found,%: C 61.89; H 9.02; 4.29; Br 24.47.  N, N-Dimethyl-M-hexyl-4-phenylbutylmonium bromide; t. square  46-48C.  Calculated for C ig,%: C 63.15; 4.09, Br 23.34.  Found,%: C 62.92; H 9.25; N 4.17; 23.52.   N, N-Dimethyl-N- (1-methylpropyl) -4eneylbutylammonium bromide; t. square  .  Calculated for:%: C 61.14; 8.98; N 4.46; Br 25.42.  Found,%: C 60.92, H 8.71, N 4.46; 25.58.  N, M-Dimetil-M-i. zobutyl-4-phenylbummonium bromide; t. square  107-109 C.  Calculated for C. | f,%: 62,19; H 9.21; N 4.27; Br 24.34.  .  Found,%: C 62.10, H 9.32; 4.06 G Br 24.53.  N, M-Diethyl-L-methyl-4-phenylbutyl ionium bromide; t. square  145-147C.  Calculated for Cjs H bVgM,%: 0.00; H 8.73; N 4.66; Br 26.61.  Found: C 60.27; H 8.93; , 84; Br 26.90.  N, M-Dibutyl-M-methyl-4-phenyl-butylbromide; t. square  70-72c.  Calculated for C ig Ne4B,% g 4.03; H 9.62; iN 3.93, Br 22.42.  Found,%: C 63.80; H 9.37; , 20, Br 22.40.  N, M-Dimethyl-M-butyl-4-phenyl-butylbromide; t. square  95-96 0.  Calculated for C ,,%: C 61.14, 98; N 4.46; Br 25.42.  Found,%: C 60.94; H 9.12; N 4.60 25.63.  N, M-Dipentil-M-ethyl-4-phenylbutylonium bromide; t. square  41-45 ° C.  Calculated for%: C, 66.31; 0.12; N 3.52; Br 20.05.  Found,%: C 66.08; H, 9.88; N 3.50; 19.86.  N, M-Dimethyl-M-ethyl-4-phenylbutylonium bromide; t. square  160-162C.  Calculated for C | 4 H2ABrN,%: C 58.74, 45; N, 4.89; Br 27.91.  Found,%: C 58.44; H 8.22; M 5.11; 27.85.  N, N, M-Triethyl-4-phenylbutylammonium bromide; t. square  ZZ-B S.  Calculated for C | {,,%: C 61.14 H 8.98; N 4.46; Br 25.42.  Found,%: C 60.85; H 8.70 VN 4.4; Br 25.70.  N, N, M Tripropyl-4-phenylbutylammonium bromide, tons square  113-115 ° C.  Calculated for C | 9 Hz4 BgM,%: C 64.03 H 9.62; N 3.93; Br 22.42.  Found,%: C 63.86; H 9/54; N 3.71 Bg 22.33.  H-methyl-M- (4-phenylbuty) -hexagide roazepiniumbromide; t. square  129-131C.  Included for% g C 62.57; H 8.65; N 4.29; Br 24.49.  Found,%; C 62.32; H 8.43; N 4.28; Br 24.57.  M-Methyl-1-M- (4-phenylbutyl) -tetrahydropyrrolium bromide; t. square  128-130 ° C. Calculated for C | 5H24Br,%: C 60.40, H 8.11; N 4.70; Br 26.79.  Found,%: C 60.47; H 7.86, N 4.86; Br 26.63.   ,,, / :. . . . , :. i Example 25.  N, N, N-Trimethyl-4-phenylbutylammonium methane sulfonate.  PacTbopiV gm, D -Ymethyl-4-fenylbutylamine in 500 ml of diethyl ether was stirred at 0 ° C in a flask equipped with a calcium sulfate drying tube with 9.1 ml of dimethyl sulfate added dropwise over 90 min.  Then the mixture was heated to room temperature and stirred for 12 hours.  The precipitate was filtered off and recrystallized from 300 ml of acetone to obtain 27.64 g of N, M, H-trimethyl-4-, -phenylbutylammonium methane sulfonate; t. pl, 122-124c.  Calculated for C | 4H25 N504,%: C 55.42; H 8.31; M 4.62; S 10.60.  Found,%: C 55.62; H 8.10; N 4.68; S 10.57.  PRI me R 26.  According to the procedure of Example 25, M- (4-phenylbutyl) -piperidine was reacted with dimethyl sulfate to obtain M-methyl-M- (4-phenylbutyl) -piperidinium methanesulfonate; t. square  54-56 S.   Calculated From IT H29NSO,%: C 59.45 N 8.51; N 4.08; S.  Found,%: C 59.23, H 8.64; N 4.05; S 9.12.  Example 27  M-heptyl-4-phenyl butylamine.  A mixture of 125 g of 4-phenylbutyl-HybriDa and 250 g of heptylamine was stirred and heated for 4 days.  After cooling to room temperature and adding 2aO ml of water, the mixture was made basic with 5N.  caustic soda. The alkaline solution was extruded with diethyl ether, the extracts were combined and washed with water, and pro-Yj f tft T rag “i sulfuric acid.  The bbd layer was separated, washed with fresh diethyl ether again. alkalized 5 n.  sodium hydroxide solution.  The product was extracted from the aqueous solution with fresh diethyl ether.  The ether extracts were combined, washed with water and dried.  After distilling off the solvent in vacuo, 186 g of product were obtained in the form of an oil, which was distilled and 135.46 g of M-heptyl-4-phenylbutylamine were obtained, t. kip  160-166 with (5mmrt. Art. ).  P p i.  meper 28.  N-Acetyl-M-heptyl-4-phenylbutylamine. To a cold, stirred solution of 25.67 g of N-rentil-4-phenylbutylamine in 70 ml of acetone containing 22.1 g of sodium carbonate and 70 ml of water, a solution of 8.1 ml of acetyl chloride in 140 ml of acetone was added dropwise over 60 minutes.  In time - ". . ,, „„ „,,,,. ,, „Addition temperature of the mixture was kept.  After the addition was complete, the mixture was allowed to warm to 25 ° C, then stirred for 12 hours at this temperature.  Then the reaction mixture was evaporated in vacuo to about 20 ml and diluted with 60 ml of fresh water.  The aqueous solution was extracted several times with diethyl ether, the extracts were combined, washed with water, 1M citric acid solution, 4 more times with water and dried.  Distillation of the solvent in vacuo gave 19.69 g of N-acetyl-M-heptyl-4-phenylbutylamine.  Example 29  M-Ethyl-M-heptyl-4-phenylbutylamine.  To a stirred solution of 0.94 mol of diborane in 220 ml of Tatrahydrofuran (THF) a solution of 19.69 g of N-acetyl-N-heptyl-4-phenylbutylamine in 50 ml of THF was added over 20 minutes.  Then the mixture was refluxed for l2 h.  After cooling to room temperature, it was stirred and 75 ml of cold (5c) 2 N was added dropwise over 20 minutes.  hydrochloric acid.  Then the mixture was scrubbed to 80 ml and diluted with 100 ml of conc.  EVERYTHING.  The mixture was stirred and refluxed for 1 hour, then the mixture was cooled to room temperature and basified with 5N.  sodium hydroxide solution.  The aqueous alkaline solution was extracted several times with diethyl ether.  The extracts were combined, washed with water and extracted with 2N.  sulfuric acid.  Acid extracts combined, alkalized 5 n.  The solution was caustic soda / the solution was extracted with diethyl ether, the extracts were combined, washed with water, dried and the solvent was distilled off in vacuum, 15.22 g of product was obtained as an oil.  The oil was distilled and 13.8 g of N-ethyl-N-heptyl-4-phenylbutylamine were obtained, t. kip  128129 С (0.1 mm Hg). Art. ).  .  PRI me R 30.  According to the procedure of Examples 28 and 29, N-heptyl-M-pentanoyl-4-phenylbutylamine was obtained, it was reduced by reaction, with diborane, and H-pentyl-H-heptyl-4-phenylbutylamine was obtained.  Example 31  TO. M-Diethyl-Mte tyl-4-phenylbutylammonium bromide.  In a flask equipped with a calcium sulfate drying tube, a solution of 4.33 g of N-ethyl-N-heptyl-4-phenylbutylamine in 35 ml of ethyl bromide was mixed and refluxed for 48 hours.  The mixture was cooled to room temperature, the excess ethyl bromide was distilled off in vacuo.  The residue was dissolved in 50 ml of ethyl acetate ± saturated with doi, the product precipitated on cooling to.  The precipitate was filtered off and recrystallized from fresh wet ethyl Acetate to give 5.5 N, H-diethyl-M-teptyl-4-phenylbutidanum nibromide as a monohydrate; PL 48-50C.  Calculated for Cai H4oBrMO,%: C, 62.67; H 10.02; N 3.48; Br 19.85.  Found,%: C 62.72; H 9.88; N 3.3 Wg 19.65. .   Example 32  According to the procedure of Example 31, prepared in Example 30, N-pentil-N-heptyl-4-phenylbutyIlamine, reacted with methyl bromide and N-heptyl-4-phenylbutylamine was obtained, reacted with methyl bromide to obtain M-heptyl-methyl-M- pentyl-4-phenylbutylammonium bromide} t. square  55-57 p.  