• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    N-Aryl-N-(4-piperidinyl)arylacetamides of the formula <IMAGE> and their salts with acids, the substituents in the formula being defined in Claim 1, are prepared. These compounds are obtained by acylating corresponding piperidine derivatives with an arylacetyl halide. The resulting compounds can be used for the drug therapy of cardiac arrhythmias.
    公开号:SU747424A3
    申请号:SU762405548
    申请日:1976-09-23
    公开日:1980-07-23
    发明作者:Санкзюк Стефан；К. Фр. Эрман Юбер
    申请人:Жансен Фармасетика (Фирма)；
    IPC主号:
    专利说明:

    alkaline or acid hydrolysis and the separation of the target product in the form of a base or salt.
    As a solvent, it is preferable to use aromatic hydrocarbons, of which benzene, toluene or xylene are most suitable.
    Of the aliphatic hydrocarbons, haloalkanes are preferably used, especially chloroform.
    The process is advisable to carry out. in the presence of a base such as alkali metal carbonate and bicarbonate, alkali metal amides, especially sodium amide, amines, especially pyridine, N, N-diethylethylamine.
    Removal of the protective group P can be carried out in accordance with known techniques. If the precipitating group is phenylmethyl and phenylmethoxycarbonyl, it is easily removed by catalytic hydrogenation using a suitable catalyst, such as palladium on activated carbon, and if the blocking group is lower alkyloxycarbonyl, it can be easily removed by acid or alkaline hydrolysis. Acid hydrols can be carried out with the use of a strong mineral acid, for example hydrochloric, hydrobromic or sulfuric, and alkaline with the use of alcohol alkali, for example potassium hydroxide in 2-propanol.
    If Ag is a phenyl having only hydroxyl groups or other substituents, it is convenient to provide protection to said hydroxyl groups in the corresponding starting materials with a suitable blocking group such as lower alkyloxycarbonyl, and to obtain a corresponding derivative of the target compound, the blocking group of which can be easily removed by alkaline hydrolysis using, for example, dilute aqueous alkali.
    The desired compound can be converted to a pharmaceutically acceptable salt of an acid by treatment with a suitable acid, for example, an inorganic acid, such as a hydrogen halide, a single acid, in particular hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, etc., or an organic acid, for example, acetic acid, propionic, 2-hydroxy-acetic, 2-hydroxypropionic, 2-oxopropionic, propandionic, butanedione, (2) -2-butandionic, (E) -2-butandione, 2-okaibutadione, 2,3-hydroxybutanedioic, 2-hydroxy-1, 2,2-propantricarboxylic benzoic, 3-phenyl -2-Propenoic, oL-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbeneolsulfonic, cyclohexanesulfamic, 2-6xyxybenzoic, 4-amino-2 oxybenzoic and other similar acids, And, on the contrary, the salt can be converted by the program, can be converted by the program, can be used by the work program, or you can convert the salt into the program, you can use the programm, you can change the work process, you can, in addition, you can use the programm to create the program, you can use the program, you can change the work process, you can, for example, you can use the program, you can change the work process, you can, or the process, to convert the similar acid, other analogous acids, etc. .
    Intermediates used as raw materials can be obtained by known methods.
    In the examples below, unless specifically indicated, the quantities of substances are given in parts by weight.
    Example 1. A mixture of 19 h of 1- {phenylmethyl) -4-piperidinone, 11.6 parts (3-pyridinamine, 120 hours of toluene and a small volume of 2-toluenesulfonic acid are stirred vigorously and heated to reflux for 5 hours (reaction vessel after separation of the calculated amount of water, the solvent is evaporated. The oily residue is dissolved in 800 parts of 2,2-oxybispropane and the solution is evaporated again. 27 parts of (phenylmethyl) -4-piperidinylidene-3-pyridinamine are obtained. in the form of a tan oil.
    To a stirred solution of 27 parts of 1- (phenylmethyl) -4-pipi-pyridinylidene-3-pyridinamine in 40 parts ethanol is added in portions of 3.8 parts sodium borohydride. After the addition is complete, the mixture is heated to. The solvent is evaporated. The oily residue is dissolved in 150 parts. 1 n. hydrochloric acid and filtered. The filter is alkalinized with ammonium hydroxide and extracted with toluene. The organic layer is dried with magnesium sulfate, filtered and evaporated. The solid residue is washed with 2,2-oxybispropane and dried, resulting in 14 hours of (phenylmethyl) -4-piperidinyl-3-pyridinamine being obtained in the form of a beige dmorph powder, mp. 131-133 C.
    A mixture of 20 parts of M- 1- (phenylmethyl) -4-piperidinyl1-3-pyridinamine, 160 hours of methanol, 30 parts of water and 12 hours of concentrated hydrochloric acid is hydrogenated at normal pressure and a temperature of 22-39s in the presence of 7 hours 10% Palladi on activated carbon. After absorption of the calculated amount of hydrogen, the hydrogenation is stopped. The catalyst is filtered, and the filtrate is evaporated. The oily residue is dissolved in water. This solution is alkalinized with ammonium hydroxide, saturated with solid potassium carbonate and then extracted with methyl benzene. The extract is dried with potassium carbonate and evaporated. The solid residue is recrystallized from a mixture of 40 parts of benzene and 32 parts of 1,1-oxybisethane, resulting in 3 parts of M- (4-piperidinyl) -3-pyridinamine, m.p. 127-129 0. Example 2. A mixture of 171.2 parts of ethyl 4-oxo-1-piperidinecarboxyl 159.5 parts of 4-chlorobenzenamine, 1520 anhydrous toluene and several crystals of 4-toluenesulfonic acid are mixed and heated with a reverse HbJM cooler for 7 including (the reaction vessel is equipped with a reflux condenser and water separator). The toluene is evaporated and the oily residue is distilled in vacuo, 46 resulting in 192 parts of oily ethyl 4-O-chlorophenyl) -imino-1-piperidinecarboxylate, mp. 171-176 ° C / 4 Hg. Example 3. According to the procedure of Example 2, using an equivalent amount of a suitable arylamine instead of the 4-chlorobenzeneamine used in Example 2, the compounds listed in Table 1 are obtained. Table 1
    2-сг-с н
    2.6- {CH, j) 2
    2-ce, b-snt-SdN ,.
    i about 5
    3.4- (CE) j-CgH
    4-Br-C H4
    2.5- (Ce),
    2-pyridine
    Example 4. A mixture of 171 parts of ethyl 4-oxo-1-piperidinecarboxylate, 162 parts of 2,6-dichlorobenzamine, 800 parts of xylene and 1 hour. The 4-toluenesulfonic acid is stirred and refluxed using a water separator. The reaction mixture is evaporated, resulting in semi-. 250 parts of ethyl 4- (2,6-dichlorophenyl) -imino -1-piperidinecarboxylate are used as a residue.
    Example 5. A mixture of 34 h of ethyl 4-oxo-1-piperidinecarboxylate, 20 h, 2-pyrimidinamine, 8 drops of acetic acid and 90 parts of toluene was stirred and refluxed for 28 hours with a water separator. The reaction mixture is evaporated, resulting in 50 parts of ethyl 4- (2-pyrimidinylimino) -1-piperidinecarboxylate as a residue.
    Example To a thermal solution of 192 parts of ethyl 4- (4-chlorophenyl) -imi160-165 / 0, 5-0.6
    142-145 / 0.01
    195-200 / 0,2
    145-147 / 0,01
    190-200 / 0.02-0.03
    165-170 / 0.01-0.02
    180-183 / 0,1
    but -1-piperidinecarboxylate in 560 parts of methanol is added in portions of 23.5 parts of sodium borohydride at 50 ° C for 1 hour. At the end, the mixture is stirred at the same temperature for 2 hours and the methanol is evaporated. The solid residue is heated with 600 hours of water and the product is extracted with benzene. The extract is dried with magnesium sulfate and evaporated. The oily residue hardens when treated with 2,2-oxybispropane. The solid is filtered off and dried, resulting in 122 parts of ethyl 4- (4-chlorophenyl) amino-1-piperidinecarboxylate; m.p. 115-118s.
    Example 7. According to the procedure of Example 6, using the equivalent amount of a suitable ethyl 4-arylimino-1-piperidinecarboxylate, the compounds shown in Table 2 are obtained.
    ciij.
