Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS3117160 A
Publication typeGrant
Publication dateJan 7, 1964
Filing dateJul 27, 1961
Priority dateJul 27, 1961
Publication numberUS 3117160 A, US 3117160A, US-A-3117160, US3117160 A, US3117160A
InventorsGerald F Holland
Original AssigneePfizer & Co C
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Aralkylamines
US 3117160 A
Abstract  available in
Images(8)
Previous page
Next page
Claims  available in
Description  (OCR text may contain errors)

United States Patent "ice 3,117,166 ARALKYLAMINES Gerald F. Holland, Groton, (301121., assignor to Chas. Pfizer & Co., Inc., New York, N.Y., a corporation of Delaware N0 Drawing. Filed July 27, 1961, Ser. No. 127,163 6 Claims. (Cl. 260570.8)

Tms invention relates to new and useful aralkylamines. More particularly, it is concerned with novel compounds of the foregoing type which have been found to be especially useful as anti-obesity agents as well as with the method of using the same.

In accordance with the prior art, d-B-phenylisopropylamine, or as it is more commonly known, d-amphetamine, is a colorless liquid which has been used to some extent as a nasal vasoconstrictor. However, its use has been somewhat restricted by the fact that it exhibits several deleterious side effects; for instance, an overdosage of this drug often results in restlessness and insomnia. In the past, it has been the common practice to administer this medicament in the form of a non-toxic acid addition salt, such as the phosphate or sulfate, the latter salt being particularly effective as a stimulant for the central nervous system. Furthermore, these two particular salts are also known for their vasomotor, respiratory, appetite suppressant and intellectual stimulatory effects. Unfortunately, they have also been found to possess a number of disturbing drawbacks; for instance, they may produce overstimulation, restlessness, insomnia and gastrointestinal disturbances, while chills, collapse and syncopy may follow overdosage. Hence, it is not advisable to use such salts in cases of hypertension or cardiovascular diseases.

In accordance with the present invention, it has now been found that certain N-substituted aralkylamines are outstanding compounds as appetite depressants without causing a marked concomitant increase in motor activity, i.e., CNS stimulation, thus differing from the d-amphetamine products of the prior art in this respect. These particular novel compounds are all selected from the group consisting of an aralkylamine base having the following general structural formula:

and the pharmaceutically acceptable acid addition salts thereof, wherein R is a member chosen from the group consisting of hydrogen, triflucromethyl, S-rnethylmercapto, amino and dimethylamino, and R is a member chosen from the group consisting of hydrogen, lower alkyl and benzyl. Typical examples of such compounds include d-N- (2,2,2-trifluoroethyl) -fl-phenylisopropylamine hydro chloride,

dl-N- (2,2,2-trifiuoroethyl) (m-trifiuoromethylphenyl)isopropylamine phosphate,

dl-N- (2,2,2-trifluoroethyl) -,6- o-methylmercaptophenyl) isopropylamine sulfate,

d-N- (2,2,2-trifiuoroethyl) -/8- (p-aminophenyl) isopropylamine dihydrobromide,

dl-N- (2,2,2-trifluoroethyl 43- (m-dimethylaminophenyl) -isopropylamine,

and the like. Furthermore, the corresponding l-com- 3,117,169 Patented Jan. 7, 1964 pounds or laevorotatory isomers have also been found to possess appetite depressant properties (although to a somewhat lesser degree than that exhibited by dland d-compounds) in addition to being useful as intermediates for the production of the dl-compounds via standard racemization techniques.

In accordance with the process employed for the preparation of these compounds, an appropriately substituted benzaldehyde starting material is first contacted with nitroethane in the presence of a Knoevenagel-Walter type catalyst [Chemische Berichte vol. 37, p. 4502 (1904)], in order to form the corresponding nitroolefin as the condensation product. The latter intermediate is then reduced to the completely saturated amine under mild conditions by the use of lithium aluminum hydride in accordance with any number of conventional organic procedures previously described in the chemical literature [e.g., see Nystrom and Brown, Journal of the American Chemical Society, P01. 70, p. 3738 (1948)], or by the use of standard catalytic hydrogenation techniques. Still other pertinent reaction procedures in this connection involve the use of Raney nickel [Annalen der chemie, vol. 571, p. 201 (1951)], for reduction purposes, provided that the S-methylmercapto group is not present in the molecule. Conversion of the fully saturated amines thus obtained to the corresponding N-monoalkylated derivatives can then be efiected, if so desired, in accordance with any number of standard N-monoalkylation procedures previously described in the literature. The next two reaction steps deal with the conversion of any of these aralkylamine base compounds to a trifiuoroacetyl derivative thereof and the subsequent conversion of the latter type compounds to the desired N-substituted aralkyl aminesv The formation of the trifluoroacetyl derivative is readily accomplished in a coventional manner and preferably by the use of the corresponding trifiuoroacetic acid anhydride, while the subsequent reduction step is readily effected by any one of the reducing agents employed in connection with the preparation of the parent aralkylamines.

In accordance with a more specific embodiment of the process of this invention, the condensation reaction between the appropriately substituted benzaldehyde compound and nitrothane is generally carried out by merely mixing the two reactants together at room temperature in approximately equimolar proportions, although a slight excess of one or the other reagent is not harmful in this respect. As previously indicated, a catalytic amount of a basic condensing agent such as a primary or secondary alkylamine or cycloalkylamine is ordinarily employed in order to effect this particular reaction successfully. In general, approximately a one-tenth molar equivalent of a catalyst of the aforementioned type has been found to afford quite satisfactory results. Although the condensation reaction often takes place at room temperature under these conditions, it is usually more desirable to conduct the reaction at an elevated temperature in an inert organic solvent medium in which both the reactants and catalyst are mutually miscible. Preferred reactioninert solvents in this connection includes methanol, ethanol, isopropanol, n-butanol, benzene, toluene, xylene, and the like. In practice, it is most convenient to reflux the two reactants in a solvent of the aforementioned type in the presence of the catalyst for a period of about five to about thirty hours, although any temperature in the range of from about 25 C. up to the boiling point of the solvent, i.e., up to about C., is feasible provided that the reaction is conducted for a period of from about four hours to about two weeks. The condensation product so obtained is most conveniently isolated from the reaction mixture by concentrating said solution under reduced pressure and then fractionally distilling the residual liquid in vacuo.