Calculated for Cgs H42BN,%: C, 66.97; H 10.26; N 3.40; Br 19.37.  Found,%: C 66.76; H 10.04; N 3.29; Вг 18,93.  Example 33  N-Teptil-4- (4-chlorophenyl) -butyramide.  it- (4 Chlorophenyl) -butyric acid was obtained by the reaction of 4-chlorobenzaldehyde with ethyl acetate and sodium cyanide to obtain ethyl 4- (chlorophenyl-4 oxobutyrate, it was hydrolyzed, and 4- (4-chlorophenyl) -4-oxo-butyric acid was obtained, then restored the 4-oxo group of the acid by reaction with zinc and. hydrochloric acid.  to a stirred solution of 1b, 15 4- (4-chlorophenyl) -butyric acid in 200 ml of benzene dropwise; In je4eHHe, 30 ml of oxalic chloride was added in 30 minutes.  After the addition was complete, the mixture was refluxed for 3 hours, then cooled to room temperature.  Unreacted oxalyl chloride was distilled off in vacuo, the remaining solution was diluted with 200 ml of diethyl ether. The mixture was cooled to 5 ° C in an ice bath, then 28.3 g of heptylamine in 30 ml of DIETHYL ester was added dropwise over 60 minutes.  The mixture was stirred at 25 ° C for 12 hours, then diluted with 100 ml of water.  The aqueous reaction mixture was extracted with diethyl ether, the extract was washed with 2N water.  hydrochloric acid, again with water, dried, the solvent was distilled off in vacuo and 24.45 g of N-heptyl-4- (4-chlorophenyl) -N-butyramide was obtained; t. square  35-38 C.  : PRI me R 34.  M-heptyl-4- (4-chlorophenyl) -butylamine.  To a stirred solution of 268 ml (0.94 mol) of diborane in THF, a solution of 24.45 g was added dropwise over 90 minutes.  I-heptyl-4- (4-chlorophenyl) -butyramide in 100 ml of THF.  The mixture was refluxed and stirred for 12 h.  After cooling, an excess of 2 N was added.  HgE to decompose the remaining diborane.  Then the solvent was removed by evaporation under reduced pressure, and the resulting residue was diluted with a 100 ml hydrochloric acid end. The acidic reaction mixture was heated to reflux and stirred for 45 minutes, followed by secondary cooling to room temperature. temperature  By adding 5 N sodium hydroxide solution. The alkaline solution was reported to the acidic solution: the reaction and the product were extracted from the alkaline solution with diethyl ether, rum.  The ether extracts were collected / washed and subjected to extraction with 2N sulfuric acid.  Next, to the acidic aqueous solution was added 5 n.  sodium hydroxide solution, and then the alkaline solution was extracted several times with diethyl ether.  The ether extracts were combined, washed with water and dried.  As a result of the further evaporation of the solvent, 21.86 g of N-H-heptyl-4- (4-chlorophenyl) -butylamine were obtained.  I and p and mep 35.  Mn-heptyl-M-methyl-4- (4-chlorophenyl) -butylamine.  i A solution of 10 g of m-n-heptyl-4- (4-chloro-phenyl) -butylamine, 9 ml of 90% muraboxylic acid and 8.7 ml of a 37% aqueous formaldehyde solution were subjected to additional decomposition visual observation of carbon dioxide.  Then the reaction mixture was cooled and kept at room temperature for 10 minutes.  Then: the reaction mixture was reheated until. 1pO ° C and kept at this temperature for 24 hours  After the mixture was cooled to ambient to room temperature, it was diluted by adding 40 ml of 4N.   after that, the excess solvent was distilled off in vacuo.  The remaining oil was diluted with water, doi, alkalinized 5 n.  with caustic soda, the solution was extracted with diethyl ether, the ether extracts were combined and the product was extracted with 2N.  sulfuric acid.  Acid extracts combined And alkalized 5 n.  caustic soda.  The alkaline solution was extracted with fresh diethyl ether, the extracts were combined, washed with water and dried -.  After the solvent was rtgon, 9, 8 g of M-heptyl-M-methyl-4- (4-chlorophenyl) -butylamine was obtained.  The amine was dissolved in 25 ml of meridate and added in one portion to a solution of 3.0 g of oxalic acid.  1 lots in 150 ml of ethyl acetate.  The precipitate was filtered off, air dried and 12.13 g of M-heptyl-M-methyl-4- (4-chlorophenyl) -butylammonium oxalate was obtained; t. square  102-104 ° C.  Calculated by Cgo length,%: C 62.24; H 3.36; N 3.63; CE 9.19.  Found,%: C 62.28; H, 8.45; N, 3.46.  CE 9.20.   Example 36  N, K-Dimethyl-L-heptyl-4- (4-chlorophenyl) -butylammonium. bromide.  A solution of 5.0 g of H-heptyl-M-methyl-4- (4-chlorophenyl) -butylamine in 100 ml of diethyl ether was stirred while bubbling into a solution of gaseous methyl bromide until saturation.  The reaction mixture was stirred at 25 ° C for 8 h, then cooled to OC, precipitated at room temperature for 48 h, then it was filtered and recrystallized from 50 ml of ethyl acetate to obtain 5.55 g of N, N-dimethyl -M-teptil-4- (4-chlorophenyl) -butylammonium bromide, t. square  58 60s  Calculated for C | 9 BN;%: C 58.39; H 8.51, N 3.58; CE 9.07; Br 20.44.  .  Found,%: C 58.16; H 8.27; N 3.5 SE 9.34; Вг 20,58.  Example 37  N, M-Diethyl-Y-he-methyl-4- (4-chlorophenyl) -butylammonium bromide.  A solution of 1.27 g of M-ethyl-M-heptyl-4- (4-chlorophenyl) -butylamine in 20 ml of ethyl bromide was refluxed and stirred for one week.  But then the reaction mixture was cooled, an excess of ethyl bromide was distilled off in vacuo and the product was obtained as an oil.  This oil was crystallized from ethyl acetate, saturated with water.  1.47 g of N, M-diethyl-M-heptyl-4- (4-chlorophenyl) -butylammonium bromide were obtained as a dihydrate; t. square  29-30s / Calculated for C VgCPO,%: C 55.45; H 9.08; 3.08; CE 7.79; Вг 17,56.  Found,%: C 55.15; H 8.87; 3.03 Cf 8.08; at 17.57.  Example 38  N, N, N-Triethyl-4- (4-chlorophenyl) -butylammonium bromide A solution of 4.3 N, M-diethyl-4- (4-chloro-phenyl) -butylamine in 35 ml ethyl bromide and stirred for 3 days.  The mixture was cooled to room temperature, you floated to oil by distilling off the excess ethyl bromide in vacuo.  The oil was crystallized from methyl ethyl ketone and 4.99 g of Y, M, M-trie were obtained. Tyl-4- (4-chlorophenyl) -butylammonium bromide; T. . Submarine  106-108 ° C.  Calculated, (, NgtVg C PN,%: C 55.10 H 7.80; N 4.02; Br 22.92; CE 10.17.   Found,%: C 55,12; H 7.83V N 4.23; VG 23.07; From 10.23.  Example 39 .  N, M-Dipentil-Y-methyl-4- (3-chlorophenyl) -butylammonium bromide.  Methyl bromide gas was bubbled into a solution of 5.0 g of N, N-dipentyl-4- (4-chlorophenyl) -butylamine in 150 ml of ethyl ether until complete.  no solution.  The reaction mixture was kept at room temperature for 2 days, then the precipitate was filtered and recrystallized from 50 ml of ethyl acetate and GOT 5/4 g of N, M-dipentyl-N-methyl-4- (4-chlorophenyl) -butylammonium bromide; t. square  81-83 s.  Calculated for C21 H3 CrM,%: C 60.21; H 8.90; N 3.34; Br 19.08; cr 8.46.  Found,%: C60,22; H 8.64, N 3.22; Br 19.30; CE 8.90.   P m and mep 40.  M-heptyl-1-methyl-4-phenylbutylamine.   A solution of 10 g of methyl 3-phenylpropyl ketone and 7.1 g of heptylamine in 80 ml of 2B ethanol containing 2 g of 5% palladium on carbon was stirred for 12 hours while in hydrogen gas at a pressure of 50 psi. inch (3.5 atm). Then the mixture was cooled to room temperature, the solvent was distilled off in vacuum and an oil was obtained, which was dissolved in 100 ml of diethyl ether, the ether solution was washed with 5 N.  sodium hydroxide solution and water.  