    H-Se-n,
    2-CE, 6-CH..j -F-CfeH
    3.4 - (ce) 2-c, Hj 3-c-n
    4-Br-C H4 2,5- (Ci} C-.Hg 2-Pyrimidine

    T.KIP. at 0.01 MG4 Hg
    Example 8. To a stirred and boiling mixture of 250 parts of ethyl 4 (2,6-dichlorophenyl) imino-1-piperi, zinc hexacrylate in 160 parts of methanol and 160 parts of 2-propanol are added in portions of 30 hours of sodium borohydride . At the end of the addition, stirring and refluxing are continued for 1 hour. The warm reaction mixture is poured into water and the product is extracted with toluene. The extract is dried and evaporated. The residue is crystallized from a mixture of 160 parts of 2,2-hydroxybispropane and 160 parts of petroleum ether, resulting in 96 parts of ethyl 4- f (2, 6-dichlorophenyl) -amine -1-piperidicarboxylate, m.p. 107.2116,.
    , Example 9: A mixture of 45 parts of ethyl 4-f (2, 6-dimethylphenyl) -imino -1-piperidinecarboxylate, 0.3 parts of platinum dioxide in 160 parts of methanol is hydrogenated at normal pressure and temperature 24-35 0. After absorption of the calculated amount of hydrogen, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The oily residue is distilled and 30 parts of an oily base are obtained - ethyl 4- f (2, 6-dimethylphenyl) amino-1-piperidinecarboxylate, T.KIP. 148-153s / 0.01 mm Hg From this distillate one. get hydrochloride salt in 1,1-oxybisethane. The precipitated solid salt is filtered and dried. 28.5 parts of ethyl 4- (2, b-dimethylphenyl} - amino} - -piperidinecarboxylate, m.p. 195, are obtained.
    A mixture of 10 hours ethyl-4- (2,6-dimethylphenyl) - amino -1-piperi, g111n carboxyl7474243
    T a b l i and a 2
    T.il. , WITH
    89-93
    99, 5
    f 140-142
    113.5
    72
    116.5
    107.2-110.3
    This solution and 135 parts of a 48% aqueous solution of hydrobromic acid are stirred at 80-110 ° C until the release of carbon dioxide stops. The red-cracked reaction mixture was evaporated in vacuo. The residue is taken up in 56 parts of toluene and the latter is evaporated again.
    The evaporation is then repeated from a mixture of 24 hours, 2-propanone and 40 parts of methylbenzene. The resulting semi-solid residue is triturated in 80 parts of hot acetone and, after cooling, bypassed Byp, the cc is a solid product. It is refined, washed successively with small amounts of absolute ethanol and acetone, and dried, resulting in 13 hours N- (2,6-dimethylphenyl) -4-piperidinamine-dihydrobromide, mp.
    Example 10 To a mixture of 165 parts of ethyl 4- (2-pyrcdinylimino) -1-piperidinecarboxylate and 736 parts of methanol, 29.5 parts of sodium borohydride (exothermic) are added to the over-heated and cooled (in an ice bath) mixture. reaction). After verification, stirring is continued for 1 h 30 min at room temperature. The reactor {mixture is evaporated. The residue is suspended in 460 parts of water and the suspension is acidified with a concentrated solution of hydrochloric acid. Then the mixture is alkalinized with ammonium hydroxide and the product is extracted with toluene. The extract is dried, filtered and evaporated. The residue is converted to the salt of oxalic acid in 2-propanol and 2,2-oxybispropane. The salt is filtered off, washed with -2, 2-hydroxybispropane and dried — from vacuum, resulting in 38 parts of ethyl 4- (2-pyridine1-amino) -1-piperidinecarboxylate oxalate.
    A mixture of 90 parts of ethyl 4- (2-pyridinylamino) -1-piperidinecarboxylate, 90 parts of potassium hydroxide and 720 parts of 2-propanol is stirred and refluxed for 2 days. The reaction mixture is evaporated, 1000 parts of water is added to the residue and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2, 2-hydroxybispropanone. As a result, 13 parts of N- (4-piperidINS1) -2-pyridinamine are obtained.
    Example 11. A mixture of 7 parts of ethyl 4- (2-pyrimidinylamino) -1-piperidinecarboxylate and 120 hours. 48% hydrobromic acid is stirred and heated under reflux for 2 hours. The reaction mixture is evaporated, the residue is diluted water and alkalinized with a dilute sodium hydroxide solution while cooling in an ice bath. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The solid residue is stirred in 2,2-hydroxy-propane. The product is filtered off and converted to the hydrochloride salt in 2-g 1-propanol. The salt is filtered off and crystallized from ethanol, resulting in 2 parts of N- (4-piperidinyl) -2-pyrimidinamine dihydrochloride hemihydrate, m.p. 268.5С.
    Example 12. A mixture of 32.5 parts of methyl 4- (phenylamino) -1- (phenylmethyl) -4-piperidinecarboxylate and 200 parts of methanol is hydrogenated at normal pressure and room temperature in the presence of 5 parts of 1C% palladium on carbon . After uptake of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The oily residue hardens when rubbing the vessel wall in 2,2-oxybispropanone. The product is filtered and dried in vacuo. The result is 20 hours (25%) methyl 4- (phenylamino-4-piperidinecarboxylate), so pl. 139 ,.
    Example 13. To a stirred solution of 58 parts of ethyl 4- (4-chlorophenyl) amino-1-piperidinecarboxylate in 240 parts of benzene was added dropwise a solution of 46.2 parts of phenylacetyl chloride in 80 parts of benzene at 40-70 ° WITH. After the addition is complete, the mixture is stirred and heated under reflux for 6 hours and 15 minutes. The reaction mixture is cooled and filtered. The filtrate is washed sequentially with water, bicarbonate solution.
    5 Sodium and water, then dried and evaporated in vacuo. The residue is crystallized from 1,1-oxybisethane, resulting in 47 parts of ethyl 4- N- (4-chlorophenyl) -N- (phenylacetyl) 0 -amino3-1-piperidinecarboxylate, m.p. 108C.
    Example 14. Following the procedure of Example 13 and using equivalent amounts of the corresponding
    5 derivatives of ethyl 4-arylamino-1-piperidinecarboxylate and arylacetylchloride, receive the compounds listed in Table 3.
    Table3
    Example 15. To a stirred solution for 8 hours, ethyl 4 (2, 6-dimethylphenyl) amino -1-11Iperidinecarboxylate in 4 parts of pyri, cine and 80 hours of benzene was added dropwise in 1.1 hours, and phenylacetyl chloride in 40 hours. benzene. After the addition is complete, the mixture is stirred and refluxed for 3 hours and 45 minutes. The reaction mixture is cooled and filtered. The benzene phase npof / is watered with water, sodium bicarbonate solution and then again with water. After evaporation, an oily residue is obtained, which solidifies upon grinding in 1,1-oxybisethane. Get 5 hours ethyl-4- N- (2,6-dimethylphenyl) - N - (phenylacetyl) amino -1 piperidinecarboxylate, so pl. .
    Example 16 To a stirred solution of 15 parts of ethyl 4 (4-chlorophenyl) aminoL-1-piperidinecarboxylate, 5.4 parts of N, N-diethylethylamine and 160 parts of benzene are added dropwise 11.07 hours 4-methoxybenzeneacetyl5ShORida at 32-40 ° C. After the addition is complete, the mixture is stirred and heated under reflux for 4 hours. The reaction mixture is cooled and filtered. The filtrate is washed successively with water, sodium bicarbonate solution and water, filtered. And evaporated in vacuo. Oily
    Continued. Tab.3
    the residue is crystallized from a mixture of 56 parts of Ifl-oxybisethane and 40 parts of hexane. The crude solid is filtered off and recrystallized from a mixture of benzene and 1,1-oxybI-ethane to give 3 parts of ethyl 4-IN- (4-chlorophenyl) -N- (4-methoxyphenyl) -acetyl-amino -1 -1- piperidinecarboxylate, so pl. .