The second reaction step of the process involves the reduction of the nitroolefin intermediate with lithium aluminum hydride in a reaction-inert organic solvent medium to afford the desired saturated amine in the form of a complex salt, which is then subsequently decomposed by the slow dropwise addition of an aqueous disodium tartrate solution or any other commonly used aqueous system that is of a slightly basic pH. This particular type reduction is best carried out in an ether solvent at a temperature that is in the range of from about C. to about 120 C. or at about the reflux temperature of the reaction mixture if the boiling point of the solvent employed is below the upper limit of the aforesaid range. Preferred ethers in this connection include such solvents as diethyl ether, di-isopropyl ether, di-n-butyl ether, dioxane, tetrahydrofuran and dimethyl cellusolve. Recovery of the desired product from the ethereal layer can then be effected by any number of conventional procedures after the aforesaid decomposition of the complex salt has taken place. For example, the thoroughly washed and dried ethereal layer can be concentrated under reduced pressure to afford the crude product as the residual liquid, which is then either vacuum distilled or employed as such to form the desired acid addition salt. Due to the fact that amines in general readily absorb carbon dioxide from the air to form solid carbonates, it is usually preferable to conduct the aforesaid distillation of the aralkylamine base in an inert atmosphere and to analyze the amine product so obtained as its hydrochloride salt rather than in the uncombined state. Alternatively, it may be found more convenient to recover the desired product from the partially concentrated ethereal layer in the form of one of its common acid addition salts.

Moreover, it is also possible to convert the aforementioned type nitroolefin intermediate directly to the corresponding fully saturated amine via catalytic hydrogenation in a reaction-inert organic solvent medium as previously indicated. This particular type reduction is ordinarily carried out in a lower saturated aliphatic hydrocarbon carboxylic acid such as formic acid, acetic acid, propionic acid, n-butyric acid, and the like, or in a lower alkanolic solvent such as methanol, ethanol, isopropanol, and so forth, although solutions consisting of mixtures of these two latter type solvents as well as the esters which they form have also been found to be highly desirable for just such purposes. Preferred mixtures in this connection range from about one part by volume of acid to about two to about ten parts by volume of alkanol, while preferred esters include methyl formate, ethyl acetate, n-butyl acetate, isoamyl acetate, methyl propionate, and the like. Although any standard catalyst for hydrogenation purposes may be used, it is preferable to employ such noble metal catalysts as ruthenium and platinum in order to ensure completeness of reaction. Specific examples of such type catalysts in their various forms include ruthenium-on-charcoal, platinum-on-charcoal, platinum oxide, and so forth. In general, the hydrogenation reaction is usually conducted at a temperature that is in the range of from about 0 C. to about 100 C. at a pressure that may vary from about psi. to about 3000 psi. of hydrogen. Completion of the hydrogenation step is signified by the termination of any further hydrogen uptake and this usually requires from about two to about four hours. Recovery of the saturated amine from the reaction mixture is easily accomplished by first removing the catalyst therefrom by means of filtration and then adjusting the filtrate to a basic pH value, followed by extraction of the basic aqueous solution with a water-immiscible organic solvent, such as a lower dialkyl ether or a halogenated hydrocarbon solvent. Alternatively, it is also possible to first remove the aforementioned reaction solvent from the filtrate via evaporation under reduced pressure and then to partition the residual liquid between the water-immiscible organic solvent and a dilute aqueous base solution such as, for example, 10% aqueous sodium hydroxide. In either case, the desired product is easily isolated from the solvent extract by concentrating said extract in the usual manner or by first converting the aralkylamine base in situ to the corresponding hydrohalide acid addition salt which then precipitates from solution almost immediately.

Conversion of the dl-aralkylamines prepared as described above to the corresponding N-monoalkylated compounds is, as previously indicated, readily effected by any number of standard procedures and preferably by the method which involves condensing an N-unsubstituted aralkylamine with the appropriate aliphatic aldehyde, followed by the reduction of the resultant Schiif base. However, it is also possible to obtain such compounds by re acting the amine with the appropriate alkyl halide or sulfate in the presence of a suitable base, such as an alkali carbonate or bicarbonate, provided that there are no amino groups in the aromatic rings, and taking care to employ no more than a sufliciently equimolar amount of said alkylating agent so as to avoid unwanted N,N- disubstitution.

Conversion of the desired aralkylamine bases, i.e., either the optically active or optically inactive aralkylamine or N-monoalkylated derivatives thereof to the corresponding N-trifluoroacetyl derivatives is then readily effected, as aforesaid, by any number of standard procedures as previously described in the literature and preferably by the method which involves the use of trifiuoroacetic acid anhydride in a reaction-inert organic solvent. without the aid of any catalyst. Preferred reaction-inert organic solvents in this connection are those which are substantially anhydrous and in which both the reactant and reagent are mutually miscible without undergoing any change in their own chemical composition. Examples of preferred solvents in this category include the halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride, s-tetrachlorethane, and the like, as well as aromatic hydrocarbons like benzene, toluene, xylene, and so forth. In general, a reaction time of from about one to five hours is generally suflicient to ensure completion of this step when the reaction is conducted at any temperature in the range of from about 0 C. up to about 50 C., although it may be found most convenient in some instances to allow the reaction mixture to stand overnight at room temperature. Upon completion of this step, the resulting solution containing the reaction mixture is successively washed with dilute aqueous acid and water in order to remove any by-products and excess starting material that may possibly be present. The desired product is then recovered from said solution by any number of set procedures, such as, for example, by evaporation of said solution under reduced pressure until incipient crystallization of the so-isolated product first begins to occur. Reduction of this intermediate by any of the general methods hereinbefore described in connection with the preparation of the corresponding parent aralkylarnines then affords the desired N-(2,2,2-trifiuoroethyl)-fi-phenylisopropylamine. As in the previous case, the preferred method in this connection is the one which involves the use of the lithium aluminum hydride technique.