After drying, the solvent was distilled off and 12.34 g of M-heptyl-1- were obtained. .  -methyl-4-phenylbutylamine.  Example 41  N-Heptyl-M-methyl-1-methyl-4-phenylbutylamine.  A solution of 12.34 g of M-heptyl-1-methyl-4-phenylbutylamine, 12.2 ml 90% but. formic acid and 11.6 ml of 37% aqueous formaldehyde were heated at 12 h.  Then cooled to room temperature.  The mixture was acidified with 4 O ml 4 N.  HC E, evaporated to 20 ml in vacuo.  Then the acidic mixture was made alkaline with 5 n.  sodium hydroxide solution, the solution was extracted several times with diethyl ether, the extracts were combined, washed with water, dried, the solvent was distilled off and 12.49 g of product was obtained as crude oil.  It was distilled and obtained 10/7 g of M-heptyl-M-methyl-1-methyl-4-phenylbutylamine, t. square  120-124C (O, 5 mmHg. Art. ).  PRI me R 42.  N, N-Dimethyl-N-Heptyl-l-methyl-phenylbutylamine.  In a stirred solution of 5.0 g of N-heptyl-M-methyl-1-methyl-4-phenylbutylamine in 150 ml of diethyl ether, ethyl bromide gas was bubbled through until saturation of the solution.  The mixture was then stirred for 4 days, during which time a white precipitate was formed, which was filtered and recrystallized from 50 ml of ethyl acetate to give 5.215 g of N, M-dimethyl-M-heptyl-1-methyl-4-phenylbutylammonium bromide; t. pl, 70-72 ° C.  Calculated for:%: C 65, H 9.80; N 3.78, Br 21.57.  Found,%: C 65,12; H 9.51; N 3.91; Br 21.64, Pr, Imer 43.  N, N, N-Tpethyl-1-methyl-4-phenylbutylammonium bromide A solution of 3.65 g of N, M-diethyl- (1-methyl-4-phenyl) -butylamine in 35 gll ethyl bromide was refluxed and mixed for 7 days.  After the mixture was cooled to room temperature and 50 ml of diethyl ether was added, a white precipitate was filtered off.  Recrystallization from 50 ml of methyl ethyl ketone gave 619 mg of N, N, N-tri-ethyl-1-methyl-phenylbutylammonium bromide; t. square  123-125 ° C. , Calculated C, - НзоВгМ,%: С 62.19; H 9.21; N 4.27; Br 24.34.  Found,%: C62,13; H9.06; I 4.29; Br 24.05.  Example 44  1-Methyl-4- (4-chlorophenyl-butylamine.  A solution of 19.08 g of methyl 3- (4-chlorophenyl) propyl ketone, 17.6 ml of formamide and 14.7 ml of 97% aqueous formic acid was heated at 160 ° 1 and mixed for 12 hours.  After the mixture was cooled to room temperature, it was diluted with 100 ml of water and the product was extracted with diethyl ether, the extracts were combined, washed with water and dried.  Evaporation of the solvent gave 20.7 g of oil, which was dissolved in 84 ml of conc.  HC and 400 ml of 25% dioxane in water, the aqueous solution was refluxed for 12 h.  After cooling to 30 ° C, the mixture was made alkaline with 5N.  NaOH.  The aqueous alkaline solution was extracted several times with diethyl ether.  The extracts were combined, washed with water, dried, the solvent was distilled off and 15.26 g of 1-methyl-4- (4-chlorophenyl) -butylamine were obtained.  Example 45 N, N-Dimethyl-l-methyl-4- (4-chlorophenyl) -butylamine 7.6 g of 1-methyl-4- (4-chlorophenyl) -butylamine reacted with 9.9 ml of 90% formic acid and 9-25 ml of 37% aqueous formaldehyde and 7.05 g of N, M-dimethyl-1-methyl-4- (4-chlorophenyl) -butylamine were obtained.  The free amine was reacted with HCE and N, N-dimethyl-l-methyl-4- (4-chlorophenyl) -butylammonium chloride was obtained; t. square  .  Calculated for C (Hji,% 5 C 59.55; H 8.07; N 5.34; CE 27.04.  Found: C 59.51, H 7.88; N 5.17; CE 27.4.  Example 46  N, N, H-Trimethyl-1-methyl-4- (4-chlorophenyl) -butylammonium bromide.  A solution of 3.02 g of N, N-dimethyl-l-methyl-4- (4-chlorophenyl) butylamine in 150 ml of diethyl ether. -mixed at 25 ° C and at the same time the methyl bromide solution was also bubbled until the solution was saturated.  Then the mixture was stirred for 24 hours, the precipitate was filtered and recrystallized from 50 ml of isopropyl alcohol to obtain 2.6 g of N, N, M-trimethyl-1-methyl-4- (4-chlorophenyl) -butylammonium bromide; t. square  204206 ° С (decomposition).  Calculated for Sc FN,%: C 52.43; H 7.23; N 4.37; Br 24.92; CE 11.05.  Found,%: C 52.5; H 7.02; N 4.21; Br 24.77; Ct 11.16.  Example 47  N, M-Diethyl-N-heptyl-4- (4-nitrophenyl) -butylammonium bromide.  A solution of 3.0 g of M-ethyl-M-heptyl-4- (4-naphtho-phenyl) -butylamine in 20 ml of ethyl bromide was stirred and heated to reflux for 4.5 days.  The mixture was cooled to 25 ° C and stored at this temperature for 72 hours.  An excess of ethyl bromide was stripped off in vacuo and the product was obtained as an oil, it was crystallized from ethyl acetate and acetone and recrystallized from ethyl acetate and acetone to obtain 2.06 g of M, H-diethyl-N-heptyl-4- (4-nitrophenyl) butyl ammonium bromide; t. square  67-69 ° C.  Calculated for Cji BrN202,%: C 58.73; H 8.68; N 6.52; Br 18.61.  Found,%: C 58.49; H 8.55; N 6.55; Вг 18,7.  Example 48  4- (4-Methoxyphenyl) -butylamine.  Ethyl 4-methoxycinnamate was hydrogenated to obtain 3- (4-methoxyphenyl) propionate.  It was reduced by reaction with lithium aluminum hydride to obtain 3- (4-methoxyphenyl) -propanol.  Propanol was reacted with methanesulfonyl chloride to obtain 3- (4-methoxyphenyl) -propylmethylsulfonate, which then reacted with sodium cyanide to obtain 4- (4-methoxyphenyl) -butyronitrile.  Calculated for C, | i | 2 | NO,%: C 75.40; H 7.48; 7.99.  .  . ; found,%: C, 75.24, H, 7.2l; N, 7.90.  Reduction of butyronitrile by reaction with diborane gave 4- {4-methoxyphenyl) -butylamine.  Example 49 N, N-Dimethyl-4- (4-methoxyphenyl) -butylamine.  To a cold stirred solution of 43.5 ml of 90% formic acid, 30.25 g of 4- (4-methoxyphenyl) -butylamine and 41.5 41.5 ml of 37% aqueous formaldeide were slowly added.  The mixture was heated at the start of carbon dioxide evolution, then the mixture was cooled to room temperature and stored for 15 minutes.  Then the mixture was again heated to 100 ° C and stirred at this temperature for 2 hours.  After cooling the mixture to e, it was acidified by adding VO l
    4n. NA B. The mixture was evaporated and diluted with water. The acidic aqueous solution was washed with diethyl ether, basified
    5H.NaOH, the product was extracted with fresh diethyl ether, the extracts were combined, washed with water and dried. After distilling off the solvent in vacuo, 26.67 g of N, M-dimethyl-4- (4-methoxyphenyl) -butylamine were obtained; bp 124-125s (5 mmHg). The amine was purified by reaction with HC and the hydrochloride obtained, which was recrystallized from 500 ml of 95% ethyl acetate in methanol; m.p. 127-129 s.
    Calculated for C, e HjjCfNO,%: C 64.05, H 9.10; N 5.75; CB 14.54.
    Found,%: C 63.88, H 8.88; N 5.77; C2 14.73.
    Example 50. N, N, N-Trimethyl-4- (4-methoxyphenyl) -butylammonium bromide.
    N, N-Dimethyl-4- (4-methoxyphenyl) -butylamine (4.35 g) reacted with methyl bromide according to the method of Example 46 and 4.95 g of N, N, M-trimethyl-4- (4-methoxyphenyl) were obtained -butylammonium bromide, which is recrystallized from acetone and methanol; m.p. U66-. 168 ° C. .
    Calculated for C | 4H2ABrNO,%: C 55.63; H 8.00; N 4, BZ; Br 26.44.
    Found,%: C 55.94, H 7.73; N 4.72; Br 26.73.
    ; Example 51. N, N-Dimethyl-3- (4-chlorophenyl) -propionamide.