    Example 17. A mixture of 20 parts of ethyl 4-, N - {2-chlorophenyl) - N- (phenylacetyl) -am: but -1-piperidinecarboxylate and 300 parts of a 48% aqueous solution of hydrobromic acid is stirred and boiled under reflux for 1 h 10 min. The hydrobromic acid solution is removed in vacuo, and water and sodium hydroxide solution are successively added to the residue. The free base is extracted with chloroform. The latter is dried and evaporated. The solid residue is washed with 1, l-oxybisethane and sued, resulting in a yield of 10 |, b. N- (2-chlorophenyl) -N- (4-piperidinyl) benzenecetamide, so pl. 135.5 ° C. Example 18. Following the procedure of Example 17 and using an equivalent amount of a suitable ethyl 4-fN-aryl-N- (arylacetyl) amino -1 -1-piperi dinocarboxylate, the compounds shown in Table 4 are obtained.
    13
    Example 19. A mixture of 5 parts of ethyl-4-N- (2,6-dimethylphenyl) -N- (phenylacetyl) -ami but -1-piperidinecarboxylate in 60 hours of a 40% aqueous solution of hydrobromic acid is heated until carbon dioxide absorption is terminated. Heating is continued for 15 minutes at 80120 ° C. The reaction mixture is evaporated. The solid residue is washed successively with toluene and acetone and dried, yielding 4.1 parts of N- (2,6-dimethylphenyl) -N- (4-piperidinyl) benzyl acetrestamide hydrobromide, mp. 251 ,.
    Example 20. A mixture of 10 parts of ethyl 4-N- (4-chlorophenyl) -N- (phenylacetyl) -1-piperidinecarboxylate and 125 parts of glacial acetic acid pre-saturated with gaseous hydrogen bromide is stirred and heated for 9 h 45 min at 62С. The reaction mixture is cooled and glacial acetic acid is evaporated in vacuo. The semi-solid residue is diluted with 150 parts of water, alkalinized with concentrated sodium hydroxide solution and the product is extracted with chloroform.
    74742414
    Table 4
    The extract is dried with sodium sulfate and evaporated. Oily residue
    g is dissolved in 56 parts of 1, l-oxybisethane and the solid base is filtered off. It is converted to the hydrochloride salt in the usual way in 1, l-oxybisethane and acetone, as a result
     get 4 hours of hydrochloride N- (4-chlorophenyl) -N- (4-piperidinyl) -benzeneacetamide, so pl. 206.5 ° C.
    Example 21. Following the procedure of Example 20 and using the equivalent
    0 the amount of a suitable ethyl 4-N-aryl-N- (arylacetyl) amino-2-piperidinecarboxylate as starting material, the following compounds are obtained:
    N- (2,6-dimethylphenyl) -N- (4-pipa128 ° C; ridinyl) -2-thiophenecetamide, m.p.
    N- (4-chlorophenyl) -N- (4-piperidinyl) -2-thiophenecetamide hydrochloride, m.p. 201.5 ° C;
    Hydrochloride 4-chloro-M- (4-chlorophenyl) -N- (4-piperidinyl) -4-benzenecetamide, m.p. 222C,
    N- (4-chlorophenyl) -4-methyl-M- (4-piperidinyl) benzene-acetamide, 5 m.p. .
    Example 22 To a stirred boiling mixture of 48 parts of 1- (1-methylethyl) -4-piperidino 1: 1 part of 4-toluenesulfonic acid and 540 parts of toluene, a solution of 30 parts of aniline in 90 hours, toluene is added dropwise. After
    . the addition is complete and the mixture is stirred and refluxed for 3 hours with a water separator. The reaction mixture is evaporated, resulting in 72 hours, N-l - (1-methylethyl) -4 piperidinylidene-3-aniline as a residue.
    To a stirred and aarpeToiviy (30-40 ° C) solution of 72 hours, (l-methylethyl) -4-piperidinylidene-aniline in 480 parts of methanol is added in portions to 20 parts of borohydride natrud. After the addition is complete, stirring is continued at room temperature overnight, the reaction mixture is evaporated and the residue is dissolved in water. The solution is extracted with 4-methyl-2-pentanone. The extract is washed with water and acidified with a dilute hydrochloric acid solution. The aqueous acid phase is made alkaline with a dilute sodium hydroxide solution to pH 9 and the product is extracted with 4-methyl 2-pentanone. The extract is washed with water, dried, filtered and
    . steam. The residue is distilled (bp 135-140 ° C / 0.2 mmHg) and the distillate is crystallized from patrol ether, resulting in 21 parts 1 (1-methylethyl) -N -, -phenyl-4 -piperidine., t, pl. 69 W
    Example 23. To a warm (400c solution of 12 parts of potassium hydroxide in 240 parts of 2-propanol were added 21 parts of ethyl 4- (4 chlorophenyl) -N C (4 methoxyphenyl) acetyl-aminoz-1-piperidinecarboxylate, mixture stir and boil under reflux for 21 h. The reaction mass is cooled, filtered and the filtrate is evaporated. The residue is taken up in water and the aqueous solution is acidified with a dilute hydrochloric solution.
    .acids. The acidic solution is washed with 1,1-oxnbisethane, alkalinized with sodium hydroxide and the free base is extracted with toluene. The latter is dried, filtered and evaporated. The residue is dissolved in 1D-oxybisethane and after a stabilization test, 10 hours are obtained. N- (4-chlorophenyl) -4-methoxy-N- (4-Piperidinyl) benzene-acetamide, m.p. 129.5 ° C.
    EXAMPLE 24 To a mixture of .MOMi and a warm (40c) solution for 12 hours, potassium hydroxide, to 200 parts of 2-propiol, 21 parts of ethyl 4-IN- (4 chlorophenyl) -N-f ( 3-methoxyphenyl) acetylJ-aMHHOj-1-piperidinecarboxylate, the mixture is stirred and refluxed for 17 hours. The reaction mixture is cooled, filtered and evaporated. The semi-solid residue is acidified with a dilute hydrochloric acid solution, washed with 1,1-oxybisethane and the aqueous acidic phase is made alkaline with sodium hydroxide solution. The free base is extracted with chloroform. The extract is dried and evaporated. The residue is crystallized from a mixture of 1,1-oxy5-isethane and -hexane, whereby 7.8 N- {4-chlorophenyl) 3-methoxy-N- (4-pynepj-schchinil) -benzeneacetamide are obtained, mp. 85/7 ° C.
    Example 25: 52 parts of 2-bromopropane, 19 parts of N- (4-piperidinyl) -3-pyridinevag, 33.3 parts of sodium carbonate, 3 parts of potassium iodide and 720 parts of methyl 2-pentanone are stirred and the mixture is refluxed for 24 hours. The reaction mass is cooled and filtered. The filtrate is evaporated. The residue was purified by silica gel column chromatography using methanol as the eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2-oxybispropane, resulting in 1.5 hours. N-D- (1-methyl-ethyl) -4-piperidinyl3-3-pyridinamine, m.p. 100.7 ° C.
    Example 26. According to the procedure of Example 25, using equivalent amounts of the corresponding base and 4 (arylamino) -4-X-piperidine as starting materials and conducting the reaction in the solvent indicated in Table 5, the compounds are obtained as free bases or as hydrochlorides after hydrochloric acid treatments listed in t ab.5,
    H
    Phenyl
    CH
    Phenyl
    3-pyridine ntan
    2-pyridine
    Phenyl
    Also
    Example 27. To a stirred mixture of 15 parts of N- (4-chlorophenyl) -4-piperidinamine, 12 parts of N, N-diethylamine in 130 parts of benzene, a solution of 10.3 parts of dropwise add drop of 10.3 parts of B-bromo-1-propene in 70 including benzene. After the addition is complete, the mixture is stirred first for 20 hours 30 minutes at room temperature and then for 40 hours at reflux. The residue is taken up in 1,1-hydroxybiset and is treated with activated carbon. The latter is filtered off and 1,1-oxybisethane is evaporated again, resulting in 2.9 hours of N- (4-chlorophenyl) -1- (2-propenyl) -4-piperidinamine, m.p. .
    Example 28. To a warm (-40 ° C stirring mixture, 5 parts N- (2,6-dimethylphenyl) -4-piperidinamine, 5 sodium carbonate, several Kssi iodide crystals in 120 parts benzene was added dropwise a solution 5.1 parts 1 iodopropane in 80 parts of benzene. After the addition is complete, stirring is continued for 40 hours under reflux. The reaction mixture is then cooled and 50 parts of water are added. The oily residue is distilled to give 10.2 hours. M- (2,6-dimethylphenyl) -1-propyl-4-piperidine aj-MHa b.p., 2 mm Hg.
