DK149805B - O-AMINOPHENETHYLPIPERIDINES USED AS INTERMEDIATES FOR THE PREPARATION OF SUBSTITUTED PIPELEMED PRODUCTS FOR THE PREPARATION OF SUBSTITUTED PIPERIDINER ERIDINES - Google Patents

Description

149805

The present invention relates to novel o-aminophenethylpiperidines for use as intermediates for the preparation of substituted piperidines having the general formula I and the pharmaceutically acceptable acid addition salts thereof as set forth in the preamble, and the o-aminophenethylpiperidines are characterized by having the characterizing part of the claim. formula II. The valuable end products disclosed in DK Publication No. 137,954 are novel and possess physiological activity, being particularly effective as antiarrhythmic and antiserotonin agents.

Agents that antagonize serotonin are of interest in experimental biology and in the treatment of various physiological disorders, such as migraine headaches, serotonin-producing tumor, toxemia in pregnancy, habitual abortion, and in the treatment of various inflammatory and allergic reactions. Methysergide and lysergide are well-known antiserotonin agents. Other serotonin antagonists which have been discussed in the literature on this subject are 2 '- (3-dimethylaminopropyl-cinnamic acid anilide and related compounds described by Krapcho et al. in J. Med. Chem. 6, 219 (1963); 7, 376 (1964); 9, 809 (1966), and 12, 164 (1969), as well as certain aminoalkyl anilides referred to in U.S. Pat.

A number of structurally unrelated chemical compounds have been used in the treatment of cardiac arrhythmia; see A. Burger, Medicinal Chemistry, 3rd ed., pages 1082-1085 (Wiley). One of the most important drugs for the clinical treatment of heart rhythm disorders is quinidine. Another chemical that has been used as an anti-arrhythmic agent is local anesthetic procainamide. Other known anti-arrhythmic agents are lidnocaine and diphenylhydanthion. None of these compounds are chemically related to the valuable end products which can be prepared with the intermediates of the present invention.

The valuable end products are substituted piperidines of the general formula: R 3 wherein R 3 represents hydrogen or alkyl having from 1 to 4 carbon atoms, 2 R represents hydrogen or alkoxy having from 1 to 4 carbon atoms, R represents alkyl having from 1 to 4 carbon atoms Represents hydrogen, alkyl having from 1 to 4 carbon atoms or a dialkyl carboxamido group wherein the dialkyl groups have from 1 to 4 carbon atoms, c R represents alkanoyl having from 1 to 4 carbon atoms, alkanesulfonyl having from 1 to 4 carbon atoms, / == \ °

I, (\ // - CH = C-C- or R7 '- S

3 represents hydrogen or alkyl having from 1 to 4 carbon atoms, R represents hydrogen, halogen, amino, hydroxy, acetoxy, alkylthio having from 1 to 4 carbon atoms or alkoxy having from 1 to 4 carbon atoms, wherein the phenyl ring, when R represents hydrogen or alkoxy, may have up to two additional alkoxy substituents having from 1 to 4 carbon atoms, as well as optically active antipodes and non-toxic, pharmaceutically acceptable salts thereof.

The novel o-aminophenethylpiperidines of the present invention have the formula II: R4

2 II

R 6 is R 5, wherein R 2, R 2, R 2 and R 2 have the meaning given above, or are salts thereof.

It will be obvious to those skilled in the art that the compounds of formulas I and II exist in at least one racemic, stereoisomeric form, since they contain one asymmetric carbon atom (the 2-position of the piperidine ring). As soon as the R 2 substituent does not represent hydrogen, an additional asymmetric carbon atom (the 5-position of the piperidine ring) is present and two racemic modifications occur. Such a mixture of racemates can be split into the individual racemic compounds on the basis of physicochemical differences, such as solubility differences; eg. by fractional crystallization of the base or as acid addition salts thereof or by chromatography.

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It should be noted that the term "non-toxic, pharmaceutically acceptable acid addition salts" as used herein refers to a combination of the compounds of this invention with relatively non-toxic, inorganic or organic acids. Examples of suitable acids which can be used are sulfur. -, phosphorus, salt, hydrobromide, hydroiodide, sulfam, methanesulfone, benzenesulfone, para-toluenesulfone, vinegar, milk, amber, maleic, mucin, fig, lemon, glucon -, benzoic, cinnamonic, isethionic and related acids.

The conversion of the intermediates (II) to the final products (I) can take place by an analogous process wherein a racemically or optically active compound of formula II is reacted with a compound of formula

R, SX

wherein R 'represents R ^ having the meaning or group set forth above

No 2 - Li and X denote a halogen atom, or together R 1 X represents an anhydride when hydrolyzed when R 1 represents -Oi • 7 wherein R represents acetoxy, if desired, hydrolyzing the resulting compound to produce the compound with Formula I, wherein R represents hydroxy, when R, S represents the nitrobenzoyl group, hydrogenates the resulting compound to prepare a compound of formula I wherein R represents amino and, if desired, decomposes a racemic compound formed in the optically active antipodes, and, if desired, converting a compound of formula I into a non-toxic, pharmaceutically acceptable salt thereof.

The compounds of formula I exhibit valuable antiarrhythmic activity in mammals. For example, these antiarrhythmic effects have been demonstrated by standard in vitro and in vivo pharmacological studies.

In the dog, e.g. electrically or aconitin-induced arrhythmia by oral or parenteral administration of the piperidines of formula I in accordance with the following in vivo study.

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The chest of an aesthetized dog opens in the midline, and right and left heart ears are revealed through small slits in the pericardium. Bipolar recording electrodes are attached to the atrial surfaces and a blunt clean cloth of 4 x 4 mm is attached to the surface of the right heart ears. Control readings are performed by various cardiac functions, including femoral arterial blood pressure and right and left atrial electrograms. Atrial arrhythmia is then induced by the application of 3-5 drops of a solution of aconitin to garments attached to the right atrium. An irregular, fast atrial velocity is produced within one minute. During the experiment, fresh aconitine (2-3 drops) is applied to the cloth at 10 minute intervals. The compound to be tested is administered intravenously 5 minutes after the first arrhythmia is established, and infusion is continued at a low rate until an effective dose is obtained which re-establishes normal heart rhythm.

Intravenous administration of as little as 0.8 mg / kg of 4-methoxy-2 '- / 2- (1-methyl-2-piperidyl) ethyl7benzanilide, which is a preferred compound of the invention, effectively restores normal heartbeat by aconitin-induced arrhythmia in the dog. A well-known antiarrhythmic agent, such as quinidine, has similarly administered an effective dose of 6.0 mg / kg. By electrical induction of arrhythmia, the effective dose of 4-methoxy-2 '- / 2- (1-methyl-2-piperidyl) ethylbenzanilide is 1.9 mg / kg. Under similar conditions, the effective dose for quinidine is 14 mg / kg.

Intraduodenal administration, which is a measure of oral efficacy, of 4-methoxy-2 '- / 2- (1-methyl-2-piperidyl) ethyl / benzanilide prevents aconitin-induced arrhythmia in the dog at a dose of less than 10 mg / kg, while the effective dose for preventing aconitine-induced arrhythmia for quinidine is greater than 14 mg / kg.