    A solution of 18.4 g of 3- (4-chlorophenyl) -propionic acid and 42.5 ml of oxalyl chloride in 200 ml of benzene was stirred and refluxed for 3 hours. Then it was cooled to room temperature and evaporated to an oil in a vacuum. Formed: the acid chloride was dissolved in 25Q ml of diethyl ether, cooled to 5 ° C, stirred while bubbling through a solution of gaseous dimethylamine. After saturating the mixture with dimethylamine, it was stirred at 25 s for 1 h, then washed with water and 2N. NSE and dried. After distilling off the solvent, 21.5 g of N, N-dimethyl-3- (4-chlorophenyl) propionamide was obtained.
    PRI j meper 52. N i M-Dimethyl-H-pentyl-3- (4-chlorophenyl) -propylammonium bromide.
    The reaction of 21.9 g of N, N-dimethyl-3- (4-Chlorophenyl) -propionamide with diborano gave 16.88 g of N, N-dimethyl-3- (4-chlorofanil) -propylamine; m.p. 147-148 s. (Hg) A solution of 5.71 g of free amine in 150 ml of diethyl ether was stirred at room temperature and at this time 3.0 g of pentyl bromide was added in one portion. The mixture was then stirred at room temperature for 12 hours, during which time a white precipitate formed, was filtered and recrystallized from 125 ml of methyl ethyl ketone and 10 ml of methanol and
    N, M-dimethyl-L-pentyl-3- (4-chlorophenyl) propylammonium bromide was obtained.
    Example 53. N, M-dimethyl-4- (4-fluorophenyl) -butylamine.
    Reduction of cyclopropyl 4-fluorophenyl ketone by reaction with sodium borohydride gave cyclopropyl-4-fluorophenyl carbinol. The reaction of this carbinol with HCF in acetic acid led to the opening of the cyclopropyl ring, chlorination and dehydration, and 1-chloro-4- (4-fluorophenyl) -3-butene was obtained. Chlorobutene reacted with dimethylamine in ethanol at 100 ° C for 48 h and M, M-dimethyl 4- (4-fluorophenyl) -3-butenylamine was obtained. A solution of 54.4 g of butenylamine in 343 Ml of ethanol containing 2.5 g of Rene nickel was hydrogenated and 47.71 g of N, M-dimethyl-4- (4-fluorophenyl) -butyl-amine was obtained; mp.115-118 ° C (12 mm Hg)
    Example 54. According to the method of Example 46, 8.77 g of N, M-dimethyl-4- (4-fluorophenyl) -butylamine were reacted with methyl bromide to give a white precipitate, which was recrystallized from acetone and methanol to obtain 9.7 g N, M, M-trimethyl-4- (4-fluorophenyl) -butylammonium bromide; m.p. 160-162 ° C.
    Calculated for C | 3 H2i BrFN,%:
    C 53.80; H 7.29; N 4; 83; Br 27.53.
    Found: C 54.09; H 7.24N 4.78 Vg 21, If ,.
    Examples 55-57. According to the methods of examples 53 and 54, the following salts were obtained, starting from the corresponding cyclopro ylphenyl ketones.
    N, N, M-Trimethyl-4- (4-ethylphenyl) -butyl "1monium bromide, so pl. 147-149 ° C.
    Calculated for C | 5,%: C 60, OO; H 8.73; N 4.66; Br 26.61.
    Found,%: C 59.76; H 8.48; Br 26.6.
    N, N, M-Trimethyl-4- (4-Chlorf | Nyl) -butylammr bromide; m.p. 211-213 ° C
    Calculated for c 13 Hg; BrCPN,%: C 50.91; H 6.90; N 4.57; In g 26.05; every 11,56.
    Found,%: C 50.86 H, 6.57; 4.52; Br 26.11, CE 11.21.
    N, N, N-Trimethyl-4- (4-bromophenyl) -butylammonium bromide; m.p. 226-. 228 ° C. .
    Calculated for C | 2, Hgi Br2,%: C 44.47 H 6.03; N 3.99; Br 45.51.
    Found,%: C 44.65; H 6.08, N 4.21 Br 45.86.
    58. 3-Phenylpropylpropyl Pilketone.
    Propyl magnesium bromide was obtained by the reaction of 24 g of magnesium with 128 g of propyl bromide in 450 ml of diethyl ether. A solution of 100 g of 4-phenyl-butyl nitrile in 70 ml of diethyl ether was added dropwise to the Grinra reagent thus obtained. After the addition was complete, the reaction mixture was refluxed for 1 h, then cooled to room temperature and stirred for 12 h. Then the reaction mixture was slowly poured into 100 g of ice and 250 ml of horses. HNEC. The organic layer was separated, washed with water and dried. Distillation of the solvent and distillation of the product gave 57.9 g of 3-phenylpropylpropyl ketone; m.p. 134137С (10 mm Hg)
    Example 59. 1-Propyl-4-phenylbutylamine.
    A solution of 57.9 g of 3-phenylpropylpropyl ketone, 46 ml of 97% formic acid and 55 ml of formamide was stirred and heated for 12 hours. Then the reaction mixture was cooled to room temperature and diluted with 100 ml of water. The aqueous mixture was extracted 3 times with 100 ml of diethyl ether, the extracts were combined, washed with water and dried. Distillation of the solvent in vacuo gave 63.2 g of N-formyl-, 1-propyl-4-phenylbutylamine. It was dissolved in 1000 ml of a 25% solution of dioxane in water containing 168 ml of conc. HCE. The acidic solution was stirred and refluxed for 12 hours. Then the mixture was cooled to a comical temperature, extracted with ethyl ether, basified with 5 and. NaOH solution, the alkaline solution was extracted with diethyl ether, the ether extracts were combined, washed with water and dried. Distillation of the solvent gave 51 g of 1-propyl-4-phenylbutylamine.
    PRI me R 60. According to the method of Example 48, 38.2 g of 1-PROPIL-4-phenylbutylamine were reacted with 51.5 ml of 90% formic acid and 40 ml of 37% formaldehyde, obtained after distillation 37 , 1 g N, N, N, -dimethyl-l-propyl-4-phenylbutylamine; bp 118-120 ° C (5 mm Hg).
    Example 61. N, N, N-Trimethyl-l-propyl-4-phenylbutylamine.
    A solution of 9.0 g of N, M-dimethyl-1-propyl-4-phenylbutylamine in 150 ml of diethyl ether, saturated with methyl bromide was stirred at 48 hours. The precipitate was filtered and recrystallized from 250 ml of acetone and 9.74 g of N, N were obtained, H-trimethyl-1-propyl-4-phenylbutylammonium bromide J so pl. 158-1 ° C.,
    Calculated for C ifjHjgBrN,%: C 61.14. H 8-, 98; N 4.46; Br 25.42.
    Found: C 61.08; H 8, N 4,48; Br 25.54.
    Example 62. N, N, M-Trimethyl-1-ethyl-4-phenylbutylammonium bromide.
    Ethyl magnesium bromide was reacted with 4-phenylbutyl nitrile to give ethyl-3-phenylpropyl ketone. The reaction of ketone with formamide and formic acid was carried out and 1-ethyl-4-phenylbutylamine was obtained. Methylation of this amine by reaction with formaldehyde and formic acid gave N, M-dimethyl-1-ethyl-4-phenylbutylamine
    Quartenization of 6.2 g of dimethylamine according to the procedure of Example 52 gave 6.56 g of N, N, trimethyl-1-ethyl-4-phenylbutylammonium bromide; m.p. 183-185s.
    Calculated for C, 5 5 C 60.00; H 8.73; N 4.66; Br 26.61.
    Found,%: C 60.02, H 8.68; N 4.56; Br 26.79.
    Example 63 1,1-Dimethyl-4-phenylbutylamine
    The reaction of isobutylnitrile with 3-phenylpropyl bromide in the presence of lithium diisopropylamide was prepared to obtain 2,2-dimethyl-5-phenylpentylnitrile. Hydrolysis of the nitrile by reaction with caustic potassium in ethylene glycol gave 2,2-dimethyl-5-phenylpentanoic acid. To a cold, stirred solution of this acid (20.6 g) and 11.1 g of trio ethylamine in 75 ml of acetone was added dropwise over 30 minutes 11.9 g of cold (from -5 to) ethyl chloroformate. After the addition was complete, the mixture was stirred for 20 minutes at. then a solution was added dropwise
    5 13 g of sodium azide in 33 ml of water for 25 minutes. The aqueous reaction mixture was stirred for another 30 minutes at then further diluted with 150 ml further. The aqueous solution was extracted
     .4 times 130 ml of toluene. The extracts were combined, washed with water, dried and heated at 100 ° C for 1 hour. Distillation of the solvent in vacuo gave a residue, which was dissolved in 150 ml
    5 8 N, NSE. The acidic solution was stirred and heated for 20 minutes at, then refluxed for another 20 minutes. After cooling to room temperature, the mixture was diluted with water, diethyl ether, alkalized with 5 and. Maon. The alkaline solution was extracted with diethyl pyramid / 1 ether, the extracts were combined, washed with WATER and dried. Removal of the solvent gave 17.2 g of 1,1-dimethyl-5-4-phenylbutylamine.
