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Preparation of DL-Amphetamine Phosphate


Procedure

1 mol of phenyl-2-nitropropene, C6H5CH=C(CH3)NO2, is dissolved with a solvent prepared by mixing 1000ml of ethanol with 500ml of acetic acid and 500ml of 12 N sulfuric acid. The resultant solution is placed in the cathode compartment of a divided electrolytic cell containing a metallic cathode of mercury, copper, or other metal of similar nature. Current is passed, using a current density of ~0.2 amp/cm2 of cathode surface. The temperature is kept at about 40C during the electrolysis which is continued until at least eight Faradays of electricity have been passed.

When the reduction is completed, the amphetamine may be separated from the solution. A convenient way of doing this is by removing the ethanol and ethyl acetate present by evaporation and then making the residual solution strongly alkaline by addition of caustic alkali. The basic layer thus formed is separated from the aqueous solution and contains the desired amphetamine freebase.

135 g (1 mol) of amphetamine freebase were stirred into 300ml of acetone in a 1000ml erlenmeyer flask. To the resultant solution there were slowly added under constant agitation 115.3 g of 85% phosphoric acid (containing 1 mol of H3PO4), care being taken to avoid any sudden rise in temperature or local overheating due to the considerable amount of heat that is evolved. During the addition of the phosphoric acid a fine, white, flocculent precipitate appears which becomes more and more dense and abundant, as the quantity of added acid increases.

When the entire quantity of the phosphoric acid has thus been added, agitation of the mixture is continued for about a half-hour or more to insure complete conversion. The precipitate is then allowed to settle, the supernatant liquid is drawn off, and the residue is filtered. The precipitate thus separated is washed with acetone and is then dried by evaporation to constant weight. It forms a fine, white, impalpable powder consisting of pure monobasic amphetamine phosphate.

Reference: Pharmaceutical Manufaturing encyclopedia (1988)


Monobasic Phosphate Of 1-Phenyl-2-Aminopropane

Theodore V. Goggia

United States Patent 2,907,468

My invention relates to a new chemical compound that is especially suited for therapeutic use. More particularly it concerns the monobasic phosphate of 1-phenyl-2-aminopropane, a method of preparing it, and therapeutic compositions containing this salt.

It is known that 1-phenyl-2-aminopropane (commonly referred to as "amphetamine") and certain of its salts have a pronounced therapeutic effect, particularly as stimulants for the central nervous system. This is evidenced by a feeling of well-being and energy, as well as by a reduction of appetite and desire to sleep. The foregoing effects render these compounds of substantial value in the treatment of various pathologic conditions, such as despondency, fatigue, alcoholism, narcolepsy, obesity and the like. Unfortunately, the beneficial effects of these known compounds are accompanied by certain deleterious effects, particularly an undesirable stimulation of the sympathetic nervous system, frequently resulting in uncontrollable jitteriness. Often a cumulative effect of repeated dosages is evidenced by a disagreeable "hang-over." Furthermore, the known compounds leave much to be desired in one or more respects, such as solubility, stability, metabolism, etc.

It is an object of my invention to provide a novel salt of 1-phenyl-2-aminopropane which possesses the above-mentioned beneficial effects to an unusual extent, and which at the same time possesses the deleterious effects referred to previously to a lesser extent than was heretofore deemed possible. A further object is to provide such a salt having improved physical properties, compared to the known salts. and which is subject to more economical utilization by the body.

Another object is to prepare the new salt in a simple, expeditious manner, whereby a high degree of purity, excellent physical form and great stability are assured. A still further object is to make available various therapeutic compositions particularly adapted for the treatment of obesity and of dysmenorrhea, in which my novel salt is combined with other therapeutically active constituents for maximum desired effect. Additional objects will become apparent from a consideration of the following description and claims.

The foregoing objects are accomplished in accordance with my invention which is particularly concerned with the monobasic phosphate salt of 1-phenyl-2-aminopropane. This novel compound will hereinafter sometimes be referred to as "monobasic amphetamine phosphate" or "amphetamine dihydrogen phosphate." Said salt formed by the combination of equimolecular amounts of the amphetamine base and phosphoric acid. It is distinguished from the dibasic (monohydrogen) and tribasic (fully neutralized) forms, since these contain two and three mots, respectively, of amphetamine for each mol of phosphoric acid. My new salt may be represented by the following structural formula:

The novel amphetamine dihydrogen phosphate may exist in the dextro- or levo- rotary forms or as a racemic mixture thereof, depending upon the form of the base from which it is derived. In practice, I prefer to employ the racemic form and the specific data hereinafter given concerning the physical characteristics of the salt apply to this form of the salt.

My monobasic amphetamine phosphate is a white, impalpable powder that is freely soluble in water and sparingly soluble or insoluble in most organic solvents. It is not demonstrably hygroscopic and is completely stable under ordinary conditions of storage. It begins to sinter at 145C., becomes a clear amorphous mass without liquefaction at 147C, and retains the latter form up to about 285C. at which point it begins to decompose with the evolution of a gas (probably CO2). Its melting point could therefore not be determined.

My new salt may be prepared by adding to amphetamine an equimolecular amount of phosphoric acid. The amount of phosphoric acid required may either be calculated beforehand or else controlled by observing the pH of the reaction mixture and discontinuing the addition as soon as the desired pH value is reached. The pH of a 10% solution of my new salt at a temperature of 25C is 4.95-5.00 determined colorimetrically and electrometrically. The neutralization reaction is strongly exothermic and, unless modified and controlled in a manner such as will be hereinafter described, results only in a chemical mass consisting of varying proportions of the three possible phosphates with, under certain circumstances, an excess of base or of acid intermingled.

I have found that the necessary control of the reaction may be achieved by having present a substantial amount of a solvent for the amphetamine. One may employ a solution of the amphetamine in water or in an organic solvent such as carbon tetrachloride, ethylene glycol, propyl alcohol, chloroform, acetone and the like. The organic solvents, particularly acetone, are preferred. The phosphoric acid is slowly added to such an amphetamine solution under constant agitation. . After the precise amount required to form the monobasic salt has been added, agitation is continued for up to a half hour or more to insure complete conversion of the base to the desired salt. When an organic solvent such as acetone is employed, the salt separates in the form of a fine, white, flocculent precipitate that becomes more and more dense and abundant as the reaction proceeds. The precipitate may be separated by filtration and, when dried, is in a very suitable form for compounding in various therapeutic preparations.

The following example will serve to illustrate the preparation of my new salt. The invention is, of course, not limited, to the details given therein.

Example

135 grams (1 mol) of amphetamine (1-phenyl-2-aminopropane) were stirred into 300 mL of acetone in a stainless-steel vessel. To the resultant solution there were slowly added under constant agitation 115.3 grams of 85% phosphoric acid (containing 1 mol of H3PO4), care being taken to avoid any sudden rise in temperature or local overheating due to the considerable amount of heat that is evolved. During the addition of the phosphoric acid a fine white, flocculent precipitate appears which becomes more and more dense and abundant, as the quantity of added acid increases.

When the entire quantity of the phosphoric acid has thus been added, agitation of the mixture is continued for about a half hour or more to insure complete conversion. The precipitate is then allowed to settle, the supernatant liquid is drawn off, and the residue is filtered. The precipitate thus separated may, if desired, be washed with acetone and is then dried by evaporation to constant weight. It forms a fine, white, impalpable powder consisting of pure monobasic amphetamine phosphate. When employing the racemic amphetamine, a racemic salt is formed having the physical characteristics hereinbefore described.

My new salt, obtained as described above, may, if desired, be ground to such a fineness that it will pass through a 100 mesh sieve. It is then ready for compounding into various forms and preparations for therapeutic use. For example, it may be incorporated in the customary extenders or excipients, such as milk sugar, and made into tablets, each containing a predetermined dosage of the salt, such as 5 or 10 mg. Another convenient and desirable form for oral administration is obtained by incorporating my new salt in the coating of a standard form of chicle chewing gum. In such case the entire dosage of the salt is preferably incorporated in an intermediate layer of the coating, so that it will be quickly available and yet protected by an outer layer.

An important advantage of my new salt lies in its ready solubility in water. It is about six times as soluble as either the dibasic phosphate or the dibasic sulfate. Thus a quicker and more intense therapeutic action is assured. The action is also less persistent from the standpoint of cumulation that may result in a "hang-over" feeling.

Based upon extensive experience in human therapy, I have determined that the monobasic amphetamine phosphate is more effective, dose for dose, than is the dibasic amphetamine sulfate, which is the best known of the amphetamine salts. This is indeed surprising, because my new salt contains less of the amphetamine base than does an equal quantity of the dibasic sulfate. It follows that the amphetamine is far more potent in the form of the monobasic phosphate, than in the form of the salt most widely used today.

While my salt is more. effective, dose for dose, than the dibasic sulfate, insofar as the desired stimulation of the central nervous system is concerned, it produces less undesirable side-effects attributable to stimulation of the sympathetic nervous system. This may be due to the fact that it contains less of the amphetamine base. However, that does not explain why the desired therapeutic effects are not similarly diminished, but rather substantially enhanced. It appears that the undesirable side-effects are distinct from the desired effects of these salts, insofar as dosage is concerned, and it is probable that the desired effects are favorably influenced by the presence of phosphoric acid. It is well known that phosphates in general are metabolized more readily than are the sulfates which are foreign to the physiologic processes of the body. Regardless of what may be the true explanation, the, fact remains that the desired effects can be produced with my new salt, while greatly diminishing or completely eliminating the undesired effects that were heretofore considered inevitable in the therapeutic use of amphetamine salts.

References Cited

The following references are of record in the file of this patent:

Patents

US 2,358,582 - Haffner et al., Aug. 22, 1944
US 2,361,373 - Alles, Oct. 31, 1944
AU 117,996 - July 10, 1943
AU 119,265 - Nov. 21, 1944

Other References

Bakas, "Zentralblatt fr Gynokologie," vol. 34, pages 1893-1898 (1938).
Chinoin, "Klinische Wochenschrift" vol. 13, page 483 (April 1939).
Stepan, "Chemical Abstracts," vol. 37, page 3565 (1943).
Torok, "Chemical Abstracts," vol. 32, page 2211 (1938).
Degering, "An Outline of Organic Nitrogen Compounds," (Univ. Lithoprinters, 1945) page 304.
Hygiea Medicinsk Tidskrift, Vol. 102, pages 1635-1642 (1940).
Decision of District CL N. J. Septi. 1, 190, 66 USPQ 440,463, 467,469,