Another in vivo test involves inhibition of chloroform-induced arrhythmia in the mouse by J.W. Lawson's method as described in J. Pharmacol. Exp. Therap., 160, 22 (1968). Intraperitoneal administration of 4-methoxy-2 '- / 2- (1-methyl-2-piperidyl) ethyl / benzanilide in the mouse prevents chloroform-induced arrhythmia at an ED ^Q value of 7.1 mg / kg while Comparison for quinidine has an ED 5g value of 83. Using this test, comparative tests were also conducted between a number of the compounds of the invention and two reference compounds to obtain the following results:

6 14980S

Antiarrhythmic activity (mouse)

Example Test compound EDjg No. 1 mg / kg 17 4-Amino-2 '- / 2- (1-methyl-2- 4.0 piperidyl) ethyl / benzanilide 18 4-acetoxy-2' - / 2- (1-methyl 2- (2,8-piperidyl) -ethyl-benzanilide 19 · 4-hydroxy-2 '- / 2; (1-methyl-1,2-1,7-piperidyl) ethyl / benzanilide 2' - / 2- (1-methyl-1) -piperidyl) - 7.2 ethylbenzanilide 21 4-chloro-2 '- / 2- (1-methyl-2- 2Sa piperidyl) ethyl7benzanilide 22 4- (methylthio) -2'; / 2- (1-methyl-25 2-piperidyl) ethyl7-benzanilide 23 4-methoxy-2 '- [2- (1-methyl-2-, 7-piperidyl) ethyl7-benzanilide 24 3-methoxy-2' - (2- (1-methyl-2- 10.0 3,4-dimethoxy-2 '- [2- (1-methyl-10,0 2-piperidyl) ethyl] benzanilide 26 3,5-dimethoxy-2' - / 2- (1-methyl-> 50c 2 -piperidyl) ethyl7benzanilide hydrogen maleate 27 2 '- / 2; (1-methyl-2-piperidyl) - 39.0 ethyl73,4,5-trimethoxybenzanilide mucathydrate a. 20¾ protection at 25 mg / kg b. 30¾ protection at 25 mg / kg c. No protection at 50 mg / kg 7 149805

Reference compound Name and formula mg 2 g of A 2 '- (3-dimethylaminopropyl) -4-methoxy-170-benzanilide L 11

W x 2 '- (2-dimethylaminoethyl) cinnam-104 anilide hydrochloride / CH 3 a 3 N 2 CH 3 NH-C-CH = CH-r f

5 KJ

x See the description for U.S.A. Patent No. 3,192,213 (Example 1)

An in vivo test demonstrating the antiarrhythmic effects of the end products in question uses the rabbit triad. In this test, the left atrium in Chenoweth's solution is heated to 30 ° C and flushed with 95¾ oxygen: 5¾ carbon dioxide. The lower end of the atrium is attached to a small hook which is fixed in the bath and the upper end is connected to a transducer for recording contractile activity. The atrium is electrically stimulated at a base rate of 30 pr. using square wave pulses of 10 milliseconds duration at 1.2-1.5 x threshold voltage. A test compound is introduced into the bath and the examination is repeated after a 5 minute break. The dependence between dose and response is found by additional doses of the test compound. The strength of a test agent can be expressed as the effective concentration that causes 50¾ of the maximum increase in the measured refractory period for the atrial stable state. This value is called EC, .q.

In the in vitro rabbit atrium test, the ECgg value for 4-methoxy-2, [1- (1-methyl-2-piperidyl) ethyl] benzanilide is 2.4 micrograms per gram. while the value for quinidine is 18.0 micrograms per milliliter. milliliter.

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The antiseronin effect of the compounds of formula I can be detected on rat uterus. According to this test, the uterine horns of a rat uterus are suspended in oxygenated saline solution at 30 ° C. The contractions of this tissue are then recorded and varying concentrations of the test compound are introduced into the bath to determine the concentration which would decrease the spasmogenic effect of 0.04 micrograms of serotonin per day. milliliters with 501. This value is called IC50 ·

A preferred antiserotonin compound prepared from an intermediate of the present invention is 2 '- 2 - (1-methyl-2-piperidyl) ethyl 7-cinnamic acid anilide, having an IC 2 Q value of 0.00185 micrograms per gram. milliliter. Another preferred compound 4-methoxy-2 '- [2- (1-methyl-2-piperidyl) -ethyl] benzanilide has an IC 50 value of 0.0046 micrograms per gram. milliliter. The antiserotonin agents, lysergide (LSD) and methysergide have an IC5Q value of 0.012 and 0.0025 micrograms, respectively. milliliter.

To produce the antiarrhythmic and antiserotonin effects in mammals, the piperidines of Formula I can be administered systemically at a non-toxic effective dose ranging from ca. 0.01 to 20 milligrams per kg of body weight of the mammal or preferably 0.1 to 10 mg / kg. Acceptable forms for systemic administration are oral and parenteral. Examples of parenteral administration are intra-muscular, intravenous, intraperitoneal and subcutaneous administration. The dosage of the therapeutic agents of formula I will vary with the form of administration and the compound selected. In general, the compound is administered at a dose substantially below the optimum dose of the compound. Next, the dose is increased by the addition of additional portions until the optimal effect under the circumstances is achieved. It will generally be found that when a composition is administered orally, greater amounts of the active ingredient will be required to achieve the same effect as can be achieved with a smaller, parenterally administered amount. In general, the compounds of this invention are preferably administered at a concentration level which generally gives effective results without causing any harmful or unintended side effects.

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The antiserotonin action of 2 '- / 2- (1-methyl-2-piperidyl) ethyl7-cinnamic acid anilide can also be detected in mice by the method of S.J. Corne et al. in Brit. J. Pharmacol., 20, 106 (1963). This test is based on the metabolism of 5-hydroxytryptophan to serotonin in the brain of mice pre-treated with a monoamine oxidase inhibitor. Depending on the route of administration and the pretreatment time, the following ED5q values are obtained: subcutaneous, 4.3 mg / kg (30 minutes pretreatment), 10 mg / kg (60 minutes ^ pretreatment), intraperitoneally, 21 mg / kg (60 minutes pretreatment). These values fall to the benefit of those obtained with methyldopa, a known serotonin inhibitor having an intraperitoneal ED 2 0 (ii of 37 mg / kg (60 minutes pre-treatment)).

The preparation of the final products I from the intermediates II can be further elucidated by Equation 1.

Equation 1 r "> R4

+ R X -> Formula I + HX

wherein R, R, R, R and R have the meaning given above, wherein R, 5 7 when R represents "R -benzoyl", further represents "NO9" but can't

7 L

be NH2 or OH. Compounds wherein R represents "N 2" are converted to compounds of formula I wherein R 7 represents "NH

7 L

ring. Compounds wherein R represents "acetoxy" are converted to compounds of formula I wherein R represents "OH" by hydrolysis. The symbol "X" represents a halide of an R 2 carbonyl or sulfonyl radical, or R 2 represents together an anhydride.