    Example 64. N, N, N-Trimethyl-1, 1-dimethyl-4-phenylbutylammonium bromide.
    Q Reaction of 17.2 g of 1,1-dimethyl-4-phenylbutylamine with 22.3 ml of 90% formic acid and 23.6 ml of 37% formaldehyde gave, after processing the reaction mixture and distillation, 17.1 g of N, M-dimethyl-1-1-dime5 tyl-4-phenylbutlamine; bp 109 ° 2 ° C (5 mm Hg). A solution of 8.5 g of the dimethylamine derivative in 100 ml of diethyl ether saturated with methyl bromide was stirred at
    Q 25-С 2 months, then filtered. The precipitate was recrystallized from 140 ml of acetone and 10 ml of methanol and 8.3 g of N, N, M-trimethyl-1,1-dimethyl-4-phenylbutylammonium bromide were obtained; m.p. .
    Calculated for C | 5 H2BrN,%: C 60, OO H8.73, N4.66, Br26.61.
    Found,%: C 59.74, H 8.77; N 4.56-, Br 26.33.
    Example 65. N, N, N-Dimethyl-4- (4-ethoxyphenyl) -6y lammonium bromide.
    A solution of 210 g of 4-ethoxycinnamic acid in 175 ml of THF was hydrogenated at 25 s in the presence of 15. g of 5% palladium on carbon and 100 g of 3- (4.-ethoxyphenyl) propionic acid were obtained; m.p. 93-95C. This acid was reduced by reaction with 30.6 g of lithium aluminum hydride and obtained, 101 g of 3- (4-ethoxyphenyl) -propanol. Reaction of this alcohol with 52 ml of methanesulfonyl chloride was obtained and 156 g of 3- (4-ethoxyphenyl) -propylmethylsulfonate were obtained, then reacting it with 43 g of sodium cyanide and obtained 45.9 g of 4- (4-ethoxyphenyl) butyl nitrile. This nitrile was reduced by diborane and 4- (4-ethoxyphenyl) -butylamine was obtained.
    Solution 15., 82 g of 4- (4-ethoxyphenyl) -butylamine, 19 g of 90% formic acid and 7.45 g of 37% aqueous formaldehyde p-stirred PF was heated at 12 h. Then the mixture was cooled to and diluted ml of water. The mixture was acidified with 4 n. net, acidic solution is evaporated and diluted with water. Then the acidic solution was made alkaline with 5 n. NaOH and aqueous alkaline solution was extracted several times with daethylether. The ether extracts were combined, washed with water and dried, the solvent was distilled off and 15.9 g of product was obtained in the form of an oil, which was distilled and 8.86 g of N, N-dimethyl-4- (4-ethylbutylphenyl) -butylamine were obtained; 142-145 ° C (7 mm Hg).
    A solution of 2, N, I-dimethyl-4- (4-ethoxyphenyl) -butylamine in 150 ml of diethyl ether saturated with methyl bromide was stirred for 72 hours at 25 ° C. The precipitate was filtered and recrystallized from. 200 ml of methyl ethyl ketone and obtained 3.27 g of N, N, N-TpH methyl-4- (4-ethoxyphenyl) -butylammonium bromide; m.p. 151-153 ° C.
    Calculated for Cig H2f, BrNO,% C, 56.96; H 8.29; N 4.43; Br 25.26.
    Found,% 5 C 56.78; H 7.99; N 4.48; Br 25.24. ,
    Examples 66-67. According to the procedure of Example 65, the following quaternary ammonium salts were prepared from the corresponding cinnamic acid;
     N, N, M-trimethyl-4- (3-chlorophenyl) -butylammonium bromide; m.p. 135-137s
    Calculated for D | zN2 | BrCtN,%: C 50.91; H 6.9; N 4.57; Br 26.05; CE 11.36.
    Found,%: C 51.14; H 6.74; L 4.73 Bg 26.22; CE 11.36.
    N, N, M-Tr. Methyl-4- (4-methylphenyl) -butylammonium bromide; m.p. 156158 ° C.
    Calculated for Ci4H24BrN,%: C 58.74; H 8.45; N 4.89; Br 27.91.
    Found,%: C 58.64; H, 8.66; M 4.96; Br 28.18. .
    Example 68.de-N, N, M-Trimethyl-1-methyl-4-phenylbutylammonium bromide.
    A solution of 5.15, M-dimethyl-1-methyl-4-phenylbutylamine in 75 ml of diethyl ether, saturated with methyl-. with bromide, stirred at 25 ° C for 12 h. The precipitate was filtered and recrystallized from acetone and methanol to obtain 7.05 g of dB -N, N, N-trimethyl-1-methyl-4-phenylbutylammonium bromide; m.p. 197-199 ° C.
    Calculated for C, 4 H24BrN,%: C 58.74: H 8.45) N 4.89; Br 27.91.
    Found,%: C 59.02; H 8.30; N 5.13; Br 28.03.
    Example 69. d (+) - N, N, N-Trimethyl-1-methyl-4-phenylbutylammonium bromide.
    63 g of methyl 3-phenylpropyl ketone reacted with 59.5 rd- (+) - N-methylbenzylamine and obtained 115 g of d - (+) - N, - (sb-methylbenzyl) -1-methyl-4-phenylbutylimine. The imine was reduced by hydrogenation in the presence of Rene nickel and the diasteomeric N- (ot-methylbenzyl) -17methyl-4-phenylbutylamine was obtained, which was purified by distillation. Amine Vza: it reacted with HCE and gave the hydrochloride salt, which after successive recrystallization from. ethyl acetate and methanol gave 33.79 g of d - (+) - N-j (o6-methylbenzyl) -1-methyl-4-phenylbutylammonium chloride; m.p. 156-158 ° C; wasps () + 46,4 °.
    Hydrogenation of 9,12 - (+) -N- (a.-methylbenzyl) -1-methyl-4-phenyl-0-tylamine in the presence of 5% palladium on coal gave debenzylation, d - (+) - 1-methyl- 4-pheny; 1-butylamine. The amine was hydrogenated for 12 hours in the presence of 25 ml of 37% aqueous formaldehyde and yielded d - (+) - N, H-dimethyl-1-methyl-4-phenylbutyylMin. This amine was converted to hydrochloride by reaction with NSE, the salt was converted from
    ethyl acetate
    and.-met.nola, so pl. 123-125s, (CH OH) Tf-12.4 °.,. . ,
    Calculated for C, C,%: C 58.55; H 9.74; N 6.15; CE 15.56.
    Found,%: C 68.60; H 9.61; N 6.15 CE 15.5.