Resolution of the dl-N-(2,2,2-trifluoroethyl)-[3-phenylisopropylamines so prepared is then efiected via crystal lization of their diastereoisomeric d-bitartrate salts from absolute ethanol and the subsequent conversion of said separated salts to their respective optical antipodes, which are usually isolated in the form of their common acid addition salts for the sake of convenience. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned appetitedepressant aralkylamines of this invention are those which form non-toxic acid addition salts containing a pharmaceutically acceptable anion, such as the hydrochloride, hydrobromide, hydriodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, oxalate, succinate, maleate, gluconate, and saccharate salts.

As previously indicated, the herein described N-(2,2,2- trifluoroethyl)-13-aralkylamines of this invention are readily adapted to therapeutic use for the treatment of overweight subjects. Furthermore, the toxicity of these compounds has been found to be quite low when administered to mice in amounts which are suflicient to achieve the desired therapeutic effect. For instance, the LD value for d-N-(2,2,2-trifluoroethyl)-fi-phenylisopropylamine hydrochloride when administered orally to mice is 162 mg./ kg. Moreover, no other harmful pharmacological side effects are observed to occur as a result of their administration. The appetite depressant activity of these particular N-(2,2,2-trifluoroethyl)-fi-aralkylamines is well illustrated below by the series of tests herein employed for just such purposes wherein both rats and dogs are the experimental test animals used. The dogs are trained to eat their daily food ration within one hour, and the food intake is measured daily over a period of about one to two weeks as well as for a two-day period prior to oral administration of the drug. The actual ingredient is given orally at one and five hours prior to food intake at dosage levels of 1-3 mg. per kg. of body weight. In the case of the rats, male albino rats are first placed on a 23 hour deprivation schedule wherein food is present in home cages for only one hour daily, starting at a time that is from one to four days prior to the drug administration. One hour before food is to be given on the test day, the rats are administered the test compounds at the -30 rug/kg. dosage level. The amount of food intake for their free hour of access to food is then measured over a one-hour period commencing one hour after the drug administration. In both cases, it has been found that when the compounds of the present invention are so administered, they drastically reduce the amount of food intake by said animals when given to them at the' aforestated dosage levels via the oral route.

In accordance with a method of treatment of the present invention, one of the herein described aralkylamines effective in suppressing the appetite can be given to an overweight subject via the oral route as previously indicated. In general, these compounds are most satisfactorily administered to said subjects in doses that are substantially of the same order of magnitude as those employed in the case of (Lamphetamine sulfate for just such purposes. Nevertheless, it is to be appreciated that still other variations may also occur in this respect, depending upon the species of animal being treated and its individual response to said medicament, as well as on the particular oral formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger dosages may be employed without causing any harmful or deleterious side effects provided that such higher levels are first divided into several smaller doses that are to be administered throughout the day.

In connection with the use of the N-monosubstituted aralkylamines of this invention for the rteatment of overweight subjects, it is to be noted that they may be administered either alone and/ or preferably in combination with a pharmaceutically acceptable carrier, and that such administration can be carried out in both single and multiple dosages. More particularly, the novel compounds of this invention can be administered in a wide variety of different dosage forms wherein they are preferably pres ent in the form of their pharmaceutically acceptable acid addition salts, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, aqueous suspensions or solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, liquid aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical com ositions can be suitably sweetened and flavored by means of various agents of the type commonly employed for just such a purpose. in general, the appetite-depressant compounds of this invention are present in such dosage forms at concentration levels ranging from about 0.5% to about by weight of the total compositions, i.e., in amounts which are sufficient to provide the desired unit dosage previously indicated.

For purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents. such as polyvinylpyrrolidone, sucrose, gelatin and acacia; in addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft elastic and hard-filled gelatin capsules; preferred materials in this connection would also include lactose or milk sugar as Well as high molecular weight polyethylene glycols. When aqueous suspensions 'and/ or elixirs are desired for oral administration, the essential active ingredient may be combined with various sweetening and flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/ or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerine, and various like combinations thereof.

This invention is further illustrated by the following examples, which are not to be construed in any way as imposing limitations upon the scope thereof. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications and equivalents thereof which readily suggest themselves to those skilled in the art without departing from the spirit of the present invention and/ or the scope of the appended claims.

Example I A solution consisting of 20.0 g. (0.115 mole) of p-trifluoromethylbenzaldehyde, 8.63 g. (0.115 mole) of nitroethane and 1.0 g. (0.0115 mole) of n-amylamine dissolved in 40 ml. of absolute ethanol was refluxed for 21 hours under a nitrogen atmosphere. The clear solution so obtained was then concentrated in vacuo at 100 C. with the aid of a hot-water bath to afford a residual liquid that was subsequently fractionated into three main portion-s upon vacuum distillation. The two fractions boiling at 168170 C./O.3-0.4 mm. Hg and 168177 C./0.250.5 mm. Hg, respectively, were combined to give a 14.5 g. (55%) yield of 1-(p-trifluoromethylphenyl)-2- nitro-l-propene, M.P. 3739 C. after one recrystallization from hexane.

Analysis.Calcd. for C H F NO C, 51.95; H, 3.49; N, 606. Found: C, 52.45; H, 3.49; N, 5.79.

Example 11 A solution consisting of 15 g. (0.087 mole) of m-trifluoromethylbenzaildehyde and 6.5 g. (0.087 mole) of nitroethane dissolved in 35 ml. of absolute ethanol containing 24 drops of n-amylamine was refluxed for five days under a nitrogen atmosphere. The clear solution so obtained was then concentrated under reduced pressure at 95100 C. with the aid of a hot water bath to afford a residual liquid that was subsequently fractionated into four main portions upon vacuum distillation. The three higher boiling fractions (B.P. 8094 C./0.40.5 mm. Hg, n 1.5005; B.P. 94104 C./0.2O.4 mm. Hg,

n 1.5059; B.P. 88-104 C./0.2 mm. Hg, 11 1.5030), which showed the absence of any aldehyde band in their infrared spectra, were subsequently combined to give a 12.7 g. (65%) yield of 1-(m-trifluorornethylphenyl)-2- nitrol-l-propene.