Examples of R 2 X reactants which can be reacted with o-aminophenethylpiperidines of formula II are: acetic anhydric anhydride, acetic anhydride, n-propionic anhydride, n-butyric anhydride, isobutyric anhydride, benzoic anhydride, benzoic anhydride, benzoic anhydride, methanesulfonic anhydride, ethanesulfonic anhydride, isopropylsulfonyl chloride, n-butanesulfonyl chloride, 4-methoxybenzoyl chloride, 3.4.5-trimethoxybenzoyl chloride, 3.5-dimethoxybenzoyl chloride, 2-methoxybenzoyl chloride, 2-chlorobenzoyl chloride

The reaction proceeds when the reactants are contacted and mixed in an inert organic solvent as reaction medium. Examples of inert organic solvents which can be used as reaction media include ether, benzene, toluene, acetonitrile, halogenated hydrocarbons such as chloroform and the like. In all cases where halide reactant such as acetyl chloride, etc. is used, it is preferable to add a hydrogen halide acceptor such as triethylamine to the reaction mixture. Pyridine is a particularly preferred reaction medium due to its suitability both as a solvent and as an acid acceptor. The temperature at which the reaction is carried out is not critical, although room temperature is preferred for convenience. The exact amounts of the reactants used are not critical. However, since the o-aminophenethylpiperidines of formula II and R 2 X reactants are consumed in equimolar amounts, the reactants are preferably used in such proportions. The reaction is generally completed in about 10 minutes. 1-24 hours depending on the reaction temperature used. The product may conveniently be separated from the reaction mixture by concentrating the reaction mixture under reduced pressure, dissolving the resulting residue in water, and adding thereto a base such as aqueous sodium hydroxide, aqueous sodium carbonate or aqueous potassium carbonate to make the mixture highly basic. The product can then be separated by solvent extraction in the form of halogenated hydrocarbon, ether, benzene, ethyl acetate, etc. In general, the product can be purified by recrystallization from organic solvents such as isopropyl ether, heptane, methanol, ethanol, isopropyl alcohol, ethyl acetate, water. acetone and the like, or it can be converted to an acid addition salt. Other purification agents include chromatography, e.g. thin-layer or column chromatography.

Conversion of the compounds of formula I to the pharmaceutically acceptable acid addition salts can be accomplished by mixing the bases of formula I with practically a chemical equivalent of any of the acids defined above. In general, the reactions are carried out in an inert solvent. Suitable solvents are, for example, methanol, benzene, ethyl acetate, ether and halogenated hydrocarbons.

Synthesis of the novel o-aminophenethylpiperidine intermediates of formula II begins with the preparation of 2-styrylpyridines of formula III, obtained by the method of L. Horwitz in J. Org. Chem., 21, 1039 (1956) by reacting an R-o-nitrobenzaldehyde and an R-2-methylpyridine. As shown in Equation 2, the nitro-2-styrylpyridines of formula III are reduced to an o-aminophenethylpyridine of formula IV. It is preferred that the reduction be carried out catalytically in a solvent using palladium-on-carbon catalyst. Suitable solvents are, for example, the lower alkanols, such as methanol, ethanol, isopropanol, etc.

Equation 2 R4 R4 NO 2 "reduction"

formula III formula IV

The o-aminophenethyl pyridines of formula IV are then formylated 3 to block alkylation of the aromatic amine when the R substituent 3 is introduced by quaternization of the pyridine nitrogen with an R halide. This conversion of the o-aminophenethyl pyridines of Formula IV to the Formyl derivative of Formula V is shown in Equation 3 and is preferably carried out with acetic acid formic anhydride.

Equation 3 nh2 ^^^^ nhcho formula IV formylation ^ formula v 12 149805

Equation 4 illustrates the alkylation of a pyridine of formula V with an alkyl iodide to form a pyridinium salt of formula VI. Depending on the desired R substituent, alkyl halides such as ethyl iodide, ethyl bromide, n-propyl iodide, 2-iodopropane, 1-iodobutane, 1-iodo-2-methylpropane, 1-chloro-2-methylpropane, 2-iodo-2 are used. -methylpropane and the like. The alkylation is carried out in an inert solvent such as acetone, acetonitrile, etc.

Equation 4 r2_

—Rs iY 2 / y ^ i Q

2 ^ R ^ @ halide R-halide L Jl NHCHO ^

"alkylation" NHCHO

formula V formula VI

Compounds of formula VI are converted to the phenethylpiperidines of formula VII by reduction according to Equation 5. The reduction is carried out catalytically using platinum as a catalyst in a suitable solvent such as the lower alkanols. The phenethylpiperidines of formula VII can also be obtained by first reducing with metal borohydrides such as sodium borohydride or potassium borohydride to form a tetrahydropyridine which is then further reduced by well known catalytic methods for the piperidines of formula VII. Eg. gives reduction of 5-diethylcarbamyl-2- (o-formamido-phenethyl-1-methylpyridinium iodide with sodium borohydride in methanol solution N, N-diethyl-6- (o-formamidophenethyl) -1-methyltetrahydropyridine-3-carboxamide, which is then hydrogenated in ethanol with a 101 palladium-on-carbon catalyst It will be appreciated that the compounds of formula VII represent the valuable end products of formula I wherein R 1 represents hydrogen and R 2 represents formyl.

Equation 5 "Reduction" 11 '3® 0 1 r3 \ 1 R · 3 Halide I Jl

1 ^> / Xnnnhcho ^^^^ NHCHO

formula VI formula VII

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Examples of the formanilides of formula VII are: 2 '- [2- (1-methyl-2-piperidyl) ethyl] formanilide, N, N-diethyl-6- (o-formamidophenethyl) -1-methyl-piperidine-3.

carboxamide.

If the o-aminophenethyl pyridines of formula IV are acylated with alkanoyl halides such as acetyl chloride, propionyl chloride, isobutyryl chloride or butyryl chloride, and the reaction sequence as shown in Equations 3-5 is repeated, compounds of formula I wherein R 1 represents hydrogen are represented and

Acidic hydrolysis of the formanilides of formula VII or the analogous alkanoylanilides yields o-aminophenethylpiperidine intermediates of formula II wherein R 1 represents hydrogen. Examples of the o-aminophenethyl piperidines obtainable in this way are: 2- (o-aminophenethyl) -1-methylpiperidine, 2- (o-aminophenethyl) -5-ethyl-1-methylpiperidine, 2- (o-aminophenethyl ) -1-isopropylpiperidine, 2- (o-aminophenethyl) -1n-butylpiperidine, 2- (2-amino-5-methoxyphenethyl) -1-methylpiperidine, 6- (o-aminophenethyl) -N, N-diethyl-1- methylpiperidine-3-carboxamide.

Reduction of some of the compounds of formula VII with lithium aluminum hydride gives o-aminophenethylpiperidine intermediates of formula II wherein R Examples of o- (N-alkylamino-phenethyl) piperidines obtainable in this way are: 2- (o-methylaminophenethyl) -1-methylpiperidine.

An alternative method for preparing compounds of formula II wherein R 1 represents hydrogen is shown in Equation 6.

