Preparation of amphetamines from phenylpropanolamines

Details Preparation of amphetamines from phenylpropanolamines Preparation of amphetamines from phenylpropanolamines

2001-10-29

2002-06-04

Barts, Samuel (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S381000, C564S374000, C560S239000, C560S232000, C560S106000, C560S105000, C560S254000

Reexamination Certificate

active

06399828

ABSTRACT:

BACKGROUND OF THE INVENTION
The instant invention relates to a novel process for the synthesis of amphetamine, methamphetamine, and related compounds from derivatives of phenylpropanolamine acid addition salts. This new process, applied to produce d-amphetamine, has several advantages over prior art d-amphetamine production routes: shorter cycle times, less labor-intensive steps, and better chemical hygiene. Certain combinations of pharmaceutically acceptable salts of d,l-amphetamine and d-amphetamine are useful in the treatment of attention deficit disorders.
Many methods of making amphetamine and related compounds are known in the prior art, including the commercially used Leukart-Wallach reaction for producing racemic amphetamine from phenylacetone. For example, in one commercial process, phenylacetone is reacted with formamide and formic acid to form (±)-N-formylamphetamine (racemic N-formylamphetamine). The racemic N-formylamphetamine is then hydrolyzed with sulfuric acid, the solution basified, and the resulting d,l-amphetamine ((±)-amphetamine; racemic amphetamine) is distilled with an overall yield of about 60%.
In the illegal syntheses of amphetamine and related compounds, such as those found on internet searches, phenylpropanolamine and pseudoephedrine, isolated from over-the-counter cough and cold products, are converted to amphetamine and methamphetamine respectively (see, for example, Otto Snow,
Amphetamine Synthesis
(Thoth Press: Spring Hill, Fla., 1998); http://www.hyperreal.org/drugs/synthesis/meth.synth.; or http://hive.lycaeum.org/book-store.htm/). Following one of the procedures used in illegal manufacture of amphetamine and related compounds, d,l-norephedrine was refluxed with hydriodic acid and red phosphorus to obtain a mixture of amphetamine and a compound believed to be a bis compound, 1-phenyl-2-(phenylisopropyl)aminopropane, in equal parts. By another procedure, heating norephedrine with thionyl chloride at reflux temperature, followed by catalytic hydrogenation of the resulting 2-amino-1-chloro-1-phenylpropane hydrochloride, gave amphetamine. To avoid the hazards of working with thionyl chloride, hydriodic acid, and red phosphorus, another route was desirable. The conversion of the hydroxyl group of phenylpropanolamine to a benzylic acyloxyester followed by removal by hydrogenolysis, the process of the instant invention, was investigated and found to be a good route. These three discrete synthetic routes are summarized in the examples of Scheme 1, with a process of the invention illustrated as the bottom pathway. In this Scheme, amphetamine is used for illustration only, these synthetic routes are applicable to related compounds with substitution patterns obvious to those skilled in the art.
Currently, dextroamphetamine is obtained from racemic amphetamine through a lengthy, labor-intensive process. It is obtained in 23% yield from racemic amphetamine via tartrate salt resolution followed by basification and distillation. In the tartrate salt resolution step, a hot solution of 37% hydrochloric acid, methanol, tartaric acid, and the racemic amphetamine is drained from a reactor into stainless steel pots, and the hot mixture is allowed to cool undisturbed for 16 hours while the d-amphetamine tartrate salt predominantly crystallizes. The solvent is then decanted from each of the stainless steel pots and the recovered d-amphetamine tartrate salt is transferred by hand to a centrifuge, where the salt is spun dry, reslurried with methanol, and centrifuged dry again. The tartrate resolution step is then repeated until the salt obtained meets the melting point and optical rotation specifications desired.
Using the process of the invention, dextroamphetamine (S-(+)-amphetamine) can be stereospecifically prepared from a phenylpropanolamine having the S configuration at the carbon bearing the amino group, e.g., 1R,2S-(−)-norephedrine or 1S,2S-(+)-norpseudoephedrine (the erythro form of phenylpropanolamine is norephedrine and the threo form is norpseudoephedrine). In the process of the invention, the otherwise higher cost of the appropriate phenylpropanolamine diastereomers useful for preparing dextroamphetamine is offset by the shorter cycle times, a less labor-intensive process, and better chemical hygiene.
SUMMARY OF THE INVENTION
The process comprises ester formation and then removal of the benzylic acyloxy group by catalytic hydrogenation or catalytic transfer hydrogenation. As pointed out above, when it is applied to the production of d-amphetamine, the process has several advantages over current d-amphetamine production routes: shorter cycle times, less labor-intensive steps, and better chemical hygiene. Further optimization of yields and operation cycle times using optimization methods known to those skilled in the art would only increase these advantages.
The general process is shown in Scheme 2 below.
In Scheme 2, R
1
is hydrogen or a lower alkyl group;
each R
2
is independently a hydrogen, halogen, lower alkyl group, lower alkoxy group, lower alkyl group substituted with 1 to 5 halogens, lower alkoxy group substituted with 1-5 halogens, or both R
2
together when on adjacent carbons constitute a —O(CH
2
)
x
O— group where x is 1 to 4, thereby forming a ring structure fused with the phenyl group;
R
3
is a C
1
-C
8
-alkyl group, a C
1
-C
12
-aralkyl group, C
1
-C
12
-alkaryl group, or a phenyl group, each optionally substituted by 1 to 5 substituents selected from halogen, hydroxy, or C
1
-C
6
-alkyl; and
HX is an equivalent of an organic or inorganic acid, preferred acids include hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid and other carboxylic acids such as benzoic acid, tartaric acid, succinic acid, aspartic acid, saccharic acid, oxalic acid, malic acid, and the like.
In step A, the phenylpropanolamine salt starting material of formula II is acylated with an acylating agent, in this example, (R
3
CO)
2
O in R
3
CO
2
H, to form the corresponding acylated phenylpropanolamine salt of formula III in a solvent at elevated temperature. In step B, the acylated phenylpropanolamine salt of formula III is hydrogenated using catalytic hydrogenation or catalytic transfer hydrogenation to obtain a compound of formula I.
For a direct route to dextroamphetamine, both b
1
R,2S-(−)-norephedrine and 1S,2S-(+)-norpseudoephedrine have the correct steric configuration at the carbon bearing the amino group necessary to produce d-amphetamine [S-(+)-amphetamine] as shown in Scheme 3. 1R,2S-(−)-norephedrine is generally commercially available. This same process produces d-methamphetamine starting with either 1R,2S-(−)-ephedrine or 1S,2S-(+)-pseudoephedrine.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms and Conventions Used
Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification and appended claims, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C
1
-C
10
alkyl means an alkyl group or radical having 1 to 10 carbon atoms. The term “lower” applied to any carbon-containing group means a group containing from 1 to 8 carbon atoms, as appropriate to the group (i.e., a cyclic group must have at least 3 atoms to constitute a ring). In general, for groups comprising two or more subgroups, the last named group is the radical attachment point, for example, “alkylaryl” means a monovalent radical of the formula Alk—Ar—, while “arylalkyl” means a monovalent radical of the formula Ar—Alk— (where Alk is an alkyl group and Ar is an aryl group). Furthermore, the use of a term designating a monovalent radical where a divalent radical i

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