    Then the hydrochloride was dissolved in 50 ml of water and the solution was made alkaline with 5N. NaOH. The solution was extracted with diethyl ether, the ether extract was shed with water, dried, the solvent was distilled off and 6-g- (+) -N, N-dimethyl-1-methyl-4-phenylbutylamine was obtained. A solution of 2.07 g of this amine in 150 ml of diethyl ether was stirred and saturated with methyl bromide. The ether solution was stored at h, the precipitated precipitate was filtered and recrystallized from 40 ml of isopropyl alcohol, 2.23 g of d - (+) - N, N, M-trimethyl-1-methyl-4-phenylbutylammonium bromide, m.p. 20b-208 ° C; (CHgOH) + + 24.9. Calculated for C, 4 H2- (BrN,%: C 58.7 H 8, 45; N 4, 89 J Bg 27, 91. Found,%: C 58.68; H 8.37; N 4.6 Bg 27.80. PRI me R 70. According to the procedure of Example 71, f - (-) -1-methyl-phenyl-butylamine was isolated and dimethylated was emitting B —N, N-dimethyl-1-methyl-4-phen butylamine, which was then quarternized by reaction with methyl bromide, yielded - (-) - H, M, M-trimethyl-1-methyl-4-phenylbut and (1) ammonium bromide; mp 210-212 ° C; oJ () - 24.9 Calculated for C |4H24BrN,%: C 58.7 H 8.45, N 4.89, Br 27.91. Found: C 58.47; H 8.27; N 4.62; Br 27.79. Example 71. N, l-Dimethyl-M-heptyl-3-phenylpropylammonium-p-toluenesulfonate 1.69 g N-methyl-N-heptyl-3-phenylpropylammonium oxalate the free base was converted into 1.29 g with: using NaOH in digtil ether 1.29 g of M-methyl-M-heptyl-3-phenylpropylamine was placed in a 50 ml round bottom flask. 1.08 g of methylp- was added; Toluenesulfonate in 10 ml of methyl ethyl ketone, the mixture was refluxed for 2 hours and cooled. The thin layer chromatography showed that no secondary amine remained. The methyl ethyl ketone was evaporated in a vacuum, and the oily substance remained. Crystallization of isethyl acetate gave 1.63 g of N, N-dimethyl-N-heptyl-3-phenylpropylammonium-p-toluenesulfonate; m.p. 91-93 C. Calculated for dL,%: C 69.24; H 9.07; N 3.23; S 7.39. Found,%: C 69.10; H 8.84; N 3.40 S 7.55. Example 72. N, N, N-Trimethyl-4- (4-nitrophenyl) -butylammonium bromide 5.14 g of N, H-dimethyl-4- (4-nitrophenyl) -butylamine in 150 ml of diethyl ether was loaded into a 300 ml round bottom flask ml. Methyl bromide was bubbled through the mixture until saturation; precipitate fell out after 10 min. The mixture was stirred at room temperature for 4 days. The precipitate was filtered and recrystallized from 75 ml of isopropanol and 6.77 g of N, N, M-trimethyl-4- (4-nitrophenyl) -butyl ammonium bromide was obtained; m.p. 162-184c. Calculated for C | s H2 | BrN202,%: C 49.22; H 6.67; N 8.83. Found,%: C 49.33; H 6.51; N 8.7b. Example 73. N, M-Diethyl-M-heptyl-4- (4-methoxyphenyl) -butylammonium-p-toluenesulfonate. 24 g of H-ethyl-M-heptyl-4- (4-labels | syphenyl) -butylamine were loaded into a 500 ml water bottle flask and 200 ml of ethyl bromide was added thereto. This mixture was refluxed for 3.5 days. Thin-layer chromatography showed a very small amount of secondary amine. The excess ethyl bromide was distilled off in vacuum, leaving the oil M, M-dimethyl-M-heptyl-4- (. 4-methoxyphenyl) -butyl, ammonium bromide, which was converted to the oxide form as follows. Apply 350 ml of resin B10-RAD, oxide form, 100-200 mesh. 1.2 mEq / ml in a water-filled column, the maslb were washed off with water and acidified slightly with a pH of 12.4 to pH 10 with 15 g of p-toluenesulfonic acid in water. The acidification solution P was converted to oil. The suspension was passed through a column with 300 ml of resin, the layer of which was turned into a tosylate form by washing with 1 l of 0.4N. p-Toluenesulfonic acid. Lyophilization of the eluate for 1.5 days: gave a residue, which was washed with hot ethyl acetate, filtered and evaporated in vacuo. 44 g of oil remained, which hardened on standing. The substance was crystallized from 300 ml of ethyl acetate and obtained N, N-diethyl-M-heptyl-4- (4-methoxyphenyl) -butylammonium-p-toluenesulfonate; m.p. 6567 C. Calculated for C 68,87; H 9.39; N 2.77; S 6.34. Found,%: C 68.64; H 8.08; N 2.80; S 6.57. Example. 74. N, M-Diethyl-M-heptyl-4- (4-hydroxyphenyl) -butylammonium bromide. 2.03 g of N, N-diethyl-M-heptyl-4- (4-methoxyphenyl) -butylammonium-p-toluenesulfrnate from Example 73 was dissolved in 1500 ml of water. The solution was washed through a column with 30 ml of resin B10-RAD, oxide form, 100-200 mesh, 1.2 meq / ml. 2.5 L of the eluate was collected, it was lyophilized for 2 days, and an oily residue remained. The oil was placed in a separatory funnel with a water-diethyl ether mixture and extracted three times with diethyl ether. The aqueous fraction was acidified to pH 2.0 with 48% hydrobromic acid. The solution was lyophilized and a brown oil was obtained with a small amount of a white oily layer, weighing 1.44 g. This substance was refluxed with 10 ml of 48% -. hydrobromic acid in 15 ml of glacial acetic acid, evaporated to dryness three times. The resulting oil was stored overnight in a desiccator with potassium hydroxide and phosphorus pentoxide. 20 ml of ethyl acetate was added to the product, the resulting precipitate was filtered and perekristallizali from 25 ml of acetone, received 460 mg. substances, so pl. 82-85 C. This substance was again dissolved in 15 ml of acetone and recrystallized and 349 ml of N, M-diethyl-M-heptyl-1- (4-hydroxyphenyl) -butylammonium bromide were obtained; m.p. 83-85s. Calculated for C2 | HzHHMO,%: C 62.99J H 9.37; N 3.54, Br 20.20. Example 75 N, M-Dimethyl-M- (2-phenylbutylammonium) -bromide. 20 g of 4-phenylbutyl chloride and 48 p of N-methyl-M-phenethylamine were placed in a 100 ml round bottom flask with boiling chips and heated for 3 days. A solid formed on heating. The aqueous solution of the substance, alkalized with caustic soda, was extracted with diethyl ether, which was then extracted with 2N. sulfuric acid and water. The combined solutions of sulfuric acid and water and washing were basified with 5N. 3 times were extracted with diethyl ether and the extracts were washed with a saturated solution of pbm sodium chloride. The ether was distilled off in vacuum and 64 g of an oily substance were obtained. Distillation gave 27.04 g of H-methyl-M- (2-phenethyl) -phenyl butylamine. 9.0 g of this substance was added to 150 ml of diethyl ether in a 300 ml round bottom flask. The bar was bothered with methyl bromide gas until the mixture was saturated. The mixture was stirred at room temperature for 5 days. The precipitate was filtered and recrystallized from 100 ml of acetone by cooling in a refrigerator. 8.96 g of N, M-dimethyl-M- (2-phenylethyl) -phenylbutylammonium bromide were obtained; mp. 98-102 ° C. H 7.79; C, 66.29; Calculated,%: 3.87; Br 22.05. Found: C 66.07; H 7.72; N3.9 Вг 22,16., Example 76. N, N-Dimethyl-N- (3-phenylpropyl) -phenylbutylammonium bromide. . Chlorohydride-phenylbutyric acid and 3-phenylpropylamine reacted to form an amide, which was then reduced with diborane and N- (3-phenylpropyl) -4-phenylbuty lamin was obtained. The amine was methylated with a mixture of murasvyina acid-formaldehyde and the starting material M-methyl-I- (3-pheny-propyl) -4-phenylbutylamine was obtained, 5.3 g of which was dissolved in 150 ml of diethyl ether: in a 300 ml round-bottom flask. Methyl bromide was bubbled through the mixture until saturation. The mixture was stirred at room temperature for 3 days. The precipitate was filtered off and crystallized from 100 ml of methyl ethyl keto n% c ethyl acetate and 5.08 g of N, M-dimethyl-M-phenylpropylphenylbutyl ammonium bromide were obtained, mp. 81-83C. Calculated for С (2НзбВгМ,%: С 67.01; н 8.03; N 3.72; Вг 21.23. Found: C 67.20; H 8.34, N 3.4 Вг 21.53V - - - -. Example 77. N, M-Diethyl-M-heptyl-4- (4-chlorophenyl) -butylammonium .l -; phosphate .24,960 g of 4-chloro-M, N diethyl-N-heptilbutylammonium bromide was divided into 4 parts of 150-200 g. Each portion was dissolved in 1 liter of water and poured into a column with 2 pounds (0.9 kg) of Dowex 1-X8 resin, oxide form. The elution of the quaternary ammonium oxide compound with water was continued until the solution became slightly alkaline (pH B). The aqueous eluate (2 l) from the ion exchange column was washed three times with 150 ml of diethyl ether. The aqueous layer was separated and acidified to pH 4.5 with dilute phosphoric acid, then lyophilized to dryness, the crystalline residue was dissolved in 1.5 l of hot acetone and 0.5 l of diethyl ether was added, the solution was cloudy. ice and acetone were added and seed crystals were added.The crystalline precipitate was filtered, washed with fresh diethyl ether and obtained 548 g, so pl. 116 119 ° C. Recrystallization from 8 liters of acetone, 1 liter of dichloromethane and 3 liters of diethyl ether to give 459 g of N, M-diethyl-M-heptyl-4- (4-chlorophenyl) -butylammonium phosphate. Calculated for Cji,%: Mol.v. 435.9; C, 57.85; H 9.02; N 3.21; P 7.10; C E 8.13. Found,%: C 57.59; H 9.21, M 3.11; R 6, CE 8,39. Example 78. N, M-Dimethyl-M-heptyl-3- (4-chlorophenylpropyl) ammonium p-toluenesulfonate. 45 ml of resin Y10-RAD, oxide form, 100-200 mesh. 1.2 mEq / ml, placed in a column and washed with water until neutral. 4.5 g of N, N-dimethyl-N-heptyl-3- {4-chlorophenyl) -propylammonium bromide was dissolved in 300 ml of water and passed through a column. 350 ml of the eluate was collected before it ceased to be alkaline. The acid was acidified with O, 2 M n -toluenesulfonic acid from an initial pH of 11.7 to a final pH of 4. Another column containing 45 ml of resin was washed until neutral with collected water. Then, a solution of O, 2 M n -toluenesulfonic acid was passed through the column before the start of the acid (300 ml). The column was then washed until it; gravel reaction. Then an aqueous suspension with a pH of 10.4 was passed through a column to terminate the acidification, 800 ml of the eluate was collected, and it was lyophilized during the day off. The remaining solid was dissolved in ethyl acetate and filtered. Crystallization of the residue from 300 ml of ethyl acetate gave 4.90 N, l-dimethyl-N-heptyl-3r (4-chlorophenylpropylammonium) -p-tolu. Sulfonate; m.p. 117-119 ° C. Calculated for C25 HaaCPNOaS,%: C 64.15; H 8.18, N 2.99; CE 7.57; e, - OS - S 6,85,
    Found,%: C 64.31; H 7.90; N 3.16; CE 7.68; S 6.91.
    Example 79. N, M-Diethyl-M-heptyl-3- (4-chlorophenyl) -propylammonium bromide.
    7.764 g of M-ethyl-M-heptyl-3 (4-chloro) -propylammonium bromide.
    7.764 g of 1-ethyl-M-heptyl-3- (4-chloro) -propylamine was loaded into a 200 ml round-bottomed flask, 90 ml of ethyl bromide was added, the mixture was refluxed for 5 days. Ethyl bromide was distilled off in a vacuum, leaving an oil that slowly solidified. The substance was recrystallized from 400 ml of ethyl acetate, seeded, 9.29 g of N.H.-diethyl-M-hexyl-3- (4-chlorophenyl) propylammonium bromide were obtained; m.p. 8385 ° C.
    Calculated for Cjo Nd Sun 2.%: C 59.33; H 8.71; N 3.46, CE 8.76, Br 19.74.
    Found,%: C 59.37; H 8.51, N 3.22; CE 8.87, Br 20.07.
    Example 80. N, N-Diethyl-N-heptyl-4- (4-chlorophenyl) -butylammonium benzene sulfonate.
    100 ml of resin B10-RAD, oxide form, 100-200 mesh, 1.2 meq / ml, were used in each column. The columns were washed with water until neutral. 9.9 g of N, M-diethyl-M-heptyl-4- (4-chlorophenyl) -butylammonium bromide was dissolved in 50 ml of water, the solution was washed in a resin, and the alaut was collected before leaving the neutral solution (300 ml). This eluate was acidified with a pH of 12.4 to 10.4 with 0.2 M p-toluenesulfonic acid. The solution became turbid with an oily suspension. This suspension was passed through a column with 100 ml of resin, which was converted from the oxide form to the benzenesulfonic acid form. 800 ml of the eluate was collected, the rest was standing in a column overnight. Collected another 3 additional portions of 800 ml of eluate. The whole substance was lyophilized over the course of the day, the remaining oil began to solidify. This oil was washed with ethyl acetate, the precipitate was removed by filtration and evaporated in vacuo to give 11.994 g of oil. This oil was washed with 100 ml of ethyl acetate, cooled in a refrigerator and infected with crystals. Crystallization went on the night and yielded 9.325 g of the product; t.cl 46-48 ° C. This substance was again crystallized in 100 ml of ethyl acetate, obtained 8.82 g; m.p. 47-49c.
    Calculated for Cg Nd SEMOZZ,%: C 65.36; H 8.53; N 2.82; CE 7.15; S 6.46.
    Found,% s C 65,34; H 8.26; M 3.14 CE 7.32; S 6.66.
    Example 81 N, M-Dirktyl-N-methyl-4-phenylbutylammonium bromide.
    5.78 F And, M-dioctyl-4-phenylbutylamine was placed in a round bottom flask
    la 300 ml in 150 ml of diethyl alcohol. Methyl bromide gas was passed through the mixture and stirred at room temperature for 48 hours. Thin layer chromatography showed small amounts of a secondary amine. The suspension was filtered, the precipitate was recrystallized from 50 ml of ethyl acetate to obtain 5.848 g of N, N; -dioctyl-N-methyl-4-phenylbutylammonium bromide-, mp. 65-67 ° C.
    0
    Calculated for C27H5oBrN,%: C, 69.29; H 10.76, N 2.99 / Vg 17.05.
    Found,%: C 69.25, H 10.56} N 3.09; Br 16.93.
    Example 82. N, N, N-Tpiethyl-l-methyl-4-phenylbutylamine.
    5 3.65 g of M, M-diethyl-1-methyl-4-phenylbutylamine and 35 ml of ethyl bromide were loaded into a round bottom flask: 100 ml and refluxed for 3 days; At the end of this period a white precipitate fell
    0 The mixture was cooled, the solution dissolved in excess, the mixture was distilled off in a vacuum, and a solid substance remained. Doba; Willy 50 ml of diethyl ether and the precipitate filtered. Diethyl
    5 the ether was distilled off in vacuo and 3.135 g of substance were obtained, KotopOeNervolly in a 100 ml round-bottom flask, j-b ml of ethyl bromide was added and refluxed for a week. Mixture
    0
    cooled and evaporated to dryness, then
    washed with 75 ml of diethyl ether and filtered; . The precipitate was recrystallized from 50 ml of methyl ethyl kitsn and obtained 619 mg of N, N, M-triethyl-1-methyl 5 -4-phenylbutylammonium bromide; mp. 123-125 ° C. .
    Calculated for C | Y,%: C 62.19; H 9.21; N 4.27; Br 24.34.
    Found,%: C 62.13; H 9.06;
    0 N 4.29; Br 24.05.
    Example 83. N-Dimethyl-M- (1-methylheptyl) -4-phenylbutylammonium bromide.
    The reaction was 4 phenylbutyl chloride
    5 with 1 methylheptylamine and obtained N- (1-methylheptyl) -4-phenylbutyramide, which, after reduction by diborane in THF, gave N- (l-methylheptyl) -phenylbutylamine. The reaction of this amine with formic acid and formaldehyde was carried out, and N-methyl-N- (1-methylheptyl) -4-phenylbutylamine was obtained. A mixture of this amine and 150 ml of diethyl ether was saturated with gaseous
    5 methyl bromide, the solution was stirred at room temperature for 3 days. The ECO filter was removed and recrystallized from ethyl acetate to give N, N-dimethyl-N- (1-methylheptyl) -4-fe0nylbutylammonium bromide, t, pl. 111 OF p.