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Equation 6 / \ s4 lw r ^^ r * 4 "reduction" *

ru j R

Formula VIII Formula IX

Pyridinium iodides of formula VIII are prepared from the corresponding aromatic aldehyde and 2-alkylpyridinium salt according to the method of L. Horwitz in J. Org. Chem. 21, 1039 (1956) and reduced by A.P. Phillips's method in J. Am. Chem. Soc., 72, 1850 (1950). Preferably, the catalytic reduction is carried out using a platinum catalyst in methanol solution.

An alternative method for preparing the compounds of formula II wherein R 1 is alkyl is shown in Equation 7.

Equation 7 r ^ N-R4 r ^ VR3 l \ * I * y 1 \ • f r Ir reducing 2), alkylation ^ 1

formula X formula XI

Reducing alkylation of o-aminophenethylpiperidines of formula X by an aldehyde such as acetaldehyde, propionaldehyde, n-butyraldehyde, isobutyraldehyde or a ketone such as acetone or butanone gives R 2 -aminophenethylpiperidines of formula XI. This method is well known in the art and reference is made to Synthetic Organic Chemistry, Wagner and Zook, Wiley, 1953, page 662.

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The preparation of the compounds of the invention is elucidated in the following Examples 1-6, while the preparation of the final products is illustrated in Examples 7-28.

Example 1 2- (o-Aminophenethyl) -1-methylpiperidine

A suspension of 2- (o-nitrostyryl) -1-methylpyridinium iodide (40.5 g, 0.11 mol) prepared according to the method of L. Horwitz in J. * Org. Chem., 21, 1039 (1956) in 200 ml of ethanol is hydrogenated in a Parr hydrogenation apparatus using 0.3 g of platinum oxide catalyst while maintaining a reaction temperature of from ca. 50 to approx. 75 ° C. When hydrogen uptake ceases (about 3 hours), the reduction mixture is filtered, the filtrate is evaporated and the resulting residue is collected in 500 ml of water. The aqueous solution is made basic with 40¾ sodium hydroxide and extracted several times with 200 ml ether portions. The ethereal extracts are combined, washed with water, dried over magnesium sulfate and the ether evaporated. Distillation of the residue thus obtained gives 20.8 g (87¾ yield) of 2- (o-aminophenethyl) -1-methylpiperidine base having a boiling point of 121-125 ° C at 0.04 mm.

Analysis calculated for C, 77.01; H, 10.16; N, 12.83.

Found: C, 76.68; H, 9.83; N, 12.76.

Treatment of the base with ethanolic hydrogen chloride in ethanol gives 2- (o-aminophenethyl) -1-methylpiperidine dihydrochloride (recrystallized from methanol isopropyl ether), mp 268.5-271.5 ° C (corr.). Calcd for ^ 4 ^ 24 ^ 2 ^ 21 C, 57.73; H, 8.31; N, 9.62.

Found: C, 57.67; H, 8.22; N, 9.60.

Example 2 2- (o-methylaminophenethyl) -1-methylpiperidine (a) 2- (o-aminophenethyl) pyridine. A solution of 2- (o-nitrostyryl) pyridine (94.3 g, 0.42 mol) in 400 ml of ethanol is reduced on a Parr hydrogenation apparatus using 2 g of 10¾ palladium-on-carbon catalyst to form 2- ( o-aminophenethyl) pyridine, mp 59-61 ° C.

149805 16

Isolation of the pyridine product is carried out in the usual manner by collecting the catalyst and evaporation of the ethanolic solvent.

(b) 2- (o-Formamidophenethyl) pyridine. A mixture of acetic anhydride and formic anhydride is prepared by mixing acetic anhydride (140 ml) and formic acid (70 ml). To this mixture is added 2- (o-aminophenethyl) pyridine (59 g, 0.3 mol) in a portion under vigorous stirring at 25 ° C. After 15 minutes, dilute the solution. 450 ml of water and concentrated in vacuo. The resulting residue is collected in 1 liter of water and made basic with 50¾ sodium hydroxide. The basic solution is extracted with chloroform, the chloroform extract is washed with water, dried over magnesium sulfate and the chloroform solvent evaporated. Crystallization of the residue from isopropyl acetate affords 57 g (83¾) of 2- (o-formamidophenethyl) pyridine melting at 78-81 ° C (uncorrected). An analytical sample (from isopropyl acetate) has a melting point of 83-83.5 ° C (cor).

Analysis calculated for C 14 H 14 N 2 O: C, 74.31; H, 6.24; N, 12.38.

Found: C, 74.56; H, 6.25; N, 12.45.

(c) 2- (o-Formamidophenethyl) -1-methylpyridinium iodide. A solution of 2- (o-formamidophenethyl) pyridine (55 g, 0.243 mol) and methyl iodide (38 g, 0.268 mol) in 500 ml of acetone is refluxed for 20 hours. The mixture is cooled to 5 ° C and filtered to give 82 g (92¾) of the pyridinium iodide, mp 199.5-201.5 ° C.

Analysis calculated for C C HH ^ IO: C, 48.92; H, 4.65; N, 7.61.

Found: C, 48.74; H, 4.83; N, 7.65.

(d) 21 - [2- (1-methyl-2-piperidyl) ethyl] formanilide. Reduction of 2- (o-formamidophenethyl) -1-methylpyridinium iodide as described in Example 1 for 2- (o-nitrostyryl) -1-methylpyridinium iodide gives 2 '- / 2- (1-methyl-2-piperidyl) ethyl7formanilide which is purified by crystallization from isopropyl ether (79¾ yield) mp 81-84.5 ° C (cor).

Analysis calculated for c15 H22 N2 O: 73> 13 »Η» 9.00; N, 11.37.

Found: C, 73.12; H, 8.75; N, 11.31.

(e) 2- (o-methylaminophenethyl) -1-methylpiperidine. A solution of 2 '- [2- (1-methyl-2-piperidyl) ethyl] formanilide (20 g, 0.0815 mol) in 100 ml of tetrahydrofuran is added dropwise to a stirred mixture of lithium aluminum hydride (4.4 g, 11 moles) in 100 ml of tetrahydrofuran. The mixture is refluxed for 75 minutes, cooled and hydrolyzed by successively adding 4.4 ml of water, 4.4 ml of 15¾ sodium hydroxide and then 13.2 ml of water. The hydrolyzed mixture is filtered, the filter cake washed with a 50 ml portion of tetrahydrofuran and the filtrate concentrated in vacuo.

The residue thus obtained is distilled to give 16.6 g of .2- (o-methylaminophenethyl) -1-methylpiperidine having a boiling point of 150-155 ° C at 0.05 mm Hg.

Example 3 2- (2-Amino-5-methoxyphenethyl) -1-methylpiperidine (a) 2 * - (2-amino-5-methoxyphenethyl) pyridine. Reduction of 2- (2-nitro-5-methoxystyryl) pyridine as described in Example 2, (a) or 2- (o-nitrostyryl) pyridine gives 2- (2-amino ~ 5-methoxyphenethyl) pyridine with a melting point of 77.5-78.5 ° C (cor.) in the form of the monohydrate obtained by crystallization from isopropyl acetate-ethanol-water.