Example III A mixture consisting of 15 g. (0.10 mole) of p-dimethylaminobenzaldehyde and 22.4 g. (0.30 mole) of nitroethane was heated under reflux until the color of the resulting solution turned dark green. A catalytic amount (1.0 ml.) of n-amylamine was then added to the cooled reaction mixture, and the latter was stored overnight at room temperature (about 25 C.) for approximately 16 hours. The clear solution so obtained was then concentrated under reduced pressure at 95-100 C. with the aid of a hot-water bath to afford 15.7 g. (76%) of a crystalline material which proved to be l-(p-dimethylarninophenyl)-2-nitro1-propene, M.P. 1l8-120 C.

Example IV The procedure described in Example III is followed except that rn-dimethylarninobenza-ldehyde is the starting material employed in place of the corresponding para isomer. Thus, when 15 g (0.10 mole) of m-dimethylaminobenzaldehyde and 22.4 g. (0.30 mole) of nitroethane react in this manner, the corresponding product obtained is 1 (m-dirnethylaminophenyl) 2 nitro 1- propene. In like manner, the use of an equimolar amount of o-dimethylaminobenzaldehyde in this reaction in place of the para isomer affords l-(o-di-methylam-inophenyl) -2-nitro-1-propene.

Example V A solution consisting of 7.9 g. (0.052 mole) of pmethylmercaptobenzaldehyde, 3.9 g. (0.052 mole) of nitroethane and 0.38 g. (0.0052 mole) of n-butylamine dissolved in 20 of absolute ethanol was refluxed for 21 hours under a nitrogen atmosphere. The clear solution so obtained was then concentrated in vacuo at 95100 C. with the aid of a hot-water bath to afford a residual liquid that was subsequently subjected to vacuum distillation. Upon cooling the resulting distillate, there was obtained a crystalline solid which amounted to a 4 g. (37%) yield of 1-(p-methylmereaptophenyl)-2-nitro-1-propene, M.P. 68.269.8 C. after one recrystallization from absolute ethanol.

AnalySiS.CalCd. for CIOHIINOZS: C, H, N, 6.69. Found: C, 57.12; H, 5.50; N, 6.39.

Example VI The procedure described in Example I is followed ex cept that 5 g. (0.033 mole) of m-methylmercaptobenzaldehyde, 2.5 g. (0.033 mole) of nitroethane and 0.24 g. (0.0033 mole) of n-butylamine are refluxed in 20 m1. of ethanol. In this manner, there was obtained a 3.9 g. yield of 1-(m-methylrnercaptophenyl)-2-nitro-1-propene, Bl. 120-130 C./0.9 mm. Hg; n 1.16430.

Example VII The procedure described in Example I is followed except that 4.6 g. (0.03 mole) of o-methylmercaptobenzaldehyde, 2.25 g. (0.03 mole) of nitroethane and 0.22 g. (0.003 mole) of n-butylamine are refluxed in 20 ml. of ethanol. In this manner, there was obtained a 4.5 g. yield of 1-(o-methylmercaptophenyl)-2-nitro-1-propene, B.P. 110 C./0.1 mm. Hg; 11 1.16430.

Example VIII In a 2-liter three-necked, round-bottomed flask equipped with a mercury-sealed stirrer and fitted with a reflux condenser and dropping funnel, there were placed 12.0 g. (0.316 mole) of lithium aluminum hydride suspended in 300 ml. of anhydrous diethyl ether. Stirring was commenced and the flask and its contents were cooled in an ice bath, while a solution consisting of 20.5 g. (0.089

mole) of 1-(p-trifluoromethylphenyl) 2-nitro-l-propene in 50 ml. of anhydrous diethyl ether was added dropwise at such a rate as to cause a gentle reflux. After the addition was complete (this step required approximately one hour), the resulting suspension was stirred at 0 C. for one hour and then allowed to warm to room temperature at which point it was stirred for an additional 16 hours. At the end of this period, 150 ml. of 20% aqueous disodium tartrate solution was slowly added to the stirred, cooled suspension at a dropwise rate with the reaction flask and its contents being immersed in an ice-bath throughout this step due to the highly exothermic nature of the reaction. The resultant suspension was subsequently stirred at room temperature for several hours. The ethereal layer was then separated from the aqueous suspension of white solids, and the aqueous layer was successively extracted with fourml. portions of diethyl ether. The combined ethereal extracts were next washed with twoml. portions of a saturated sodium chloride solution and subsequently dried over anhydrous sodium sulfate. After removal of the drying agent by means of filtration, the dried ethereal filtrate was concentrated in vacuo to a volume of 100 ml., cooled in an ice bath and subsequently saturated with dry hydrogen chloride gas. The crystalline acid addition salt so prepared crystallized from solution almost immediately; it was collected by means of filtration, washed with anhydrous diethyl ether and dried in vacuo to constant weight. In this manner, there was obtained a 14.4 g. (68%) yield of (ll-,8-(p-trifluoromethylphenyl) isopropylamine hydrochloride, M.P. 195.5197.5 C. after one recrystallization from ethanol-diethyl ether.

Analysis.Calcd. for C H ClF N: C, 50.11; H, 5.41; N, 5.85; Cl, 14.79. Found: C, 50.40; H, 5.47; N, 5.97; Cl, 14.6.

Example IX To a rapidly stirred and cooled suspension of 12.5 g. (0.33 mole) of lithium aluminum hydride in 700 ml. of anhydrous diethyl ether, there was slowly added a solu tion consisting of 12.7' g. (0.055 mole) of l-(m-trifluoromethylphenyl)-2-nitro-1-propene dissolved in 60 ml. of anhydrous diethyl ether in accordance with the procedure described in Example VIII. After the addition was complete (this step required approximately 30 minutes) theresulting suspension was refluxed gently for one hour and then cooled to room temperature. At this point, 750 ml. of 40% aqueous disodium tartrate solution was slowly added at a dropwise rate in order to decompose the complex salt and excess reagent. The ethereal layerwas then separated from the aqueous suspension of white solids, and the aqueous layer was successively extracted with two-200 ml. portions of diethyl ether. The combined ethereal extracts were then washed with two-150 ml. portions of a saturated sodium chloride solution and subsequently dried over anhydrous sodium sulfate. After removal of the drying agent by means of filtration, the dried ethereal filtrate was concentrated in vacuo to 100 ml., cooled in an ice bath and saturated with dry hydrogen chloride gas. The acid addition salt so produced crystallized from solution on standing overnight; it was subsequently collected by means of filtration, washed with anhydrous diethyl ether and dried in vacuo until constant weight was attained. In this manner, there was obtained a 3.5 g. (66%) yield of dl-fi-(m-trifluoromethylphenyl)- isopropylamine hydrochloride, M.P. 161 C. after one recrystallization from ethanol-diethyl ether.

Analysis.Calcd. for C l-l ClF Nz C, 50.11 H, 5.47; N, 5.85. Found: C, 50.36; H, 5.37; N, 5.24.

Example X To a rapidly stirred, cooled suspension of 19.4 g. (0.510 mole) of lithium aluminum hydride in 100 ml. of tetrahydrofuran, there was slowly added a solution consisting of 17.4 g. (0.0845 mole) of 1-(p-dimethylaminophenyl)- 2-nitro-l-propene in 80 ml. of anhydrous tetrahydrofuran. After the addition Was complete, the resulting suspension was refluxed gently for three hours, and then cooled to room temperature. At this point, 500 ml. of 40% aqueous disodium tartrate solution was slowly added at a dropwise rate in order to decompose the complex salt and excess reagent. The ethereal layer was then separated from the aqueous suspension of white solids, and the aqueous layer was successively extracted with two-200 ml. portions of diethyl ether. The combined ethereal extracts were then washed with two-150 ml. portions of a saturated sodium chloride solution and subsequently dried over anhydrous sodium sulfate. After removal of the drying agent by means of filtration, the dried ethereal filtrate was concentrated in vacuo to 100 ml., cooled in an ice bath and saturated with dry hydrogen chloride gas. The acid addition salt so produced crystallized from solution on standing overnight; it was subsequently collected by means of filtration, washed with anhydrous diethyl ether and dried in vacuo until constant weight was attained. In this manner, there was obtained a 11 g. (72%) yield of dl-fi-(p-dimethylaminophenyl)isopropylamine dihydrochloride, M.P. 205-206 C. after one recrystallization from ethanol-diethyl ether.

Analysis.-Calcd. for C H CI N C, 52.59; H, 8.03; N, 11.15. Found: C, 52.88; H, 8.12; N, 11.44.

Example XI The procedure described in Example X is followed except that the starting material employed is l-(rn-dimethylaminophenyl)-2-nitro-1-propene in lieu of the corresponding para isomer. Thus, when identical quantities of starting material and reagent as was used in the previous example are made to react in this manner, the corresponding product obtained in dl-B-(m-dimethylaminophenyl) isopropylamine dihydrochloride. In like manner, the use of 1-(o-dimethylaminophenyl)-2-nitro-1-propene as the starting material in this procedure affords dl-B-(o-dimethylaminophenyl)isopropylamine dihydroch oride as the product which is obtained.

Example XII In a 1000 ml. three-necked, round-bottomed flask equipped with a mercury-sealed stirrer and fitted with a reflux condenser and dropping funnel, there was placed 2.18 g. (0.0575 mole) of lithium aluminum hydride suspended in 200 ml. of anhydrous diethyl ether. Stirring was commenced and the fiask and its contents were cooled in an ice bath, while a solution consisting of 2.0 g. (0.00957 mole) of 1-(p-methylmercaptophenyl)-2-nitro-l-propene in 100 ml. of anhydrous diethyl ether was added dropwise at such a rate as to cause a gentle reflux. After the addition was complete (this step required approximately one hour), the resulting suspension was stirred at C. for one hour and then allowed to warm to room temperature at which point it was stirred for an additional 16 hours. At the end of this period, 100 ml. of 20% aqueous disodium tartrate solution was slowly added to the cooled, Well-stirred suspension at a dropwise rate with the reaction flask and its contents being immersed in an ice-bath throughout this step due to the highly exothermic nature of the reaction. Upon completion of this step, 100 ml. of water was added to the reaction mixture and the resultant suspension was stirred at room temperature for several hours. The ethereal layer was then separated from the aqueous suspension of white solids, and the aqueous layer was successively extracted with four-50 ml. portions of diethyl ether. The combined ethereal extracts were next washed with two- 80 ml. portions of a saturated sodium chloride solution and subsequently dried over anhydrous sodium sulfate. After removal of the drying agent by means of filtration, the dried ethereal filtrate was concentrated in vacuo to a volume of 200 ml., cooled in an ice bath and subsequently saturated with dry hydrogen chloride gas. The crystalline acid addition salt so produced crystallized from solution almost immediately; it was collected by means of filtration, washed with anhydrous diethyl ether and dried in vacuo to constant weight. In this manner, there was obtained a 1.3 g. (63%) yield of dl-B-(p-methylmercaptophenyl)isopropylamine hydrochloride, M.P. 190- 191 C. after one recrystallization from ethanol-diethyl ether.

Analysis.Calcd. for C H ClNS: C, 55.15; H, 7.41; N, 6.43. Found: C, 54.76; H, 7.46; N, 6.27.

Example XIII The procedure in Example XII is followed except that 3.9 g. (0.019 mole) of 1-(rn-rnethylmercaptophenyl)-2- nitro-l-propene is reacted with 6 g. (0.16 mole) of lithium aluminum hydride in 250 ml. of anhydrous diethyl ether. In this manner, there was obtained a 1.5 g. yield of dl-B-(m-methylmercaptophenyl)isopropylamine hydro chloride, 134-135 C. after one recrystallization from ethanol-diethyl ether.

Example XIV The procedure described in Example XII is followed except that 4.5 g. (0.021 mole) of 1-(o-methylmercaptophenyl) 2 -nitro-1-propene is reacted with 6.4 g. (0.17 mole) of lithium aluminum hydride in 250 ml. of anhydrous diethyl ether to afford a 2 g. yield of a'l-B-(o-methylmercaptophenyl)isopropylamine hydrochloride, M.P. 145-146 C. after one recrystallization from ethanol-diethyl ether.

Analysis.Calcd. for C H ClNS: C, 55.15; H, 7.41; N, 6.43. Found: C, 54.76; H, 7.46; N, 6.27.

Example XV A solution consisting of 13.0 g. (0.0542 mole) of all- 18-(p-trifiuorornethylphenyl)isopropylamine hydrochloride dissolved in 150 ml. of water was made alkaline with 20% aqueous sodium hydroxide, and the liberated amine obtained as an oil was successively extracted with three- 100 ml. portions of diethyl ether. The combined ethereal extracts were then washed with threeml. portions of water and one-50 rnl. portion of a saturated sodium chloride solution and subsequently dried over anhydrous sodium sulfate. After removal of the drying agent by means of filtration and the ethereal solvent by means of evaporation under reduced pressure, there was obtained and 11.0 g. (almost quantitative) yield of a'l-fl-(p-trifluoromethylphenyl) isopropylamine.

Example XVI The procedure described in Example XV is followed except that the product of Example IX is the starting material employed. In this particular case, as in the previous example, the corresponding dl-amine base is the product obtained. Thus, when dl fi-(m-trifiuoromethylphenyl)isopropylamine hydrochloride is subjected to the procedure of the previous example, there is obtained an almost quantitative yield of Ill-,8-(m-trifluoromethylphenyl)isopropylamine as the residual material. Subsequent vacuum distillation of the latter afforded three main fractions having the following characteristic properties: (1) the first cut boiling at 3060 C./0.60.7 mm. Hg amounted to 21.6% by weight of the total and possessed a refractive index value of 11;, 1.4564 at 285 C.; (2) the second cut boiling at 6074 C./0.40.6 mm. Hg amounted to 62.2% by weight of the total and possessed a refractive index of n 1.4572 at 28.5 C.; (3) and finally, the last out boiling at 66 C./0.40.5 mm. Hg amounted to 16.2% by weight of the total and possessed a refractive index value of 11 1.4584 at 285 C.

Example XVII A solution consisting of 4.0 g. (0.0224 mole) of Lil-,8- (p-methylmercaptophenyl)isopropylarnine hydrochloride dissolved in 50 ml. of water is made alkaline with 20% aqueous sodium hydroxide, and the liberated amine obtained as an oil is successively extracted with three-35 11 ml. portions of diethyl ether. The combined ethereal extracts are then washed with three-50 ml. portions of water and one-l5 ml. portion of a saturated sodium chloride solution, and subsequently dried over anhydrous sodium sulfate. means of filtration and the ethereal solvent by means of evaporation under reduced pressure, there is obtained an almost quantitative yield of dl-fl-(p-methylmercaptophenyl isopropylamine.

The exact procedure described in the aforegoing paragraph is again repeated employing dl-B-(o-methylmercaptophenyl)isopropylarnine hydrochloride and dl-jB-(mmethylmercaptophenyl)isopropylamine hydrochloride as respective starting materials in lieu of the corresponding para isomer. In each case, the corresponding free a lamine base is the product obtained, viz., dl-fl-(o-methylmercaptophenyl)isopropylamine and dl-fi-(m-methylmercaptophenyl)isopropylamine, respectively.

Example XVIII A solution consisting of 12.55 g. (0.050 mole) of a l-,6-

(p-dimethylaminophenyl)isopropylamine dihydrochloride dissolved in 100 ml. of water is made alkaline with 20% aqueous sodium hydroxide, and the liberated amine base so obtained is successively extracted with three-100 ml. portions of diethyl ether. The combined ethereal extracts are then successively washed with three-50 ml. portions of water and one-50 ml. portion of a saturated sodium chloride solution, and subsequently dried over anhydrous sodium sulfate. After removal of the drying agent by means of filtration and the ethereal solvent by means of evaporation under reduced pressure, there is obtained an almost quantitative yield of dl-jS-(p-dimethylaminophenyl)isopropylamine as the residual material. Subsequent vacuum distillation of the latter material afforded three distinct fractions having the following characteristic properties: (1) the first cut boiling at 104-1 14 C./0.30.4 mm. Hg amounted to 15.5% by weight of the total and possessed a refractive index value of n 1.5488 at 28 C.; (2) the second cut boiling at 104-114 C./'0.2 mm. Hg amounted to 31.8% by weight of the total and possessed a refractive index value of 11 1.5492 at 28 (1.; (3) and finally, the third cut boiling at 114 C./ 0.3 mm. Hg amounted to 52.7% by weight of the total and possessed a refractive index value of H 1.55" at 28 C.

Example XIX The exact procedure described in Example XVIII is followed except that dl-fl-(m-dimethylaminophenyl)isopropylamine dihydrochloride and al-fi-(o-dimethylaminophenyl)isopropylamine dihydrochloride are the respective starting materials which are individually employed in lieu of the corresponding para isomer. In each case, the corresponding free dl-amine base is the product obtained, viz., ell-,B-(m-dimethylaminophenyl)isopropylamine and dl ,8 (o dimethylaminophenyl)isopropylamine, respectively.

Example XX The procedure employed to prepare d-[S-(p-aminophenyl)isopropylamine is essentially the same as that described for the corresponding dl-compound by T. M. Pat

rick, Jr., et al., in the Journal of the American Chemical Society, vol. 68, pp. 1154-1155 (1946), except that 10 g. of d-amphetamine is used as starting material in place of the benzedrine employed by the authors. The compound thus obtained was subsequently isolated in the form of the hydrochloride acid addition salt by dissolving it in a diethyl ether-ethyl acetate mixture and introducing excess dry hydrogen chloride gas into said solution mixture. In this manner, there was obtained pure crystalline d-B-(p-aminophenyl)isopropylamine dihydrochloride, [a] +17.7 (C, 1.0; H

Analysis.-Calcd. for C H clgN z C, 48.33; H, 7.26;

After removal of the drying agent by 12 N, 12.61; Cl, 31.50. Found: C, 48.10; H, 7.33; N, 12.61; Cl, 31.41.

Example XXI The N-monoalkyl derivatives of each of the previously reported aralkylamine bases are prepared by individually subjecting these compounds to the condensation procedure described in Chemical Reviews, vol. 26, p. 297 (1940), followed by a catalytic hydrogenation of the resultant SchilI base or by treatment of the latter intermediate with lithium aluminum hydride in accordance with the procedure described in Examples IX-X. Thus, when 3.5 g. (0.02 mole) of dl-B-(p-dimethylaminophenyl)isopropylamine is treated with 0.6 g. (0.02 mole) of formaldehyde in 10 ml. of boiling ethanol and the resultant aldimine is reduced by means of 4.6 g. (0.12 mole) of lithium aluminum hydride in 200 ml. of te-trahydrofuran in accordance with the procedure of Example X, the corresponding product obtained is dl-B-(p-dimethylaminophenyl -N-methylisopropylamine.

In like manner, each of the other amine bases reported in Examples XV-XX react with various other aldehydes such as acetaldehyde, propionaldehyde, n-butyraldehyde, benzaldehyde, and the like, as does dl-fi-(p-dimethylaminophenyl)isopropylamine, to yield aldimines which are subsequently reduced to the corresponding N-monoalkyl derivatives. Thus, when 4.1 g. (0.02 mole) of a l- ,B-(m-trifluoromethylphenyl)isopropylamine and 2.1 g. (0.02 mole) of benzaldehyde are warmed together in 8 ml. of glacial acetic acid and the resultant aldimine intermediate is reduced with 4.6 g. (0.12 mole) of lithium aluminum hydride in 200 ml. of tetrahydrofuran in the manner of Example IX, the corresponding product obtained is dl-fi-(m-trifluoromethylphenyl) N benzylisopropylamine. Similarly, when 315 g. (0.02 mole) of dl- ,6-(o-methylmercaptophenyl)isopropylamine and 1.16 g. (0.02 mole) of n-pro-piona-ldehyde react in this manner and the resultant aldimine is reduced by 4.6 g. (0.12 mole) of lithium aluminum hydride, the corresponding product obtained is dl-fl-(o-methylmercaptophenyl)-N- propylisopropylamine.

Example XXII To a solution consisting of 20 g. (0.15 mole) of d-B- phenylisopropylamine dissolved in m1. of benzene, there was slowly added 3 6 g. (0.17 mole) of trifluoroacetic anhydride in a dropwise manner with constant agitation being maintained throughout the addition. Aifiter the addition was complete, the resulting reaction mixture was stirred for two hours at room temperature (25 C.) and then successively washed with equal portions of 6 N HCl and water. Upon removal of most of the benzene solvent via concentration in the usual manner under reduced pressure, there was obtained a crude crystalline residual material which was subsequently recrystallized from petroleum ether. In this way, there was obtained a 63% yield of d-N-trifluoroacetyl-fl-phenylisopropylamine, M.P. 84-85 C.

Example XXIII In a 500 ml. three-necked, round-bottomed flask equipped with a mercury-sealed stirrer and fitted with a reflux condenser and dropping funnel, there was placed 2.18 g. (0.0575 mole) of lithium aluminum hydride sus pended in 200 ml. of anhydrous diethyl ether. Stirring was commenced and the flask and its contents were cooled in an ice bath, while a solution consisting of 2.2 g. (0.00957 mole) of d-N-trifluoroacetyl-fl phenylisopropylamine in 25 ml. of anhydrous diethyl ether was added dropwise at such a rate as to cause a gentle reflux. After the addition Was complete (this step required approximately one hour), the resulting suspension was stirred at 0 C. for one hour and then allowed to warm to room temperature at which point it was stirred for an additional 16 hours. At the end of this period, 100 ml. of 20% aqueous disodium tartrate solution was slowly added to the cooled, Well-stirred suspension at a dropwise rate with the reaction flask and its contents being immersed in an ice bath throughout this step due to the highly exothermic nature of the reaction. Upon completion of this step, 100 ml. of water was added to the reaction mixture and the resultant suspension was stirred at room temperature for several hours. The ethereal layer was then separated from the aqueous suspension of white solids, and the aqueous layer was successively extracted with four-O ml. portions of diethyl ether. The combined ethereal extracts were then washed with two-80 ml. portions of a saturated sodium chloride solution and subsequently dried over anhydrous sodium sulfate. After removal of the drying agent by means of filtration and the ethereal solvent by means of evaporation under reduced pressure, there was obtained a residual liquid which subsequently distilled in vacuo to afford a fraction boiling at 5256 C./ 0.05 mmg. Hg after a small forerun was first removed. In this manner, there was obtained a 70% yield of d-N- (2,2,2-trifluoroethyl) 18 phenylisopropylamine having a refractive index value of n 1.4601.

Treatment of a diethyl ether-ethyl acetate solution of this compound with excess dry hydrogen chloride gas afforded d N (2,2,2,-trifluoroethyl) ,8 pheuylisopropylaminehydrochloride, M.P. 20 5.5206 C. after one recrystallization from ethanol-diethyl ether.

Analysis.-Calcd. for C H ClF N: C, 52.07; H, 5.96; N, 5.52. Found: C, 52.12; H, 6.16; N, 5.64.

Example XXIV The procedure described in the previous two examples is repeated employing as starting material in place of d- S-phenylisopropy-lamine an equimolar amount of any one of the products reported in Examples XV-XXL In this way, the following new compounds are obtained:

d l-N- (2,2,2-triflu oroe thyl -B (-p trifiuoromethylphenyl) isopropylamine dl-N- 2,2,2-trifluoroethyl) -/S- m-trifluoromethylphenyl is opropyl amine d l-N- (2,2,2-trifluoroethyl) -flpmethylme-rcaptophenyl isopropylamine d [-1 (2,2,2-trifiuoro ethyl 49- (m-methylmercaptophenyl) isopropylamine d l-N- 2,2,2-trifluoroethyl) -B- o-methylmercaptophenyl isopropyl amine d-N-( 2,2,2-trifluoroethyl) -fi-(p-aminophenyl) isopropylamine dlN-( 2,2,2-trifiuoroethyl) -fi- (p-dimethylaminophenyl) isopropylamine d l-N- (2 ,2,2-trifluoroethyl 8- (m'dimethyl aminophenyl) isopropylamine dl-N-( 2,2,2-trifiuoroethyl) 8-( o-dimethylaminophenyl isopropyl amine dl-N- 2,2,2-trifluoroethyl -B- (p-dirnethylaminophenyl) N-methylisopropylamine d l-N-( 2 ,2,2trifluoroethyl) 3- (mtrifiuoromethylphenyl -N-benzylisopropylamine dl-N- 2,2,2-trifluoroethyl) -,8( o-methylmercaptophenyl -N-propylisopropylamine Example XXV The non-toxic acid addition salts of each of the d]- amine bases obtained in Examples X)GIIXXIV other than the previously reported hydrochlorides are prepared by either one or two general methods. In the case of the hydrohalide salts, such as the hydrochloride, hydrobromide and hydriodide, this is accomplished by first dissolving the amine base in absolute ether followed by the introduction of the appropriate hydrogen halide gas into the solution until saturation is effected, whereupon the desired salt precipitates from said solution. The crystalline product so obtained is then washed with a fresh portion of ether to afford the hydrohalide acid addition salt in pure form. Thus, when 4.6 g. (0.02 mole) of d-N- (2,2,2- trifiuoroethyl) B (p aminophenyl)isopropyl- 14 amine is dissolved at room temperature in 40 ml. of absolute diethyl ether and dry hydrogen bromide gas is bubbled into the solution, the corresponding hydrogen bromide acid addition salt soon precipitates therefrom. The precipitate so obtained is then separated from the rev action mixture by means of filtration and washed with two-15 ml. portions of cold diethyl ether to afford the pure d N (2,2,2 trifiuoroethyl) -/3-(p-am.inophenyl)isopropylamine dihydrobromide.

In the case of the corresponding nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, oxalate, succinate, maleate, glucon-ate and sacchara-te salts, the respective acid and the appropriate amine base are both separately dissolved in ethanol and the two alcoholic solutions are then mixed, followed by the addition of diethyl ether to the resulting reaction solution in order to effect precipitation of the desired acid addition salt therefrom. Thus, when equimolar amounts of dl-N-(2,2,2-trifluoroethyl) 8 (m trifiuoromethylphenyl)isopropylamine and ortho phosphoric acid react in this manner, the corresponding product obtained is dl-N-(2,2,2-trifluoroethyl) -;S-(m-trifiuoromethy1phenyl) isopropylamine phosphate. In like manner, equimolar amounts of dl-i -(2,2, 2 trifluoroethyl) i3 (o methylmercaptophenyl)isopropylamine and concentrated sulfuric acid react to afford the corresponding sulfate.

Example XXVI A dry solid pharmaceutical composition is prepared by blending the following materials together in the proportions by weight specified below:

d-N-(2,2,2-trifluoroethyl)-B-phenylisopropylamine hydrochloride 5 Potato stairch 15 Sucrose 15 Alginic acid l5 Polyvinylpyrrolidone l8 Dicalcium phosphate 30 Magnesium stearate 2 After the dried composition is thoroughly blended, tablets are punched from the resulting mixture, each tablet being of such size that it contains 50 mg. of the active ingredient.

Example XX VII A dry solid pharmaceutical composition is prepared by combining the following materials in the proportions by weight specified below:

d N-(2,2,2-trifiuoroethyl)-,'3-(p am-inophenyl) -isopropylamine dihydrobromide 10 Calcium carbonate 45 Polyethylene glycol (average molecular weight, 6000) 2O Lactose 25 and the pharmaceutically acceptable acid addition salts thereof, wherein R is a member chosen from the group consisting of hydrogen, trifluorome-thyl, S-methylmercap- 15 to, amino and dimethylamino, and R is a member chosen 6. dl N (2,2,2-trifluoroethy1)-/8-(m-din1ethylaminofrom the group consisting of hydrogen, lower alkyl and phenyDisopropylamine. benzyl.

2. d N-(2,2,2-trifl th 1)-ph li l i References Cited in the file of this patent hydrochlorlde- 5 FOREIGN PATENTS phenynisopmpylamine phosphate 870,541 Great Britain June 14, 1961 4. dl N (2,2,2 trifiuoroethy1)-p3-(o-methy1mercapt0- OTHER REFERENCES phenynlsopmpylamme sulfaie' Yale: J. of Med. and Pharm. Chem, Vol. 1, No. 2,

5. d N (-2,2,2-trifluor-oethy1)-,8-(p-aminophenyl)iso- 10 a propylamine dihydrobrornide. pages 133 (1959)

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
GB870541A * Title not available
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3198834 *Jul 27, 1964Aug 3, 1965Snc Science Union Et CompagnieOptical isomers of trifluoromethylated phenethylamines
US3458576 *May 11, 1966Jul 29, 1969Great Lakes Carbon CorpReduction of arylnitroalkenes
US3911016 *Jul 27, 1972Oct 7, 1975DegussaN-fluoroalkylated phenylethylamine
US3996381 *Aug 14, 1974Dec 7, 1976Astra Lakemedel AktiebolagAmphetamine derivatives
US4129598 *May 24, 1974Dec 12, 1978SynthelaboPhenylethylamine derivatives
US4148923 *Jan 16, 1978Apr 10, 1979Synthelabo1-(3'-Trifluoromethylthiophenyl)-2-ethylaminopropane pharmaceutical composition and method for treating obesity
US6991911Dec 15, 2003Jan 31, 2006Dade Behring Inc.Assay for entactogens
US7022492Dec 15, 2003Apr 4, 2006Dade Behring Inc.Ecstasy haptens and immunogens
US7037669Mar 22, 2004May 2, 2006Dade Behring Inc.Assays for amphetamine and methamphetamine using stereospecific reagents
US7115383Mar 22, 2004Oct 3, 2006Dade Behring Inc.Assays for amphetamine and methamphetamine
Classifications
U.S. Classification564/381, 514/910, 568/936, 564/212, 564/375, 564/304, 568/927
Cooperative ClassificationY10S514/91, C07C215/08