Process for the preparation of 2,2-diphenyl-4-(dimethylamino)-pentane nitrile

A process for the preparation of 2,2-diphenyl-4-(dimethylamino)-pentane nitrile. A charge mixture is prepared comprising diphenylacetonitrile, 1-(dimethylamino)-2-halopropane, a base, water, a water-immiscible organic solvent, and a quaternary salt selected from a group consisting of tetrabutylammonium halides, tetrabutylammonium hydrogen sulfate, cetyltrimethylammonium halides, benzyltriphenylphosphonium halides, and methyltrialkyl (C.sub.8 -C.sub.10) ammonium halides. The mixture is heated under an inert atmosphere to effect formation of 2,2-diphenyl-4-(dimethylamino)-pentane nitrile by reaction of diphenylacetonitrile, 1-(dimethylamino)-2-halopropane and a base.

BACKGROUND OF THE INVENTION 
This invention relates to the manufacture of methadone and more 
particularly to an improved process for preparing the methadone precursor 
2,2-diphenyl-4-(dimethylamino)-pentane nitrile. 
Methadone hydrochloride, i.e. 6-(dimethylamino)-4,4-diphenyl-3-heptanone 
hydrochloride is widely used as a narcotic analgesic, particularly in 
clinical treatment for withdrawal from heroin addiction. Methadone is 
prepared by reaction of 2,2-diphenyl-4-(dimethylamino)-pentane nitrile 
with an ethylmagnesium halide. 
##STR1## 
Conventionally the amino nitrile precursor is prepared by the reaction of 
diphenylacetonitrile with 1-(dimethylamino)-2-halopropane and base. See 
Schultz et al. Journal of the American Chemical Society, 69, 188 and 2458 
(1947). In this reaction the base abstracts a proton from the 
diphenylacetonitrile and induces formation of a cyclic ethylenimmonium ion 
intermediate from the 1-(dimethylamino)-2-halopropane 
##STR2## 
The carbanion can react at either of two sites on the ethylenimonium ion 
to produce either the desired intermediate 
2,2-diphenyl-4-(dimethylamino)-propane nitrile or its isomer 
2,2-diphenyl-3-methyl-4-(dimethylamino)-butyronitrile. 
##STR3## 
When the synthesis of the intermediate is carried out, approximately equal 
proportions of both the methadone precursor and its isomer are formed. 
In order to drive the reaction of diphenylacetonitrile and 
1-(dimethylamino)-2-halopropane substantially to completion, it is 
necessary to azeotropically remove water from the reaction zone. A lengthy 
reaction period is required to azeotrope off the water and obtain the 
desired conversion of approximately 85%. As a consequence, the 
productivity of the methadone manufacturing process is relatively low. 
After completion of the above-described reaction, the methadone precursor 
must be isolated from its isomer and other components of the reaction 
mixture. This is conventionally accomplished by acidifying the reaction 
mixture with hydrochloric acid thereby forming the hydrochlorides of both 
amino nitrile isomers, which then concentrate in the aqueous phase. 
Thereafter, the phases are separated and an oil comprising the isomers is 
precipitated by addition of NaOH. Separation of the isomers is carried out 
by dissolving the oil in isopropyl alcohol and crystallizing 
2,2-diphenyl-4-(dimethylamino)-pentane nitrile from the solution. 
SUMMARY OF THE INVENTION 
Among the several objects of the present invention may be noted the 
provision of an improved process for the manufacture of methadone and in 
particular an improved process for the synthesis of the 
2,2-diphenyl-4-(dimethylamino)-pentane nitrile precursor; the provision of 
such a process which eliminates the need for azeotropic removal of the 
water by-product of the reaction; the provision of such a process which 
improves the productivity of the step of synthesizing the precursor; the 
provision of such a process which affords high yields of the precursor in 
a significantly shortened reaction cycle; and the provision of such a 
process which includes an improved method for recovery of the precursor. 