Analysis calculated for C C ^H ^ gl ^O₂O: C, 68.27; H, 7.37; N, 11.37.

Found: C, 68.04; H, 7.30; N, 11.30.

(b) 2- (2-Formamido-5-methoxyphenethyl) pyridine. Formulation of 2- (2-amino-5-methoxyphenethyl) pyridine as described in Example 2 (b) for 2- (o-aminophenethyl) pyridine gives 711 yield of 2- (2- ormamido-5-methoxyphenethyl) pyridine . An analytical sample obtained by crystallization from isopropyl acetate has a melting point of 93.5-94 ° C (cor).

Analysis calculated for C, 70.29; H, 6.29; N, 10.93.

Found: C, 70.28; H, 6.51; N, 10.98.

(c) 2- (2-Formamido-5-methoxyphenethyl) -1-methylpyridinium iodide. The pyridinium iodide is obtained by treating 2- (2-formamido-5-methoxyphenethyl) pyridine with methyl iodide according to the method described in Example 2 (c) for 2- (o-formamidophenethyl) pyridine. Analytically pure 2- (2-form amido-5-methoxyphenethyl) -1-methylpyridinium iodide is obtained in a yield of 95 ° and has a melting point of 184-186.5 ° C (cor.).

Analysis calculated for ^ 16 ^ 19 * ^ 2 ^ 2: 48.25; H, 4.81; N, 7.04.

Found: C, 48.18; H, 4.84; N, 7.16.

(d) 2- (2-Amino-5-methoxyphenethyl) -1-methylpiperidine. Catalytic reduction of 2- (2-formamido-5-methoxyphenethyl) -1-methylpyridinium iodide as described in Example 1 for 2- (o-nitrostyryl) -1-methylpyridinium iodide gives 2- (2-formamido-5-methoxyphenethyl) - l-methylpiperidine. This material is deformylated in 1N methanolic hydrogen chloride to give 2- (2-amino-5-methoxyphenethyl) -1-methylpiperidine.

Another method of preparing 2- (2-formamido-5-methoxyphenethyl) -1-methylpiperidine is to reduce 2- (2-form-amido-5-methoxyphenethyl) -1-methylpyridinium iodide first with sodium borohydride to form of 2- (2-formamido-5-methoxyphenethyl) -1-methyltetra-hydropyridine, which is then catalytically reduced with palladium-on-carbon. This procedure is described in Example 4 (d).

Example 4 6-Ro-aminophenyl thyl) -N, N-thyl-1-methylpiperidine-3-carboxamide

Cracemate A and Racemate B) (a) N, N-diethyl-6- (o-nitrostyryl) nicotinamide. Reaction of o-nitrobenzaldehyde C41.7 g, 0.276 mol) with N, N-diethyl-6-methylnicotinamide (53.1 g, 0.276 mol) in the presence of acetic anhydride (56.3 g, 0.552 mol) according to L. Horwitz's method in J. Org. Chem., 21, 1039 (1956) gives 67.4 g (75¾) of N, N-diethyl-6- (o-nitrostyryl) nicotinamide. Crystallization from acetonitrile affords the analytically pure nicotinamide, mp 145-147 ° C (cor).

Analysis calculated for δ 8 19 19 303: 0, 66.44; H, 5.89; N, 12.92.

Found: C, 66.62; H, 6.01; N, 12.68.

(b) 6- (o-Aminophenethyl) -N, N-diethylnicotinamide ♦, N, N-die thyl-6- (o-nitrostyryl) nicotinamide (16.3 g, 0.05 mol) reduced in 150 ml of ethanol under Using 0.1 g of 10¾ palladium-on-carbon catalyst according to the method described in Example 2 (a) for 2- (o-aminophenethyl) pyridine gives 6- (o-aminophenethyl) -N, N-diethylnicotinamide base. Addition of ethanolic hydrogen chloride to the nicotinamide base in ethanol gives 6- (o-aminophenethyl) -N, N-diethylnicotinamide, dihydrochloride, mp 224-226 ° C (cor).

Analysis calculated for C ^ gi ^ ^ C CN ^O: C, 58.38; H, 6.80; N, 11.35:

Found: C, 58.21; H, 6.86; N, 11.31.

(c) 5-Diethylcarbamyl-2- (o-formamidophenethyl) -1-methylpyridinium iodide. Formylation of 6- (o-aminophenethyl) -N, N-diethylnicotinamide as described in Example 2 (b) for 2- (o-formamidophenethyl) pyridine gives 6- (o-formamidophenethyl) -N, N-diethylnicotinamide, then methyl is as described in Example 2 (c) for 2- (o-formamidophenethyl) -1-methylpyridinium iodide to form 5-diethylcarbamyl ~ 2- (o-formamido-phenethyl) -1-methylpyridinium iodide. This product is used in the following step without further purification.

(d) N, N-diethyl-6- (o-formamidophenethyl) -1-methylpiperidine-3-carboxamide. A 50¾ sodium hydroxide solution (9.6 g, 0.12 mol) in 45 ml of water is added to a solution of 5-diethylcarbamyl-2- (o-formamidophenethyl) -1-methylpyridinium iodide (46.7 g, 0.1 mol ) in 300 ml of methanol. Sodium borohydride (4.56 g, 0.12 mol) is added portionwise with stirring. After 2 hours, the mixture is evaporated and water (500 ml) is added to the resulting residue. This mixture is extracted with ether, the ethereal extracts are washed with water, dried over magnesium sulfate and the ether is evaporated. The resulting residue consisting of N, N-diethyl-6- (o-formamidophenethyl) -1-methyltetrahydro-pyridine-3-carboxamide is hydrogenated in a Parr apparatus in 200 ml of ethanol using 4 g of 101 palladium-on-carbon as a catalyst at a temperature of 50-70 ° C and N, N-diethyl-6- (o-chloramidophenethyl) -1-methylpiperidine-3-carboxamide is obtained.

(e) 6- (o-Aminophenethyl) -N, N-diethyl-1-methylpiperidine-3-carboxamide N, N-diethyl-6- (o-formamidophenethyl) -1-methylpiperidine-3-carboxamide is hydrolyzed to 6- ( o-aminophenethyl) -N, N-diethyl-1-methylpiperidine-3-carboxamide as described in Example 3 (d) for 2- (o-methylaminophenethyl) -1-methylpiperidine.

(£) Cleavage of 6- (o-aminophenethyl) -N, N-diethyl-1-methylpiperidin-3-carboxamide in racemate A and racemate B. Crude 6- (o-aminophenethyl) -N, N-diethyl- 1-methylpiperidine-3-carboxamide (11 g) containing a 1: 1 mixture of racemate A and racemate B obtained in the preceding steps by reduction of N, N-diethyl-6- (o-formamidophenethyl) -1- Methylpiperidine-3-carboxamide is dissolved in 50 ml of benzene and loaded onto a 4 cm diameter chromatographic column packed to a height of 45 cm with silica gel (300 g, 100-200 mesh). The column is eluted with the following solvent combinations and 100 ml fractions are collected: fractions 1-2, benzene; fractions 3-39, ethyl acetate-ethanol 7: 3 plus O, 2¾ of 58¾ ammonium hydroxide; fractions 40-70, ethyl acetate-ethanol 1: 1 plus 0.5¾ of 58¾ ammonium hydroxide; fractions 71-78, ethanol plus 0.5¾ of 58¾ ammonium hydroxide. Fractions 13 to 44 are combined and concentrated to give ca. 4-5 g of pure race food A as an oil. Evaporation of the combined fractions 55-72 gives 3.2 g of pure racemate B as an oil.

