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     A few procedures for the resolution of racemic (meth)amphetamine
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The dextro isomer of amphetamine and methamphetamine is the d, (+), D or S
isomer; the levo isomer is the l, (-), L or R isomer. The racemic mixtures may
be referred to as d,l or (+,-) or DL or (R)(S). Classical resolution techniques
are often tedious and usually afford poor yields. The best published procedure
seems to be that of Rusznak et al. below which utilizes a selective extraction
rather than the usual crystallization.

Selective Extraction of d-Methamphetamine with d-Tartaric Acid:

Rusznak et al., Resolution of Phenylisopropylamines, Hung. Teljes, 12,208 (Cl.
C07B), 28 Sep. 1976, Appl. 1,516, 08 Nov. 1974; C.A. 85: 192337q, p. 518 (1976).

Phenylisopropylamines and phenylisopropylmethylamines and various substituted
amines were resolved with 0.5 mole tartaric acid in benzene-water containing
0.5 mole sodium hydroxide or potassium hydroxide by selective extraction of
either enantiomer.

A mixture of 0.1 mole (13.52 g.) phenylisopropylamine (or 14.92 g.
methamphetamine base) in 60 ml benzene, 0.05 mole d-tartaric acid (7.50 g.) in
30 ml water, and 2 g sodium hydroxide (reagent grade or titrated equivalent) in
3 ml water was kept 4 hours with intermittent shaking, and the organic phase
evaporated to give 98% L-phenylisopropylamine. The aqueous phase was extracted
with benzene at pH 13 and evaporated to give 96% D-enantiomer.

Selective Crystallization of Methamphetamine with d-Tartaric Acid:

Rusznak et al., Resolution of 1-Phenylisopropyl methyl amine, Hung. Teljes,
12,210 (Cl. C07B), 28 Sep. 1976, Appl. 1,520, 04 Dec. 1974; C.A. 85: 192335n,
p. 518 (1976).

Phenylisopropylmethylamine was resolved by treatment with 0.4-6 moles of dextro
tartaric acid in water or aqueous ethanol containing 0.4-6 moles hydrogen
chloride.

A mixture of phenylisopropylmethylamine 150, d-tartaric acid 82.5, and H2O 330 g
was treated with HCl to pH 4 to deposit 120 g L-phenylisopropylmethylamine-
d-tartrate salt, which gave 88 g L-phenylisopropylmethylamine. The D-enantiomer
(58 g as the HCl salt) was isolated from the filtrate.

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British Patent no: 508,757 It is known there is no recognisable difference
in the action in respect of pharmacological effect between racemates and
the optical components of parahydroxymethamphetamine. it has now been
unexpectedly ascertained that in contrast, optically active amines of
higher efficacy can be obtained from amphetamine and its N homologous
derivatives by splitting racemate into its active components by means of
optically active acids. 
 
Example: 
 
85 parts of racemic methamphetamine are introduced into a solution of 100
parts of d-tartaric acid in 1000 parts of methyl alcohol. After protracted
standing about 100 parts of the precipitated salt are aspirated off and
extracted with hot ethyl alcohol. Since the d-tartrate of dextrorotary
methamphetamine is readily soluble in both methyl and ethyl alcohol
whereas the d-tartrate of levorotary methamphetamine is sparingly soluble
both in methyl alcohol and hot ethyl alcohol an extremely simple
separation of the d-tartrates of the optical antipodes of the base is
effected. 
 
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US patent : 2,276,508

my invention relates to a novel method for the separation of the optically
active isomers of amphetamine and it compromises methods wherein the laevo
and dextro isomers, in the form of their neutral salts with d-tartaric
acid, are separated by the fractional crystallisation from an alcohol
solution of such salts, the neutral d-tartrate of the laevo amine being
obtained as a crystalline material, and it more particularly relates to
the separation of the laevo-isomer, in the form of its neutral salt with
d-tartaric acid, and the recovery of the laevo amine, as free base, from
such neutral salt; all as more fully hereinafter set forth and as claimed. 
 
It is known in the art (leithe,- "Ber. D. Chem. Gesell." (1932) p664) that
d-amphetamine d-bitartrate may be obtained as a crystalline acid
tartrate, from the racemic (- methylphenethylamine, by reacting the racemic
amine with sufficient d-tartaric acid to form a mixture of the tartrates of
the d- and l- amine and then fractionally crystallising the bitartrate of
the d-amine from an alcohol solution of the mixture of acid tartrates so
obtained. To obtain the d-amine as the free base, the acid tartrate may be
decomposed with caustic alkali and the free base recovered by distillation
in vacuo. By using l-tartaric acid in such method, the l-amphetamine 
l-bitartrate is obtained as a crystalline material by fractional 
crystallisation. This acid tartrate may likewise be decomposed with alkali
to obtain the l-amine as a free base.
 
That is, either dextro or laevo -amphetamine have been previously obtained
from the racemic form by certain known prior methods. But in such prior
methods, the separation of the desired isomer is effected by the fractional
crystallisation of acid tartrates. And in those methods, d-tartaric acid is
used to obtain the dextro amine and l-tartaric acid to prepare the laevo
amine. However while those processes are operable chemically, they have
serious disadvantages, particularly with regard to the separation of
l-amphetamine by means of d-tartaric acid, in that while d-tartaric acid is
readily available and comparatively cheap, l-tartaric acid at the present
time is both difficult to obtain and expensive in pure form (d tartaric acid
comes from fruit, l-tartaric acid is 'unnatural'). Thus by the method
outlined above d-amphetamine may be readily and cheaply prepared while the
laevo form can only be obtained at great expense.
 
I have discovered a method whereby both optically active forms of
amphetamine, and especially the laevo form may be prepared by the use of
d-tartaric acid alone. This novel method greatly simplifies the process and
makes the therapeutically useful isomers readily available.
 
Broadly, the method according to this invention comprises the separation of
l-amphetamine from dl-amphetamine by treatment with d-tartaric acid for the
production of a mixture of neutral d-tartrates and crystallisation from a
solution, it having been found that l-amphetamine may be readily separated
by crystallisation from a solution of the neutral d-tartrates.
 
The method according to this invention may be applied to , for example,
racemic amphetamine, or to any mixture of the optically active isomers
thereof in which the laevo form is present in amount not substantially less
than the dextro form.
 
Again, the method according to this invention is applicable to mixtures rich
in the laevo form, such as result from initial separation of the dextro form
by methods heretofore known, as, for example, by crystallisation from a
solution of a mixture of acid d-tartrates.
 
Where it is desired to effect separation of the laevo form from a mixture a
mixture rich in the dextro form, it will usually be necessary to first
effect separation of a part of the dextro form by methods heretofore known
and then to apply the method in accordance with this invention to the
remaining mixture.
 
As will be appreciated, the method in accordance with this invention, while
primarily of the greatest advantage for effecting separation of l-(-
methylphenethylamine, provides also procedure for the separation of 
d-amphetamine.
 
As more specifically illustrative of the method in accordance with this
invention for the separation of the l-enantiomorph form, for example,
racemic amphetamine, by the use of d-tartaric acid alone and with
separation also of d-amphetamine, the following procedure may be
employed and will be found to be efficient.
Two mols, for example, 270 grams, of racemic amphetamine base are
reacted with one mol (150 grams) of d-tartaric acid, thereby forming a
dl-amphetamine d-tartrate, a neutral salt. The neutral salt thus
obtained is fully dissolved by the addition of sufficient, say about 1 litre,
of absolute ethanol, and heating to about boiling point. The solution is then
allowed to cool to room temperature with occasional stirring to effect
crystallisation. The crystals are filtered off and will be found to contain
a preponderance of the laevo enantiomorph. On recrystallisation the
preponderance of the l-enantiomorph is increased and the process is
repeated until no further change in optical rotation is effected and a
reading of [(]20(D = -6.5 is obtained in a concentration of 8 grams per
100 cc of aqueous solution. The product thus obtained is 
l-amphetamine d-tartrate. The residual solid in the mother
liquors is repeatedly and systematically crystallised, yielding a further
fraction of l-amphetamine d-tartrate which may be purified by
recrystallization. d-amphetamine may be readily recovered from
the mother liquors by the addition of tartaric acid thereto for the 
formation of acid tartrates and separation of d-amphetamine
d-bitartrate by crystallisation.
 
The free base of either optically active isomer may be obtained by addition
to the d-tartrate in the case of the laevo isomer and the d-bitartrate in
the case of the dextro isomer of alkali in excess, as for example, by the
addition of an aqueous solution of caustic soda, which will cause the base
to separate as an oil which may be recovered and purified by any well known
procedure.
 
As a further example, one mol of racemic -amphetamine base is
reacted with 1.2 mols of tartaric acid and the resulting bitartrate is
dissolved in, for example, 80% ethanol, with heating almost to the boiling
point. The solution is then allowed to cool to about 60(C and filtered hot.
Repeated crystallisation is then carried out until crystals having an optical
rotation [(]20(D = +30.8 are obtained in a concentration of 8 grams per 
100cc of aqueous solution. The product thus obtained is pure 
d-amphetamine d-bitartrate. The residual solid in the mother 
liquors is repeatedly and systematically crystallised, yielding a further
fraction of d-amphetamine d-bitartrate which may be purified by
recrystallisation.
 
The residual solid in the mother liquors now remaining comprises a
preponderance of l-amphetamine d-bitartrate, which may now be
separated by effecting neutralisation of the excess of d-tartaric acid
present with production of neutral tartrates and effecting separation of the
l-amphetamine d-tartrate by crystallisation.
Neutralisation of the excess tartaric acid may be effected where, as in the
case of the example above, the mother liquors comprise alcoholic solutions
by dividing the total volume of the mother liquors into equal parts,
removing, for example, by evaporation, the alcohol from one part, adding
excess alkali, liberating the free base, which, as has been indicated,
separates as an oil, separating and drying the free base with for example,
caustic potash and then adding the free base to the other portion of the
mother liquors with heating to forma solution. Such procedure will result in
the formation of a neutral d-tartrate solution. From the solution so formed
l-amphetamine d-tartrate may be separated by repeated
crystallisation and the free base may be recovered as described
above.
 
Following the procedure in accordance with this invention, other salts of
the optically active isomers may be obtained from the free bases of the
isomers by exact neutralisation of either base, with an organic or inorganic
acid corresponding to the salt desired. Thus, by way of example, any desired
organic or inorganic salt of the optically active isomers, in addition to
the tartrates initially obtained, as for example, sulphates, hydrochlorides,
oleates, etc., may be obtained by exact neutralisation of either optically
active base with the acid corresponding to the desired salt.
Following the procedure according to this invention it will be apparent that
the l-enantiomorph may be initially separated from the racemic 
amphetamine, or from any mixture of the optically active isomers
in which the dextro form is not in substantial excess; and that following
the separation of the laevo form the dextro form may be recovered from the
mother liquors by the addition thereto of d-tartaric acid for the formation
of acid d-tartrates and crystallisation.
 
Again, as will now be evident, where the l-amphetamine is to be
separated from a mixture of the optically active isomers in which the dextro
form is in substantial excess, or in preponderance, the dextro form will
first be separated by crystallisation following treatment with d-tartaric
acid to form d-bitartrates and the laevo form will then be recovered by
crystallisation following neutralisation with the formation of neutral
d-tartrates.
 
Thus, it will now be understood that the method in accordance with this
invention comprises essentially the separation of l-amphetamine
from a racemic amphetamine and from the various mixtures of d-
and l-amphetamine in which the laevo form is present in amount
not substantially less than the dextro form with the use of d-tartaric acid
for the formation of neutral d-tartrates and separation of
l-amphetamine d-tartrate by crystallisation , whether the
procedure be for the initial separation of the l-amphetamine
d-tartrate, as from racemic amphetamine, or a mixture in which
the dextro form is not in substantial excess, or is preceded by preliminary
separation of the dextro form by known methods, as in the case of mixtures
in which the dextro form predominates.
 
It will be understood that proceeding in accordance with this invention the
free base, l-amphetamine may be readily obtained from the
l-amphetamine d-tartrate by treatment of the d-tartrate with
alkali in excess, resulting in separation of the free base as an oil which
may be recovered and purified by any well known method.

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RESOLUTION OF AMPHETAMINE AND METHAMPHETAMINE

        The dextro isomer of amphetamine and methamphetamine is the d, (+), 
D or S isomer; the levo isomer is the l, (-), L or R isomer.  The racemic 
mixtures may be referred to as d,l or (+,-) or DL or (R)(S).
        Classical resolution techniques are often tedious and usually 
afford poor yields.  The best published procedure seems to be that of 
Rusznak et al. below which utilizes a selective extraction rather than the 
usual crystallization.

Selective Extraction of d-Methamphetamine with d-Tartaric Acid:

Rusznak et al., Resolution of Phenylisopropylamines, Hung. Teljes, 12,208 
(Cl. C07B), 28 Sep. 1976, Appl. 1,516, 08 Nov. 1974; CA 85, 192337q (1976).

        Phenylisopropylamines and phenylisopropylmethylamines and various 
substituted amines were resolved with 0.5 mole tartaric acid in benzene-water 
containing 0.5 mole sodium hydroxide or potassium hydroxide by selective
extraction of either enantiomer.
        A mixture of 0.1 mole (13.52 g.) phenylisopropylamine (or 14.92 g. 
methamphetamine base) in 60 ml benzene, 0.05 mole d-tartaric acid (7.50 g.) 
in 30 ml water, and 2 g sodium hydroxide (reagent grade or titrated equiv.)
in 3 ml water was kept 4 hours with intermittent shaking, and the organic 
phase evaporated to give 98% L-phenylisopropylamine.  The aqueous phase was 
extracted with benzene at pH 13 and evaporated to give 96% D-enantiomer.

Other solvents such as toluene or xylene are likely to give similar results.

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Selective Crystallization of Methamphetamine with d-Tartaric Acid:

Rusznak et al., Resolution of Meth. , Hung. Teljes, 12,210 (Cl. C07B), 
28 Sep. 1976, Appl. 1,520, 04 Dec. 1974; C.A. 85:  192335n, p. 518 (1976).

        Phenylisopropylmethylamine was resolved by treatment with 0.4-6 moles 
of dextro tartaric acid in water or aqueous ethanol containing 0.4-6 moles 
hydrogen chloride.
        A mixture of phenylisopropylmethylamine 150, d-tartaric acid 82.5, 
and H2O 330 g was treated with HCl to pH 4 to deposit 120 g L-phenylisopropyl-
methylamine-d-tartrate salt, which gave 88 g L-phenylisopropylmethylamine.  
The D-enantiomer (58 g as the HCl salt) was isolated from the filtrate.

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Two mols, for example, 270 grams, of racemic amphetamine base are reacted 
with one mol (150 grams) of d-tartaric acid, thereby forming dl-amphetamine 
d-tartrate, a neutral salt. The neutral salt thus obtained is fully dissolved 
by the addition of sufficient, say about 1 liter, of absolute ethanol, and 
heating to about the boiling point. The solution is then allowed to cool to 
room temperature with occasional stirring to effect crystallization. The 
crystals are filtered off and will be found to contain a preponderance of 
the levo enantiomorph.

The residual solid in the mother liquors is repeatedly and systematically 
crystallized, yielding a further fraction of amphetamine d-tartrate which 
may be purified by recrystallization. d-amphetamine may be readily recovered 
from the mother liquors by the addition of tartaric acid thereto for the 
formation of acid tartrates and separation of d-amphetamine d-bitartrate by 
crystallization.

The free base of either optical isomer may be obtained by addition to the 
d-tartrate in the case of the levo isomer and the d-bitartrate in the case 
of the dextro isomer of alkali in excess, as, for example, by the addition 
of an aqueous solution of caustic soda, which will cause the base to 
separate as an oil which may be recovered and purified by any well-known 
procedure. The base is exactly neutralized with sulfuric acid to give the 
sulfate.

References

Merck Index 2918 PDR pp. 1450, 1711 
OCDS Vol. 1 p.70 (1977) 
I.N. p. 301 
REM p.881 
Nabenhauer, F.P.; U.S. Patent 2,276,508; March 17, 1942.

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