Briefly, therefore, the present invention is directed to a process for the 
preparation of 2,2-diphenyl-4-(dimethylamino)-pentane nitrile. In this 
process, a charge mixture is prepared comprising diphenylacetonitrile, 
1-(dimethylamino)-2-halopropane, a base, water, a water-immiscible organic 
solvent, and a quaternary salt selected from the group consisting of 
tetrabutylammonium halides, tetrabutylammonium hydrogen sulfate, 
cetyltrimethylammonium halides, benzyltriphenylphosphonium halides, and 
methyltrialkyl (C.sub.8 -C.sub.10) ammonium halides. The charge mixture is 
heated under an inert atmosphere to effect formation of 
2,2-diphenyl-4-(dimethylamino)-pentane nitrile by reaction of 
diphenylacetonitrile, 1-(dimethylamino)-2-halopropane and base. 
Other objects and features will be in part apparent and in part pointed out 
hereinafter.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 
In accordance with the present invention, it has been discovered that 
substantially improved productivity is realized where the reaction of 
diphenylacetonitrile with 1-dimethylamino-2-halo-propane and base is 
carried out in the presence of a quaternary ammonium or phosphonium salt. 
The quaternary salt exercises a catalytic effect on the reaction, markedly 
increasing the reaction rate and thereby permitting the improved 
productivity to be realized. Obviated is the need for azeotropic removal 
of reaction by-product water to drive the reaction forward. 
Advantageous yields are also provided by the process of the invention. 
Although the yields obtained are the same for the catalyzed and 
uncatalyzed processes where the reaction is carried fully to completion, 
for shortened reaction cycles of 2-4 hours which provide the highest 
productivity the process of the invention provides superior yields. The 
proportions of 2,2-diphenyl-4-(dimethylamino)-pentane nitrile produced 
relative to its isomer, 2,2 
diphenyl-3-methyl-4-(dimethylamino)-butyronitrile, are the same as in the 
uncatalyzed process. 
Certain particular catalysts have been found to have an especially 
advantageous effect in promoting the reaction between 
diphenylacetonitrile, base and 1-dimethylamino-2-halopropane. The most 
preferred catalysts include tetrabutylammonium chloride, 
tetrabutylammonium bromide, tetrabutylammonium iodide, and 
tetrabutylammonium hydrogen sulfate. Other effective catalysts include 
cetyltrimethylammonium chloride, cetyltrimethylammonium bromide, 
cetyltrimethylammonium iodide, benzyltriphenylphosphonium chloride, 
benzyltriphenylphosphonium bromide, benzyltriphenylphosphonium iodide, and 
the corresponding methyltrialkyl (C.sub.8 -C.sub.10) ammonium halides. 
To carry out the synthesis of the precursor, a reactor is charged with 
organic solvent, 1-dimethylamino-2-halopropane, diphenylacetonitrile, 
base, quaternary salt catalyst, and an aliquot of water. 
Preferably the base is sodium hydroxide or potassium hydroxide. 
Alternatively, sodium carbonate, trisodium phosphate, potassium carbonate, 
tripotassium phosphate and similar highly alkaline alkali metal salts may 
be used. The t-butoxides and azides of sodium and potassium may also be 
utilized but are not preferred because of the explosion hazard that they 
present. Where either sodium or potassium hydroxide is utilized as the 
base, it is conveniently introduced into the charge as an aqueous 
solution, typically having a strength of 50% by weight. 
Essentially any suitable water-immiscible organic solvent can be utilized 
for the reaction. Aromatic solvents are preferred, however, and toluene 
and xylene are most preferred. Toluene is a highly suitable solvent 
because the reaction proceeds rapidly and satisfactorily at toluene 
atmospheric reflux temperature. The use of a xylene solvent permits even 
higher reaction temperatures under atmospheric reflux conditions. Benzene 
is an effective solvent for the reaction but is not preferred both because 
of its toxic properties and also because of the need to maintain the 
reaction under pressure to achieve the desired reaction temperatures. 