Example 5 2- (o-Aminophenethyl) -5-ethyl-1-methylpiperidine (racemate A and racemate B) (a) 5-ethyl-2- (o-nitrostyryl) pyridine. Reaction of o-nitrobenzaldehyde (100 g, 0.66 mol) with 5-ethyl-2-methylpyridine (80 g, 0.66 mol) in the presence of acetic anhydride (135 g, 1.32 mol) according to L. Horwitz's method in J. Org. Chem., 21, 1039 (1956) gives 54.4 g (32¾) of 5-ethyl-2- (o-nitrostyryl) pyridine. An analytical sample obtained by crystallization from isopropyl ether has a melting point of 52.5-54.5 ° C (cor).

Analysis calculated for C> 70.85; H, 5.55; N, 11.02.

Found: C, 71.01; H, 5.40; N, 10.96.

(b) 2- (o-Aminophenethyl) -5-ethylpyridine. Reduction of 5-ethyl-2- (o-nitrostyryl) pyridine as described in Example 2 (a) for 2- (o-nitro-styryl) pyridine gives 2- (o-aminophenethyl) -5-ethylpyridine, m.p. , 5-52.5 ° C (cor) by recrystallization from isopropyl ether-heptane.

(c) 5-ethyl-2- (o-formamidophenethyl) pyphidine. Reaction of 2- (o - - - aminophenethyl) -5-ethylpyridine with acetic anhydride and formic acid according to the method described in Example 2 (b) for 2- (o-aminophenethyl) pyridine gives deformylated product 5-ethyl-2- ( o-Formamidophenethyl) pyridine, which can be recrystallized from isopropyl ether, mp 62-63.5 ° C (corr.).

Analysis calculated for C- HH ^ gO: C, 75.56; H, 7.13; N, 11.02.

Found: C, 75.53; H, 7.07; N, 10.96.

(d) 5-ethyl-2- (o-formamidophenethyl) -1-methylpyridinium iodide. Reaction of 5-ethyl-2- (o-formamidophenethyl) pyridine with methyl iodide in acetone according to the method described in Example 2 (c) for 2- (o-formamidophenethyl) pyridine gives a 731 yield of analytically pure 5-ethyl 2- (o-Formamidophenethyl) -1-methylpyridinium iodide, mp 134.5-136.5 ° C.

Analysis calculated for ^ 27 ^ 21 ^ 2 ^ C, 51.53; H, 5.34; N, 7.07.

Found: C, 51.79; H, 5.35; N, 6.84.

(e) 5-ethyl-2-Co-formamidophenethyl) -1-methylpiperidine. Reduction of 5-ethyl-2- (o-formamidophenethyl) -1-methylpyridinium iodide as described in Example 4 (d) for the corresponding N, N-diethyl-3-carboxamide gives 5-ethyl-2- (o-formamidophenethyl) - 1-methylpiperidine consisting of a 1: 1 mixture of racemate A and racemate B.

(f) 2- (o-Aminophenethyl) -5-ethyl-1-methylpiperidine as racemate A and racemate B. Racemate B is isolated from racemate A plus B

the mixture of 5-ethyl-2- (o-formamidophenethyl) -1-methylpiperidine by treatment of 19.8 g of the mixture with oxalic acid (9.15 g, 0.0723 mole) dihydrate in 200 ml of ethanol to give 14.3 g of a crystalline solid (oxalic acid salt), mp 166-170 ° C. Selective crystallization of this material from ethanol gives 8.2 g of racemate B of 2- (o-formamido-phenethyl) -5-ethyl-1-methylpiperidine as the oxalic acid salt, mp 174-176 ° C.

Analysis calculated for C27 H26 N2 ° C C2H2 ° 4: C, 62.62; H, 7.74; N, 7.69.

Found: C, 62.45; H, 7.46; N, 7.76.

The oxalic acid salt of 2- (o-formamidophenethyl) -5-ethyl-1-methylpiperidine (racemate B) is converted to the free base by treatment with potassium hydroxide.

Hydrolysis of the free formamidobase is carried out by stirring with 125 ml of 1N methanolic hydrogen chloride for 24 hours. Concentration of the methanolic mixture in vacuo gives a residue which is collected in water and made basic with 50¾ sodium hydroxide. Extraction of the basic mixture with ether and concentration of the ether extract yield 5.5 g of 2- (o-aminophenethyl) -5-ethyl-1-methylpiperidine B racemate as the free base.

149805 21

The parent liquid of the oxalic acid salt remaining from the isolation of 2- (o-formamidophenethyl) -5-ethyl-1-methylpiperidine (racemate B) and enriched with 2- (o-formamidophenethyl) -5-ethyl-1-methylpiperidine -your (racemate A) is converted to the free base. Deformylation of 6.7 g of 5-ethyl-2- (o-formamidophenethyl) -1-methylpiperidine base in 250 ml of 1N methanolic hydrogen chloride gives 5.1 g of hydrochloride salt, mp 235-238 ° C. This salt is selectively crystallized from ethanol-isopropyl ether to give 4.4 g of material which is then converted to the free base to obtain 3.3 g of 2- (o-aminophenethyl) -5-ethyl-1-methyl-piperidine (racemate A ) as an oil.

Example 6

2 '- Z 2 - (1-methyl-2-piperidyl) ethyl-7-cinnamic acid anilide

Cinnamoyl chloride (6.0 g., 0.036 mole) is added to a solution of 2- (o-aminophenethyl) -1-methylpiperidine (7.8 g., 0.036 mole) in 100 ml of pyridine at once and with vigorous stirring. Stirring is continued for 3 hours and the pyridine solution is then concentrated in vacuo. The resulting residue is collected in 150 ml of water and basified with 40¾ sodium hydroxide. The basic solution is extracted with several ether portions of each 200 ml which are combined, washed with water, dried over magnesium sulfate and the ether solvent is evaporated. The residue thus obtained crystallizes and is further purified by crystallization from isopropyl ether to give 8.7 g (70¾ yield) of analytically pure 2 '- / 2- (1-methyl-2-piperidyl) ethyl7-cinnamic acid anilide melting at 101.5 -103.5 ° C. (Corr.)

Analysis calculated for C, 79.27; H, 8.10; N, 8.04.

Found: C, 79.24; H, 8.35; N, 8.09.

Example 7 21- / 2- (1-methyl-2-piperidyl) ethyl7-α-methylcinnamic acid anilide, mucate.