    Table 5
    COOC, j, Hy 2Нсе-Н, О
    148.6 Methylisopropylketone
    2Не-1 / 2Н, О 168.7 The same
    CoPs,
    Example 29. To 0.5 hours of a solution for 2 hours thiophene in 40 parts of ethanol to 5% bavly, 2 parts of cyclopentanone, 5.5 parts of N- (4-piperidinyl) -2-pyrimnacinamine and 120 parts of methanol and hydrogenated at normal pressure and room temperature in the presence of 2 parts 10% 0 palladium on coal. After uptake of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in 4-methyl-2-pentanone in a mixture of 5% chloroform, washed twice with a dilute solution of sodium hydroxide, dried, filtered and evaporated. The residue is crystallized from 2, 2-hydroxybispropane.
    0 The product is filtered and dried, resulting in 2.3 hours. Of N- (1-cyclopentyl-4-piperidinyl) -2-pyrimidinamine, m.p. 118 C.
    Example 30. KO, 5h. Thinning 2 parts of thiophene in 40 parts of ethanol was added 4 parts of acetone, 4.5 parts of N- (4-piperidinyl) -2-pyrimidinamine and 120 parts of methanol, then hydrogenated under normal pressure and room temperature with the addition of 2 hours. 10% palladium on carbon as a catalyst. After uptake of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in three.
    chloromethane. The solution is successively washed with a dilute sodium hydroxide solution and water, dried, filtered and evaporated, resulting in 3 hours — 1- {1-methylethyl) -4-piperidinyl-1-2-pyrimidinamine ..
    Example 31. To a suspension of 2 parts of lithium aluminum hydride stirred under reflux for 120 hours, 1.1 oxybisethane is added dropwise a solution of 13 parts of ethyl 4-m- (2, b-dimethylphenyl) -amine -1-piperndinecarboxylate in 40 h. 1, bisetana. At the end of the addition, stirring and refluxing are continued for 20 hours. The reaction mixture is cooled to and 7 hours of water are added. The resulting precipitate is filtered off, washed on the filter with 1,1-oxybisethane and the filtrate is evaporated. The oily residue is distilled, resulting in 5.8 parts of N- (2, b-dimethylphenyl) -methyl-4-piperidinamine, b.p. EO-EZ S / O, 003 mm Hg On standing, the distillate solidifies to N- (2, b-dimethylphenyl) 1-methyl-4-piperidinamine with mp. .
    Example 32. To a stirred suspension 5h. N- {4-chlorophenyl) -N- (4-piperidinyl). -BenoJ auetamide, 5 parts of sodium carbohydrate, several KpHCTajDioB potassium iodide in 200 parts of butanol are added in drops 4 parts of 2-bromopropane at room temperature . After the addition is complete, the mixture is stirred and refluxed for 20 seconds. A second portion is then added 4 hours. 2-bromopropane and stirring and refluxing is continued for another 19 hours. Next, the reaction mixture is cooled, filtered and the filtrate is evaporated . From the oily base, the hydrochloride in 1,1-oxybisethane and acetone is obtained in the usual manner. The solid salt is filtered off and crystallized from a mixture of acetone - 2-propanol, B resulting in 2 hours. N - (4-chlorophenyl) - N - p - (1-methyl ethyl) -4-piperidinyl} -benzene-acetamide-hydrochloride, t. square
    Example 33. Following the procedure of Example 33, using an equivalent amount of a suitable bromide and N-apyl-N- (4-piperidinyl) arylacetamide as the starting product, the following compounds are obtained in the form of hydrochlorides, shown in Table 6.
    Table 6
    Example 34. To a stirring warm (40c) mixture of 5 parts of N- (4-chlorophenyl) - N- (4-piperidinyl) -beneolacetamide, 5 parts of sodium carbonate, several potassium iodide crystals and 200 parts of n-butanol were added 3.75 parts of bromocyclopentane, then stirred and refluxed for 21 hours and 30 minutes. A second portion of .5 parts of bromocyclopentane was then added and stirring and refluxing continued for another 30 minutes. The reaction mass is cooled, filtered and the filtrate is evaporated. Oil extension Table 6
    the different residue solidifies upon grinding in 1,1-oxybisethane. The solid product is filtered off and crystallized from 1,1-oxybisethane, resulting in a yield of 1.1 parts. H- (4-chloropentyl) -N- (1-cyclopentyl-4- piperidinyl) benzene-acetamide, m.p. 139 ,.
    Example 35. Following the procedure of Example 34, using equivalent amounts of the corresponding bromide and M-aryl-M- (4-piperidinyl) aryl acetamide as starting materials, the compounds shown in Table 7 are obtained.
    Table 7
     ABOUT
    -X X
      -
    2,5- (ce) fe-C, K ,,
    n
    2.6- (ce)
    cn
    sn
    2-ce-CfcH4
    4-ce-SeH4
    ntan
    4-ce-SbH4
    4-se-with H4
    4-Cg-C H
    4-se-with H4
    Example Jb.K is stirred at reflux for 5 hours, N- (4-chloropentyl) -N- (4-piperidinyl) -benzene-acetamide, 5 parts sodium bicarbonate and 200 hours, benzene is added in portions of 6.7 including methyl biclopropane and stirring and boiling continue for 23 hours. The reaction mixture is cooled and filtered. The filtrate is evaporated. The semi-solid residue is dissolved in a mixture of benzene - 1,1-oxybisethane. The undissolved impurities are filtered off, the filtrate is evaporated again. From the oily free base, hydrochloride is obtained in the usual way, after crystallization of the crude salt from chloroform mixture 1,1-oxybisethane is obtained 1.5 hours. N- (4-chlorophenyl) -N-p- (cyclopropylmethyl) -4-piperidinyl benzene-acetamide-hydrochloride m.p. 224 S.,
    Example 37. To a stirred solution of 5 h, N- (4-chlorophenyl) -N- (4-piperidinyl) benzene-adamide, 3.8 parts of N, M-diethylethylamine in 200 parts of benzene are added in portions of 5 hours. bromo-1-propene. After the addition is complete, the mixture is heated for 21 hours at 50-60 ° C. The reaction mass is cooled and filtered. The filtrate is washed successively with water, sodium bicarbonate solution and water, dried with potassium carbonate and evaporated. The oily residue is converted to hydrochloride in 1D-oxybisethane and acetone, resulting in 4 parts of N- (4-chlorophenyl) N-1 - (2-propenyl) -4-piperidine-3-dinyl-3-benzenecetamide hydrochloride, m.p. . 225.5
    Continuation of table 7
    T, pl. , with
    Ks-ha-Ag,
    102.5 129.1 87.5 133.1 128.6 157.5 155.0 143.5
    Example 38. According to the procedure of Example 37, using an equivalent amount of the corresponding N-aryl-N- (4-piperidinyl) arylacetamide, M- (2,6-dimethylphenyl) -N- 1- (2-propenyl) -4- hydrochloride is obtained pi-, peridinyl3-2-thiophenecetamide, m.p. 203 ,, and N- (2,6-dimethylphenyl) -N- t (2-propane) -4-piperidinyl-benzene-acetamide hydrochloride, m.p. 214 ° C.
    Example 39. To a warm suspension of 5 parts of M- (4-chlorophenyl) -N- (4-piperidinyl-benzene-acetamide, 5 parts of sodium carbonate, several potassium iodide crystals in 200 hours of n-butyl nol are added 4 hours chloro-2-methylpropane at 30-40 C. The mixture is stirred and boiled with a reflux cooler for 140 hours, at which time 35 hours of 2-chloro-2-methylpropane are added, after 15 hours - 4 hours, 2- chlorine-2-methylpropane, after the next 8 hours - 10 hours, then after 16 hours - 11 hours, and finally, after 47 hours - 10 hours. The reaction mixture is cooled, filtered and the filtrate is evaporated. The semi-solid residue is dissolved in toluene. dimethoxy ethane-1, 1-hydroxybisethane. The solution is filtered off from impurities and the filtrate is again evaporated. Hydrochloride in 1,1-oxybisethane is obtained in the usual way from an oily residue; 0.9 parts of the crude solid are recrystallized from acetone; N- (4-chlorophenyl) ) -N- 1- (1-dimethylethyl) -4-piperidinyl3-benzene-amide hydrochloride, mp 221 C.
    Example 40. A mixture of 4 parts of iodoethane, 5 parts of N- (2,6-dimethylphenyl) -N- (4-piperidinyl) benzenecetamide, 5 parts of sodium carbonate, several crystals of potassium iodide in 200 parts of benzene is stirred and baled t under reflux for 23 hours. The reaction mass is filtered while hot and the filtrate is evaporated in vacuo. The solid residue is crystallized from 1,1-oxybisethane, resulting in 2 hours of N- (4-chlorophenyl) -m- (1-ethyl-4-piperidinyl) benzene-acetamide, t.pcs. 86, 5 °
    Example 41. According to the procedure of Example 40, using an equivalent amount of the corresponding H-aryl-H- (4-piperidinyl) -arylacetamide, 2-chloro-N- (4-chlorophenyl) -N- (1-ethyl-4-piperidinyl) hydrochloride ) -benzeneacetamide, t.Sh1.234, N- (4-chlorophenyl) -N- (1-ethyl-4-piperidinyl) 3-methylbenzeneacetamide, mp, 78.5 ° C, N- (4-chlorophenyl) -N- (1-ethyl-4-piperidinyl) -4-methylbenzeneacetamide, m.p. , N- (4-chlorophenyl) -N- (1-ethyl-4-piperRschnyl) -4-fluorobenzene-acetamide, m.p. 62,
    Example 42: to a mixture of 5 parts of 4-chloro-I- (4-chlorophenyl) - N - (4-piperidinyl) benzene-acetamide, stirred under reflux and 5 parts of sodium carbonate, 0.4 parts of potassium iodide and 200 parts of butanol are added 4.7 parts of 1-iodopropane and the mixture is stirred and refluxed for 22 hours. Then a second portion of 4.5 parts is added. 1-iodopropane and stirring and boiling continue within 27 hours and 30 minutes Next, the reaction mass is cooled, filtered and the filtrate is evaporated. The semi-solid residue is dissolved in toluene. The solution is filtered off from undissolved impurities and the filtrate is evaporated again. The residue is crystallized from 1,1-oxybisethane at and 0.9 parts of 4-chloro-M- (4-chlorophenyl) -N-.O-propyl-4-piperidinyl) -benzeneacetamide are obtained m.p. 118, bs
    Example 43. To a stirred solution of 4 parts of N- (4-chlorophenyl) N- (4-piperidinyl) benzene-acetamide and 3 parts of N, N-diethylamine in 200 parts of benzene are added in portions of 4 parts of 1-iodopropane and everything is stirred at reflux for 47 hours. Then a second portion of 4 hours of 1-iodopropane is added and stirring and boiling continue for another 20 hours and 20 minutes. The reaction mass is cooled and filtered. The filtrate is washed with water, dried and evaporated in vacuo. From the oily base, hydrochloride in 1,1-oxybisethane is obtained in a manner known per se.
    The precipitated solid salt is filtered off and dried, as a result of which 3.5 parts of N- (4-chlorophenyl) -N- (1-propyl-4-piperidinyl) benzene-acetamide-hydrochloride a, m.p. 233 ,. Example 44. According to the method
    of Example 43, using the equivalent amount of the corresponding iodashkan and M-aryl-M- (4-piperidinyl) aryl acetamide, the following compounds are obtained:
    N- (2,6-dimethylphenyl) -N- (1-ethyl-4-piperidinyl) -2-thiophenecetamide hydrochloride, m.p. 258 ° C;
    N- (4-chlorophenyl) -Ne - (1-ethyl-4-piperidinyl) -2-thiophenecetamide hydrochloride, m.p. 220 ,.
    N- (4-chlorophenyl) -N- (1-ethyl-4-piperidinyl) benzeneacetamide hydrochloride, m.p. ,
    4-chloro-y- (4-chlorofo-nyl) -N- (1-ethyl-4-piperidinyl) benzene-acetamide hydrochloride, m.p. ,
    N- (4-chlorophenyl) -N- (1-propyl-4-piperidinyl) -2-thiophenecetamide, m.p. 24lc.
    5 Example 45. A mixture of 4.5 parts of N- (1-cyclopentyl-4-piperidinyl) -2-pyrimidinamine, 3.4 parts of H-methylbenzoyl acetyl chloride, 2 parts of sodium carbonate and 180 parts of xylene are stirred and baled t under reflux for 17 h. Then an additional 9 hours of 3-methylbenzeneacetyl chloride are added dropwise. After the addition is complete, stirring and boiling continue for another 67 hours. Cool the reaction mass, add water to it, and separate the layers. The organic phase is extracted with a dilute hydrochloric acid solution. The combined aqueous phases are washed with benzene and alkalinized with a dilute sodium hydroxide solution while cooling in an ice bath. The product is extracted twice with chlora form. The extracts are then combined, dried, filtered and evaporated. The residue is converted to the oxalate salt in 2-propanol. The salt is filtered off and crystallized twice, first from ethanol and then from methanol, as a result of which 1 part is obtained. N- (1-cyclopentyl-4-piperidinyl) -3-methyl-N- (2-pyrimidinyl) benzeneacetamide oxalate m.p. 204.1 C.
    Example 46 Following the procedure of Example 45 and using equivalent amounts of the corresponding M-aryl-4-piperidinamine and arylacetyl chloride as starting materials, the compounds are obtained as a base or as an acid salt after treatment with an appropriate acid, as shown in Table 8.
    Example 47. A mixture of 5 parts of methyl-1- (1-methylethyl) -C- (phenyl lin) -4-piperidinecarboxylate, 24 parts of 4-chlorobene-acetyl chloride, 4 parts of sodium carbonate and 180 parts of xylene is stirred and boiled under reflux for 32 hours. The reaction mixture is cooled, washed with dilute sodium hydroxide solution, extracted with dilute hydrochloric acid solution and three layers are obtained; The oil and water phases are basified with a dilute sodium hydroxide solution. The product is extracted with 4-methyl-2-pentanone. The extract is washed with water, dried, filtered and evaporated. The remainder is transferred to the chaff Table 8
    acidic salt in 2-propanol. The salt is filtered off and crystallized from a mixture of 2-propanol - 2,2-oxybispropane, resulting in 5 hours (48%) methyl oxalate-4- {n- (4-chlorophenyl) -acetyl-K-phenylamino -1- { 1-methylethyl) -4-piperidinecarboxylate, t, area G54.2C.
    Example 48. Following the procedure of Example 47 and using equivalent amounts of the corresponding 4-arylamino-4-piperidinecarboxylate and
    60 arylacetyl chloride as starting materials, the compounds are obtained as a free base or as a salt after treatment with a suitable acid and are listed in Table 9.
    /:9
    Example 49. To a stirred mixture of 4.4 hours, 1- (1-methylethyl) -N-phenyl-4-piperidinamine, 5.3 parts of sodium carbonate and 180 parts of benzene were added dropwise 5 parts of benzene-acetyl chloride. After the addition is complete, stirring is continued overnight at reflux. Then the reaction mass is cooled, washed successively with water, sodium bicarbonate solution and again with water, dried, filtered and evaporated. The residue is taken up in hydrochloride in 2,2-hydroxy-propane and 2-propanol. The precipitated salt is filtered off and
    747424
    30 table
    crystallized from a mixture of 2-propanol - 2,2-oxybispropane, which gives 2.5 hours N-l - (1-methylethyl) -4-piperidinyl 3-M-phenylbenzene-acetamide-hydrochloride, so pl. 184,
    Example 5Q. Following the procedure of Example 49 and using equivalent amounts of the corresponding N aryl-4-piperidinamine and arylacetyl chloride as starting materials, the compounds are obtained in the form of a base or in the form of a salt after treatment with the corresponding acid and are listed in Table 10.
    Example 51. A suspension of 1.25 parts of sodium amide in 56 parts of benzene is stirred under a nitrogen atmosphere and heated to. Then a solution of n-part of N- (4-chlorophenyl) -1- (1gmethylethyl) -4-piperidinamine in 56 parts of benzene is added dropwise. After the addition is complete, the mixture is stirred and refluxed under JB for 16 hours and 45 minutes. The mixture is then cooled before and a mixture of 7.8 parts of 3,4-dichlorobenzeneacetyl chloride in 88 parts of benzene is added to it. After stirring and refluxing for another 2 hours, the reaction mixture is cooled and 80 hours is added to it. water, then acidified with a dilute solution
    Table 10
    hydrochloric acid. The aqueous acidic phase is made alkaline with sodium hydroxide solution and the free base is extracted with chloroform. The extract is dried, filtered and evaporated. The residue is dissolved in a mixture of 80 parts of 1,1-oxybisethane and 120 hours of so
    J3 dignity. The solution is cooled to -10 ° C and left at this temperature overnight, then filtered from insoluble impurities and the filtrate is evaporated again. The residue is dissolved in 120 parts of 1,1-oxybisethane, the asset is treated with 1% charcoal, filtered and evaporated. The residue is crystallized from hexane at, resulting in 2.2 h.
    §5 3, 4-dichloro-M- (4-chlorophenyl) -N- 1 - (1-methyl) -4-piperidiyl1-benzenecetam yes, mp. 101.7 ° C. Example 52 Following the procedure of Example 51 and using equivalent amounts of the corresponding N-aryl-4-piperidinamine and arylacetyl chloride B as starting materials, the following compounds are obtained in base form or as a salt after treatment with the appropriate acid: 4-bromo-H- (4 -chlorophenyl) -K-l- (1-methyl-ethyl) -4-piperidinyl-benzene-acetamide, m.p. 118.1 ° C; 4-chloro-M- (2,6-dimeti phenyl) -N-l - (1-methylethyl) -4-piperid nyl-benzene-acetamide hydrochloride, m.p. 268.2 ° C N- (4-chlorophenyl) -4- (1-methylethyl) N- 1- (1-methylethyl) -4-piperidinylZ-benzenecetamide, mp. 104 ,. Example 53. 5 parts of 4-chloro-M- {4-chlorophenyl) -N-fl-(1-methylethyl) -4-piperidinyl-3-benzene-acetamide are dissolved in a mixture of 60 parts of 1,1-oxybisethane and 16 hours. acetone. The resulting solution is acidified with a saturated solution of hydrogen chloride in 2-propane. The precipitated salt is filtered off and dried, yielding 7.5 parts of 4-chloro-M- (4-chlorophenyl) -N-1-{1-methylethyl) -4-piperidinyll-benzolacetamide hydrochloride, m.p. 266, Example 54.6h (l-methylethyl) -4-piperidinyl -N-phenyl -2-thioenacetamide (E) -2-butenioate is converted to the free base by treatment with a dilute sodium hydroxide solution. The product is extracted with chloroform. The extract is washed with water, dried, filtered and evaporated. The residue is converted to oxalate in 2-propanol. The salt is filtered and dried, yielding 3.2 parts of N-l - (1-methyl or ethyl) -4-piperidine or} N-phenyl-2-thio1) enacetamide-oxalate, m.p. 167.4 ° C. Example 55. From an aqueous solution of 2.8 parts of N- (2,6-dimethylphenyl) -N- (1-propyl-4-piper NILE) -2-thiophenecetamide dihydrochloride, free base was isolated by alkalizing a solution with sodium bicarbonate. The free base is extracted with 1,1-oxybisethane. The extract is dried and evaporated. The oily residue is dissolved in 56 parts of hexane and, after cooling, a solid base precipitates out. It is filtered off and dried, whereby I get 1.6 parts of N- (2,6-dimethylphenyl) -N- (1-propyl-4-piperidiyl) -2-thiophenacetate amide, so pl. 62.5 ° C. Example 56. From 3.9 parts of (E) -2-N- (1-cyclopentyl-4-piperidinyl) -3-methyl-N- (3-pyridinyl) benzene-acetamide butenedioate, the base was isolated using dilute hydroxide solution on three . After extrusion with 2, 2-hydroxybisane, the extract is washed with water, dried and evaporated. The residue is converted to oxalate in ethanol. The salt is filtered off and crystallized from ethanol-2,2-oxybispropane, to give 3 parts of N- (1-cyclopentyl-4-piperidinyl) -3-methyl-N- (3-pyridinyl) benzene-acetamide oxalate, m. square 19 2, 6c. Example 57 a) A mixture of 50 parts of 4- (phenylamino) -1- (phenylmethyl) -4-piperidinecarboxamide and 600 parts of concentrated hydrochloric acid was heated under reflux for 16 hours. After cooling, the reaction mixture was concentrated in vacuo up to a volume of 400 hours, resulting in precipitation. It is filtered off, washed with water and acetone, dried, giving 43 parts of 4- (phenylamino) -1- (feiylstil) -4-piperidinecarboxylic acid digindrochloride, mp. 261-263 C (with diff.). b) A mixture of 19 parts of 4- (phenylamino) -1- (phenylmethyl) -4-piperidinecarboxylic acid dihydrochloride, 14.4 parts of sulfuric acid and 64 parts of ethanol is stirred and boiled under reflux for 16 hours. The solvent decant. The residue is dissolved in water. The aqueous solution is alkalinized with ammonium hydroxide and extracted with a mixture of methyl benzene - 2,2-oxybispropane. The combined organic salts are dried with magnesium sulfate, filtered and evaporated. The oily residue is dissolved in 200 parts of 2,2-oxybispropane and hydrogen chloride gas is passed into the solution. The precipitated hydrochloride is filtered off, washed with 2-propanol, filtered off again and dried, resulting in 11.5 parts of ethyl 4- (phenylamino) -1 - (phenylmethyl) -4-piperidinecarboxylate dihydrochloride, mp. 212-214, 4c. c) To a solution of 101.4 parts of ethyl 4- (phenylamino) -1- (phenylmethyl) -4-piperidinecarboxylate mixed in and heated under reflux in 640 parts of dry benzene, a solution of 172 parts of 70% is added dropwise dihydrobis- (2-methoxyethoxy) sodium aluminate in 160 parts of dry benzene. After the addition is complete, stirring is continued for another 2 h 30 min at 80 s. Then the reaction mixture is cooled, poured into ice-water, alkalinized with sodium hydroxide solution and the product is extracted with benzene. The extract is washed twice with water, dried, filtered and evaporated. The residue is taken up in hydrochloride in 2-propanol and, after cooling, the product is filtered off. It is boiled again in acetonitrile and salt.
    filtered again after cooling. After extraction with 1,1-oxybisethane, the last prog is water, dried and evaporated to give 56.6 parts of 4- (phenylamino) -1- (phenymethyl) -4-piperidinemethanol as an oily residue. .
    d) to a solution of 32 parts of 4- (phenylamino) -1- (phenylmethyl) -4-piperidinemethanl in 90 parts of benzene, 0.2 .h of N, N, N-triethylbenzenemethylamide loni chloride and 150 parts of 60% - sodium hydroxide solution. After vigorous stirring, 10.9 parts of dimethyl sulfate are added dropwise at a temperature below 30 ° C. After the addition is complete, stirring is continued at room temperature for 2 hours and 30 minutes: and after adding the second portion of 2.6 parts of dimethyl sulfate, for 1h 30 IVBIH. The reaction mixture is cooled in water.
    with ice and add 200 parts of water. The organic phase is separated and the aqueous phase is extracted with benzene. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is purified on a chromatographic column with silica gel, using a mixture of chloroform - 3% methanol, saturated with ammonia, as eluent. Pure fractions are collected, the eluent is evaporated, and 24.8 parts of 4 (methoxymethyl) -M-phenyl-1- (phenylmethyl) -4-piperidinamine are obtained.
    e) A mixture of 10 parts of 4 -. (methoxymethyl) -N-phenyl-1- (phenylmethyl) -4-piperidinamine and 200 parts of acetic acid is hydrogenated at normal pressure and room temperature in the presence of 2 parts of 10% palladium on coal as a catalyst. After uptake of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The oily residue is dissolved in water, cooled and alkalinized with ammonium hydroxide. The product is extracted with chloroform. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified on a chromatographic column with silica gel using a mixture (90:10 by volume) of chloroform - methanol saturated with gaseous ammonia as eluent. The pure fractions are collected and the eluent is evaporated, which gives 4.5 parts of 4- (methoxymethyl) -M-pheny-4-piperidinamine.
    e) Acid 10 parts of 2-bromopropane, 9 parts of 4- (methoxymethyl) -M-phenyl-4-piperidinamine, 4.9 parts of N, M-diethylethylamine and 72 parts of N, N-dimethyl acetate, amide is stirred and boil with reflux for 10.25 hours. After cooling, the resulting M, H-diethylethylamine hydrobromide is filtered. 1 and the filtrate is diluted with water. The product is extracted with xylene. The extract is thoroughly washed with water, dried, filtered and evaporated. The residue is purified on a silica gel chromatography column using chloroform-methanol (90:10) as eluent. The pure fractions are collected and the eluent is evaporated, resulting in 5.7 parts (42.6%) of 4- (methoxymethyl) - 1- (1-methylethyl) - N-phenyl-4-piperidinamine.
    g) To a stirred mixture of 5.5 parts of 4- (methoxymethyl) -1- (1-methylethyl) -N-phenyl-4-piperidine1 to 56 parts of benzene a solution of 13.8 parts of benzene-acetyl chloride in 45 is added dropwise. including benzene at 26-32 ° C. At the end of the addition, stirring is continued, first for 1 hour at 26-32 ° C,
    and then for 3.6 hours at 38-55s. After cooling, the precipitated product is filtered and converted into hydrochloride in a mixture of 2-propanol - acetone (5: 1 by volume). The salt is filtered and dissolved in absolute ethanol. After vyderzhivaniya at room temperature, the precipitated product is filtered off, washed with a small amount of acetone and dried, giving 1.05 parts of N-4- (methoxymethyl) -1- (1-methylethyl) -4-piperidinyl 1-β-phenyl hydrochloride zolacetamide, t. square 249, lc.
    Example 58. According to the procedure of steps 1-4 of example 57, using the equivalent amount of the corresponding alkyl sulfate in step d), the following intermediates are obtained:
    4- (methoxymethyl) -N- (3-methylphenyl) -1 - (phenylmethyl) -4-piperidium amine
    4- (methoxymethyl) -N- (4-methylphenyl) -1- (phenylmethyl) -4-piperidinamine
    4- (methoxymethyl) -N- (2-methylphenyl) -1- (phenylmethyl) -4-piperidinamine
    I- (4-fluorophenyl) -4- (methoxymethyl) -1- (phenylmethyl) -4-piperidinamine;
    4- (ethoxymethyl) -N-phenyl- - (fechilmethyl) -4-piperidinamine;
    4- (ethoxymethyl) -N- (4-fluorophenyl) -1 - (phenylmethyl) -4-piperidinamine.
    Example 59. Following the procedure of step g) of Example 57 and using equivalent amounts of the corresponding M-aryl-4-piperidinamine and arylacetyl chloride as starting materials, the following products are obtained:
    (methoxymethyl) -1 - (phenylmethyl) -4-piperidinyl -N-phenylbenzene-acetamide;
    N- 4- (methoxymethyl) -1- (phenylmethyl) -4-piperidinyl -N- (3-methylphenyl) benzene-acetamide /
    (methoxymethyl) -1- (phenylethyl) -4-piperidinylZ-M- (4-methylbenyl) benzene-acetamide,
    N- 4- (methoxy / 1-methyl) -1- {phenyl-. methyl) -4-piperidinylZ-M- (2-me ylphenyl) -beneol acetamide,
    N- 4- (fluorophenyl) -N- (4-methoxymethyl) -1 - (phenylmethyl) -4-piperidini-beneol acetamide;
    N (ethoxymethyl) -1- (phenylmethyl) -4-piperidinyl -N-fanylbenzoacetamide,
    (ethoxymethyl) -1- (phenylmethyl) -4-piperidinyl -N- (4-fluorophenyl) benzene-acetamide)
    N- 4- (methoxymethyl) -1- (phenylmethyl) -4-piperidinylZ-M-phenyl-4-methibenzene acetamide)
    N- | 4- (methoxymethyl) -1- (phenylmethyl) -4 piperidinyl-M-phenyl-4-methobenzene-acetamide;
    N- 4- (methoxymethyl) -1- (phenylmethyl) -4 piperidinyl-M-phenyl-2-thiofacetamide.
    Example 60. Following the procedure of step g) of example 57, starting from the corresponding starting materials, the following compounds are obtained:
    N- 4- (methoxymethyl) -4-piperidinyl - N-phenyl benzene-acetamide,
    N- - (methoxymethyl) -4-piperidinyl -N- (3-methylphenyl) -benzeneacetamide,
    N- 4- (methoxymethyl) -4-piperidinylJ - N- (4-methylphenyl) -benzeneacetamide;
    N- (4- (methoxymethyl) -4-piperidinyl -N- (2-methylphenyl) -benzeneacetamide;
    (fluorophenyl) -N-4- (methoxymethyl) -4-piperidinyl benzene-acetamide;
    N- 4- (ethoxymethyl) -4-piperidinyl -N-phenylbenzene-acetamide;
    N- 4- (ethoxymethyl) -4-piperidinyl -N- (4-fluorophenyl) benzene-acetamide;
    N- 4- (methoxymethyl) -4-piperidinyl -N-phenyl-4-methylbenzeneacetamide
    N- 4- (methoxymethyl) -4-piperidinyl -N-phenyl-4-methoxybenzene-acetamide)
    N- 4- (methoxymethyl) -4-piperidinyl - M-phenyl-2-thiophenecetamide.
    Example 61 To the mixture, 7.5 parts of N- (4-chlorophenyl) -2- (1-methylethyl) -4-piperidinamine and 80 of 4-methyl-2-pentanone are stirred, and 9 parts of 4- carbonate are added dropwise. (2-chloro-2-hydroxyethyl) -phenyl-ethyl. After the addition is complete, the mixture is heated to reflux and then stirred for 1 hour at room temperature. After cooling, the precipitated product is filtered off and stirred for 30 m in a mixture of alkaline water and chloroform. The mixture is separated. Organic phase
    dried, filtered and evaporated. The oily residue is purified by chromatography on a column of silica gel using chloroform-methanol (90:10 o6beNiy) as eluent. The pure fractions are collected and the eluent is evaporated to give 5.5 parts of carbonate | 4- 2- (4- chlorophenyl) -1- (1-methylethyl) -4- (piperidinyl) amino-2-oxol ethyl-phenyl-ethyl.
    A mixture of 5.5 parts of (4-chlorophenyl) -1- (1-methylethyl) -4- (piperidinyl) amino-2-oxoethyl-3-phenyl-ethyl carbonate and 50 parts of a 10% sodium hydroxide solution is stirred for 90 min at 45 ° C. The reaction mixture is cooled to room temperature and acidified with acetic acid to pH 5.5-6.0. The product is extracted
    0 chloroform. The extract is dried, filtered and evaporated. The oily residue is purified by chromatography on a silica gel column using chloroform-methanol (80:20 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The oily residue is converted to the hydrochloride in 4-methyl-2-pentanone. The salt is filtered off and dried in vacuo for 12 hours at 60 ° C., which gives 1.9 parts of N- (4-chlorophenyl) -4-oxo-N-jl- (1-methylethyl) -4-piperidinyl-benzeneacetamide monohydrochloride ,
    5 m.p. 242.9 ° C.
    权利要求:
    Claims (12)
    [1]
    The invention The method of producing N-apyl-N- (1-L-4-piperidinyl) acetamides of the general formula
    Jb
    lfC-CHj-ATi
    I it r 0
    where L is hydrogen, C -C-alkyl,
    Su-C-cycloalkyl, cyclopropylmethyl or propenyl; And g - unsubstituted phenyl or
    phenyl substituted with one or two halides or
    .-alkyl, pyridinyl or 2-pyrimidinyl; Aq is unsubstituted phenyl or
    phenyl substituted with one or two halides,
    methyl, hydroxyl or methoxy, thienyl, X - hydrogen,.; alkoxycarbonyl or methoxymethyl, or their salts, characterized in that the compound of the general formula
    X
     vJXjjHUH-AP where L, Ar and X have the above decree anng meaning or L is a Protective group P, when L in the target product is hydrogen, is acylated with arylate by a tylhalide YH-eHg Ar, where Ar | has the above values or has a protective group for oxy derivatives, Y is a halogen, inert in the reaction conditions of the solvent with a subsequent extraction of the target product as a base or salt or removal of the protective groups by catalytic hydrogenation, alkaline or acidic hydrolysis and isolation of the target product in as base or salt.
    [2]
    2. A method according to claim 1, characterized in that aromatic hydrocarbons are used as the solvent.
    [3]
    3. The method according to claim 2, wherein tl and h and y and the fact that as an aromatic hydrocarbon used benzene, toluene or xylene,
    [4]
    4. The method according to claim 1, 1 and 2, so that haloalkanes are used as the solvent.
    [5]
    5. A process according to claim 4, characterized in that chloroform is used as a gal alkane. ,,
    [6]
    6. The method according to claims 1-5, which is carried out in that the process is carried out in the presence of a base.
    [7]
    7. The method according to claim 6, which is also distinguished by the fact that an alkali metal carbonate or bicarbonate is used as the base.
    [8]
    8. The method according to claim 6, distinguishing with the fact that alkali metal amides are used as the base.
    [9]
    9. The process according to claim 8, wherein the process is carried out in the presence of sodium amide.
    [10]
    10. The method according to claim 6, wherein it is used that amines are used as the base.
    [11]
    11. The method according to claim 10, that is, that the process is carried out in the presence of 3 pyridine.
    [12]
    12. The method according to claim 10, wherein the process is carried out in the presence of N, N-diethylamine. The priority of September 23, 1997, on the basis of L and Ar, is all the values, Kpoivie L is hydrogen J Ar is unsubstituted phenyl or phenyl substituted by one or two halides, methyl, methoxy groups, thienyl group, X is hydrogen or alkoxycarbonyl. 12.08.76 by the sign of Ar - phenyl, substituted by one or two hydroxyl, X - methoxymethyl, L - hydrogen. Sources of information taken into account in the examination 1. Heterocyclic compounds ed. R. Elderfield, v.6, M. , And. L , I960, p. 358.
    类似技术:
    公开号 | 公开日 | 专利标题
    US4126689A|1978-11-21|N-aryl-n-|-arylacetamides
    US5606065A|1997-02-25|Process for preparing N-alkylene piperidino compounds and their enantiomers
    CA1080232A|1980-06-24|N-|-n-phenylamides and carbamates
    US3164600A|1965-01-05|1-aralkyl-4-|-piperidines and related compounds
    US4472403A|1984-09-18|Quinoline derivatives and pharmaceutical compositions and methods for treating cardiovascular disease with such compounds
    CA2332538C|2005-08-02|Novel 4-phenylpiperidines for the treatment of pruritic dermatoses
    US5290790A|1994-03-01|4-| piperidines substituted at position 1, their preparation and also their therapeutic applications
    CA2514940A1|2004-08-19|Quinoline-derived amide modulators of vanilloid vr1 receptor
    JP2007524707A|2007-08-30|Aryl and heteroaryl piperidine carboxylic acid derivatives, their preparation and their use as FAAH enzyme inhibitors
    US4179569A|1979-12-18|N-|-N-phenylamides
    SU747424A3|1980-07-23|Method of producing n-aryl-n-| acetamides or salts thereof
    US4775761A|1988-10-04|3-|- and 3-|-1H-indazoles
    US4369184A|1983-01-18|1-|-4-aryl-4-piperidinecarboxylic acid derivatives
    US3041344A|1962-06-26|1-|-4-piperidinecarboxamides
    US4197304A|1980-04-08|N-Aryl-N-|-arylacetamides
    US4196210A|1980-04-01|N-Aryl-N-|-arylacetamides
    DE60036924T2|2008-08-14|5-HT1F AGONISTS
    CA2072520A1|1992-12-28|2-| ethanol derivatives, their preparation and their therapeutic application
    US5789425A|1998-08-04|Imidazolidinone derivatives, their acid adducts and therapeutic drugs for senile dementia
    CA2502704A1|2004-05-13|Novel piperidine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors
    US4806649A|1989-02-21|3-|- and 3- |-1H-indazoles
    US4151286A|1979-04-24|N-aryl-N-|-arylacetamides
    US4853470A|1989-08-01|3-|- and 3-|-1H-indazoles
    US4710573A|1987-12-01|3-|-and 3-|-1H-indazoles
    US2486794A|1949-11-01|1-alkyl-4-|-piperidyl-|-alkylketones and their production
    同族专利:
    公开号 | 公开日
    YU39973B|1985-06-30|
    DE2642856C2|1990-06-21|
    BG27543A3|1979-11-12|
    AU510029B2|1980-06-05|
    ATA702976A|1981-02-15|
    IT1073893B|1985-04-17|
    IE43802L|1977-03-23|
    FI61482C|1982-08-10|
    SE7610501L|1977-03-24|
    FI61482B|1982-04-30|
    RO70079A|1982-10-26|
    DK150478C|1987-10-05|
    DK150478B|1987-03-09|
    AT363935B|1981-09-10|
    JPS6016417B2|1985-04-25|
    PL117323B1|1981-07-31|
    FR2325377B1|1980-04-18|
    CS222663B2|1983-07-29|
    NO147672C|1983-05-25|
    YU233676A|1983-01-21|
    LU75837A1|1977-05-04|
    IE43802B1|1981-06-03|
    AU1787876A|1978-03-23|
    GB1539473A|1979-01-31|
    NL187267B|1991-03-01|
    NO147672B|1983-02-14|
    SE427839B|1983-05-09|
    PT65631B|1978-07-05|
    FR2325377A1|1977-04-22|
    NZ181972A|1978-07-28|
    CA1068271A|1979-12-18|
    PT65631A|1976-10-01|
    JPS5239683A|1977-03-28|
    HU172964B|1979-01-28|
    IL50522A|1979-09-30|
    DK427876A|1977-03-24|
    PH12497A|1979-04-05|
    ES451768A1|1978-05-01|
    NL187267C|1991-08-01|
    GR58469B|1977-10-14|
    CH628623A5|1982-03-15|
    PL192578A1|1979-02-26|
    IL50522D0|1976-11-30|
    NL7610513A|1977-03-25|
    NO763054L|1977-03-24|
    DE2642856A1|1977-03-24|
    FI762698A|1977-03-24|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    ZA765684B|1975-09-23|1978-04-26|Janssen Pharmaceutica Nv|Novel n-aryl-n--arylacetamides|
    JPH0249269B2|1986-05-08|1990-10-29|Hekitoku Kk|
    JO2769B1|2005-10-26|2014-03-15|جانسين فارماسوتيكا ان. في|Fast Dissociting Dopamine 2 Receptor Antagonists|
    JO2642B1|2006-12-08|2012-06-17|جانسين فارماسوتيكا ان. في|Fast Dissociating Dopamine 2 Receptor Antagonists|
    JO2849B1|2007-02-13|2015-03-15|جانسين فارماسوتيكا ان. في|Fast -Dissociating Dopamine 2 Receptor Antagonists|
    RU2489431C2|2007-04-23|2013-08-10|Янссен Фармацевтика Н.В.|Thiazoles as quick-dissociating antagonists of dopamine 2 receptor|
    AU2008240727C1|2007-04-23|2013-10-03|Janssen Pharmaceutica N.V.|Pyridine derivatives as fast dissociating dopamine 2 receptor antagonists|
    MX2009011415A|2007-04-23|2009-11-05|Janssen Pharmaceutica Nv|4-alkoxypyridazine derivatives as fast dissociating dopamine 2 receptor antagonists.|
    WO2010000456A1|2008-07-03|2010-01-07|Janssen Pharmaceutica Nv|Substituted 6--pyridazines as 5-ht6 receptor antagonists|
    SI2307374T1|2008-07-31|2017-05-31|Janssen Pharmaceutica Nv|Piperazin-1-yl-trifluoromethyl-substituted-pyridines as fast dissociating dopamine 2 receptor antagonists|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US61513175A| true| 1975-09-23|1975-09-23|
    US71375676A| true| 1976-08-12|1976-08-12|
    [返回顶部]