KR830001683B1 - Preparation method of quaternary ammonium arrhythmia treatment - Google Patents

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Preparation method of quaternary ammonium arrhythmia treatment

The present invention relates to a process for the preparation of quaternary ammonium salts of phenylpropylamine and phenylbutylamine, useful for the treatment of arrhythmias and prolonging the action potential of heart tissue.

Despite the extensive amount of research and relatively large number of drugs for treating heart disease, mortality from cardiovascular disorders is still surprisingly high. It is known that the weakening of the cardiovascular system begins and continues in youth. In about half of the population by age 50, about 50% of one or more coronary arteries appear, and less than 1/5 of these ages have a complete, unoccluded artery (Rissanen, Advan. Cardiol. 4). , 99 (1970).

The mechanism of action of various arrhythmia treatments is largely explained as an effect on the electrophysiological properties of myocardium and conducting tissue. The electrical potential difference in the myocardium is caused by the difference in ion concentration through the heart cell membrane; The cell membrane is selectively permeable to various ions passing through pores or channels.

When the myocardium is at rest, non-diffusing macroanions are present in high concentrations in the cell, causing the interior to become negatively charged. During the action potential, the permeability of sodium rapidly increases to the inside, and the inflow of the positive charges becomes positive.

The cell membrane then becomes completely unresponsive to the additional passage of sodium ions until tissue repolarization occurs. The free reaction period is very long because repolarization occurs 100 times slower than depolarization. Any drug that shortens the duration of the cardiac action potential necessarily shortens the refractory and consequently increases the likelihood of re-talk rhythm under certain abnormal conditions. If repolarization is delayed, of course the refractory is extended.

Many drugs have been used to treat heart failure. Of these, quinidine, procainamide and lidocaine are best known and widely used. All these drugs mainly directly affect the conductivity of the membrane, increasing or decreasing various ion flows.

Recently, various quaternary ammonium salts have been found useful in the treatment of arrhythmia. These inflammations include a drug called Bretallium (see US Patent No. 3,038,004). Bretlium is a salt of (-bromobenzyl) ethyl dimethyl ammonium cation. This has been shown to be effective in the treatment of ventricular impairment, which has not been well treated with other conventional drugs (cf. Morgan et al., J. Pharm. Sci., 65. 467 (1976)). However, it has many side effects including sympathetic excitability and sympathetic inhibitory effect.

Several researchers have recently been interested in the development of quaternary ammonium compounds that are useful as arrhythmia and fibrillation inhibitors and at the same time cause no adverse effects on the autonomic nervous system (see Lucchesi et al., "Pharmacological Modification of Arrhythmias After Experimentally Induced). Acute Myocardial Infarction "American Heart Association Monograph No. 47 December, 1975). Dimethyl quaternary ammonium salts of propanolol have shown effective arrhythmic action against various experimentally induced cardiac arrhythmias (see Schuster et al., J. Pharmacol.Exp. Ther., 184, 213 (1973)). And Kniffen et al., J. Pharmacol.Exp. Ther., 187 260 (1973)).

The present invention provides a method for producing some phenylbutyl ammonium salts and phenylpropylammonium salts, which are effective in extending the cardiac action potential duration time. This compound is effective in prolonging infertility in myocardium and conducting tissue, and thus is useful in reducing the vulnerability of the heart to arrhythmias.

The present invention is directed to a method of preparing a special and potent arrhythmia treatment that is optionally useful for prolonging action potential and ultimately refractory to cardiac tissue to prevent ventricular fibrillation and other recurrent arrhythmias. In addition, the present invention provides pharmaceutical formulations useful in the treatment of cardiac arrhythmias.

Many cardiovascular drugs commonly used reduce the rate of rise of action potentials, thereby reducing the conductivity of the intact heart. This action can be predisposed to a variety of recurrent arrhythmias, including ventricular fibrillation and palpation, and the most severe arrhythmia, with shortened refractory.

The compounds of the present invention are particularly effective in prolonging both the action potential and the refractory phase of heart tissue. Furthermore, they can selectively perform their actions at concentrations that prolong reactivity, without inhibiting the rate of rise of action potential. Therefore, the compounds of the present invention are useful for treating and preventing various types of arrhythmia due to single or overlapping recurrent rhythms. This compound can typically be used for the treatment of arrhythmias such as ventricular lamp, ventricular fibrillation, preventricular-excitement, atrial fibrillation, and supraventricular tachycardia.

The present invention is characterized by reacting a tertiary amine of the general formula (II) with a compound of the general formula (III) and replacing the leaving group by X if Y is a leaving group other than X, and the general formula (I) Provided are methods for preparing quaternary ammonium salts of phosphorus phenyl alkylamines.

In the above formula,

n is 1 or 2;

R ¹ is hydrogen or alkyl having 1 to 2 carbon atoms;

R ² is hydrogen or alkyl of 1 to 3 carbon atoms;

R ³ is alkyl having 1 to 4 carbon atoms or phenylalkyl having an alkyl group of 1 to 4 carbon atoms;

R ⁴ is alkyl having 1 to 8 carbon atoms, R ⁵ is alkyl having 1 to 10 carbon atoms, or

Or R ⁴ and R ⁵ together with the adjacent nitrogen to which they are attached complete a heterocyclic ring having 4 to 7 carbon atoms;

R ⁶ and R ⁷ are independently hydrogen, hydroxy, halogen, nitro, alkoxy having 1 to 3 carbon atoms or alkyl having 1 to 3 carbons, provided that at least one of R ⁶ and R ⁷ is hydrogen or n is 1 And R and R are independently groups other than nitro, then R ⁵ is alkyl having 6 to 10 carbon atoms;

X is a therapeutically acceptable anion;

R ⁸ , R ⁹ and R ¹⁰ together are selected from R ³ , R ⁴ , R ⁵ and R ¹¹ , where R ¹¹ is

R ³ , R ⁴ , R ⁵ and R ¹¹ are each not used more than once;

R ¹² is not selected above R ³ , R ⁴ , R ⁵ is or R ¹¹ and Y is X or another leaving group.

In the above general formula

R ¹ represents hydrogen or alkyl having 1 to 2 carbon atoms, namely methyl and ethyl.

R ² represents alkyl having 1 to 3 carbon atoms, namely methyl, ethyl, isopropyl, and n-propyl, as well as hydrogen.

R ³ is a phenyl (C ₁ -C ₄ ) alkyl group having 1 to 4 carbon atoms, i.e. methyl, ethyl, n-propyl, n-butyl and isopropyl and alkyl having 1 to 4 carbon atoms, ie phenylmethyl, phenylethyl, 3 -Phenylpropyl, 4-phenylbutyl and phenylisopropyl.

R ⁴ is alkyl having 1 to 8 carbons including methyl, ethyl, n-propyl, n-butyl, isopentyl, 2-methylbutyl, 2-methylpentyl, 1-ethylpentyl, n-heptyl, n-octyl, Isooctyl and the like.

R ⁵ is methyl, ethyl, n-pentyl, isohexyl, 2-ethylhexyl, n-heptyl, 3-methylheptyl, 1,2-dimethylheptyl, 1,2-dimethyloctyl, 1,1-dimethylheptyl, n Alkyl having 1 to 10 carbon atoms such as -nonyl, n-decyl and the like, and an alkyl group associated therewith, when n is 1 and R ⁶ and R ⁷ are not nitro, R ⁵ is alkyl having 6 to 10 carbon atoms.

In addition to R ⁴ and R ⁵ each representing an alkyl group, R ⁴ and R ⁵ together with the adjacent nitrogen to which they are attached complete a heterocyclic ring having 4 to 7 carbon atoms. Rings of this kind include pyrrolidine, piperidine, hexahydroazepine, octa-hydroazocin.

As mentioned above, R ⁶ and R ⁷ are selected from hydrogen, hydroxy, halogen, alkoxy having 1 to 3 carbon atoms, nitro and alkyl having 1 to 3 carbon atoms. Typical halogen groups are fluorine, chlorine and bromine. Examples of alkoxy having 1 to 3 carbon atoms include methoxy, ethoxy and isopropoxy, and alkyl groups having 1 to 3 carbon atoms include methyl, ethyl and n-propyl.

The compounds of the present invention are quaternary ammonium salts and therefore require an anion defined by X in the general formula. Any anion that produces a therapeutically acceptable salt with an ammonium cation can be used. Commonly used anions include chloride, bromide, sulfonate, p-toluenesulfonate, methanesulfonate, p-bromo phenylsulfonate-, phosphate, carbonate, oxalate, succinate, citrate, benzoate, acetate and the like. to be. Preferred anions commonly used are bromide.

The phenylpropyl ammonium salt and phenylbutyl ammonium salt of the present invention can be prepared by various known chemical methods. Generally, N, N-dialkyl-3-phenylpropylamine or N, N-dialkyl-4-phenylbutylamine is reacted with a simple, almost animal or excess alkylating agent such as alkyl halide, alkylsulfate, alkyltosylate, etc. .

In more detail, the following disubstituted propyl- or butylamines of the general formula can be reacted with alkylating agents of the general formula R ⁵ -X in a solvent such as diethyl ether.

The quaternary ammonium salts prepared by the process mentioned here are characteristically present as white solids with high crystallinity. In general, when the tertiary amine is reacted with the alkylating agent as described above, since the resulting salt precipitates in the solution, it can be recovered by filtration. The salt thus formed can be readily purified by conventional methods such as recrystallization with a suitable organic solvent, ie methyl acetate, acetone, methane, organic solvents such as benzene and the like.

Another method of preparing the quaternary ammonium salts of the present invention is to react the tertiary amine with phenylpropyl or phenylbutyl derivatives having good leaving groups in the 1-position. Good leaving groups are already well known to those skilled in the art and include chloro, bromo, methanesulfonyl, p-toluenesulfonyl, azide and the like. This latter process is used to prepare tertiary amines, such as methylethyl n-octylamine, with almost animal amounts of phenylpropyl derivatives such as 3- (3-bromophenyl) propyl chloride or (4-methoxyphenyl) butyl bromide. It is reacted with the same phenylbutyl derivative. Generally, this condensation reaction is carried out in an inert solvent such as diethyl ether or benzene, but may also be carried out in the absence of solvent if desired. Condensation reactions are often almost complete within 1 to 10 days at temperatures of about 50 ° to 200 ° C. The product, quaternary ammonium salt, is usually crystalline, recovered by filtration and can be recrystallized if desired.

Preferred compound groups according to the invention are phenylpropyl ammonium salts and phenylbutyl ammonium salts, wherein one of the alkyl substituents of the ammonium nitrogen atom is lower alkyl such as methyl or ethyl. A particularly preferred method for preparing these compounds is the addition of a suitable tertiary amine to a solution saturated with an alkylating agent such as methyl or ethyl halide. For example, solvents such as diethyl ether, diisopropyl ether, ethyl acetate, acetonitrile and the like are readily saturated with alkylating agents such as methyl bromide or ethyl chloride. Quaternization generally occurs very rapidly when tertiary amines are added to this solution, producing the corresponding salt as a solid precipitate.

R ⁶ or R ⁷ is a hydroxyl group is phenyl (propyl or butyl) ammonium salt, R ⁶ or R ⁷ is methoxy in the presence of a phenylpropyl ammonium salts or phenylbutyl quaternary ammonium from the ammonium salt hydroxide to form a side and glacial acetic acid It can be prepared by treating with hydrobromic acid under.

The anion which binds to the quaternary ammonium cation moiety of the salt of the invention is defined as X- in the above general formula. Particular anions that form part of the salts of the present invention are not critical in themselves, unless the salt is pharmacologically acceptable as a whole and the anion moiety imparts various undesirable properties to the salt. The most preferred anion is a halide, and when a halide such as chloride or bromide is the anion site of a salt, it can be replaced with another anion if necessary for some reason. This substitution is carried out either directly by substitution reactions in the solution by dilysis or by the use of ion exchange resins or by the conversion of quaternary salts to the corresponding hydroxides, followed by neutralization of the hydroxides by reaction with the appropriate acid. It can be performed by. For example, quaternary ammonium halides can be reacted with aqueous silver oxide to produce the corresponding quaternary ammonium hydroxides. The hydroxides are reacted with acids such as methanesulfonic acid, formic acid, butyric acid, nitric acid and the like to produce quaternary ammonium salts with anions corresponding to the acids used.

Starting materials required to synthesize the salts of the present invention are known compounds or can be readily prepared by known methods. As noted above, a preferred method for preparing quaternary ammonium salts is to react the tertiary amine with an alkylating agent. Necessary tertiary amines can be prepared by various methods. For example, phenylpropyl halide or phenylbutyl halide can be reacted with a primary amine such as n-octylamine or isopentylamine to obtain the corresponding secondary amine. This secondary amine is reacted with an alkylating agent to give the corresponding tertiary amine. There is a particularly convenient method if a tertiary amine in which one of the alkyl groups is methyl is desired. That is, reacting a suitable primary or secondary amine with formaldehyde and formic acid. Primary and secondary amines are also readily prepared by reduction of suitable phenylalkyl amides. For example, an amide such as N-n-heptyl-3- (3-nitrophenyl) propion-amide is reduced to give the corresponding N-n-heptyl-3- (3-nitrophenyl) propylamine. The latter compound is reacted with formaldehyde and formic acid to give N-methyl-N-n-heptyl-3- (3-nitrophenyl) propylamine.

Another method of preparing amines is to reduce methiation of metones. For example, starting materials required to prepare the salts having the above general formula wherein R ¹ is hydrogen and R ² is alkyl having 1 to 3 carbons may be selected from primary amines, ie amines of general formula R ⁵ NH ₂ , with phenylethyl or phenylpropyl. It is obtained by reacting with (alkyl having 1 to 3 carbon atoms) ketone. For example, a ketone such as 2-phenylethyl n-propyl ketone is reacted with iso-octylamine in the presence of a suitable catalyst such as palladium on hydrogen and carbon to condense and reduce N-iso-octyl-1-n-propyl-3-phenyl Obtain propylamine. Furthermore, such amines are alkylated and quaternized to yield the compounds of the present invention.

The following quaternary ammonium salts are examples of compounds prepared with the present invention.

N-ethyl-N-methyl-N-isopropyl-4-phenylbutyl-ammonium chloride;

N, N-di-n-propyl-N-n-octyl-3- (4-isopropylphenyl) propyl ammonium methylsulfonate;

N-ethyl-N-n-heptyl-N-n-octyl-1,1-diethyl-3- (3-ethoxyphenyl) propyl ammonium fluoride;

N, N-di-n-octyl-N-isopropyl-4- (3-fluorophenyl) butyl ammonium acetate;

N, N, N-tri-n-propyl-1-ethyl-4-phenylbutyl-ammonium succinate;

N-n-propyl-N-n-hexyl-N- (3-methylheptyl) -4- (3-ethylphenyl) butyl ammonium ttrade;

N, N-di-n-butyl-N- (3-ethylheptyl) -1-ethyl-1-methyl-3- (3-ethoxyphenyl) propyl ammonium benzenesulfonate;

N-ethyl-N-isobutyl-N-n-nonyl-4- (3-nitrophenyl) butyl ammonium fluoride;

N-methyl-N- (3-ethylpentyl) -N- (3-methyl-octyl) -1,1-diethyl-4- (3-bromophenyl) butyl ammonium p-toluene-sulfonate;

N, N-diethyl-N-n-heptyl-4-phenylbutyl-ammonium ironide;

N-ethyl-4-phenylbutyl pyridinium butyrate;

N-n-butyl-3- (3-erroloxyphenyl) propylpyridinium oxalate;

N-ethyl-4- (4-n-propoxyphenyl) butylhexa-hydroazenium chloride;

N, N-diethyl-N-n-hexyl-3-phenylpropylammonium bromide;

N, N-diethyl-N-n-decyl-3-phenylpropyl ammonium bromide;

N-ethyl-4-phenyloctahydroazononium hydroxide;

N, N-di- (2-methylheptyl-N-n-propyl-1,1-diethyl-4- (3-methoxyphenyl) butyl ammonium bromide;

N, N-di-n-propyl-N-n-octyl-1-ethyl-1-methyl-3- (4-ethoxyphenyl) propyl ammonium fluoride;

N-ethyl-N-n-octyl-N-n-propyl-1-ethyl-1-n-propyl-3- (3-nitrophenyl) propyl ammonium iodide;

N, N-di-n-pentyl-N-ethyl-1-methyl-4- (3-iodophenyl) butyl ammonium benzenesulfonate, and N, N-diethyl-Nn-heptyl-4- (4-fluoro Rophenyl) -butyl ammonium methanesulfonate.

Certain compounds of the present invention have asymmetric centers and exist as optical isomers. Examples of compounds of the above general formula wherein R ¹ and R ² are different are present as d-isomers, 1-isomers and racemic mixtures. Generally these compounds are used as racemic mixtures, but separation of the mixtures into optically active isomers can be readily accomplished if desired. This separation can be accomplished by reacting the amine precursor with an optically active substrate to produce the diastereomer, separating the diastereomer by conventional means such as crystallization, and stripping off the optically active substrate. For example, a typical cleavage method is the reaction of d1-1-ethyl-3-phenylpropylamine with optically active d or 1, α-methylbenzylbromide. Repeated crystallization of the product yields the separated diastereomers followed by optically active d and 1-ethyl-3-phenylpropylamine by de-benzylation and hydrogenolysis. The obtained compound can be alkylated and quaternized by the method described above.

As noted above, the compounds of the present invention are particularly important because they are effective in the treatment and prevention of recurrent arrhythmias and exhibit selective and potent effects in prolonging the action potential persistence of heart tissue. Thus, the compounds of the present invention are effective in the treatment of arrhythmias by extending the electrical systolic, reducing the incidence of the heart against recurrent rhythms and ventricular fibrillation. The effect of the compound of the present invention was that the stop potential, activity potential, amplitude, duration, and elevation rate by standard electrophysiological methods in the in vitro test of normal dog Perkinji fibers overinjected with 35 ° C. ring gel solution and stimulated at 1 Hz. And effective incompatibility can be measured and analyzed. For example, N, N-diethyl-Nn-heptyl-4- (4-chlorophenyl) -butylammonium bromide has a duration of action potential of 20 Perkinji fibers that is continuously stimulated at 1 Hz at a concentration of 2 x 10 ^-8 moles. % Extend effect. Likewise, N, N-dimethyl-Nn-heptyl-1-methyl-4-phenylbutylammonium bromide is extended by 25% under the same conditions.

In addition to the in vitro test effects of prolonging action potential duration and refractory, some compounds according to the invention were also tested in complete dogs. In a representative experiment with an electrically induced ventricular fibrillation, a dose of about 0.1 micromolar to about 50 micromolar per kg body weight prior to fibrillation induction was observed to significantly reduce cardiac involvement in fibrillation. It became. Compounds of the invention have also been shown to convert experimentally induced crude, ventricular fibrillation or rapid tachycardia to normal blood pulsation rates by prolonged refractory in vitro and in vivo tests. This action demonstrates that the compounds of the present invention are effective when acute inadequate ventricular rates occur, especially in the case of preventricular-excited tachyarrhythmias.

The present invention also provides a method for treating arrhythmia by administering an effective amount of the arrhythmia to a patient suffering from arrhythmia and having a need for treatment or a patient who may develop into arrhythmia. The compound is preferably used for suppressing recurrent arrhythmias in the human body and preventing accidental death due to ventricular fibrillation. Thus, the compound may be most usefully used for prophylactic treatment. The compounds may be administered orally or parenterally, and conventional oral dosage forms are most preferred for prophylactic treatment. The actual dose of the compound to be administered in accordance with the present invention is determined by each situation, including the compound to be administered, the method of administration, the arrhythmia to be treated, and other considerations. However, representative oral dosages for prophylactic treatment are about 50 μg to about 500 μg of the active compound of the present invention per kg body weight. Intravenous doses range from about 20 μg to about 200 μg per kg body weight.

The dosage compound may be formulated by mixing with any of a variety of suitable pharmaceutical excipients and carriers, such as lactose, sucrose, starch powder, cellulose, calcium sulfate, sodium benzoate and the like. These prescriptions may be tableted or filled into gelatin capsules for convenient oral administration. Gelatin capsules suitable for oral administration for the prophylactic treatment of heart disease include, for example, about 1 to about 1 compound of the present invention such as N-N-diethyl-Nn-heptyl-4- (4-nitrophenyl) butylammonium bromide About 5 mg can be contained. Such a prescription may be administered orally by about 1 or 2 capsules per day and may be extended depending on the particular situation and the condition of the patient.

For parenteral administration, the compounds of the present invention may be formulated as intramuscular or intravenous injections. When treating a patient suffering from severe cardiac arrhythmias with the compound of the present invention, it is desirable to rapidly convert the compound of the present invention into a normal pulsating rhythm and then maintain a normal state by oral administration.

For parenteral administration, the compounds of the invention are formulated with a pharmaceutically acceptable carrier and diluent to prepare an injection solution. Commonly used diluents and carriers include water or saline solutions, buffered aqueous solutions, and dispersants and surfactants may also be used if desired. The compound of the present invention can also be administered in combination with other known arrhythmia therapeutics that exhibit potent autonomic control. Such drugs include apridine, quinidine, propranols and the like.

Representative formulations suitable for intramuscular injections include a suitable solubilizer and about 0.1 to 25.0 mg of N, N-di-n-pentyl-Nn-propyl-4-phenylbutylammonium methanesulfonate alone or about 100 to 200 mg It may be combined with other arrhythmia treatments such as quinidine, and the volume of about 2 ml is added to sterile water. Such formulations are injected 1 to 4 times daily and may be extended depending on the specifics of the patient being treated.

The invention is further elucidated as the following representative examples. The following examples illustrate the compounds encompassed by the present invention and in no case limit the present invention.

Example 1

N- (n-nonyl) -4-phenylbutylamine

A solution of 30 g of 4-phenylbutyl chloride and 77 g of n-nonylamine is heated at 100 ° C. for 48 hours. The reaction mixture is cooled and added to 5000 ml of water. The aqueous reaction mixture is alkaline by adding 5N sodium hydroxide solution. The aqueous alkaline solution is extracted several times with diethyl ether and the extracts are collected, the solvent is evaporated off under reduced pressure to give an oil. This oil is distilled off to obtain 30.2 g of N- (n-nonyl) -4-phenylbutylamine.

Example 2

N- (n-nonyl) -N-methyl-4-phenylbutylamine

28.2 ml of a 90% aqueous formic acid solution is cooled (5 ° C.), and a solution of 30.2 g of N- (n-nonyl) -4-phenylbutylamine and 27 ml of 37% aqueous formaldehyde is added in small portions over 10 minutes. The reaction mixture is stirred and heated at 100 ° C. for 12 h. The reaction mixture is cooled to 25 ° C, acidified by adding 90 ml of 4N hydrochloric acid, and the acidic solution is concentrated to about 20 ml. The mixture is then diluted with water and the aqueous acidic solution is washed with diethyl ether to make alkali by adding 5N sodium hydroxide, and the alkali solution is extracted three times with 100 ml of diethyl ether, the ether extracts are collected, washed with water and dried. The solvent is evaporated under reduced pressure to give 30.16 g of the product as an oil. Distillation of the oil yields 24.99 g of N- (n-nonyl) -N-methyl-4-phenylbutylamine with a boiling point of 124 to 127 ° C. at 0.01 Torr.

Example 3

N- (n-nonyl) -N-methyl-4-phenylbutyl ammonium oxalate

To a stirred solution of 24.99 g of N- (n-nonyl) -4-phenylbutylamine in about 300 ml of isopropyl alcohol was added 7.8 g of oxalic acid in 120 ml of isopropyl alcohol at one time. The product crystallized in the solution is filtered to give 23.9 g of N- (n-nonyl) -N-methyl-4-phenylbutyl ammonium oxalate having a melting point of 118 to 120 ° C.

Elemental Analysis (C ₂₂ H ₃₇ NO ₄ )

Theoretic: C 69.62, H 9.83, N 3.69

Experimental Value: C 69.81, H 9.60, N 3.89

Example 4

N, N-dimethyl-N- (n-nonyl) -4-phenyl butylammonium bromide

7 g of N- (n-nonyl) -N-methyl-4-phenylbutyl ammonium oxalate is suspended in diethyl ether and reacted with 5N sodium hydroxide solution. The organic layer is separated and the solvent is evaporated to remove 5.3 g of N- (n-nonyl) -N-methyl-4-phenylbutylamine. The latter compound is dissolved in 150 ml of diethyl ether and stirred in a flask equipped with a drying tube filled with 25 ° C calcium sulfate. The methyl bromide gas is saturated in the ethereal solution and the mixture is left at room temperature for 48 hours. The solid precipitate formed is collected by filtration and recrystallized from 50 ml of ethyl acetate and 80 ml of cyclohexane. The crystalline product is collected by filtration and dried in a desiccator to give 2.27 g of N, N-dimethyl-N- (n-nonyl) -4-phenyl butylammonium bromide having a melting point of 59 to 61 ° C.

Elemental Analysis (C ₂₁ H ₃₈ BrN)

Theoretic: C 65.61, H 9.96, N 3.64, Br 20.78

Found: C 65.94, H 9.82, N 3.68, Br 20.55.

EXAMPLES 5 TO 24

The following compounds are obtained by reacting a tertiary amine with an alkyl bromide in the same manner as described in Example 4.

N, N-di-n-heptyl-N-methyl-4-phenylbutyl ammonium bromide melting point 84 to 86 ° C

Elemental Analysis (C ₂₅ H ₄₆ BrN)

Theoretic: C 68.16, H 10.52, N 3.18, Br 18.14

Found: C 67.88, H 10.56, N 3.27, Br 18.01.

N, N-dimethyl-N-n-octyl-4-phenylbutyl ammonium bromide melting point 47 to 50 ° C

Elemental Analysis (C ₂₀ H ₃₆ BrN)

Theoretic: C 64.85, H 9.08, N 3.78, Br 21.57

Experimental Value: C 64.67, H 9.51, N 3.56, Br 21.49

N, N-di-n-heptyl-N-methyl-4-phenylbutyl ammonium bromide melting point 65 to 67 ° C

Elemental Analysis (C ₂₃ H ₄₂ BrN)

Theoretic: C 66.97, H 10.26, N 3.40, Br 19.37

Experimental Value: C 66.73, H 10.11, N 3.36, Br 19.45

N, N-di-n-pentyl-N-methyl-4-phenylbutyl ammonium bromide melting point 61 to 63 ° C

Elemental Analysis (C ₂₁ H ₃₈ BrN)

Theoretic: C 65.61, H 9.96, N 3.64, Br 20.78

Experimental Value: C 65.32, H 9.87, N 3.57, Br 21.00

N, N-dimethyl-N-isopropyl-4-phenylbutyl ammonium bromide melting point 162 to 164 ° C

Elemental Analysis (C ₁₅ H ₂₆ BrN)

Theoretic: C 60.00, H 8.73, N 4.66, Br 26.61

Found: C 59.85, H 8.48, N 4.54, Br 26.71.

N, N-dimethyl-N-n-propyl-4-phenylbutyl ammonium bromide melting point 93-95 ° C

Elemental Analysis (C ₁₅ H ₂₆ BrN)

Theoretic: C 60.00, H 8.73, N 4.66, Br 26.61

Found: C 59.73, H 8.45, N 4.40, Br 26.59.

N, N-dimethyl-N-n-pentyl-4-phenylbutyl ammonium bromide melting point 76 to 78 ° C

Elemental Analysis (C ₁₇ H ₃₀ BrN)

Theoretic: C 62.19, H 9.21, N 4.27, Br 24.34

Found: C 61.89, H 9.02, N 4.29, Br 24.47.

N, N-dimethyl-N-n-hexyl-4-phenylbutyl ammonium bromide melting point 46 to 48 ° C

Elemental Analysis (C ₁₈ H ₃₂ BrN)

Theoretic: C 63.15, H 9.42, N 4.09, Br 23.34

Found: C 62.92, H 9.25, N 4.17, Br 23.52.

N, N-dimethyl-N- (1-methylpropyl) -4-phenyl-butyl ammonium bromide melting point 98 to 100 ° C

Elemental Analysis (C ₁₆ H ₂₈ BrN)

Theoretic: C 61.14, H 8.98, N 4.46, Br 25.42

Found: C 60.92, H 8.71, N 4.46, Br 25.58.

N, N-dimethyl-N-isobutyl-4-phenylbutyl-ammonium bromide melting point 113 to 115 ° C

Elemental Analysis (C ₁₆ H ₂₈ BrN)

Theoretic: C 61.14, H 8.98, N 4.46, Br 25.42

Found: C 61.00, H 8.86, N 4.48, Br 25.55.

N, N-di-n-propyl-N-methyl-4-phenylbutyl-ammonium bromide melting point 107 to 109 ° C

Elemental Analysis (C ₁₇ H ₃₀ BrN)

Theoretic: C 62.19, H 9.21, N 4.27, Br 24.34

Found: C 62.10, H 9.32, N 4.06, Br 24.53.

N, N-diethyl-N-methyl-4-phenylbutyl ammonium bromide melting point 145 to 147 ° C

Elemental Analysis (C ₁₅ H ₂₆ BrN)

Theoretic: C 60.00, H 8.73, N 4.66, Br 26.61

Found: C 60.27, H 8.93, N 4.84, Br 26.90.

N, N-di-n-butyl-N-methyl-4-phenylbutyl ammonium bromide melting point 70 to 72 ° C

Elemental Analysis (C ₁₉ H ₃₄ BrN)

Theoretic: C 64.03, H 9.62, N 3.93, 22.42

Experimental value: C 63.80, H 9.37, N 4.20, 22.40

N, N-dimethyl-N-n-butyl-4-phenylbutyl ammonium bromide melting point 95 to 96 ° C

Elemental Analysis (C ₁₆ H ₂₈ BrN)

Theoretic: C 61.14, H 8.98, N 4.46, Br 25.42

Experimental Value: C 60.94, H 9.12, N 4.60, Br 25.63

N, N-di-n-pentyl-N-ethyl-4-phenylbutyl-ammonium bromide melting point 41 to 45 ° C

Elemental Analysis (C ₂₂ H ₄₀ BrN)

Theoretic: C 66.31, H 10.12, N 3.52, Br 20.05

Found: C 66.08, H 9.88, N 3.50, Br 19.86

N, N-dimethyl-N-ethyl-4-phenylbutyl ammonium bromide melting point 160 to 162 캜

Elemental Analysis (C ₁₄ H ₂₄ BrN)

Theoretic: C 58.75, H 8.45, N 4.89, Br 27.91

Experimental Value: C 58.44, H 8.22, N 5.11, Br 27.85

N, N, N-triethyl-4-phenylbutyl ammonium bromide melting point 58 to 60 ° C

Elemental Analysis (C ₁₆ H ₂₈ BrN)

Theoretic: C 61.14, H 8.98, N 4.46, Br 25.42

Experimental Value: C 60.85, H 8.70, N 4.49, Br 25.70

N, N, N-tri-n-propyl-4-phenylbutyl ammonium bromide melting point 113 to 115 ° C

Elemental Analysis (C ₁₉ H ₃₄ BrN)

Theoretic: C 64.03, H 9.62, N 3.93, Br 22.42

Experimental Value: C 63.86, H 9.54, N 3.71, Br 22.33

N-methyl-N- (4-phenylbutyl) hexahydroazepnium bromide melting point 129-131 ° C

Elemental Analysis (C ₁₇ H ₂₈ BrN)

Theoretic: C 62.57, H 8.65, N 4.29, Br 24.49

Experimental Value: C 62.32, H 8.43, N 4.28, Br 24.57

N-methyl-N- (4-phenylbutyl) -tetrahydro-pyrrolium bromide melting point 128 to 130 ° C

Elemental Analysis (C ₁₅ H ₂₄ BrN)

Theoretic: C 60.40, H 8.11, N 4.70, Br 26.79

Experimental Value: C 60.47, H 7.86, N 4.86, Br 26.63

Example 25

N, N, N-trimethyl-4-phenylbutyl ammonium methanesulfate

A solution of 17 g of N, N-dimethyl-4-phenylbutylamine in 500 ml of diethyl ether was stirred in a flask with calcium sulfate at 0 ° C. and 9.1 ml of dimethyl sulfate was added dropwise over 90 minutes. The reaction mixture is warmed to room temperature and stirred for 12 hours. The precipitates were collected by filtration and recrystallized from 300 ml of acetone to obtain 27.64 g of N, N, N-trimethyl-4-phenylbutylammonium methane-sulfonate having a melting point of 122 to 124 ° C.

Elemental Analysis (C ₁₄ H ₂₅ NSO ₄ )

Theoretic: C 55.42, H 8.31, N 4.62, S 10.60

Experimental Value: C 55.62, H 8.10, N 4.68, S 10.57

Example 26

N- (4-phenylbutyl) piperidine was reacted with dimethylsulfate according to the procedure of Example 25 to obtain N-methyl-N- (4-phenyl-butyl) piperidinium methanesulfonate having a melting point of 54 to 56 ° C. Get

Elemental Analysis (C ₁₇ H ₂₉ NSO ₄ )

Theoretic: C 59.45, H 8.51, N 4.08, S 9.33

Experimental Value: C 59.23, H 8.64, N 4.05, S 9.12

Example 27

N-n-heptyl-4-phenylbutylamine

125 g of 4-phenylbutyl chloride and 250 g of n-heptylamine are stirred and heated at 110 ° C. for 4 days. The reaction mixture is cooled to room temperature, 200 ml of water is added, and 5N sodium hydroxide is added to make alkaline.

The aqueous alkaline solution is extracted with diethyl ether, the ether extracts are combined and washed with water, and the product is extracted with aqueous sulfuric acid solution. The acidic layer is separated, washed with fresh diethyl ether, and 5N sodium hydroxide is added to re-alkaline. The product is extracted from alkaline aqueous solution into fresh diethyl ether. Collect ether extracts, wash and dry with water. The solvent is evaporated off under reduced pressure to give 186 g of product as an oil. The oil is distilled to yield 135.46 g of N-n-heptyl-4-phenylbutylamine having a boiling point of 160 to 166 ° C. at 5 Torr.

Example 28

N-acetyl-N-n-heptyl-4-phenylbutylamine

To a cold stirring solution of 25.67 g of N-n-heptyl-4-phenylbutylamine in 70 ml of acetone containing 22.1 g of sodium carbonate and 70 ml of water was added dropwise over 60 minutes an 8.1 ml solution of acetyl chloride in 140 ml of acetone. The temperature of the weighted reaction mixture is maintained below about 30 ° C. After the addition is completed, the reaction mixture is warmed up to 25 ° C. and stirred at that temperature for 12 hours.

The reaction mixture is concentrated under reduced pressure to about 20 ml and diluted with 60 ml of water. The aqueous solution was extracted several times with diethyl ether, and the ether extracts were combined, washed once with water and 1M citric acid, further washed four times with water, and dried. The solvent is evaporated off under reduced pressure to yield 19.69 g of N-acetyl-N-n-heptyl-4-phenylbutylamine.

Example 29

N-ethyl-N-n-heptyl-4-phenylbutylamine

A solution of 19.69 g of N-acetyl-N-n-heptyl-4-phenylbutylamine in 50 ml of THF was added dropwise to a stirred solution of 0.94 mol of diborane in 220 ml of tetrahydrofuran (THF) over 20 minutes. The reaction mixture is heated at reflux for 12 hours. After cooling the reaction mixture to room temperature, 75 ml of cold (5 ° C.) 2 N hydrochloric acid was added dropwise over 20 minutes, followed by stirring. The reaction mixture is then shrunk to about 80 ml and diluted with 100 ml of concentrated hydrochloric acid. The acidic mixture is stirred and heated with reflux for 1 hour. The reaction mixture is cooled to room temperature and made alkaline by adding 5N sodium hydroxide. The aqueous alkaline solution is extracted several times with diethyl ether. Collect ether extracts, water, wash and extract with 2N sulfuric acid. The acidic extracts are collected and 5N sodium hydroxide is made alkaline. The aqueous alkaline solution is extracted with diethyl ether, the ether extracts are combined, washed with water, dried and the solvent is evaporated off under reduced pressure to give 15.22 g of product as an oil. The oil formed is distilled off to obtain 13.8 g of N-ethyl-N-n-heptyl-4-phenylbutylamine having a boiling point of 128 to 129 캜 at 0.1 Torr.

Example 30

According to the methods of Examples 28-29, Nn-heptyl-Nn-pentanoyl-4-pentylbutylamine was prepared and reduced by reaction with diborane to give Nn-pentyl-Nn-heptyl-4-phenylbutylamine Get

Example 31

N-N-diethyl-N-n-heptyl-4-phenylbutyl ammonium bromide

In a flask equipped with a calcium sulfate drying tube, a solution of 4.33 g of N-ethyl-N-n-heptyl-4-phenylbutylamine in 35 ml of ethyl bromide is stirred and heated under reflux for 48 hours. The reaction mixture is cooled to room temperature and excess ethyl bromide is removed by evaporation under reduced pressure. The residue is taken up in 50 ml of saturated cytin ethyl acetate with water and cooled to 0 ° C. to precipitate the product. The precipitates are collected by filtration and recrystallized from fresh ethyl acetate to give 5.5 g of N-N-diethyl-N-n-heptyl-4-phenylbutyl ammonium bromide as monohydrate having a melting point of 48 to 50 ° C.

Elemental Analysis (C ₂₁ H ₄₀ BrNO)

Theoretic: C 62.67, H 10.02, N 3.48, Br 19.85

Experimental Value: C 62.67, H 9.88, N 3.32, Br 19.65

Example 32

As in Example 31, Nn-pentyl-Nn-heptyl-4-phenylbutylamine prepared in Example 30 was reacted with methyl bromide to Nn-heptyl-N-methyl-Nn-pentyl-4-phenylbutyl ammonium Obtain bromide Melting Point 55 ~ 57 ℃

Elemental Analysis (C ₂₃ H ₄₂ BrN)

Theoretic: C 66.97, H 10.26, N 3.40, Br 19.37

Experimental Value: C 66.76, H 10.04, N 3.29, Br 18.93

Example 33

N-n-heptyl-4- (4-chlorophenyl) butyramide

4- (4-chlorophenyl-n-butyric acid reacts 4-chloro benzaldehyde with ethyl acetate and sodium cyanide to obtain ethyl 4- (4-chlorophenyl) -4-oxo-butyrate, and the ethylbutyrate derivative Hydrolysis gives 4- (4-chlorophenyl) -4-oxobutyric acid which is then reacted with zinc and hydrochloric acid to reduce the 4-oxo group of the acid 4- (4-chlorophenyl)-in 200 ml of benzene. To the stirred solution of 16.15 g of n-butyric acid was added 35 ml of oxaryl chloride over 30 minutes, and after the addition was completed, the reaction mixture was heated under reflux for 3 hours and cooled to room temperature. After evaporation off, the remaining solution is diluted with 200 mL of diethyl ether The reaction mixture is cooled in an ice bath to 5 ° C. and 23.3 g of n-heptylamine in 30 mL of diethyl ether are added dropwise over 60 minutes. Stir at 25 ° C. for hours The aqueous reaction mixture is extracted with diethyl ether, the ether extract is washed with water, washed with 2N hydrochloric acid, washed with water and dried again, and the solvent is evaporated to remove the melting point from 35 to 38. 24.45 g of Nn-heptyl-4- (4-chlorophenyl) -butyramide at ° C are obtained.

Example 34

N-n-heptyl-4- (4-chlorophenyl) butylamine

268 ml of 0.94 M diborane solution in THF is stirred and to this is added dropwise a solution of 24.45 g of N-n-heptyl-4- (4-chlorophenyl) butyramide in 100 ml of THF over 90 minutes. The reaction mixture is then heated to reflux and stirred for 12 hours. The reaction mixture is cooled to 5 ° C. in an ice bath and excess 2N hydrochloric acid is added to decompose the remaining diborane. The solvent is then evaporated off under reduced pressure and the residue is diluted with 100 mL of concentrated hydrochloric acid. The acid reaction mixture is heated to reflux, stirred for 45 minutes and cooled back to room temperature. The acidic solution is alkaline with 5N sodium hydroxide solution and the product is extracted from the alkaline solution into diethyl ether. The ether extracts are combined, washed with water and washed with 2N sulfuric acid. The aqueous acid solution is made alkaline with 5N sodium hydroxide solution, and the alkaline solution is extracted several times with diethyl ether. Collect ether extracts, wash with water and dry. Evaporate the solvent to afford 21.86 g of N-n-heptyl-4 (4-chlorophenyl) butylamine.

Example 35

N-n-heptyl-N-methyl-4- (4-chlorophenyl) butylamine

A solution of 9 g N-n-heptyl-4- (4-chlorophenyl) butylamine 9 ml 90% formic acid and 8.7 ml 37% aqueous formaldehyde is heated at 100 ° C. until evolution of carbon dioxide is observed. The reaction mixture is cooled and stored at room temperature for 10 minutes. The reaction mixture is again heated to 100 ° C. and maintained at that temperature for 12 hours. After cooling again at room temperature, it was diluted with 40 mL of 4N hydrochloric acid and the excess solvent was removed by evaporation under reduced pressure, the remaining oil was diluted with water and made alkaline by adding 5N sodium hydroxide, and the alkaline solution was extracted with diethyl ether. The ether extracts are combined and the product is extracted into 2N sulfuric acid. The acid extracts are collected, washed with water and dried. Evaporate the solvent to afford 9.8 g of N-n-heptyl-N-methyl-4- (4-chlorophenyl) butylamine. The amine thus formed is dissolved in 25 ml of ethyl acetate and added to a 3.0 g solution of oxalic acid in 150 ml of ethyl acetate at once. The precipitate formed is collected by filtration and dried with air to give 12.13 g of N-n-dityl-N-methyl-4- (4-chlorophenyl) butyl ammonium oxalate having a melting point of 102 to 104 < 0 > C.

Elemental Analysis (C ₂₀ H ₃₂ ClNO ₄ )

Theoretic: C 62.24, H 8.36, N 3.63, C 9.19

Experimental Value: C 62.28, H 8.45, N 3.46, C 9.20

Example 36

N, N-dimethyl-N-n-heptyl-4- (4-chlorophenyl) -butylammonium bromide

A solution of 5.0 g of N-n-heptyl-N-methyl-4- (4-chlorophenyl) butylamine in 100 ml of diethyl ether is stirred at 25 ° C. and methyl bromide gas is injected until saturated. The reaction mixture was cooled to 0 ° C. under stirring at 25 ° C. for 18 hours to form a solid precipitate. The precipitate was left at room temperature for 48 hours, collected by filtration and recrystallized with 50 ml of ethyl acetate to give 5.55 g of N, N-dimethyl-Nn-heptyl-4- (4-chlorophenyl) butylammonium bromide having a melting point of 58 to 60 ° C. Get

Elemental Analysis (C ₁₉ H ₃₃ BrClN)

Theoretic: C 58.39, H 8.51, N 3.58, Cl 9.07, Br 20.44

Experimental Value: C 58.16, H 8.27, N 3.58, Cl 9.34, Br 20.58

Example 37

N, N-diethyl-N-n-heptyl-4- (4-chlorophenyl) -butylammonium bromide

A solution of 20 ml of ethyl bromide and 1.27 g of N-ethyl-N-n-heptyl-4- (4-chlorophenyl) butylamine is heated under reflux and stirred for 1 week. The reaction mixture is cooled and excess ethyl bromide is evaporated off under reduced pressure to afford the product as an oil. The oil is recrystallized from ethyl acetate saturated with water to give 1.47 g of N, N-diethyl-N-n-heptyl-4- (4-chlorophenyl) ammonium bromide having a melting point of 29 to 30 ° C as a dihydrate.

Elemental Analysis (C ₂₁ H ₄₁ BrClNO)

Theoretic: C 55.45, H 9.08, N 3.08, Cl 7.79, Br 17.56

Experimental Value: C 55.15, H 8.87, N 3.03, Cl 8.08, Br 17.57

Example 38

N, N, N-triethyl-4- (4-chlorophenyl) butylammonium bromide

A solution of 4.3 g of N, N-diethyl-4- (4-chlorophenyl) butylamine and 35 ml of ethyl bromide is heated under reflux and stirred for 3 days. The reaction mixture is cooled to room temperature and the excess ethyl bromide is evaporated under reduced pressure and concentrated to an oil. The oil formed is recrystallized in methylethyl ketone to give 4.99 g of N, N, N-triethyl-4- (4-chlorophenyl) butylammonium bromide having a melting point of 106 to 108 < 0 > C.

Elemental Analysis (C ₁₆ H ₂₇ BrClN)

Theoretic: C 55.10, H 7.80, N 4.02, Br 22.91, Cl 10.17

Experimental Value: C 55.12, H 7.83, N 4.23, Br 23.07, Cl 10.23

Example 39

N, N-di-n-pentyl-N-methyl-4- (4-chlorophenyl) -butylammonium bromide

To a 5.0 g solution of N, N-di-n-pentyl-4- (4-chlorophenyl) butylamine in 150 ml of diethyl ether is injected methyl bromide gas until the solution is saturated. The reaction mixture is left at room temperature for 2 days and the precipitate formed is collected by filtration. The precipitate was recrystallized in 50 ml of ethyl acetate to obtain 5.4 g of N, N-di-n-pentyl-N-methyl-4- (4-chlorophenyl) butylammonium bromide having a melting point of 81 to 83 占 폚.

Elemental Analysis (C ₂₁ H ₃₇ BrClN)

Theoretic value: C 60.21, H 8.90, N 3.34, Br 19.08, Cl 8.46

Experimental Value: C 60.22, H 8.64, N 3.22, Br 19.30, Cl 8.90

Example 40

N-n-heptyl-1-methyl-4-phenylbutylamine

A solution of 10 g of methyl 3-phenylpropylketone and 7.1 g of n-heptylamine in 80 ml of 2B ethanol containing 2 g of 5% palladium on carbon is stirred for 12 hours at 50 ° C. under hydrogen pressure between 50 (p.s.i). The reaction mixture is cooled to room temperature and the solvent is removed by evaporation under reduced pressure to yield an oil. This oil is taken up in 100 ml of diethyl ether and the ethereal solution is washed with 5N sodium hydroxide and water. After drying the solution, the solvent is evaporated to afford 12.34 g of N-n-heptyl-1-methyl-4-phenylbutylamine.

Example 41

N-n-heptyl-1-methyl-1-methyl-4-phenylbutylamine

A solution of 11.6 mL of 37% aqueous formaldehyde, 12.2 mL of 90% formic acid, and 12.3 g of N-n-heptyl-1-methyl-4-phenylbutalamine are heated at 100 ° C. for 12 hours and cooled to room temperature. 40 ml of 4N hydrochloric acid was added to the reaction mixture, acidified, evaporated under reduced pressure, and concentrated to 20 ml. The acidic mixture is made alkaline with 5N sodium hydroxide and the alkaline solution is extracted several times with diethyl ether. The ethereal extracts are combined, washed with water, dried and the solvent is removed by evaporation to give 12.4 g of crude product as crude oil. The oil is distilled off to give 10.7 g of N-n-heptyl-N-methyl-1-methyl-4-phenyl-butylamine. The boiling point is from 120 to 124 ° C at 0.5 Torr.

Example 24

N, N-dimethyl-N-n-heptyl-1-methyl-4-phenylbutylammonium bromide

A solution of 5.0 g of N-n-heptyl-N-methyl-1-methyl-4-phenylbutylamine in 150 ml of diethyl ether is stirred and methyl bromide gas is injected until the solution is saturated. When the reaction mixture is stirred for 4 days, a white precipitate is formed during this time. The precipitate is collected by filtration and recrystallized from 50 ml of ethyl acetate to give 5.215 g of N, N-dimethyl-N-n-heptyl-1-methyl-4-phenylbutylammonium bromide having a melting point of 70 to 72 캜.

Elemental Analysis (C ₂₀ H ₃₆ BrN)

Theoretic: C 64.85, H 9.80, N 3.78, Br 21.57

Experimental Value: C 65.12, H 9.51, N 3.91, Br 21.64

Example 43

N, N, N-triethyl-1-methyl-4-phenylethyl ammonium bromide

A solution of 3.65 g of N, N-diethyl- (1-methyl-4-phenyl) butylamine in 35 ml of ethyl bromide is heated to reflux and stirred for 7 days. The reaction mixture was cooled to room temperature, 50 ml of diethyl ether was added, and the white precipitate formed was filtered. The precipitate is recrystallized from methylethyl ketone to give 619 mg of N, N, N-triethyl-1-methyl-4-phenylbutyl ammonium bromide having a melting point of 123 to 125 ° C.

Elemental Analysis (C ₁₇ H ₃₀ BrN)

Theoretic: C 62.19, H 9.21, N 4.27, Br 24.34

Experimental Value: C 62.13, H 9.06, N 4.29, Br 24.05

Example 44

1-methyl-4- (4-chlorophenyl) butylamine

A solution of 14.7 ml of 97 percent aqueous formic acid, 17.6 ml of formaldehyde and 19.07 g of methyl 3- (4-chlorophenyl) propyl ketone are heated at 160 ° C. and stirred for 12 hours. The reaction mixture is cooled to room temperature, diluted with 100 ml of water and extracted with diethyl ether. Collect ether extracts, wash with water and dry. The solvent is evaporated to give 20.7 g of oil, which is dissolved in 84 ml of concentrated hydrochloric acid and 400 ml of 25% dioxane aqueous solution. This aqueous solution is heated to reflux for 12 hours. The reaction mixture is cooled to 30 ° C., made alkaline with 5N sodium hydroxide, the aqueous alkaline solution is extracted several times with diethyl-ether, the ether extracts are combined, washed with water, dried and the solvent is evaporated to 1-methyl- 15.26 g of 4- (4-chlorophenyl) butylamine are obtained.

Example 45

N, N-dimethyl-1-methyl-4- (4-chlorophenyl) butylamine

7.6 g of 1-methyl-4- (4-chlorophenyl) -butylamine was reacted with 9.9 ml of 90 percent formic acid and 9.5 ml of 37 percent aqueous formaldehyde to yield N, N-dimethyl-1-methyl-4- (4-chloro 7.05 g of phenyl_butylamine are obtained The freeamine is reacted with hydrogen chloride to produce N, N-dimethyl-1-methyl-4- (4-chlorophenyl) butyl ammonium chlorite having a melting point of 109 to 111 ° C.

Elemental Analysis (C ₁₃ H ₂₁ Cl ₂ N)

Theoretic: C 59.55, H 8.07, N 5.34, Cl 27.04

Experimental Value: C 59.51, H 7.88, N 5.17, Cl 27.39

Example 46

N, N, N-trimethyl- [1-methyl-4- (4-chlorophenyl) butyl] -ammonium bromide

A solution of 3.02 g of N, N-dimethyl-1-methyl-4- (4-chlorophenyl) butylamine in 150 ml of diethyl ether is stirred at 25 ° C. while methyl bromide is passed through until the solution is saturated.

The reaction mixture is stirred for 24 hours and the formed precipitate is collected by filtration. The precipitate is recrystallized from 50 ml of isopropyl alcohol to give 2.6 g of N, N, N-trimethyl-1-methyl-4- (4-chlorophenyl) butyl ammonium bromide having a melting point of 204 to 206 캜 (decomposition).

Elemental Analysis (C ₁₄ H ₂₃ BrClN)

Theoretic value: C 52.43, H 7.23, N 4.37, Br 24.92, Cl 11.05

Experimental Value: C 52.54, H 7.02, N 4.21, Br 24.77, Cl 11.16

Example 47

N, N-dimethyl-N-n-heptyl-4- (4-nitrophenyl) butyl ammonium bromide

A solution of 3.0 g of N-ethyl-N-n-heptyl-4- (4-nitrophenyl) butylamine dissolved in 20 ml of ethyl bromide is stirred and heated under reflux for 4 general. The reaction mixture is cooled to 25 ° C. and stored at that temperature for 72 hours. Excess ethyl bromide is removed by evaporation under reduced pressure and the product is obtained as an oil. The oil formed was crystallized from ethyl acetate and acetone and recrystallized from ethyl acetate and acetone to give 2.06 g of N, N-diethyl-Nn-heptyl-4- (4-nitrophenyl) butylammonium bromide having a melting point of 67 to 69 ° C. Get

Elemental Analysis (C ₂₁ H ₃₇ BrN ₂ O ₂ )

Theoretic: C 58.73, H 8.68, N 6.52, Br 18.61

Experimental Value: C 58.49, H 8.55, N 6.55, Br 18.56

Example 48

4- (4-methoxyphenyl) butylamine

Hydrogenation of ethyl 4-methoxycinnamate gives ethyl 3- (4-methoxyphenyl (propionate. The latter compound is reduced by reaction with lithium aluminum hydride to give 3- (4-methoxyphenyl) Propanol is obtained by reacting propanol with methanesulfonylchloride to give 3- (4-methoxyphenyl) propyl methylsulfonate which is reacted with sodium cyanide to give 4- (4-methoxyphenyl) butyronitrile.

Elemental Analysis (C ₁₁ H ₁₃ NO)

Theoretic: C 75.40, H 7.48, N 7.99

Experimental Value: C 75.24, H 7.21, N 7.90

Butyronitrile is reduced by reaction with diborane to give 4- (4-methoxyphenyl) butylamine.

Example 49

N, N-dimethyl-4- (4-methoxyphenyl) butylamine

Cool and stir 43.5 ml of 90% formic acid solution, and slowly add 30.35 g of 4- (4-methoxyphenyl) butylamine and 41.5 ml of 37% aqueous formaldehyde. The reaction mixture is heated at 100 ° C. until carbon dioxide starts to evolve and the mixture is cooled to room temperature and stored for 15 minutes. The mixture is again heated at 100 ° C. and stirred for 12 h. After cooling to 30 ° C, 80 ml of 4N hydrochloric acid is added to acidify. The mixture is concentrated by evaporation and diluted with water. The acidic aqueous solution is washed with diethyl ether and made alkaline by adding 5N sodium hydroxide. The product is extracted from the alkaline solution into diethyl ether. Collect ether extracts, wash with water and dry. The solvent is removed by evaporation under reduced pressure to give 26.67 g of N, N-dimethyl-4- (4-methoxyphenyl) butylamine having a boiling point of 124 to 125 ° C at 5 Torr. This amine is further purified by reaction with hydrogen chloride to obtain a hydrochloride salt which is recrystallized from 500 ml of 95 percent ethyl acetate in methanol. Melting Point 127-129 ℃

Elemental Analysis (C ₁₃ H ₂₂ ClNO)

Theoretic: C 64.05, H 9.10, N 5.75, Cl 14.54

Experimental Value: C 63.88, H 8.88, N 5.77, Cl 14.73

Example 50

N, N, N-trimethyl-4- (4-methoxyphenyl) butyl ammonium bromide

N, N-dimethyl-4- (4-methoxyphenyl) butylamine (4.35 g) was reacted with methyl bromide according to the procedure of Example 46 to give N, N, N-trimethyl-4- (4-methoxyphenyl 4.95 g of butyl ammonium bromide are obtained and recrystallized from acetone and methanol.

Elemental Analysis (C ₁₄ H ₂₄ BrNO)

Theoretic: C 55.63, H 8.00, N 4.63, Br 26.44

Experimental Value: C 55.94, H 7.73, N 4.72, Br 26.73

Example 51

N, N-dimethyl-3- (4-chlorophenyl) pyrrionamide

A solution of 18.4 g of 3- (4-chlorophenyl) -propionic acid and 42.5 ml of oxalyl chloride in benzene 200 is stirred and heated under reflux for 3 hours. The solution is cooled to room temperature and evaporated under reduced pressure to concentrate into an oil. The formed acid chloride is dissolved in 250 ml of diethyl ether, cooled to 5 ° C, and gaseous dimethylamine is injected into the solution while stirring. The reaction mixture is saturated with dimethylamine and stirred at 25 ° C. for 1 hour, washed with water and 2N hydrochloric acid and dried. The solvent is evaporated to afford 21.9 g of N, N-dimethyl-3- (4-chlorophenyl) propionamide.

Example 52

N, N-dimethyl-N-n-pentyl-3- (4-chlorophenyl) -propyl ammonium bromide

N, N-dimethyl-3- (4-chlorophenyl) pyropyionamide and diborane were reacted to produce N, N-dimethyl-3- (4-chlorophenyl) propylamine having a boiling point of 147 to 148 ° C at 30 Torr. Get 16.88 g To a solution of 5.71 g of free amine in 150 ml of diethyl ether, 3.0 g of n-pentylbromide is added at a time and stirred at room temperature. The reaction mixture is stirred for 12 hours at room temperature, during which time a white precipitate is formed. The precipitate is collected by filtration and 125 ml of methylethyl ketone and methane are recrystallized from 10 ml to yield N, N-dimethyl-N-n-pentyl-3- (4-chlorophenyl) propyl ammonium bromide.

Example 53

N, N-dimethyl-4- (4-fluorophenyl) butylamine

The cyclopropyl-4-fluorophenyl ketone is reduced by reaction with sodium borohydride to give cyclo-propyl-4-fluorophenyl carbinol. Cyclocarbinol is reacted with hydrogen chloride in acetic acid to decompose the cyclopropyl ring, add chlorine, and dehydrate to obtain 1-chloro-4- (4-fluorophenyl) -3-butene. Chlorobutene is reacted with dimethylamine at 100 ° C. for 58 hours to give N, N-dimethyl-4- (4-fluorophenyl) -3-butylamine. A solution of 54.4 g of butenylamine in 343 ml of ethanol containing 2.5 g of Raney Nickel was hydrogenated to give N, N-dimethyl-4- (4-fluorophenyl) having a boiling point of 115 to 118 ° C. at 12 Torr. 47.71 g of butylamine are obtained.

Example 54

According to Example 46, 8.77 g of N, N-dimethyl-4- (4-fluorophenyl) butylamine was reacted with methyl bromide to obtain a white solid, which was crystallized from acetone and methanol to have a melting point of 160 to 162 캜. 9.7 g of N, N, N-trimethyl-4- (4-fluorophenyl) butyl ammonium bromide are obtained.

Elemental Analysis (C ₁₃ H ₂₁ BrFN)

Theoretic: C 53.80, H 7.29, N 4.83, Br 27.53

Experimental Value: C 54.09, H 7.24, N 4.78, Br 27.76

EXAMPLE 55-57

According to Examples 53 and 54, the following salts are prepared with suitable cyclopropyl phenylketone as starting material. N, N, N-trimethyl-4- (4-ethylphenyl) butyl ammonium bromide melting point 147 to 149 ° C

Elemental Analysis (C ₁₅ H ₂₆ BrN)

Theoretic: C 60.00, H 8.73, N 4.66, Br 26.61

Experimental Value: C 49.76, H 8.48, N 4.65, Br 26.66

N, N, N-trimethyl-4- (4-chlorophenyl) butylammonium bromide melting point 211 to 213 ° C

Elemental Analysis (C ₁₃ H ₂₁ BrClN)

Theoretic value: C 50.91, H 6.90, N 4.57, Br 26.05, Cl 11.56,

Experimental Value: C 50.86, H 6.75, N 4.52, Br 26.11, Cl 11.21.

N, N, N-trimethyl-4- (4-bromophenyl) butylammonium bromide melting point 226 to 228 ° C

Elemental Analysis (C ₁₃ H ₂₁ Br ₂ N)

Theoretic: C 44.47, H 6.03, N 3.99, Br 45.51

Found: C 44.65, H 6.08, N 4.21, Br 45.86.

Example 58

3-phenylpropyl-n-propyl ketone

Propyl magnesium bromide is prepared by reacting 24 g of magnesium with propyl bromide in 450 ml of diethyl ether. The prepared Grignard reagent is stirred and a solution of 100 g of 4-phenylbutyl-nitrile in 70 ml of diethyl ether is added dropwise thereto. After completion of the dropwise addition, the reaction mixture was heated to reflux for 1 hour, cooled to room temperature and stirred for another 12 hours. The reaction mixture is slowly poured into 100 g of ice and 250 ml of concentrated hydrochloric acid. The organic layer is separated, washed with water and dried. The solvent is evaporated and the product distilled to give 57.9 g of 3-phenylpropyl-n-propyl ketone having a boiling point of 134 to 137 ° C. at 10 Torr.

Example 59

1-n-propyl-4-phenylbutylamine

A solution of 57.9 g of 3-phenylpropyl-n-propyl ketone, 46 ml of 97 percent formic acid and 55 ml of formaldehyde is stirred and heated at 160 ° C. for 12 hours. The reaction mixture is cooled to room temperature and diluted with 100 mL of water. The aqueous mixture is extracted three times with 100 ml of diethyl ether, the ether extracts are combined, washed with water and dried. The solvent is evaporated off under reduced pressure to give 63.2 g of N-formyl-1-n-propyl-4-phenylbutylamine. The N-formylamine formed is dissolved in 1000 ml of 25% aqueous dioxane solution containing 168 ml of concentrated hydrochloric acid. The acidic solution is stirred and heated with reflux for 12 hours. The mixture is cooled to room temperature, extracted with diethyl ether, and made alkaline by addition of 5N sodium hydroxide. The alkaline solution is extracted with diethyl ether, the ether extracts are combined, washed with water and dried. The solvent is evaporated to afford 51 g of 1-n-propyl-4-phenylbutylamine.

Example 60

According to Example 49, 38.2 g of 1-n-propyl-4-phenylbutylamine was reacted and distilled with 51.5 ml of 90 percent formic acid and 40 ml of 37 percent aqueous formaldehyde, with a boiling point of 118 to 120 ° C. at 5 Torr. , 37.1 g of N-dimethyl-1-n-propyl-4-phenylbutylamine is obtained.

Example 61

N, N, N-trimethyl-1-n-propyl-4-phenylbutyl ammonium bromide

A solution of 9.0 g of N, N-dimethyl-1-n-propyl-4-phenylbutylamine in 150 ml of diethyl ether is saturated with methyl bromide gas and stirred at 25 ° C. for 48 hours. The precipitated product is collected by filtration and recrystallized from 250 ml of acetone to obtain 9.74 g of N, N, N-trimethyl-1-n-propyl-4-phenylbutylammonium bromide having a melting point of 158 to 160 ° C.

Elemental Analysis (C ₁₆ H ₂₈ BrN)

Theoretic: C 61.14, H 8.98, N 4.46, Br 25.42

Experimental Value: C 61.08, H 8.90, N 4.28, Br 25.54

Example 62

N, N, N-trimethyl-1-ethyl-4-phenylbutylammonium bromide

Ethyl magnesium bromide is reacted with 4-phenylbutylnitrile to give ethyl 3-phenylpropyl ketone, and the ketone is reacted with formamide and formic acid to give 1-ethyl-4-phenylbutylamine. The amine is methylated by reaction with formaldehyde and formic acid to give N, N-dimethyl-1-ethyl-4-phenylbutylamine. 6.2 g of dimethylamine was quaternized according to the procedure of the previous example to obtain 6.56 g of N, N, N-trimethyl-1-ethyl-4-phenylbutylammonium bromide having a melting point of 183 to 185 ° C.

Elemental Analysis (C ₁₅ H ₂₆ BrN)

Theoretic: C 60.00, H 8.73, N 4.66, Br 26.61

Experimental Value: C 60.02, H 8.68, Br 26.79

Example 63

1,1-dimethyl-4-phenylbutylamine

Isobutylnitrile is reacted with 3-phenylpropyl bromide in the presence of lithium diisopropylamide to give 2,2-dimethyl-5-phenyl-pentylnitrile. The nitrile is hydrolyzed by reaction with potassium hydroxide in ethylene glycol to give 2,2-dimethyl-5-phenyl-pentanoic acid. To a cold stirring solution of 20.6 g of pentanoic acid and 11.1 g of triethylamine in 75 ml of acetone, 11.9 g of cold (0 to -5 ° C) ethyl chloroformate was added dropwise over 30 minutes. After the addition, the reaction mixture was stirred for 20 minutes at 0 ° C. and a solution of 13 g of sodium azide in 33 ml of water was added dropwise over 25 minutes. The aqueous reaction mixture was stirred for another 30 minutes at 0 ° C. and diluted with 150 ml of water. The aqueous solution is extracted four times with 130 ml of toluene, the toluene extracts are collected, washed with water, dried and heated at 100 ° C. for 1 hour. The solvent is removed by evaporation under reduced pressure to give a residue which is dissolved in 150 ml of 8N hydrochloric acid. The acidic solution is stirred, heated at 1000 ° C. for 20 minutes and then heated at reflux for 20 minutes. The reaction mixture is cooled to room temperature, diluted with water, washed with diethyl ether, and made alkaline by addition of 5N sodium hydroxide. The alkaline solution is extracted with diethyl ether, the ether extracts are combined, washed with water and dried. Evaporate the solvent to afford 17.2 g of 1,1-dimethyl-4-phenylbutylamine.

Example 64

N, N, N-trimethyl-1,1-dimethyl-4-phenylbutylammonium bromide

17.2 g of 1,1-dimethyl-4-phenylbutylamine was reacted with 22.3 m of 90% formic acid and 23.6 ml of 37% formaldehyde, the reaction mixture was completed and the product was distilled off, having a boiling point of 109 to 112 캜 at 5 Torr. 17.1 g of N, N-dimethyl-1,1-dimethyl-4-phenylbutylamine is obtained.

A solution of 8.5 g of the nedylamine derivative in 100 ml of methyl bromide saturated diethyl ether is stirred at 25 ° C. for two months and filtered. The precipitate is recrystallized from 140 ml of acetone and 10 ml of methanol to obtain 8.3 g of N, N, N-trimethyl-1,1-dimethyl-4-phenylbutyl ammonium bromide having a melting point of 194 to 196 ° C.

Elemental Analysis (C ₁₅ H ₂₆ BrN)

Theoretic: C 60.00, H 8.73, N 4.66, Br 26.61

Experimental Value: C 59.72, H 8.77, N 4.56, Br 26.33

Example 65

N, N, N-trimethyl-4- (4-methoxyphenyl) butylammonium bromide

A solution of 210 g of 4-ethoxycinnamic acid in 1775 ml of tetrahydrofuran is hydrogenated at 25 ° C. in the presence of 15 g of 15 percent palladium on carbon to obtain 100 g of 3- (4-ethoxyphenyl) propionic acid having a melting point of 93 to 95 ° C. The acid thus formed is reduced by reaction with 30.6 g of lithium aluminum hydride to obtain 101 g of 3- (4-ethoxyphenyl) propane. The alcohol thus produced is reacted with 52 ml of methanesulfonyl chloride to give 156 g of 3- (4-ethoxyphenyl) propylmethyl sulfonate. This is reacted with 43 g of sodium cyanide to give 45.9 g of 4- (4-ethoxyphenyl) -butyl nitrile. The nitrile is reduced by reaction with diborane to afford 4- (4-ethoxyphenyl) butylamine. A solution of 15.82 g of 4- (4-ethoxyphenyl) butylamine, 19 g of 90% formic acid and 7.45 g of 37% aqueous formaldehyde is stirred and heated at 100 ° C. for 12 hours. The reaction mixture is cooled to 25 ° C. and diluted with 100 ml of water. 4N hydrochloric acid is added to the aqueous reaction mixture to make acid. The acidic solution is evaporated to concentrate and diluted with water. 5N sodium hydroxide is added to the acidic solution to make it alkaline, and the aqueous alkaline solution is extracted several times with diethyl ether. Collect ether extracts, pour water and dry. The solvent is evaporated to give 15.9 g as product oil. The oil is distilled to yield 8.86 g of N, N-dimethyl-4- (4-ethoxyphenyl) butylamine having a boiling point of 142 to 145 ° C. at 7 Torr.

A solution of 2.9 g of N, N-dimethyl-4- (4-ethoxyphenyl) butylamine in 150 ml of diethyl ether saturated with methyl bromide is stirred at 25 ° C. for 72 hours. The formed precipitate is collected by filtration and recrystallized from 200 ml of methyl ethyl ketone to obtain 3.27 g of N, N, N-trimethyl-4- (4-ethoxyphenyl) butylammonium bromide having a melting point of 151 to 153 占 폚.

Elemental Analysis (C ₁₅ H ₂₆ BrNO)

Theoretic: C 56.96, H 8.29, N 4.43, Br 25.26

Experimental Value: C 56.78, H 7.99, N 4.48, Br 25.24

Examples 66 to 67

According to Example 65 the following quaternary ammonium salts are prepared from suitable cinnamic acid.

N, N, N-trimethyl-4- (3-chlorophenyl) butylammonium bromide melting point 135 to 137 ° C

Elemental Analysis (C ₁₃ H ₂₁ BrClN)

Theoretic: C 50.91, H 6.90, N 4.57, Br 26.05, Cl 11.56.

Found: C 51.14, H 6.74, N 4.73, Br 26.22, Cl 11.36.

N, N, N-trimethyl-4- (4-methylphenyl) butyl-ammonium bromide melting point 156 to 158 ° C

Elemental Analysis (C ₁₄ H ₂₄ BrN)

Theoretic: C 58.74, H 8.45, N 4.89, Br 27.91

Experimental Value: C 58.64, H 8.66, N 4.96, Br 28.18

Example 68

dl-N, N, N-trimethyl-1-methyl-4-phenylbutylammonium bromide

A solution of 5.15 g of dl-N, N-dimethyl-1-methyl-4-phenylbutylamine in 75 ml of diethyl ether saturated with methyl bromide is stirred at 25 ° C. for 12 hours. The precipitate formed is collected by filtration and recrystallized from acetone and methanol to obtain 7.05 g of a melting point of 197-199 ° C. dl-N, N, N-trimethyl-1-methyl-4-phenylbutylammonium bromide.

Elemental Analysis (C ₁₄ H ₂₄ BrN)

Theoretic: C 58.74, H 8.45, N 4.89, Br 27.91

Experimental Value: C 59.02, H 8.30, N 5.13, Br 28.03

Example 69

d (+)-N, N, N-trimethyl-1-methyl-4-phenylbutyl ammonium bromide

(CH₃OH)가 +46.4°인 d(+)-N-(α-메틸벤질)-1-메틸-4-페닐부틸암모늄 클로라이드 33.79g을 얻는다. 탄소상의 5퍼센트 팔라듐의 존재하에 d(+)-N-(α-메틸벤질)-1-메틸-4-페닐부틸아민 9.12g을 수소화시켜 탈벤질화하여 d(+)-1-메틸-4-페닐부틸아민을 얻는다. 이렇게 생성된 아민을 37퍼센트 수성 포름알데히드 25㎖ 존재하에 12시간동안 50℃에서 수소화하여 d(+)-N, N-디메틸-1-메틸-4-페닐부틸아민을 얻는다. 이 아민을 염화수소와 반응시켜 하이드로클로라이드염으로 전환시키고 염을 에틸아세테이트와 메탄올로부터 재결정하여 융점 123내지 125℃ [α]

(CH₃OH)가 +12.4°인 물질을 얻는다.63 g of methyl-3-phenylpropyl ketone is reacted with 59.5 g of d (+)-α-methylbenzylamine to give 115 g of d (+)-N- (α-methylbenzyl) -1-methyl-4-phenylbutylimine . The resulting imine is reduced by hydrogenation in the presence of Ranickel to give N- (α-methylbenzyl) -1-methyl-4-phenylbutylamine, a diastereomer, which is purified by distillation. The amine is reacted with hydrochloric acid to form a hydrochloride salt, which is then crystallized from ethyl acetate and methanol to have a melting point of 156 to 158 캜;

33.79 g of d (+)-N- (α-methylbenzyl) -1-methyl-4-phenylbutylammonium chloride having (CH ₃ OH) of + 46.4 ° is obtained. 9.12 g of d (+)-N- (α-methylbenzyl) -1-methyl-4-phenylbutylamine in the presence of 5 percent palladium on carbon was hydrogenated to debenzyl to give d (+)-1-methyl-4 Obtain phenylbutylamine. The amine thus produced is hydrogenated at 50 ° C. for 12 hours in the presence of 25 ml of 37% aqueous formaldehyde to give d (+)-N, N-dimethyl-1-methyl-4-phenylbutylamine. The amine was reacted with hydrogen chloride to convert it into a hydrochloride salt, and the salt was recrystallized from ethyl acetate and methanol to give a melting point of 123 to 125 DEG C. [α]

Obtain a material with (CH ₃ OH) of + 12.4 °.

Elemental Analysis (C ₁₃ H ₂₂ ClN)

Theoretic: C 68.55, H 9.74, N 6.15, Cl 15.56

Experimental Value: C 68.60, H 9.61, N 6.15, Cl 15.55

The hydrochloride salt is taken up in 50 ml of water and the aqueous solution is alkaline with 5N sodium hydroxide. The aqueous alkali solution is extracted with diethyl ether, the ether extract is washed with water, dried and the solvent is evaporated to remove d (+)-N, N-dimethyl-1-methyl-4-phenylbutylamine. A solution of 2.07 g of amine in 150 mL of diethyl ether is stirred and saturated with methyl bromide. The ether solution was stored at 25 ° C. for 48 hours, the resulting precipitate was collected by filtration and recrystallized from 40 ml of isopropyl alcohol to form d (+)-N, N, N-trimethyl-1-methyl-4-phenylbutylammonium bromide Get 2.23 g

(CH₃OH) +24.9°Melting Point 206-208 ℃ [α]

(CH ₃ OH) + 24.9 °

Elemental Analysis (C ₁₄ H ₂₄ BrN)

Theoretic: C 58.74, H 8.45, N 4.89, Br 27.91

Experimental Value: C 58.68, H 8.37, N 4.63, Br 27.80

Example 70

1 (-)-1-methyl-4-phenylbutylamine was isolated and dimethylated according to Example 71 to give 1-N, N-dimethyl-1-methyl-4-phenylbutylamine. This is quaternized with methyl bromide to give 1 (-)-N, N, N-trimethyl-4-phenylbutyl ammonium bromide.

(CH₃OH) 24.9°Melting point 210 to 212 ° C. [α]

(CH ₃ OH) 24.9 °

Elemental Analysis (C ₁₄ H ₂₄ BrN)

Theoretic: C 58.74, H 8.45, N 4.89, Br 27.91

Experimental Value: C 58.47, H 8.27, N 4.62, Br 27.79

Example 71

N, N-dimethyl-N-n-heptyl-3-phenylpropylammonium-p-toluenesulfonate

N-methyl-N-n-heptyl-3-phenylpropyl ammonium oxalate is converted to its free base by sodium hydroxide in diethyl ether. 1.29 g of N-methyl-N-n-heptyl-3-phenylpropylamine is placed in a 50 ml round bottom flask. 1.08 g of methyl p-toluene sulfonate in 10 ml of methyl ethyl ketone are added. The mixture is refluxed for 2 hours and cooled. Thin layer chromatography can confirm that no secondary amine remains. Evaporation of methylethyl ketone in vacuo leaves an oily substance. This was recrystallized from ethyl-acetate to obtain 1.63 g of N, N-dimethyl-N-n-heptyl-3-phenylpropyl ammonium p-toluenesulfonate having a melting point of 91 to 93 캜.

Elemental Analysis (C ₂₅ H ₃₉ NO ₄ S)

Theoretic: C, 69.24, H, 9.07, N, 3.23, S, 7.39

Experimental Value: C, 69.10, H, 8.84, N, 3.40, S, 7.55

Example 72

N, N, N-trimethyl-4- (4-nitrophenyl) butylammonium bromide.

5.14 g of N, N-dimethyl-4 (4-nitrophenyl) -butylamine is placed in 150 mL diethyl ether in a 300 mL volume round bottom flask. If methylbromide is injected into the mixture until it is saturated, a precipitate appears after 10 minutes. The mixture is stirred for 4 days at room temperature. The solid is filtered off and recrystallized from 75 ml isopropane to give 6.77 g. Isopropane was recrystallized to 100 ml to obtain 6.44 g of N, N, N-trimethyl-4- [4-nitrophenyl] butylammonium bromide having a melting point of 182 to 184 占 폚.

Elemental Analysis (C ₁₃ H ₂₁ BrN ₂ O ₂ )

Theoretic: C, 49.22, H, 6.67, N, 8.83

Experimental Value: C, 49.33, H, 6.51, N, 8.76

Example 73

N, N-diethyl-N-n-heptyl-4 (4-methoxyphenyl) butylammonium-p-toluene sulfonate

24 g of N-ethyl-N-n-heptyl-4- (4-methoxyphenyl) butylamine is placed in a 500 ml round bottom flask and 200 ml of ethyl bromide is added. The mixture is refluxed for 2 generals. Thin layer chromatography confirms that little secondary amine remains. Excess ethyl bromide is evaporated in vacuo to give an oil of N, N-diethyl-N-n-heptyl-4 (4-methoxyphenyl) butylammonium bromide, which is converted to the hydroxide form in the following manner. Using a column filled with BIO-RAD (hydroxyl-side type, 100 to 200 mesh 1.2 meq // ml) resin in water, the oil is dissolved in water and passed through the column. The collected 800 ml was partially acidified with 15 g of p-toluenesulfonic acid in water to lower the pH from 12.4 to 10. Acidifying the solution makes it oily. This suspension is passed over a column of 300 ml of resin, which has previously been washed with 1 L of 0.4N p-toluenesulfonic acid solution and converted to tosylate type. The eluate is 4 liters in total. After lyophilization for 1 general, a residue is formed, which is dissolved in hot ethyl acetate, filtered and evaporated in vacuo. 44 g of oil is produced, which solidifies upon standing. It is recrystallized from 300 ml of ethyl acetate to give 36.76 g of N, N-diethyl-N-n-heptyl-4 (4-methoxyphenyl) butylammonium p-toluenesulfonate.

Elemental Analysis (C ₂₉ H ₄₇ NO ₄ S)

Theoretic: C, 68.87, H, 9.37, N, 2.77, S, 6.34

Experimental Value: C, 68.64, H, 9.08, N, 2.80, S, 6.57

Example 74

N, N-diethyl-N-n-heptyl-4 (4-hydroxyphenyl) butylammonium bromide

2.03 g of N, N-diethyl-N-n-heptyl-4 (4-methoxyphenyl) butylammonium p-toluenesulfonate prepared in Example 73 is dissolved in 1500 ml of water. This was washed on a column packed with 30 m of BIO-RAD (hydroxide type, 100 to 200 mesh, 1.2 meq / ml) resin, 2.5 liters of eluate was collected and freeze-dried for 2 days to leave an oily residue. The oil is placed in an aliquot containing a water / diethyl ether mixture and extracted three times with diethyl ether. The aqueous extract is acidified with 48% bromic acid to pH 2.0. Drying this yields 1.44 g of brown oil with a small layer of white oil. This material is refluxed for 5 hours in 10 ml of 48% bromic acid / 15 ml of glacial acetic acid. Cooling it and evaporating to dry leave an oily substance. This oily material is treated with 50 ml glacial acetic acid and evaporated to dryness three times. The resulting oil is stored overnight in a desiccator containing potassium hydroxide and phosphorus pentoxide. 20 ml of ethyl acetate are added to the product and the precipitate formed is filtered and recrystallized from 15 ml acetone to give 460 mg of material having a melting point of 82 to 85 ° C. This material is redissolved in 15 ml acetone and recrystallized to obtain 349 mg of N, N-diethyl-N-n-heptyl-4- (4-hydroxyphenyl) butyl ammonium bromide having a melting point of 83 to 85 ° C.

Elemental Analysis (C ₂₁ H ₃₈ BrNO)

Theoretic: C, 62.99, H, 9.57, N, 3.50, Br, 19.95

Experimental Value: C, 63.22, H, 9.37, N, 3.54, Br, 20.20

Example 75

N, N-dimethyl-N- (2-phenethyl) phenylbutylammonium bromide

20 g of 4-phenyl-n-butylchloride and 48 g of N-methyl-N-phenethyl-amine are placed in a 100 ml round bottom flask containing boiling debris and heated at 100 ° C. for 3 days. Solid material is produced during heating. An aqueous solution of the alkalinized material with sodium hydroxide is extracted with diethyl ether, which is extracted with 2N sulfuric acid and water. The combined sulfuric acid / water solution is alkaline with 5N sodium hydroxide and extracted three times with diethyl ether. The ether extract is washed with saturated sodium chloride. The ether solvent is removed by evaporation in vacuo to give 64 g of oily material. This is distilled to give N-methyl-N- (2-phenethyl) phenyl butylamine.

9.0 g of N-methyl-N- (2-phentyl) phenylbutyl amine are added to 150 ml of diethyl ether in a 300 ml volume round bottom flask. Methyl bromide gas is injected into the mixture until it is saturated and the mixture is stirred for 5 days at room temperature. The solid material was filtered and recrystallized in 100 ml of acetone while cooling in a refrigerator to obtain 8.96 g of N, N-dimethyl-N- (2-phenethyl) phenylbutyl ammonium bromide having a melting point of 98 to 102 캜.

Elemental Analysis (C ₂₀ H ₂₈ BrN)

Theoretic: C, 66.29, H, 7.79, N, 3.87, Br, 22.05

Experimental Value: C, 66.07, H, 7.72, N, 3.91, Br, 22.16

Example 76

N, N-dimethyl-N- (3-phenylpropyl) phenylbutylammonium bromide

Phenylbutyric acid chloride is reacted with 3-phenylpropyl amine to obtain an amide and reduced with diborane to give N- (3-phenylpropyl-4-phenylbutylamine. The amine is methylated with formic acid / formaldehyde to start with N- 5.3 g of methyl-N- (3-phenylpropyl) phenylbutylamine are dissolved in 150 ml diethyl ether in a 300 ml round bottom flask, methyl bromide gas is injected until saturated and the reaction is stirred at room temperature for 3 days. The solid material formed was collected by filtration and recrystallized from 100 mL methyl ethyl ketone and ethyl acetate to obtain 5.08 g of N, N-dimethyl-N-phenylpropyl-phenylbutylammonium bromide.

Elemental Analysis (C ₂₁ H ₃₀ BrN)

Theoretic: C, 67.01, H, 8.03, N, 3.72, Br, 21.23

Experimental Value: C, 67.20, H, 8.34, N, 3.49, Br, 21.53

Example 77

N, N-diethyl-N-n-heptyl-4- (4-chlorophenyl) butylammonium phosphate

960 g of 4-chloro-N, N-diethyl-Nn-heptylbutyl ammonium bromide are divided into four, 150 to 200 g each, each of which is dissolved in 1 L of water and filled with 2 pounds of Dowexl-X ₈ (hydroxyde) resin. Pour on one column. The quaternary ammonium hydroxide compound is eluted with water and continued until the solution is about alkaline (pH about 8).

The aqueous eluate (2 L) from the ion exchange column was washed three times with 150 mL of diethyl ether, the aqueous layer was separated, acidified with dilute phosphoric acid until pH 4.5 and freeze-dried. The crystalline residue is dissolved in 1.5 L of acetone (heat) and 0.5 L of diethyl ether is added to the solution. The solution is placed in anhydrous acetone-ice bath and seed crystals are added. The crystalline material is collected by suction filtration and washed with fresh diethyl ether to give 548 g of material having a melting point of 116 to 119 ° C.

Recrystallization from 8 L of acetone, 1 L of dichloromethane and 3 L of diethyl ether gave N, N-diethyl-N-n-heptyl-4- (4-chlorophenyl) -butylammonium phosphate.

Elemental analysis (C ₂₁ H ₃₉ NO ₄ ClP) (two molecular weight 435.973)

Theoretic: C, 57.85, H, 9.02, N, 3.21, P, 7.10, Cl, 8.13

Experimental Value: C, 57.59, H, 9.21, N, 3.11, P, 6.88, Cl, 8.39

Example 78

N, N-dimethyl-N-n-heptyl-3 (4-chlorophenyl-propylammonium) p-toluene sulfonate

45 ml of BIO-RAD (hydroxide, 100-200 mesh, 1.2 meq / ml) resin is placed in a column and washed with water until neutral. 4.50 g of N, N-dimethyl-N-n-heptyl-3- (4-chlorophenyl) -propylammonium bromide is dissolved in 300 ml of water and passed through a tube. Collect 350 ml until the eluate is no longer basic. To this was added 0.2M p-toluenesulfonic acid to initially acidify pH 11.7 to pH 10.4. The other column filled with 45 ml of resin is washed until the water passed through is neutral. The 0.2 M p-toluenesulfonic acid solution was passed through the column until acid came out of the column, washed with water until neutral and the aqueous suspension, pH 10.4, passed through the column to complete acidification and collecting 800 mL of eluate. Lyophilize over days. A solid residue is left which is dissolved in ethyl acetate and the insolubles are filtered off. Recrystallization from 300 ml of ethyl acetate solution gave 4.90 g of N, N-dimethyl-N-n-heptyl-3 (4-chloro-phenylpropyl ammonium p-toluene sulfonate.

Melting Point 117-119 ℃

Elemental Analysis (C ₂₅ H ₃₈ ClNO ₃ S)

Theoretic: C, 64.15, H, 8.18, N, 2.99, Cl, 7.57, S, 6.85

Experimental Value: C, 64.41, H, 7.90, N, 3.16, Cl, 7.68, S, 6.91

Example 79

N, N-diethyl-N-n-heptyl-3 (4-chlorophenyl) propylammonium bromide

7.764 g of N-ethyl-N-n-heptyl-3 (4-chloro) propylamine is placed in a 200 ml volumetric flask. 90 ml of ethyl bromide is added and the mixture is refluxed for 5 days. Ethyl bromide is removed by evaporation in vacuo, leaving oil, which slowly solidifies. This material is recrystallized from 400 ml of ethyl acetate to give 9.29 g of N, N-diethyl-N-n-heptyl-3 (4-chlorophenyl) propylammonium bromide.

Melting Point 83 ~ 85 ℃

Elemental Analysis (C ₂₀ H ₃₅ BrClN)

Theoretic: C, 59.33, H, 8.71, N, 3.46, Cl, 8.76, Br, 19.74

Experimental Value: C, 59.37, H, 8.51, N, 3.22, Cl, 8.87, Br, 20.07

Example 80

N, N-diethyl-N-n-heptyl-4- (4-chlorophenyl) butylammonium benzenesulfonate

100 ml of BIO-RAD (hydroxide type, 100-200 mesh, 1.2 meq / ml) resin is used for each column. The column is washed with water until neutral. 9.9 g of N, N-dimethyl-N-n-heptyl-4 (4-chlorophenyl) butylammonium bromide is dissolved in 50 ml of water. It is washed on resin and the eluate is collected until the column effluent is neutral again (300 ml). This eluate is acidified to pH 12.4 with 10.4 using 0.2 M p-toluenesulfonic acid. The solution becomes an oily suspension. This suspension is passed through a 100 ml column of resin converted from the hydroxide type to the benzene sulfonic acid type. Collect 800 ml of the eluate and leave the rest in the column overnight. More 800 ml of eluate is collected and freeze-dried over two days to form an oil residue that begins to solidify. This oil is taken up in ethyl acetate, the solid is filtered off and evaporated in vacuo to give 11.994 g of oil. The oil is dissolved in 100 ml of ethyl acetate cooled in a refrigerator, and crystallized by adding crystal nuclei. Crystallization overnight yields 9.325 g of product having a melting point of 46-48 ° C. This material is recrystallized again in 100 ml of ethyl acetate to obtain 8.82 g of product having a melting point of 47 to 49 캜.

Elemental Analysis (C ₂₇ H ₄₂ ClNO ₃ S)

Theoretic: C, 65.36, H, 8.53, N, 2.82, Cl, 7.15, S, 6.46

Experimental Value: C, 65.34, H, 8.26, N, 3.14, Cl, 7.23, S, 6.66

Example 81

N, N-di-n-octyl-N-methyl-4-phenylbutylammonium bromide

5.787 g of N, N-di-n-octyl-4-phenylbutylamine is dissolved in 150 ml of diethyl ether in a 300 ml round bottom flask. Methyl bromide gas is injected into the mixture until saturated and the mixture is stirred for 48 hours at room temperature. A small amount of secondary amine is detected by thin layer chromatography. The solid is filtered from the suspension and recrystallized from 50 ml of ethyl acetate to give 5.848 g of N, N-di-n-octyl-N-methyl-4-phenylbutyl ammonium bromide having a melting point of 65 to 67 ° C.

Elemental Analysis (C ₂₇ H ₅₀ BrN)

Theoretic: C, 69.20, H, 10.76, N, 2.99, Br, 17.05

Experimental Value: C, 69.25, H, 10.56, N, 3.09, Br, 16.93

Example 82

N, N, N-triethyl-1-methyl-4-phenylbutylammonium bromide

3.65 g of N, N-diethyl-1-methyl-4-phenylbutylamine and 35 ml of ethyl bromide are placed in a 100 ml volumetric flask and refluxed for 3 days. At the end of reflux a white precipitate forms. Cooling the mixture and evaporating excess solvent in vacuo leaves an oily semisolid. 50 ml of diethyl ether is added and the solid is filtered off. Evaporation of diethyl ether in vacuo leaves 3.135 g of product, which is placed in a 100 ml round bottom flask and 35 ml of ethyl bromide is added and refluxed for one week as described above. The mixture was cooled, evaporated to dryness, dissolved in 75 mL of diethyl ether and the solid was filtered off and recrystallized from 50 mL methyl ethyl ketone to give 619 mg of N, N, N-triethyl-1-methyl-4-phenylbutylammonium bromide Get

Melting point 123-125 ℃

Elemental Analysis (C ₁₇ H ₃₀ BrN)

Theoretic: C, 62,19, H, 9.21, N, 4.27, Br, 24.34

Experimental Value: C, 62.13, H, 9.06, N, 4.29, Br, 24.05

Example 83

N, N-dimethyl-N- (1-methylheptyl) -4-phenylbutyl ammonium bromide

Reacting 4-phenylbutytyl chloride with 1-methylheptylamine to give N- (1-methylheptyl) -4-phenylbutylamide which is reduced by reaction with diborane in tetrahydrofuran to give N- (1- Methylheptyl) -4-phenylbutylamine is obtained. The amine thus formed is reacted with formic acid and formaldehyde to give N-methyl-N- (1-methylheptyl) -4-phenylbutylamine.

In a mixture of 5.07 g of N-methyl-N- (1-methylheptyl) -4-phenylbutylamine and 150 ml of diethyl ether, methyl bromide gas is saturated and stirred at room temperature for 3 days. The precipitate is collected by filtration and recrystallized from ethyl acetate to obtain 3.76 g of N, N-dimethyl-N- (1-methylheptyl) -4-phenylbutylammonium bromide having a melting point of 111 to 113 ° C.

Elemental Analysis (C ₂₀ H ₃₆ BrN)

Theoretic: C, 64.85, H, 9.80, N, 3.78, Br, 21.57

Experimental Value: C, 64.64, H, 9.65, N, 3.68, Br, 21.45

Example 84

N, N-diethyl-N- (3-methylbutyl) -4 (4-nitrophenyl) butylammonium bromide

Reacting 4- (4-nitrophenyl) butyryl chloride with 3-methylbutylamine to give the corresponding amide, which is reduced by reaction with diborane to give N- (3-methylbutyl) -4- (4- Nitrophenyl) butylamine is obtained.

15.4 g of sodium carbonate in 70 ml of water is placed in a 500 ml three-necked round bottom flask containing 19.183 g of N-3-methylbutyl-4 (4-nitrophenyl) butylamine in 70 ml acetone. The mixture is cooled to 30 ° C. or lower, and 11.35 ml of acetyl chloride in 70 ml of acetone is added dropwise while maintaining the temperature at 30 ° C. or lower. At the end of the dropwise addition of acetyl chloride, a precipitate is formed. The suspension is stirred overnight at room temperature. Acetone is evaporated in vacuo. The mixture is diluted with 100 ml of water and extracted three times with dimethyl-ether, the ether extracts are combined, washed once with water, washed once with 2N hydrochloric acid, washed four times with water and washed once with saturated sodium chloride. The ether solution is dried and all solvents are evaporated in vacuo to afford 21.81 g of N-3-methylbutyl-N-acetyl-4 (4-nitrophenyl) butylamine.

220 ml of 1 M diborane in tetrahydrofuran is placed in a 1 L three-neck round bottom flask. 21.81 g of the above prepared N- (3-methylbutyl) -N-acetyl-4 (4-nitrophenyl) butylamine in 100 L tetrahydrofuran is added dropwise. The mixture is refluxed overnight, and after cooling, 200 ml of 2N hydrochloric acid is added to decompose the excess diborane. Tetrahydrofuran is removed by evaporation. 100 ml of concentrated hydrochloric acid is added and the mixture is refluxed for 45 minutes to decompose the diborane complex. The mixture is cooled, alkaline with 5N sodium hydroxide and extracted three times with diethyl ether. Collect ether extracts, wash once with water and extract twice with 2N sulfuric acid. The acidic extract is alkaline with 5N sodium hydroxide and extracted three times with dimethyl ether. The ether extract is washed with saturated sodium chloride, dried and the solvent is evaporated off in vacuo to yield 19.82 g of N-ethyl-N- (3-methylbutyl) -4 (4-nitrophenol) butylamine. 3.383 g of N-methyl-N- (3-methylbutyl) -4 (4-nitrophenyl) butylamine and 40 ml of ethyl bromide are placed in a 100 ml round bottom flask and heated under reflux for 5 days. A solid precipitate is formed during the reaction, excess ethyl bromide is evaporated in vacuo and the residue is recrystallized from 75 ml of methylethylketone to give N, N-diethyl-N- (3-methylbutyl) -4 (4 2.28 g of nitrophenyl) butylammonium bromide are obtained.

Melting Point 114-116 ℃

Elemental Analysis (C ₁₉ H ₃₃ BrN ₂ O ₂ )

Theoretic: C, 56.85, H, 8.29, N, 6.98, Br, 19.91

Experimental Value: C, 56.62, H, 8.11, N, 6.69, Br, 19.62

Example 85

N, N-diethyl-N-n-hexyl-3-phenylpropylammonium bromide

5.21 g of N-ethyl-N-n-hexyl-3-phenylpropylamine is placed in a 200 ml round bottom flask and 100 ml of ethyl bromide is added. The mixture is refluxed for 5 days. Excess ethyl bromide is removed by evaporation in vacuo to give N, N-diethyl-N-n-n-hexyl-3-phenylpropyl ammonium bromide as an oil.

Example 86

N, N-diethyl-N-n-hexyl-3-phenylpropammo p-niumtoluenesulfonate

Two columns are filled with 40 ml of BIO-RAD (hydroxide type, 100-200 mesh, 1.2 meq / ml) resin. One column was washed with water until neutral, and N, N-diethyl-Nn-hexyl-3-phenylpropylammonium bromide prepared in Example 85 was dissolved in 200 ml of water and washed on a column to remove bromide with hydroxide. Switch. The dihydrate column is acidified to pH 7 with 0.2N p-toluenesulfonic acid. The other column is washed with 0.2N p-toluenesulfonic acid until acid wash and with water until neutral. The partially acidified aqueous solution is passed through a tosylate column and about 1 L of water is collected. It was freeze-dried and recrystallized from 50 mL ethyl acetate to obtain 8.10 g of N, N-diethyl-N-n-hexyl-3-phenylpropyl ammonium p-toluenesulfonate having a melting point of 61 to 63 캜.

Elemental Analysis (C ₂₆ H ₄₁ NSO ₃ )

Theoretic: C, 69.76, H, 9.23, N, 3.13, S, 7.16

Experimental Value: C, 69.84, H, 8.96, N, 2.92, S, 7.22

Example 87

N, N-diethyl-N-n-heptyl-3-phenylpropylammonium p-toluene sulfonate

5.302 g of N-ethyl-N-n-heptyl-3-phenylpropylamine and 50 ml of ethyl bromide are placed in a 100 ml round bottom flask. The mixture is refluxed for 6 days. Excess ethyl bromide is removed by evaporation in vacuo to form an oily substance. This material is recrystallized from 150 ml of ethyl acetate containing a trace amount of acetone to obtain 6.35 g of N, N-diethyl-N-n-heptyl-3-phenylpropylammonium bromide having a melting point of 60 to 62 캜. This material is second recrystallized from ethyl acetate containing trace amount of acetone and left at room temperature to obtain 3.34 g of N, N-diethyl-N-n-heptyl-3-phenylpropyl ammonium bromide having a melting point of 65 to 68 ° C.

Both columns are filled with 10 ml BIO-RAD (hydroxide, 100-200 mesh) resin, and one column is washed with water until the wash water is neutral. 5.387 g of N, N-diethyl-N-n-heptyl-3-phenylpropylammonium bromide is dissolved in water and washed on resin to convert to the hydroxide form. Collect the eluate until alkaline disappears. The eluate is acidified to pH 6 with a 0.2N p-toluenesulfonic acid solution. The other column is washed with 0.2N p-toluenesulfonic acid until pickled iron is released. The column is washed with water until neutral. The partially acidified solution above is washed on a tosylate column. Collect 500 ml of the wash and lyophilize overnight to obtain a semi-solid material. This material was recrystallized in 40 mL ethyl acetate to obtain 2.16 g of N, N-diethyl-N-n-heptyl-3-phenylpropylammonium p-toluenesulfonate.

Melting Point 74-76 ℃

Elemental Analysis (C ₂₇ H ₄₃ NSO ₄ )

Theoretic: C, 70.24, H, 9.32, N, 3.03, S, 6.94

Experimental Value: C, 70.01, H, 9.15, N, 2.84, S, 6.93

Example 88

N, N, N-trimethyl-3- (4-nitrophenyl) propylammonium bromide

1.12 g of N, N-dimethyl-3 (4-nitrophenyl) propylamine is added to 150 ml of diethyl ether in a round bottom flask. Methyl bromide is injected into the mixture until saturated and the mixture is stirred for 2 days at room temperature. The solid is filtered and 50 ml isopropane is recrystallized from 50 ml to give 1.49 g of a product having a melting point of 180 to 181 ° C.

Elemental Analysis (C ₁₂ H ₁₉ BrN ₂ O ₂ )

Theoretic: C, 47.54, H, 6.32, N, 9.24, Br, 26.35

Experimental Value: C, 47.29, H, 6.07, N, 9.13, Br, 26.66

Claims (1)

A method of producing a quaternary ammonium salt of phenyl-alkylamine of general formula (I), characterized by reacting a tertiary amine of general formula (II) with a compound of general formula (III).

In which n is 1 or 2; R ¹ is hydrogen or alkyl having 1 to 2 carbon atoms; R ² is hydrogen or alkyl of 1 to 3 carbon atoms; R ³ is alkyl having 1 to 4 carbons or phenyl-alkyl having 1 to 4 carbons; R ⁴ is alkyl having 1 to 8 carbons; R ⁵ is alkyl of 1 to 10 carbon atoms, or R ⁴ and R ⁵ complete a heterocyclic ring of 4 to 7 carbon atoms with adjacent nitrogen to which they are requested; R ⁶ and R ⁷ are independently hydrogen, hydroxy, halogen, nitro, alkoxy having 1 to 3 carbon atoms, or alkyl having 1 to 3 carbons, provided that at least one of R ⁶ and R ⁷ is hydrogen and n is 1 If R ⁶ and R ⁷ are independently a group other than nitro, then R ⁵ is alkyl having 6 to 10 carbon atoms and when R ¹ , R ² , R ⁶ and R ⁷ are each hydrogen, R ³ , R ⁴ and R ⁵ may be methyl or ethyl, respectively, but not both; R ⁸ , R ⁹ and R ¹⁰ together are selected from R ³ , R ⁴ , R ⁵ and R ¹¹ ,

Each of R ³ , R ⁴ , R ⁵ and R ¹¹ may not be used more than once; R ¹² is R ³ , R ⁴ , R ⁵ or R ¹¹ not selected above; Y is an exit group.