By using the equivalent mole amount of α-methylcinnamoyl chloride instead of cinnamoyl chloride in Example 6, the substituted phenethylpiperidine is obtained as the free base. The mucate salt is prepared by dissolving the free base in methanol and adding mucic acid to the methanolic solution until the solid mucic acid is no longer dissolved. Undissolved mucic acid is removed by filtration and the filtrate is concentrated. The residue which is left is crystallized from ethanol-ethyl acetate to give analytically pure 2 '- / 2- (1-methyl-2-piperidyl) ethyl7-a-methylcinnamic acid anilide, mucate, m.p. 156.5 C.

(deck) (corr.) ·

Analysis calculated for C_II, nN? N-1/2 ·. c, 69.35; H, 7.54; N, 5.99.

Found: C, 69.25; H, 7.59; N, 5.89.

Example 8 N-crude thyl-2 '- [2- (1-methyl-2-piperidyl) ethyl] cinnamic acid anilide mucate.

By using the equivalent mole amount of 2- (o-methylaminophenethyl)

1-methylpiperidine instead of 2- (o-aminophenethyl) -1-methylpiperidine in Example 6 yields N-methyl-2,4-2- (1-methyl-2-piperidyl) ethyl7-cinnamon anilide. The mucate salt is prepared as in Example η and crystallized from methanol to give analytically pure N-methyl-2,2 - [2- (1-methyl-2-piperidyl) ethyl] cinnamic acid anilide, mucate in 38¾ yield and m.p. ).

Analysis calculated for ^ 4 ^ 30 ^ 04 1/2 CgH ^ And *. C, 69.35; H, 7.54; N, 5.99. Found: C, 69.38; H, 7.56; N, 5.97.

Example 9 4'-Methoxy-21- [1- (1-methyl-2-piperidyl) -ethyl] cinnamic acid anilide.

Using an equivalent mole amount of 2- (2-amino-5-methoxy-phenethyl) -1-methylpiperidine instead of 2- (o-aminophenethyl) -1-methylpiperidine in Example 6. the phenethylpiperidine is obtained as a free base. Analytically pure 4'-methoxy-2 '- [2- (1-methyl-2-piperidyl) ethyl] cinnamic acid anilide is obtained by crystallization of the crude free base from isopropyl acetate and has a melting point of 126.5-127.5 ° C. (Corr.).

Calcd for C24 ** 302-22: C, 76.15; H, 7.99; N, 7.40.

Found: C, 76.37; H, .7.93; N, 7.36.

Example, 6- (o-cinnamide phenethyl) -N, N-diethyl-1-methylpiperidine-3-carboxamide, mucate (Racemate A).

Reaction of Racemat A obtained from Example 4 (f) of 6- (o-amino-phenethyl) -N, N-diethyl-1-methylpiperidine-3-carboxamide (5.1 g., 0.16 23 149805 mol) with cinnamoyl chloride (3.2 g., 0.19 mol) in 70 ml of pyridine according to the procedure of Example 6 gives 7.3 g of the piperidine carboxamide as the free base. The free base gives reaction with mucic acid in the boiling methanol mucate salt. This methanol-soluble mucate salt is dissolved in methanol and precipitated therefrom by the addition of isopropyl ether. Crystallization from ethanol-isopropyl ether gives 3.4 g of 6- (o-cinnamide phenethyl) -N, N-diethyl-1-methylpiperidine-3-carboxamide, mucate hydrated with water, m.p. 79-110 ° C.

Analysis calculated for ^^ 28 ^ 37 ^ 3 ^ 2 '1/2 ^ 6 ^ 10 ^ 8' ^^ ^ O! 64.45; H, 7.50; N, 7.27.

Found: C, 64.38; H, 7.69; N, 6.89.

Crystallization of this material from methanol gives a methanol-solvated mucate salt. The methanol solvate is removed by drying at 82 ° C, in vacuo for 24 hours to give a methanol-free product, mp 117-120 ° C. (Corr.).

Example H.

6- (o-cinnamide phenethyl) -N, N-diethyl-1-methylpiperidine-3-carboxamide cinnamate (Racemate B).

Reaction of Racemat B obtained from Example 4 (f) of 6- (o-amino-phenethyl) -N, N-diethyl-1-methylpiperidine-3-carboxamide (4.1 g., 0.13 mol) with cinnamoyl chloride (2.6 g., 0.015 mol) in 49 ml of pyridine according to the method described in Example 6 gives 6.0 g. Of the free base. The free base is collected in 100 ml of ethanol and treated with cinnamic acid (1.98 g,

O, 013 mol). The cinnamic acid salt of 6- (o-cinnamide phenethyl) -N, N-diethyl-1-methylpiperidine-3-carboxamide is precipitated from the ethanolic solution by the addition of isopropyl ether to give 5.3 g of solid, mp 156-160 ° C.

Crystallization from methanol-isopropyl ether gives analytically pure Racemate B, which has a melting point of 158-164 ° C. (Corr.).

Analysis calculated for C 9ftH, -14.0 O-CQ H 5 O-: C, 74.59; H, 7.61; N, 7.05. Found: C, 74.33; H, 7.89; "'N, 7.07.'

Example. 1 2 2 '-Cl- (5-ethyl-1-methyl-2-piperidyl) -ethyl7-cinnamic acid anilide, hydrochloride (Racemate A).

24 149805

Reaction of the 2 '- (o-aminophenethyl) -5-ethyl-1-methylpiperidine (3.3 g.) Obtained in Example 5 (f) with cinnamoyl chloride (2.7 g., 0.016 mole). in 50 ml. pyridine according to the method described in Example 24 gives 4.2 g. of the hydrochloride salt, mp 184-186 ° C. Crystallization of the salt from isopropanol gives 3.6 g., (65¾) 2'-L2- (5-ethyl-1-methyl-2-piperidyl) -ethylcinnamaldehyde, hydrochloride (Racemate A), mp 184-187 ° C. (Corr.).

Calcd for C ^HH ClCl₂O: C, 72.70; H, 8.05; N, 6.78.

Found: C, 72.82; H, 8.37; N, 6.45.

Example 13 2 '- / T - (5-Ethyl-1-methyl-2-piperidyl) -ethyl7-cinnamic acid anilide hydrate (Racemate B).

The Racemat B obtained from Example 5 (f) of 5-ethyl-21 - (o-formamide-phenethyl) -1-methylpiperidine as free base (5.5 g, 0.0224 mol) is reacted with cinnamoyl chloride (4.1 g., 0.0246 mol) in 75 ml. pyridine according to the method of Example 24 to give 2 '- [2- (5-ethyl-1-methyl-2-piperidyl) ethyl] cinnamic acid anilide (Racemate B). This substance is purified by crystallization from acetone containing traces of water and a yield of 3.4 g is obtained. 2 * - [2- (5-Ethyl-1-methyl-2-piperidyl) ethyl] cinnamic acid anilide, hydrate, m.p. -98 ° C. (Corr.).

Analysis calculated for C ^: C, 76.10; H, 8.69; N, 7.10; Η2Ρ, 4.57.

Found: C, 76.24; H, 8.47 J * N, 7.19; H20,4,29.

Example 14 2'-L2- (1-methyl-2-piperidyl) ethyl] -2-thiophenecarboxanilide, mucate.