    Calculated for,%: C 64.85} and 9.80; N ZLv) Br 21, S, Found,%: C-64.64, H 9.65}
    权利要求:
    Claims (1)
    [1]
    5 N 3.68; Br 21.4. Example 84. M, M-Diethyl-M- (3-methylbutyl) -4- {4-nitrophenyl) -butyl-monium bromide. A reaction was carried out with 4- (4-nitrophenyl) -6-trichyl chloride with 3-Netnyl-butylamine and the corresponding amide was obtained, which was reduced by diborane, and N- (3-methyl-butyl) -4- (4-nitrophenyl) -butylamine was obtained. 15.4 g of sodium carbonate in 70 ml of water was loaded into a 500 ml three-neck flask containing 19.183 g of N-3-methylbutyl-4- (.4-nitrophenyl) -butylamine in 70 ml of acetone. The mixture was cooled below 30% and 11 ml of acetylchloride in 70 ml of acetone was added dropwise, keeping the temperature below 30 s. After the addition was complete, a precipitate formed, the suspension was stirred overnight at room temperature. The acetone was distilled off in vacuo. The mixture was diluted with 100 ml of water and extracted three times with diethyl ether. The ether extracts were combined, washed with water, 2N.NS2, four times with water, once with water saturated with sodium chloride, the ether solution was dried and the entire solvent was distilled off in vacuo to give 21.81 g of N-3-methyl-butyl-N-acetyl- 4- {4-nitrophenyl) -butylamine. 220 ml of 1 M diborane in THF were placed in a three-neck round bottom flask, 1 l. 21.81 g of M- (3-methylbutyl) -acetyl-4- (4-nitrophenyl) -butylamine in 100 ml of THF was added dropwise. The mixture was refluxed overnight. After cooling, add 200 ml of 2N HC to decompose the excess of borane. THF drove off. Doba 100 ml conc, HCE and the mixture were deflamed for 45 minutes to decompose the dibo complex. The mixture was cooled, basified with 5 N MaOH and extracted three times with diethyl ether. The extracts were combined, washed once with water, and extracted twice with 2N sulfuric acid. The acidic extracts were basified with 5N NaOH and extracted three times with diethyl ether. The ether extracts were washed with a solution of NaCE, dried, the solvent was distilled in vacuum and 19.82 N-ethyl-N- (3-methylbutyl) -4 - ((- nitrophenyl) -butylamine was obtained. 3.383 g of this amine and 40 ml of ethyl bromide were loaded 100 ml in a round-bottom flask and refluxed for 5 days. A precipitate fell, an excess of ethyl bromide was distilled off in vacuum, the residue was recrystallized from 75 ml of methyl ethyl ketone and 2.28 g of N, J-diethyl-N- (3-ml-methyl) - 4- (4-nitrophenyl) -butylammonium bromide, mp 114–11bc. Calculated for C 9 NezBrM202,%: C 56.85; H 8.29; N 6.98; Br 19.91. : C 56.62; H 8.11; N 6.69; Br 19.62. ep 85. N, H-Diethyl-M-hexyl-3-phenylpropylammonium bromide 5.21 g of M-ethyl-M-hexyl-3-phenylpropylamine was loaded into a 200 ml round-bottom flask. 100 ml of ethyl bromide was added and the mixture was refluxed for 5 days. Then an excess of ethyl bromide and a mixture of deftegs were given for 5 days, then an excess of ethyl bromide was distilled off in a vacuum, leaving the oil N, M-diethyl-N-hexyl-3-phenylpropylammonium bromide Example 86. M, M-Diethyl-M-hex. Sil-3-phenyl-propyl-ammonium-tolyolesulfonate. Two columns were filled with 40 ml of WYU-RAD resin, oxide form 10.0-200 mesh. 1.2 eq / ml One column was washed with water until neutral. Obtained in example 85 N, M-diethyl-M-hexyl-3-phenyl-propyl-ammonium bromide with 200 ml of water and passed through a flask, turning the bromide into Oxide. This water column was acidified. whether to a pH of 7.02 n. p-toluenesulfonic acid. The second column was washed with 0.2 n. P-toluenesulfonic acid solution. before the appearance of acidic washing. Then it was washed with water until neutral. A partially acidic aqueous solution was passed through a tosylate column. About 1 liter of water was collected about 1 liter, it was lyophilized, the precipitate was recrystallized from 50 ml of ethyl acetate and 8.10 N, N-diethyl-N-hexyl-3-phenylpropylammonium p-toluenesulfonate was obtained; m.p. 61-bZs. Calculated for.) NOj S,% s C 69.76; N.3.13; S 7.16; n 9.23. Found,%: C 69.84; H 8.96 jN 2.92; S 7.22. Example 87 N, M-Diethyl-M-heptyl-3-phenylpropylammonium p-toluenesulfonate. 5.302 g of N-ethyl-N-heptil-3-phenylpropylamine and 50 ml of ethyl bromide were loaded into a 100 ml round-bottomed flask. The mixture was refluxed for 6 days, the excess ethyl bromide was distilled off in vacuo, and an oily substance remained. This substance was crystallized from 150 ml of ethyl acetate containing traces of acetone, and 6.35 g of N, M-diethyl-H-heptyl-3-phenylpropylammonium bromide was obtained, mp. 60-62 p. This substance was recrystallized again from ethyl acetate with traces of acetone and allowed to stand at room temperature; 3.34 g of N, M-diethyl-L-heptyl-3-phenylpropylammonium bromide were obtained; m.p. 65-68c. Two columns were filled with 10 ml of WYU-RAD resin, oxide form, 100,200 meshes. One of them Was washed with water until neutral water reaction. 5.387 g of N, M-diethyl-M-heptyl-3-phenylpropylammonium bromide was dissolved in water and passed through a resin to convert to the oxide form. The eluate was collected until its alkalinity ceased, then the eluate was acidified to pH 6 with 0.2 g. L-toluenesulfonic. The second column was washed with 0.2 n. p-toluenesulfonic acid until the appearance of acidic wash water. This column was washed with iodine until neutral, the above partially acidified solution was passed through this tooylate column, collected 500 ml of water. She was lyophilized overnight and obtained a semi-solid. It was recrystallized from 40 ml of ethyl acetate and a half. Chile 2.16 g of N, N-diethyl-N-heptyl-3-phenylpropylammonium p-toluenesulfonat1 t7Hy / 7 4-7 b s, Calculated in d. C, 70.24; H 9.39 / N 3.03; S 6.94, Found,%: C 70, .01; n 9.15; N 2.84; S 6.93; For example .88, N, N, N-trimethyl-3- (4-nitrophenyl ) propylammonium bromide, 1.12 g of N, N-dimethyl-3- (4-nitp6-phenyl) -propylamine was added to 150 ml of diethyl ether in a round-bottomed column. be. Methyl bromide was bubbled through the mixture until saturation. The mixture was stirred at room temperature for 2 days. The precipitate was filtered off and recrystallized from 50 ml of isopropanol; 1.49 g, T, mp, 180–181 °, were obtained; .. Calculated for C, 2H | 9BrM2021% C, 47.54; H 6.32; N 9.24; Br 26.32, Found; C, 47.29; H 6.07; N 9.13 Bg 26.66, Claims. Method for preparing phenylalkylamine derivatives of general formula 01g- (CH2) n- cn a1 xKg 74536030 where n 2, RJ is hydrogen or alkyl C. hydrogen or alkyl Cj; Rg is alkyl Cj. 4 phenylalkyl .... Ci.4, R. - alkyl j Rg - alkylC1 - | o; Rj- together with the nitrogen atom form a hetero1-cyclic ring with 4-7 carbon atoms; Ry is hydrogen, oxyhalide, nitro, alkoxy groups. or alkyl C i-a P U lovii, that if R or R 7 is hydrogen, and the other is different from the nitro group, and n is 1, then Rj is alkyl (Sb-) o; X is an anion, characterized in that the tertiary amine / where R, (j is ONE of Rg, R4, R5 and RII, and (CH,) is c-i4-R, X introduces so interaction with Rii: X, where R, jj- Rjj, R4 5 or Rfi./ ;. „X has the above meaning, with the subsequent release of the target product,.; Sources of information taken into account in examination 1, M Sh1kovsky MD, Medicinal Products, 1972, t. 1, s, 237,
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    同族专利:
    公开号 | 公开日
    FI65425B|1984-01-31|
    NZ189162A|1980-10-24|
    LU80670A1|1979-04-13|
    AU524727B2|1982-09-30|
    AR222813A1|1981-06-30|
    EG14601A|1984-09-30|
    FR2411824B1|1985-03-29|
    YU297578A|1982-10-31|
    DE2862243D1|1983-06-09|
    DD139842A5|1980-01-23|
    JPS5495520A|1979-07-28|
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    JPS6214538B2|1987-04-02|
    RO76881A2|1981-08-30|
    GB2011388B|1982-04-28|
    EP0002604B1|1983-05-04|
    AU4255478A|1979-06-28|
    BE872832A|1979-06-18|
    DK150475C|1987-10-26|
    EP0002604A1|1979-06-27|
    ATA904378A|1980-12-15|
    IL56212A|1982-08-31|
    IE782489L|1979-06-19|
    FI65425C|1984-05-10|
    PT68907A|1979-01-01|
    ES476152A1|1980-05-16|
    ZA787111B|1980-08-27|
    DK150475B|1987-03-09|
    DK567778A|1979-07-31|
    HU178220B|1982-03-28|
    FR2411824A1|1979-07-13|
    IL56212D0|1979-03-12|
    IE47693B1|1984-05-30|
    AT363065B|1981-07-10|
    FI783845A|1979-06-20|
    CS857778A2|1985-07-16|
    CH640506A5|1984-01-13|
    PH14394A|1981-06-25|
    CA1093072A|1981-01-06|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4336269A|1979-12-10|1982-06-22|Eli Lilly And Company|Para-nitrophenylalkylamines|
    DE2952382A1|1979-12-24|1981-07-16|Basf Ag, 6700 Ludwigshafen|PHENYLPROPYLAMMONIUM SALTS, METHOD FOR THE PRODUCTION THEREOF AND AGENTS CONTAINING THESE COMPOUNDS|
    DE3263407D1|1981-08-29|1985-06-05|Basf Ag|Fungicides containing phenylpropylammonium salt, and process for combating fungi|
    DE3421810A1|1984-06-12|1985-12-12|Basf Ag, 6700 Ludwigshafen|PHENYLALKYLAMINE - BIOREGULATORS|
    JPH0119375B2|1984-12-13|1989-04-11|Seitai Kagaku Kenkyusho Kk|
    JPH02268142A|1989-04-10|1990-11-01|Toubishi Yakuhin Kogyo Kk|Novel compound having muscle relaxing action and production thereof|
    NZ516888A|1999-07-30|2004-02-27|Vertex Pharma|Acyclic and cyclic amine derivatives|
    TWI356054B|2004-03-31|2012-01-11|Activus Pharma Co Ltd|Quaternary ammonium compound, producing method the|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US86178977A| true| 1977-12-19|1977-12-19|
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