Although the reactant ratios are not highly critical it is preferred to 
charge a moderate excess of 1-dimethylamino-2-halopropane so as to 
maximize the conversion of diphenylacetonitrile. An excess of base is also 
preferably charged. 
Substantial improvement in reaction rate as compared to the uncatalyzed 
process is achieved if the concentration of the quaternary salt catalyst 
is at least about 7 mole percent based on the diphenylacetonitrile 
concentration. Preferably at least about 10% of the catalyst is used. 
Higher concentrations of catalyst can be employed but are generally 
unnecessary. 
In order to inhibit the oxidation of diphenylacetonitrile and the formation 
of by-product benzoquinone, the reaction is preferably carried out under 
an inert atmosphere, for example, under a nitrogen blanket. As noted, it 
is convenient to conduct the reaction at toluene reflux temperature. This 
may typically be in the range of between about 88.degree. and about 
95.degree. C. Xylene reflux permits higher reaction temperatures. As a 
general proposition, the reaction should be carried out at a temperature 
of at least about 80.degree. C. Where the reaction is carried out at 
toluene reflux and with catalyst concentration of 10 mole percent based on 
diphenylacetonitrile, an 85-99% conversion to total amino nitriles is 
obtained, with a 40-45% conversion to the desired isomer, 
2,2-diphenyl-4-(dimethylamino)-pentane nitrile. 
The exact mechanism by which the quaternary salt acts as a catalyst in 
accelerating the reaction rate is not known. Quaternary ammonium and 
phosphonium salts are known to be so called "phase transfer" catalysts 
which promote certain reactions by conveying reactants or intermediates 
into the phase in which reaction occurs. According to the literature, it 
is generally believed that anionic or nucleophilic intermediate species 
formed in the aqueous phase combine with the quaternary ammonium or 
phosphonium cation to provide an intermediate whose distribution between 
phases favors the organic phase to a significantly greater extent than 
does the distribution of the nucleophile itself. It is further thought 
that the combined species reacts in the organic phase with another 
organic-soluble reactant, e.g., an alkyl halide, to produce the desired 
product, thereby regenerating the quaternary salt which returns to the 
aqueous phase and is available for further combination with the 
nucleophile. 
Although this mechanism may be at work in the reactions of the invention, 
it does not appear to explain either the need for water removal during the 
uncatalyzed reaction nor the specific effect of the quaternary salt in 
eliminating this need. Despite the fact that I am thus unable to provide a 
definitive explanation of the mechanism involved, I have nonetheless found 
that certain quaternary salt catalysts have a highly advantageous effect 
on the rate, productivity and yield of the precursor formation reaction 
where the conditions outlined above are maintained. 
In the process of the invention, a further improvement over the 
conventional method is provided in the steps for recovery of 
2,2-diphenyl-4-(dimethylamino)-pentane nitrile from the reaction mixture. 
In accordance with the improved method, the basic aqueous phase containing 
catalyst, reaction salts and excess base, is separated from the organic 
phase. The organic phase is then washed with water for removal of residual 
water-soluble impurities. After the washing step is complete, the solvent 
is stripped off, preferably under vacuum, to leave an oil which comprises 
the methadone precursor, its isomer 
2,2-diphenyl-3-methyl-4-(dimethylamino)-butyronitrile, and any unreacted 
diphenylacetonitrile or 1-dimethylamino-2-halopropane. To separate the 
isomers and isolate the methadone precursor, the oil is dissolved in a 
suitable solvent such as isopropyl alcohol and the resultant solution is 
cooled, thereby effecting crystallization of the desired precursor 
material. 
Methadone is prepared by the Grignard reaction between 
2,2-diphenyl-4-(dimethylamino)-pentane nitrile and an ethylmagnesium 
halide such as ethylmagnesium bromide. 
The following examples illustrate the invention. 
EXAMPLE 1 
To a reaction flask containing toluene (125 ml) was charged 
1-dimethylamino-2-chloropropane hydrochloride (50 g), diphenylacetonitrile 
(50 g), a 50% aqueous solution of sodium hydroxide (80 g), water (40 ml), 
and a methyltrialkyl (C.sub.8 -C.sub.10) ammonium chloride sold under the 
trade designation Adogen 464 by Ashland Chemical (4 g). The charge mixture 
was heated to reflux under a nitrogen atmosphere and stirred at reflux 
temperature for two hours. Heat was then withdrawn and the reaction 
mixture allowed to cool for about 30 min. 
After cooling the reaction mixture was transferred to a separatory funnel 
where it was mixed with distilled water (approximately 200 ml) and 
thereafter allowed to separate (2-3 min). After the phases had separated, 
the bottom water layer, which had a pH of approximately 13, was drawn off. 
The organic phase (approximately 220 ml) was then transferred to a beaker 
and additional water (100 ml) was added. The contents of the beaker were 
stirred and hydrochloric acid was added until the pH of the water phase 
was reduced to 2-3. This required approximately 25 ml of acid. Addition of 
acid formed the hydrochloride salt of 2,2 
diphenyl-4-(dimethylamino)-pentane nitrile and 
2,2-diphenyl-3-methyl-4-(dimethylamino)-butyronitrile which thereupon were 
extracted into the water phase. After the extraction was complete the 
phases were separated, providing an aqueous product layer (approximately 
220 ml) and an extracted organic layer (approximately 130 ml). Thereafter 
another aliquot of water (50 ml) was added to the extracted organic layer 
and the pH of the water phase again adjusted to 2-3. The aqueous phase was 
separated and combined with the aqueous phase from the initial stage of 
the extraction to provide an aqueous product phase having a total volume 
of approximately 280 ml. The spent organic phase (approximately 120 ml) 
containing unreacted organic starting materials was discarded. 
To the aqueous product phase, a 50% sodium hydroxide solution was added 
with stirring until the pH was increased to approximately 13. This 
required approximately 40 ml of caustic solution. Addition of caustic 
converted the hydrochloride salts to the free amines which commenced to 
separate from the organic phase. The mixture was heated to 
60.degree.-65.degree. C. to promote separation, and transferred to a 
separatory funnel where the bottom aqueous phase was separated and 
discarded. Adequate separation required approximately 30 min. The oil 
layer remaining in the separatory funnel was then transferred to a beaker 
with isopropyl alcohol (57 g), thereby producing an alcohol solution of 
the amino nitrile isomers. This solution was stirred, cooled to 
approximately 10.degree. C., and maintained at that temperature for about 
1/2 to 1 hr. so as to crystallize the product 
2,2-diphenyl-4-(dimethylamino)-pentane nitrile. The crystalline product 
was recovered by filtration, washed with two aliquots of cold (less than 
10.degree. C.) isopropyl alcohol (20 ml each), dried and weighed. Yield 
was 32.3 g (45%) of the product which exhibited a melting point of 
89.degree.-90.degree. C. As a basis of comparison, the melting point of 
the methadone precursor produced by the conventional commercial process 
was measured at 90.2-91.0. The melting point of a mixture of equal weights 
of the commercial material and the material of this example was 
89.5.degree.-90.2.degree. C. 
EXAMPLE 2 
Several reactions between diphenylacetonitrile, 
1-(dimethylamino)-2-chloropropane and base were carried out to compare the 
results achieved with no catalyst vs. the results achieved in the presence 
of various quaternary ammonium and phosphonium salts. 
In the first run of this example, a 350 ml, round bottom, 3-neck flask 
equipped with a mechanical stirrer, nitrogen flow, a thermometer, and a 
condenser was charged with diphenylacetonitrile (25 g, 0.13 moles) 
1-dimethylamino-2-chloropropane hydrochloride (25 g), 50% aqueous sodium 
hydroxide solution (40 g), water (20 ml), and toluene (65 ml). No catalyst 
was charged. The charge mixture was stirred under nitrogen, heated to 
reflux and held at reflux for 2 hr. Heating was then terminated, and the 
reaction mixture was cooled to less than 80.degree. C. and transferred to 
a separatory funnel using 100 ml of water. 
In the separatory funnel the phases were allowed to separate and the water 
phase was drawn off the bottom and discarded. The toluene phase (91 ml, 84 
g) was submitted for amino nitrile assay. The product was not recovered. 
In the remaining reaction runs of this example, the charge was the same as 
in the initial run except that a quaternary ammonium or phosphonium salt 
catalyst was also included in the charge mixture. Reaction and separation 
were carried out in the same manner as for the first run. 
Table I sets forth, for each of the runs of this example, the catalyst 
used, the amount of catalyst, the volume and weight of the washed toluene 
phase recovered after the separation of the water phase and the relative 
proportions of diphenylacetonitrile and amino nitriles in the toluene 
phase after washing. 
TABLE I 
__________________________________________________________________________ 
Catalyst Toluene Phase 
diphenyl- 
Run No. 
type amount 
Wt. 
Vol. 
acetonitrile w/w% 
aminonitrile w/w% 
__________________________________________________________________________ 
1 none -- 84 g 
91 ml 
22.4 77.6 
2 tetrabutyl- 
3.6g 
88 96 1.5 98.5 
ammonium chloride 
3 tetrabutyl- 
4.2 88 95 0.1 99.3 
ammonium bromide 
4 benzyltriethyl- 
3.0 90 95.5 
18.4 81.6 
ammonium chloride 
5 benzyltriethyl- 
3.5 95.5 
88 16.4 83.6 
ammonium bromide 
6 phenyltrimethyl- 
2.8 93 86 25.5 74.5 
ammonium bromide 
7 cetyltrimethyl- 
4.7 92 86 10.0 90.0 
ammonium bromide 
8 Benzyltriphenyl- 
phosphonium chloride 
5.0 93 100 12.5 87.5 
9 (n-Butyl)-triphenyl- 
5.2 90 98 17.9 82.1 
phosphonium bromide 
__________________________________________________________________________ 
EXAMPLE 3 
To a reaction flask of the type described in example 2, were charged 
diphenylacetonitrile (50 g) 1-dimethylamino-2-chloropropane hydrochloride 
(50 g) 50% sodium hydroxide solution (80 g), water (40 ml), toluene (125 
ml) and tetrabutylammonium bromide (4.2 g). The charge mixture was stirred 
for 5 min. and then sampled for analysis. Stirring was resumed and the 
charge mixture heated to reflux with a sample being taken when the mixture 
had been heated to 75.degree. C. Stirring was continued at reflux with 
periodic samples being taken from the reaction mixture to determine the 
extent of conversion at various periods thoughout the reaction cycle. 
These samples were analyzed to provide a profile for the reaction. 
To provide a comparative profile, another reaction was run with the same 
amounts of the same components of the charge mixture, except for the 
tetrabutylammonium bromide catalyst which was omitted in the second run. 
Samples were taken during the reaction cycle and analyzed to provide the 
data for a reaction profile for the case of no catalyst. 
The reaction profiles obtained from the runs of this example are shown in 
the single FIGURE of the drawing. As this drawing demonstrates, where the 
quaternary ammonium salt catalyst is used the reaction is substantially 
complete after two hours whereas a considerably longer reaction period is 
required to achieve the maximum extent of reaction where no catalyst is 
charged. 
In view of the above, it will be seen that the several objects of the 
invention are achieved and other advantageous results attained. 
As various changes could be made in the above methods without departing 
from the scope of the invention, it is intended that all matter contained 
in the above description or shown in the accompanying drawing shall be 
interpreted as illustrative and not in a limiting sense.