2-Thiophenecarbonyl chloride (11.7 g., 0.08 mol) is added in one portion to 2- (o-aminophenethyl) -1-methylpiperidine (10.0 g., 0.046 mol) in 50 ml. pyridine with stirring. The mixture is stirred for 0.5 hours and concentrated in vacuo to give a residue which is collected in 50 ml. water made basic (pH 9-10) with potassium carbonate. The aqueous mixture is extracted with ether, the ethereal extract is washed with water and concentrated after drying over magnesium sulfate to give thiophene-carboxanilide base.

25 U9805

The mucate salt is prepared by dissolving the free base in ethanol and adding mucic acid to the ethanolic solution until solid mucic acid is no longer dissolved. Insoluble mucinic acid is removed by filtration and the ethanolic filtrate is diluted with ethyl acetate to initially cloud. This gives 14.0 g. Of the mucate salt crystallized from ethanol-ethyl acetate to give 6.4 g. Of analytically pure Z '- ((C1-C1-methyl-Z-piperidyl) -ethyl-7-thiophenecarboxanilide, m.p. 146 ° C.

(Corr.) ·

Analysis calculated for C CHH₂NN₂OS 1/2 CHHiq ° 8: c> 60.95; H, 6.74; N, 6.46; S, 7.40.

Found: C, 60.83; H, 6.57; N, 6.43; S, 7.22.

Example 15 21-Z2 ~ (1-methyl-2-piperidyl) ethyl7-acetanilide mucate.

By using the equivalent mole amount of acetyl chloride instead of cinnamoyl chloride in Example 6, 2 '- / 2- (1-methyl-2-piperidyl) ethyl / acetanilide is obtained as the free base. The crude free base is converted to the crystalline mucate by the method of Example 26 and crystallized from ethanol to give analytically pure 2 '- / 2- (1-methyl-2-piperidyljethyl / acetanilide, mucate, m.p. 174.5 ° C (corr.).

Analysis calculated for C 16 H 24 N 2 O 2 C 6 H 10 ° 8: C '62> 44ί H> 8 »00i N> 7.66. Found: C, 62.47; H, 8.29; N, 7.79.

Example 16 21- / 2- (1-methyl-2-piperidyl) ethyl7-methanesulfonanilide.

Reaction of methanesulfonyl chloride (5.7 g., 0.05 mole) with 2- (o-aminophenethyl) -1-methylpiperidine (9.8 g., 0.045 mole) in 75 ml. pyridine by the method described in Example 24 gives 5.6 g. (41¾) of analytically pure 2 '-jj- (1-methyl-2-piperidyl) ethyl] methanesulfonanilide (crystallized from ethanol), m.p. 91.5-93.5 ° C. (Corr.).

Analysis calculated for C 15 H 24 N 2 2 S: C, 60.78; H, 8.16; N, 9.45.

Found: C, 60.55; H, 8.12; N, 9.54.

149805 26

Example 17 4-Amino-21-β- (1-methyl-2-piperidyl) -ethylbenzanilide.

Reaction of 4-nitrobenzoyl chloride (6.5 g., 0.035 mol) and 2- (o-. Aminophenethyl) -1-methylpiperidine (6.0 g., 0.02 75 mol) in 35 ml. pyridine by the method described in Example 24 gives 2 '- / 2- (1-methyl-2-piperidyl) ethyl7-4-nitrobenzanilide. Crystallization from ethyl acetate gives analytically pure material, mp 162-163.5 ° C.

Analysis calculated for ^ 21 ^ 25 ^ 3 ^ 3: ^ 8.64; H, 6.86; N, 11.44.

Found: C, 68.58; H, 6.84; N, 11.30.

Reduction of 2 '(1-methyl-2-piperidyl) ethyl, 4-nitrobenzanilide (6.5 g., 0.018 mol) in 100 ml. ethanol using 2 g of palladium-on-carbon catalyst (10¾) of Example 2 (a) gives 4-amino-2'-J / 2- (1-methyl-2-piperidyl) -ethyl7benzanilide. Crystallization of the product from acetonitrile gives the analytically pure substance, mp 147-148.5 ° C. (Corr.).

Analysis calc'd for 211.27N3: 74.74; H, 8.07; N, 12.45.

Found: C, 74.75; H, 8.06; N, 12.47.

Example in 8 4-Acetoxy-2,2-2- (1-methyl-2-piperidyl) -ethylbenzanilide.

Reaction of 2- (o-aminophenethyl) -1-methylpiperidine with p-acetoxy-benzoyl chloride in pyridine according to Example 1 gives 4-acetoxy-2 '- / 2- (1-methyl-2-piperidyl) -ethyl-benzanilide. Analytically pure product is obtained by crystallization from isopropyl ether, mp 88-108 ° C. (Corr.).

The broad melting point of the analytically pure material is due to polymorphism.

Analysis calculated for ^ 23 ^ 28 ^ 2 ^ 31 H, 7.42; N, 7.36.

Found: C, 72.79; H, 7.38; N, 7.31.

Example 19 4-Hydroxy-2'-Z2- (1-methyl-2-piperidyl) -ethyl-benzanilide.

4'-Acetoxy-21- / 2- (1-methyl-2-piperidyl) ethyl / benzanilide suspended in 1N sodium hydroxide is stirred until dissolved. occurs. The pH of the aqueous solution is adjusted to 9 with 6N hydrochloric acid and an oil precipitate extracted with ethyl acetate. The product is isolated by removal of the ethyl acetate and crystallized from ethanol to give analytically pure 4 * hydroxy-2 '- /, 2- (1-methyl-2-piperidyl) ethyl] benzanilide, mp 178.5-182.5 ° C. (Corr.) ·

Analysis calc'd for 21.26 ° 2 ° C: C, 74.52; H, 7.74; N, 8.28.

Found: C, 74.59; H, 7.47; N, 8.31.

Examples 20-27

Other benzanilides

The benzanilides listed in Table I are prepared according to the methods of Examples 17-19, as will be readily understandable to those skilled in the art.

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Claims (2)

149805 o-Aminophenethylpiperidines for use as intermediates for the preparation of substituted piperidines of the general formula: R * 3 in which R 1 represents hydrogen or alkyl having from 1 to 4 carbon atoms, 2 represents hydrogen or alkoxy having from 1 to 4 carbon atoms, R represents alkyl having from 1 to 4 carbon atoms, R 1 represents hydrogen, alkyl having from 1 to 4 carbon atoms, or a dialkylcarboxamido group wherein the dialkyl groups have from 1 to 4 carbon atoms, R represents alkanoyl having from 1 to 4 carbon atoms, alkanesulfonyl having from 1 to 4 carbon atoms, 0 ~ c "or R7_C2 ^ wherein R4 represents hydrogen or alkyl having from 1 to 4 carbon atoms, R represents hydrogen, halogen, amino, hydroxy, acetoxy , alkylthio having from 1 to 4 carbon atoms or alkoxy having from 1 to 4 carbon atoms and wherein the phenyl ring, when R represents hydrogen or alkoxy, may have up to 2 additional alkoxy substituents having from 1 to 4 carbon atoms, or optically active antibodies, or not pharmaceutically acceptable salts thereof, characterized in that they have the formula: