Europäisches Patentamt

(19) European Patent Office *EP001442006B1*

Office européen des brevets (11) EP 1 442 006 B1
(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.7: C07C 209/00
of the grant of the patent:
24.08.2005 Bulletin 2005/34 (86) International application number:
PCT/US2002/034400
(21) Application number: 02802245.7
(87) International publication number:
(22) Date of filing: 28.10.2002 WO 2003/037843 (08.05.2003 Gazette 2003/19)

(54) PREPARATION OF AMPHETAMINES FROM PHENYLPROPANOLAMINES

VERFAHREN ZUR HERSTELLUNG VON AMPHETAMINEN AUS PHENYLPROPANOLAMINEN
PREPARATION D’AMPHETAMINES A PARTIR DE PHENYLPROPANOLAMINES

(84) Designated Contracting States: • REINER LUCKENBACH: "Beilstein Handbuch

AT BE BG CH CY CZ DE DK EE ES FI FR GB GR der Organischen Chemie, vol. XII, 4th Ed., 4th
IE IT LI LU MC NL PT SE SK TR Suppl., p. 2586 to 2591" 1984 , SPRINGER
VERLAG , BERLIN . HEIDELBERG . NEW YORK
(30) Priority: 29.10.2001 US 20488 TOKYO XP002235852 page 2586 -page 2591
• HANS-G. BOIT: "Beilsteins Handbuch der
(43) Date of publication of application: Organischen Chemie, vol. XII, 4th Ed., Third
04.08.2004 Bulletin 2004/32 Suppl. page 2664 to page 2669" 1973 ,
SPRINGER VERLAG , BERLIN . HEIDELBERG .
(73) Proprietor: Boehringer Ingelheim Chemicals, Inc. NEW YORK XP002235853 page 2664 -page 2669
Peterburg, VA 23805 (US) • DATABASE CROSSFIRE BEILSTEIN [Online]
BEILSTEIN INSTITUT ZUR FOEDERUNG DER
(72) Inventors: CHEMISCHEN WISSENSCHAFTEN,
• BOSWELL, Robert F., FRANKFURT AM MAIN, DE;
Boehringer Ingelheim Chem. Inc Database-Accession no. 4271306 (Reaction ID),
Petersburg, VA 23805 (US) XP002235854 & ANAL. CHEM., vol. 58, no. 8,
• LO, Young, S., 1986, pages 1643-1648,
Boehringer Ingelheim Chemicals, Inc • DATABASE CROSSFIRE BEILSTEIN [Online]
Petersburg, VA 23805 (US) BEILSTEIN INSTITUT ZUR FOEDERUNG DER
CHEMISCHEN WISSENSCHAFTEN,
(74) Representative: Kläs, Heinz-Gerd FRANKFURT AM MAIN, DE;
Boehringer Ingelheim GmbH, Database-Accession no 2103532 ( Reaction ID),
Abteilung Patente XP002235855 & JOURNAL OF THE AMERICAN
55216 Ingelheim/Rhein (DE) CHEMICAL SOCIETY., vol. 103, no. 20, 1981,
pages 6157-6163, DC US
(56) References cited: • LLEWELLYN H. WELSH: "The constitution of
FR-A- 2 389 597 US-A- 2 802 828 Acetylephedrine and acetyl-psi-ephedrine"
JOURNAL OF THE AMERICAN CHEMICAL
• HANS-G. BOIT: "Beilsteins Handbuch der SOCIETY., vol. 69, 1947, pages 128-136,
Organischen Chemie, vol. XIII, 4th Ed., Third XP002244101 DC US
Suppl., pages 1718, 1719, 1724, 1725" 1973 , • HANS-G. BOIT: "Beilsteins Handbuch der
SPRINGER VERLAG , BERLIN . HEIDELBERG . organischen Chemie, vol. XIII, 4th Edition, 3th
NEW YORK XP002235851 page 1718, Suppl., pages 1724-1725" 1973 ,
EP 1 442 006 B1

paragraphs 2 and 3, page 1724, last paragraph SPRINGER-VERLAG , BERLIN . HEIDELBERG .

to page 1725, paragraph 3 NEW YORK XP002244102 page 1274, paragraph
3 -page 1275, paragraph 3

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give
notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in
a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art.
99(1) European Patent Convention).

Printed by Jouve, 75001 PARIS (FR)

 EP 1 442 006 B1

Description

Background of the Invention

5 [0001] 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.
10 [0002] 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
15 of about 60%.
[0003] 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, Florida, 1998); http://www.hyperreal.org/drugs/synthesis/meth.synth.; or http://hive.lycaeum.org/
20 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 com-
pound believed to be a bis compound, 1-phenyl-2-(phenylisopropyl)aminopropane, in equal parts. By another proce-
dure, heating norephedrine with thionyl chloride at reflux temperature, followed by catalytic hydrogenation of the re-
sulting 2-amino-1-chloro-1-phenylpropane hydrochloride, gave amphetamine. To avoid the hazards of working with
25 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
30 to those skilled in the art.

35

40

45

50

[0004] Currently, dextroamphetamine is obtained from racemic amphetamine through a lengthy, labor-intensive proc-
55 ess. 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 undis-
turbed for 16 hours while the d-amphetamine tartrate salt predominantly crystallizes. The solvent is then decanted

2
 EP 1 442 006 B1

from each of the stainless steel pots and the recovered d-amphetamine tartrate salt is transferred by hand to a centri-
fuge, 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.
[0005] Using the process of the invention, dextroamphetamine (S-(+)-amphetamine) can be stereospecifically pre-
5 pared 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 phe-
nylpropanolamine diastereomers useful for preparing dextroamphetamine is offset by the shorter cycle times, a less
labor-intensive process, and better chemical hygiene.
10
Summary of the Invention

[0006] The process comprises ester formation and then removal of the benzylic acyloxy group by catalytic hydro-
genation or catalytic transfer hydrogenation. As pointed out above, when it is applied to the production of d-ampheta-
15 mine, 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.
[0007] The general process is shown in Scheme 2 below.

20

25

30
[0008] In Scheme 2, R1 is hydrogen or a lower alkyl group;

each R2 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 R2 together when on adjacent
35 carbons constitute a -O(CH2)xO- group where x is 1 to 4, thereby forming a ring structure fused with the phenyl
group;
R3 is a C1-C8-alkyl group, a C1-C12-aralkyl group, C1-C12-alkaryl group, or a phenyl group, each optionally sub-
stituted by 1 to 5 substituents selected from halogen, hydroxy, or C1-C6-alkyl; and
HX is an equivalent of an organic or inorganic acid, preferred acids include hydrofluoric acid, hydrochloric acid,
40 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.

[0009] In step A, the phenylpropanolamine salt starting material of formula II is acylated with an acylating agent, in
45 this example, (R3CO)2O in R3CO2H, 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.
[0010] For a direct route to dextroamphetamine, both 1R,2S-(-)-norephedrine and 1S,2S-(+)-norpseudoephedrine
have the correct steric configuration at the carbon bearing the amino group necessary to produce d-amphetamine
50 [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.

55

3
 EP 1 442 006 B1

10

15

20

25

Detailed Description of the Invention

Definition of Terms and Conventions Used

30
[0011] 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.
35 [0012] In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding
the group, for example, C1-C10 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
40 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 is suitable shall be construed to designate the divalent radical and vice versa. Unless otherwise specified,
conventional definitions of terms control and conventional stable atom valences are presumed and achieved in all
formulas and groups.
45 [0013] The terms "alkyl" or "alkyl group" mean a branched or straight-chain saturated aliphatic hydrocarbon mono-
valent radical having 1-10 carbons. This term is exemplified by groups such as methyl, ethyl, n-propyl, 1-methylethyl
(isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), and the like. It may be abbreviated "Alk".
[0014] The terms "alkenyl" or "alkenyl group" mean a branched or straight-chain aliphatic hydrocarbon monovalent
radical of 2-10 carbons containing at least one carbon-carbon double bond. This term is exemplified by groups such
50 as ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl, de-
cenyl, and the like.
[0015] The terms "alkynyl" or "alkynyl group" mean a branched and straight-chain aliphatic hydrocarbon monovalent
radical of 2-10 carbons containing at least one carbon-carbon triple bond. This term is exemplified by groups such as
ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl, decynyl, and the like.
55 [0016] The terms "alkoxy" or "alkoxy group" mean a monovalent radical of the formula AlkO- where Alk is an alkyl
group. This term is exemplified by groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-
butoxy, pentoxy, and the like.
[0017] The terms "aryloxy" or "aryloxy group" mean a monovalent radical of the formula ArO-, where Ar is aryl. This

4
 EP 1 442 006 B1

term is exemplified by groups such as phenoxy, naphthoxy, and the like.

[0018] The terms "alkylcarbonyl", "alkylcarbonyl group", "alkanoyl", or "alkanoyl group" mean a monovalent radical
of the formula -C(O)Alk, where Alk is alkyl or hydrogen.
[0019] The terms "aryl" or "aryl group" mean a substituted or unsubstituted aromatic carbocyclic monovalent or di-
5 valent radical of from 6 to 14 carbon atoms having a single ring (e.g., phenyl or phenylene) or multiple condensed rings
(e.g., naphthyl or anthryl). Unless otherwise specified, the aryl ring may be attached at any suitable carbon atom which
results in a stable structure and, if substituted, may be substituted at any suitable carbon atom with one or more
substituents selected from halogen, alkyl, alkoxy, aryl, acyl, nitro, cyano, and the like which results in a stable structure.
Exemplary aryl groups include phenyl, naphthyl, anthryl, phenanthryl, indenyl, heptalenyl, biphenyl, biphenylenyl, azu-
10 lenyl, pentalenyl, and the like. It may be abbreviated "Ar".
[0020] The terms "arylcarbonyl", "arylcarbonyl group", "aroyl" or "aroyl group" mean a monovalent radical of the
formula -C(O)Ar, where Ar is aryl as defined above.
[0021] The terms "acyl" or "acyl group" mean a monovalent radical of the formula -C(O)R, where R is a substituent
selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, and the like, each may be optionally substituted
15 with one or more groups selected from halogens, alkoxy, hydroxy, nitro, cyano, alkyl aryl, and the like. Preferably R is
a lower alkyl or phenyl, each optionally substituted. As such, the terms comprise alkylcarbonyl groups and arylcarbonyl
groups.
[0022] The term "acylating agent" means a reactant that, when reacted with a compound having a nucleophilic site
capable of reaction with the acylating agent, causes an acyl group to be covalently bound to one or more sites on the
20 compound. Acylating agents include, but are not limited to, reagents having the formula RC(O)X, in which X is a halogen,
an acyloxy group of formula R'C(O)O-, where R' has the same meaning of the R group defined in the previous para-
graph. As such, the term encompasses carboxylic acids, carboxylic acid anhydrides, lower esters of carboxylic acids,
and acid halides. Preferably, the acylating agents are acid halides or acid anhydrides. Such acylating agents may be
mono-, di-, tricarboxylic, or polycarboxylic acylating agents. The acid anhydrides may be symmetrical, asymmetrical,
25 or mixed anhydrides. In addition, acylating agents include in situ-generated o-acyl isoureas, compounds produced
from the reaction of an acid (e.g., bromoacetic acid) and a carbodiimide (e.g., DIC and DCC), and isolated o-acyl
isoureas. Exemplary and preferred acylating agents include acetyl chloride, acetyl bromide, propionyl chloride, benzoyl
chloride, acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, hexanoic anhydride, formic acetic
anhydride, benzoic anhydride, trifluoroacetylchloride, methyl trifluoroacetate, ethyl trifluoroacetate, and the like.
30 [0023] The term "acetylating agent" means an acylating agent wherein the acyl group is acetyl.
[0024] The terms "acylation", "acylating", and the like refer to a chemical reaction whereby an acyl group is added
to another compound or moiety using an acylating agent.
[0025] The terms "acetylation", "acetylating", and the like refer to a chemical reaction whereby an acetyl group is
added to another compound or moiety using an acetylating agent.
35 [0026] The term "aliphatic group" means a non-aromatic straight or branched chain hydrocarbon group. As such,
the term comprises alkyl, alkenyl, and alkynyl groups.
[0027] The term "alicyclic group" means a non-aromatic cyclic hydrocarbon group. As such, the term comprises
cycloalkyl, cycloalkenyl, and cycloalkynyl groups.
[0028] The term "carboxylic acid" means an organic acid of the formula RC(O)OH, where R is a substituent selected
40 from hydrogen or a substituent selected from a lower aliphatic group, lower alicyclic group, an aryl group, an aryl-alkyl
group, or an alkyl-aryl group optionally substituted by halogen, alkyl, alkoxy, aryl, etc. This term is exemplified by formic
acid, acetic acid, propanoic acid, butanoic acid, 2-methylpropanoic acid, pentanoic acid, propenoic acid, 2-methylpro-
penoic acid, 2-butenoic acid, cinnamic acid, benzoic acid, cyclobutanecarboxylic acid, salicylic acid, and the like.
[0029] The term "dicarboxylic acid" means an organic acid of the formula R(C(O)OH)2, where R is either a bond (i.
45 e., oxalic acid) or a divalent hydrocarbon group selected from a C1-C6 alkylene group optionally substituted with hydroxy,
halogen, alkoxy, and the like, lower alicyclic group, an aryl group, an aryl-alkyl group, or an alkyl-aryl group. This term
is exemplified by oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumeric acid, phthalic
acid, isophthalic acid, terephthalic acid, saccharic acid and the like.
[0030] The term "tricarboxylic acid" means an organic acid of the formula R(C(O)OH)3, where R is either a bond (i.
50 e., oxalic acid) or a substituent selected from a lower aliphatic group, lower alicyclic group, an aryl group, an aryl-alkyl
group, or an alkyl-aryl group optionally substituted with hydroxy, halogen, alkoxy, and the like. This term is exemplified
by citric acid.
[0031] The terms "alkylcarbonyloxy" or "alkylcarbonyloxy group" mean a monovalent radical of the formula -OC(O)
Alk, where Alk is alkyl optionally substituted with hydroxy, halogen, alkoxy, and the like.
55 [0032] The terms "arylcarbonyloxy" or "arylcarbonyloxy group" mean a monovalent radical of the formula -OC(O)Ar,
where Ar is aryl optionally substituted with hydroxy, halogen, alkoxy, and the like.
[0033] The term "precious metal catalyst" means a solid metal catalyst in whatever form suitable and effective for
achieving the hydrogenation reactions of the instant invention. Exemplary and preferred precious metal catalysts in-

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 EP 1 442 006 B1

clude platinum, palladium, ruthenium, osmium, iridium, rhodium, and the like, or mixtures thereof, the metal or alloy
provided in the form of: (a) a finely divided (e.g., powder, granules, etc.) or high surface area (e.g., porous, sponge,
gauze platinum or palladium black) metal or alloy, (b) a precursor compound (e.g., the oxide) converted into the active
catalyst before or during hydrogenation, or (c) distributed on an inorganic support, generally of high surface area, such
5 as carbon, activated carbon, silica, alumina, or other metal oxides (e.g., calcium oxide), metal carbonates (e.g., calcium
carbonate), metal sulfates (e.g., barium sulfate), or the like, wherein the supported precious metal is preferably present
at 0.5 wt.% to 10 wt.%, more preferably 1 wt.% to 5 wt.%.

Experimental Results
10
[0034] In the following experiments the analytical methods used include quantitative and qualitative analyses per-
formed by high performance liquid chromatography (HPLC) and gas-liquid chromatography (GLC) methods.

I. PRIOR ART SYNTHESIS METHODS

15
[0035] For comparison purposes, the two prior art synthesis methods mentioned hereinabove were tested and the
results obtained.

1. Iodination of Norephedrine Hydrochloride and Reduction to Amphetamine

20
[0036]

25

30

[0037] A 100 mL round bottom flask with a magnetic stirrer was charged with 20 mL 57% HI solution. (1R,2S)-(-)-
norephedrine (10.0 g, 0.066 mol) was then added to the flask with stirring. Red phosphorus (1.0 g) was added to the
stirred mixture and the reaction mixture temperature then increased to 40°C within a few minutes. The reaction mixture
35 was then heated to 100°C and samples were withdrawn at intervals for HPLC analysis. The results were as follows:

a. 2 hours (58% norephedrine, 6.8% amphetamine, 6% bis compound);

b. 4 hours (50% norephedrine, 10.2% amphetamine, 14.7% bis compound);
c. 6 hours (41% norephedrine, 15.6% amphetamine, 17.7% bis compound); and
40 d. 22 hours (48.95% amphetamine, 48.5% bis compound).

After 22 hours at 100°C, the reaction mixture was cooled and filtered to remove the phosphorus. An oily layer separated
(1.3 g, identified by GLC as bis compound). The aqueous layer was basified with 50% sodium hydroxide solution and
extracted with ether. The ether extract was dried over anhydrous magnesium sulfate and concentrated to obtain 4.1 g
45 of yellow oil, identified by HPLC as consisting of 83.23% amphetamine and 16.27% bis compound). The calculated
yield of amphetamine was therefore 3.41 g (38.3%)

50

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 EP 1 442 006 B1

2. Preparation of 2-Amino-1-chloro-1-phenylpropane Hydrochloride from Norephedrine Hydrochloride and

Reduction to Amphetamine

[0038]
5

10

[0039] A 100 mL round bottom flask with a magnetic stirrer was charged with thionyl chloride (24.47 g, 15 mL) and
15 norephedrine hydrochloride (5.38 g). The mixture was stirred and heated at reflux temperature for about 1 hour and
allowed to cool to ambient temperature. The excess thionyl chloride was removed by evaporation on a rotary evaporator.
The residue in the flask was triturated with ether (50 mL) and the solid collected. The crude solid product was recrys-
tallized from methanol-isopropyl ether and the purified solid collected (2.83 g, 48%). The purified 2-amino-1-chloro-
1-phenylpropane hydrochloride was then subjected to hydrogenolysis as follows. A solution of 2-amino-1-chloro-1-phe-
20 nylpropane hydrochloride (2.38 g, 0.0137 mol) in a mixture of 50 mL ethanol/16 mL water was prepared and transferred
to a Parr bottle. Under a nitrogen atmosphere, a portion of 10% palladium on carbon catalyst was added to the solution
in the Parr bottle. The Parr bottle was then installed on a Parr shaker apparatus and an inert atmosphere produced
and maintained in the bottle. The Parr bottle was then pressurized with hydrogen to about 50 psi and was shaken until
the hydrogen uptake ceased. The contents of the Parr bottle was filtered to remove the catalyst and the filtrate was
25 evaporated under reduced pressure to remove the ethanol. The remaining aqueous solution was basified with 50%
sodium hydroxide solution. The oily top layer with was extracted with ether and the ether layer was separated from the
aqueous layer. The ether extract was dried with drying agent and filtered to remove the drying agent. The filtrate was
concentrated to obtain crude amphetamine as an oil (1.70 g, 72.3%).

30 II. THE PROCESS OF THE INVENTION

[0040] The process of the invention and experimental results using the process of the invention are discussed below.
Norephedrine hydrochloride is commercially available and was used to illustrate in the reactions useful in this process.
These conditions can also be applied to ephedrine hydrochloride or pseudoephedrine hydrochloride to produce d-
35 methamphetamine. Furthermore, those skilled in the art should know to apply this process for the preparations of many
amphetamine related compounds as covered in Scheme 2. Literature procedures for making amphetamine and meth-
amphetamine report retention of configuration at the carbon bearing the amino group (see, e.g., Noggle, DeRuiter, and
Clark, J. Chrom. Sci. 25, 38-42 (1987); Allen and Kiser, J. Forensic Sciences 32(4), 953-962 (1987)). Therefore d,l-
norephedrine and d,l-norpseudoephedrine are expected to give the same product, d,l-amphetamine, and 1R,2S-(-)-
40 norephedrine and 1S,2S-(+)-norpseudoephedrine are expected to give dextroamphetamine [d-amphetamine, S-(+)-
amphetamine]. Also, d,l-ephedrine and d,l-pseudoephedrine are expected to give the same product, d,l-methamphet-
amine, and 1R,2S-(-)-ephedrine and 1S,2S-(+)-pseudoephedrine are expected to give dextromethamphetamine [d-
methamphetamine, S-(+)-methamphetamine]. Abbreviations used in the following tables are NE for norephedrine, O-Ac-
NE for O-acetylnorephedrine, N-AcNE for N-acetylnorephedrine, O,N-diAcNE for O,N-diacetylnorephedrine, Amp for
45 amphetamine, and N-AcAmp for N-acetylamphetamine. These compounds were synthesized and used as references
for HPLC analyses.

50

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 EP 1 442 006 B1

A. Preparation of 2-Amino-1-acetoxy-1-phenylpropane Hydrochloride (O-Acetylnorephedrine) from

Norephedrine Hydrochloride

[0041]
5

10

15 [0042] A three-necked 100 mL round bottom flask equipped with thermocontroller, stirrer, condenser, and gas bubbler
was charged with 18.77 g (0.10 mol) d,l-norephedrine hydrochloride, acetic acid (18 mL), and acetic anhydride (12.24
g, 0.12 mol). The reaction mixture was warmed with a heating mantle with thermocontroller set for 80°C. After the
reaction mixture cleared, it was held at 80°C for 2 hours. Heptane (36 mL) was added to the 80°C reaction mixture
slowly with rapid stirring, then the mixture was allowed to cool to ambient temperature. The slurry was stirred overnight
20 at ambient temperature and the solid was collected by filtration. The granular solid was dried under ambient conditions
overnight to obtain 18.13 g of product (89.99% yield).

B. Preparation of 2-Amino-1-acetoxy-1-phenylpropane Hydrochloride (O-Acetylnorephedrine) from

Norephedrine Hydrochloride and Reduction to Amphetamine without Isolation of the Intermediate
25
[0043]

30

35

[0044] The following method is an example wherein the reduction of the intermediate O-acetylnorephedrine is per-
formed without isolating the O-acetylnorephedrine.
[0045] A 100 mL 3-necked round bottom flask equipped with a magnetic stirrer, condenser, and thermocontroller,
40 was charged with d,l-norephedrine hydrochloride (9.39 g, 0.050 mol), acetic anhydride (6.12 g, 0.060 mol), and acetic
acid (18 mL). The reaction mixture is heated with heating mantle with a thermocontroller set at 80°C. When the tem-
perature reached about 60°C, the reaction mixture became exothermic and the temperature rose to 84°C. The reaction
mixture was cooled to 80°C and held at 80°C for 2 hours. HPLC analysis of reaction mixture at this point showed
90.69% O-acetylnorephedrine and 6.88% O,N-diacetylnorephedrine. The reaction mixture was stirred overnight at
45 ambient temperature and then diluted with 20 mL ethanol. The resulting solution was transferred to a Parr bottle, which
was purged with nitrogen gas and about 1 g of 10% palladium-carbon catalyst (50% water) was added. The Parr bottle
was installed on a Parr shaker apparatus and inerted with nitrogen. The Parr bottle was then pressurized with hydrogen
to 45 psi and then shaken under hydrogen pressure at ambient temperature. In 10 minutes a 3 psi pressure drop was
observed. The Parr bottle temperature controller was set to 55°C and the pressure increased from 42 psi to 47 psi.
50 The pressure changes over the next 5 to 6 hours were recorded. The heat was then turned off and the reaction mixture
was allowed to cool to ambient temperature. The final pressure was recorded and the Parr bottle was depressurized
and purged with nitrogen gas. The mixture was filtered to remove the catalyst and the filtrate was analyzed and found
to consist of 2.45% norephedrine, 57.59% amphetamine, 20.71% O-acetylnorephedrine, 10% N-acetylamphetamine,
and 3.75% O,N-diacetylnorephedrine. The calculated yield was 3.89 g (57%)
55
C. Further Examples of Acetylation of Norephedrine Hydrochloride

[0046] As illustrated above, O-acetylnorephedrine hydrochloride can be prepared in good yield from norephedrine

8
 EP 1 442 006 B1

hydrochloride by heating with acetic anhydride (preferably 1.2 to 2.0 equivalents) in acetic acid (preferably 1 to 2 mL/
g of norephedrine hydrochloride) in a mildly exothermic reaction at 50-80°C for 2 hours, although exothermic reaction
temperatures could exceed 80°C. Generally, when less than a 20% excess of acetic anhydride is used, some unreacted
norephedrine remains, for example, when a 10% excess of acetic anhydride was used, it reacted with only about 80%
5 of the norephedrine hydrochloride. It was found that the amount of acetic acid used does not appear to be critical, as
the reaction proceeded well with either 1 or 2 mL/g of norephedrine hydrochloride and could be agitated without difficulty
at 1 mL/g. When no acetic acid was used, however, the product obtained consisted of a mixture 16.71 % norephedrine,
67.08% O-acetylnorephedrine, and 14.43% O,N-diacetylnorephedrine. Results of other laboratory preparations are
summarized in Table 1.
10
Table 1.
Summary on Acetylations of Norephedrine Hydrochloride
Experiment % Yield % O- AcNE % Amp % N- AcNE % NE % N- AcAmp % O,N- diAcNE
15 A * 90.8 - - <1 - 6.3
C 80.1 92.98 - - - - 3.74
D 52.2 98.43 - - 1.57 - -
E 26.8 97.5 - - 2.5 - -
20
F 85.5 95.7 - - - - -
G 56.9 100 - - - - -
H 95.2 - - - - - -
25 I 90.0 - - - - - -
L 82.7 89.44 0.832 - - - 9.06
Z 99.18 89.39 - - - - -
* Product was not isolated: reaction mixture carried on to reduction step (Experiment B, Tables 3, 4, and 7).
30

(i). Side Products

[0047] Table 1 lists the side products found in various acetylation experiments. Small amounts of unreacted nore-
phedrine and O,N-diacetylnorephedrine, were found as side products in the isolated products. The signal for amphet-
35
amine in experiment L may be an artifact.

(ii). Crystallization Solvent

[0048] To increase the rate of crystallization of the O-acetylnorephedrine hydrochloride salt and aid in removing
40
acetic acid and any excess acetic anhydride that may be present, the reaction mixture was treated with heptane (Ex-
periment I), methyl tert-butyl ether (Experiments F and H), ethanol (Experiment G), isopropanol, methyl isobutyl ketone,
acetonitrile, ethyl acetate, tetrahydrofuran, or other solvent in which the product has little solubility. The solid product
that formed was collected by filtration. Heptane is a preferred solvent, as the solid produced was dense and did not
appear to be solvated as much as with other solvents tried.
45

(iii). Rate of the Acetylation Reaction

[0049] The rate of the acetylation reaction is demonstrated by the results of high performance liquid chromatography
analyses (HPLC) of a reaction at various time intervals (Experiment A). These results are given in Table 2 and show
50
that the reaction is almost complete within 20 minutes of the reaction mixture becoming clear.

55

9
 EP 1 442 006 B1

Table 2.
O-Acetylation of (±)-Norephedrine Hydrochloride
Time (minutes) %NE %N-AcNE %O-AcNE % O,N-diAcNE
5
0* 21.14 - 71.68 4.79
20 3.48 - 89.53 5.49
40 <2 - 91.91 6.11

10 90 <1 - 90.92 6.47

120 <1 - 90.80 6.30
* zero time: point at which the heated reaction mixture was observed to become clear

15 (iv). Chemical Reactivities of Norephedrine Free Base and Salts

[0050] The commercially available precursor to dextroamphetamine is 1R,2S-(-)-norephedrine. Attempts were made
to O-acetylate the norephedrine free base, but produced mostly N-acetylamphetamine according to an analysis of the
carbonyl region of the infrared spectra. In one experiment, norephedrine free base in acetic acid was treated with 0.5
20 equivalents of sulfuric acid and then treated with 1.1 equivalents of acetic anhydride with heating to 63°C to obtain a
clear solution. Catalytic reduction followed by basification gave an oil that was composed of 13.96% amphetamine and
68% norephedrine, an indication that the acetylation procedure on a sulfate salt was only partially successful. In another
experiment, a 0.10 mol portion of norephedrine hydrochloride was acetylated with a 20% excess of acetic anhydride
in 2 mL acetic acid/g of salt and progress of the reaction followed for 2 hours (Table 2). The reaction mixture was diluted
25 with 130 mL water and subjected to catalytic hydrogenation for 22 hours to obtain 10.4 g of oil. The long reaction time
is attributed to the presence of acetic acid in the reduction mixture. Yield of amphetamine from norephedrine hydro-
chloride based on the weight of product and HPLC analysis is 66% (Experiments A and B). For these experiments, it
can be seen that the best results were obtained with the salts of phenylpropylamine or norephedrine, particularly the
hydrochloride salt.
30
D. Catalytic Transfer Hydrogenation of O-Acetylnorephedrine

[0051]

35

40

[0052] A 500 mL 3-necked round bottom flask equipped with stirrer, addition funnel, condenser, and thermocontroller
was charged with O-acetylnorephedrine hydrochloride (47.0 g, 0.205 mol), 131 mL of water, and 1.0 g of 10% palladium
45 on carbon (50% water) catalyst. A solution of ammonium formate (HCOONH4; 15.50 g, 0.246 mol) in 20 mL water was
then prepared. The reaction mixture in the 3-necked round bottom flask was then heated in a water bath temperature
controlled to 71°C. When the reaction mixture temperature reached 68°C, approximately 6 mL of the ammonium for-
mate solution was added in 2 mL increments to the reaction mixture at 5 minute intervals. When evolution of gas began
to subside, the remainder of ammonium formate solution was added dropwise and the reaction mixture stirred in the
50 water bath for approximately 1 hour. The water bath temperature controller was then turned off and the reaction mixture
was allowed to cool to ambient temperature while stirring overnight. The cooled reaction mixture was then filtered to
remove the catalyst and the filtrate was treated with 26 mL (0.50 mol) of 50% sodium hydroxide solution. The basified
reaction mixture was then transferred to a separatory funnel and allowed to stand for 0.5 hour. The bottom aqueous
layer was separated from the top oily layer and the oily layer was recovered (40.83 g). The oil was analyzed and the
55 analysis had the following results: GLC weight-% assay: 60.18% amphetamine; Karl Fischer titration: 23.15% water;
HPLC analysis: 79.03% amphetamine, 14.6% N-acetylnorephedrine, 5.49% N-acetylamphetamine, and 0.76% nore-
phedrine; calculated yield: 24.6 g amphetamine (88.8%).

10
 EP 1 442 006 B1

E. Catalytic Hydrogenation of O-Acetylnorephedrine Hydrochloride

[0053]

10

[0054] A Parr bottle was charged with O-acetylnorephedrine hydrochloride (11.43 g) and 75 mL of water. The Parr
bottle was flushed with nitrogen and the catalyst added. The bottle was then shaken on a Parr apparatus with an initial
15 pressure of 55 psi. After 2 hours, the pressure drop was 4 psi (on tank). The Parr bottle was shaken for another hour
to ensure completion of hydrogenolysis and then depressurized and flushed with nitrogen. The contents of the Parr
bottle was then filtered to remove the catalyst and the filtrate was basified with 15 mL of 50% sodium hydroxide solution
and the mixture was allowed to stand overnight. The mixture was then transferred to a separatory funnel to separate
the bottom aqueous layer from the top oily layer; the oily layer was recovered (7.00 g). The oil was analyzed and the
20 analysis had the following results: GLC weight-% assay: 63.02% amphetamine; HPLC analysis: 87.22% amphetamine,
10.8% N-acetylnorephedrine, 0.37% N-acetylamphetamine; Karl Fischer analysis: 23.699% water; calculated yield:
4.41 g amphetamine (65.33%).

F. Further Examples of the Reduction of O-Acetylnorephedrine Hydrochloride to Amphetamine

25
[0055] Reduction of O-acetylnorephedrine hydrochloride to amphetamine is accomplished by either catalytic hydro-
genation or catalytic transfer hydrogenation. Catalytic hydrogenation can be achieved in about four hours at room
temperature in water using 10% palladium on carbon catalyst (50% wet with water) at 50-55 psi hydrogen pressure
on a Parr shaker. Using this method, most of the hydrogen uptake occurs within 2 hours. Catalytic transfer hydrogen-
30 ation using ammonium formate and 10% palladium on carbon (50% wet with water) in water is complete in 20-30
minutes from initiation of the reaction if the ammonium formate solution is added in one portion.

1. Catalytic Hydrogenation

35 [0056] Results of laboratory hydrogenation Experiments are shown in Tables 3 and 4. In Table 4, the weight-% am-
phetamine was determined by GLC and the % composition was determined by HPLC.

Table 3.
Reaction Conditions used in the Catalytic Hydrogenation of O-Acetylnorephedrine Hydrochloride
40
Experiment g (mol) Solvent (mL) mL/g Time (hours) Crude yield g (%)
AA 10.04 H2O (100) 4.96 3.75 6.9 (>100%)
(0.044)

45
BB 6.00 (0.026) H2O (50) 25 1.5 3.44 (98)
EtOH (100)
CC 11.48 (0.05) H2O (100) 8.7 4.5 -
B 22.95 H2O (114) 6.54 23 10.4 (77)
(0.10)** HOAc (36)
50
N 11.48 H2O (50) 4.36 4 5.18 (76.7)
(0.050)
T 22.95 (0.10) H2O (70) 3.05 22.5 13.65 (>100)

55 V 11.45 H2O (75) 6.55 2 7.00 (>100)

(0.050)
** From Experiment A

11
 EP 1 442 006 B1

Table 3. (continued)
Reaction Conditions used in the Catalytic Hydrogenation of O-Acetylnorephedrine Hydrochloride
Experiment g (mol) Solvent (mL) mL/g Time (hours) Crude yield g (%)
5
Y 22.95 (0.10) H2O (137) 5.97 2+2* 14.66 (>100)
* Reduction judged to be >95% complete in 2 hours but given another 2 hours on Parr apparatus to make sure hydrogen uptake was complete.

10 Table 4.
Analysis of Catalytic Hydrogenation Products
Experiment %Yield Wt % % O-AcNE % Amp % N-AcNE % NE % % O,N-
(crude) Amp N-AcAmp diAcNE
15 B 77* 75.23 - 86.3 6.7 1.3 2.7 2.67
N 76.7 83.07 - 82.7 15.73 0.8 0.21 -
T 101 68.86 - 91.16 4.65 0.26 2.55 -
V 104 63.02 - 87.72 10.8 0.07 0.37 -
20
Y 109 73.12 0.32 93.92 4.79 0.63 0.24 -
*calculated from norephedrine hydrochloride

[0057] The solubility of O-acetylnorephedrine hydrochloride in water is 5.5 mL/g (Experiment X). Hydrogenation
25
reactions at water concentrations equal to or more than 5.5 mL/g appear to be about 90-95% complete in 2 hours
(Experiment T). The presence of acetic acid seems to retard the reduction (Experiment B). Ethanol reduces the solubility
of the salt and thus may require a larger volume of solvent for hydrogenation to proceed readily (Experiment BB). If
either acetic acid or ethanol is used, an extra step in the work-up to remove the organic solvent is necessary. This
makes water an excellent solvent for the catalytic reduction as the volume is not excessive, it is not flammable, and it
30
is inexpensive. Rigorous purging of the hydrogenation vessel with an inert gas before charging the palladium catalyst
is not required with water, as it would be with a flammable solvent. The amphetamine obtained from Experiments T,
V, and Y was separated from the aqueous solution after basification rather than extracting with a solvent. The crude
amphetamine was shown by Karl Fischer water analysis to contain 23-24% water. This accounts for yields greater
than 100% and lower weight-% amphetamine values.
35

2. Catalytic Transfer Hydrogenation

[0058] For catalytic transfer hydrogenation, a mixture of O-acetylnorephedrine hydrochloride, water, and 10% pal-
ladium on carbon (50% wet with water) can be treated with 1.2 equivalents of ammonium formate and heated until an
40
exothermic reaction accompanied by evolution of gas occurs. The reaction is completed when the evolution of gas
subsides.
[0059] Results of Experiments using catalytic transfer hydrogenation are shown in Table 5. These reactions were
done at temperatures between 60°C-80°C except for the higher temperature attained in the exotherm.

45 Table 5.
Catalytic Transfer Hydrogenation of O-Acetylnorephedrine Hydrochloride With Ammonium Formate
Experiment % Wt % Amp % O-AcNE % Amp % N-AcNE % NE % % O,N-
Yield N-AcAmp diAcNE
50
DD 81.9 57.40 - - - - - -
M 67.0 81.80 - 86.23 9.57 - 1.9 -
O 73.4 92.18 - 91.75 4.76 1.05 1.87 -

55 P 45.9 - - 96.16 2.64 0.43 0.59 -

Q 83.6 - - 90.19 7.91 0.63 0.84 -
R 89.3 71.52 - 88.86 7.87 0.92 1.97 -

12
 EP 1 442 006 B1

Table 5. (continued)
Catalytic Transfer Hydrogenation of O-Acetylnorephedrine Hydrochloride With Ammonium Formate
Experiment % Wt % Amp % O-AcNE % Amp % N-AcNE % NE % % O,N-
5 Yield N-AcAmp diAcNE
S 90.4 70.0 - 81.19 13.84 0.43 4.22 -
U 147.0 60.18 - 79.03 14.60 0.76 5.49 -

10
[0060] The quantities of reactants for the catalytic transfer hydrogenation reactions presented in Table 5 are shown
in Table 6.

Table 6.
Reactant Quantities in Catalytic Transfer Hydrogenolysis
15
Experiment O-AcNE•HCl Solvent* Grams of Crude Yield (% % Amp.
Ammonium yield)
Formate (mol)
DD 4.98 g 100 mL 4.98 g 2.4 g 57.4 Area-%
20
(0.0217 mol) methanol (0.08 mol) (81.9%)
M 4.98 g 10 mL water 5.03 g 1.97 g 86.2 Area-%
(0.0217 mol) (AF) (0.08 mol) (67%)
10 mL MeOH
25 (OAcNE)
O 5.74 g 20 mL water 3.15 g 2.48 g 92.18 Wt-%
(0.025 mol) (OAcNE) 10 mL (0.05 mol) (73.4%)
water (AF)

30 P 5.74 g 20 mL water 2.36 g 1.55 g 96.16 Area-%

(0.025 mol) (OAcNE) (0.0375 mol) (45.9%)
10 mL water
(AF)
Q 5.74 g 20 mL water 1.58 g 2.82 g 90.2 Area-%
35 (0.025 mol) (OAcNE) (0.025 mol) (83.6%)
10 mL water
(AF)
R 11.48 g 33 mL water 3.78 g 6.03 g 71.5 Wt-%**
40
(0.05 mol) (OAcNE) (0.06 mol) (89.3%)
20 mL water
(AF)
S 22.95 g 69 mL water 7.56 g 12.2 g 70.0 Wt-%**
(0.10 mol) (OAcNE) (0.12 mol) (90.4%)
45 10 mL water
(AF)
U 47.0 g 131 mL water 15.50 g 40.87 g 60.18 Wt-%**
(0.205 mol) (OAcNE) (0.246 mol) (147%)
20 mL water
50
(AF)
* 2 volumes of solvent shown where ammonium formate (AF) solution is added to OAcNE•HCl solution separately
** amphetamine layer was separated without extraction into ether after basification

55 [0061] When a large excess of ammonium formate is used, a white solid sublimes into the condenser. Sublimation
was not observed with only a 10-20% excess of ammonium formate. A 10-20% excess of ammonium formate appears
to be sufficient for complete reaction. The exotherm and evolution of gas were also seen at about 52°C in Experiment
DD that was conducted in methanol.

13
 EP 1 442 006 B1

3. Comparison of Hydrogenolysis Reactions

[0062] In both types of the hydrogenolysis reactions, workup, with one exception, consists of filtering the reaction
mixture to remove the palladium on carbon catalyst, basifying the filtrate to pH 14, separation of the aqueous layer
5 from the amphetamine layer, and distillation of the amphetamine. That exception was Experiment DD where the filtered
reaction mixture was concentrated and the residue taken up in water and basified. The two types of hydrogenolysis
reactions are comparable in efficiency, with the catalytic transfer hydrogenation being the faster. However, there is a
question of safety as there is an induction period with the catalytic transfer hydrogenation reaction accompanied by
considerable evolution of gas when the reaction begins. The reaction can be partially controlled by initial addition of
10 only about 25% of the ammonium formate as an aqueous solution and heating the mixture until the reaction begins.
The remainder of the ammonium formate solution can then be added at a suitable rate.
[0063] Ammonium formate appears to catalyze the rearrangement of O-acetylnorephedrine hydrochloride to N-
acetylnorephedrine. Three samples of O-acetylnorephedrine hydrochloride (Experiment Z recrystallized) were stirred
with water for six hours respectively at room temperature, at 60°C, and at 60°C with ammonium formate added. Samples
15 were taken at intervals for HPLC analyses. At room temperature, the percentage of O-acetylnorephedrine hydrochloride
decreased from 99.30 to 99.12% over a period of 6 hours and the percentage of N-acetylnorephedrine increased from
0.10% to 0.21%. At 60°C, the percentage of O-acetylnorephedrine hydrochloride decreased from 99.18 to 97.79 with
the percentage of N-acetylnorephedrine increasing from 0.21% to 1.1% over a 6 hour period. With the ammonium
formate mixture at 60°C, the percentage of O-acetylnorephedrine hydrochloride dropped to 91.23% within 30 minutes
20 and to 77.20% by 6 hours while the amount of N-acetylnorephedrine increased from 7.51% to 20.95%. The catalytic
hydrogenation route therefore appears to be preferable to catalytic transfer hydrogenation in view of the induction
period, gas evolution, and rearrangement potential.
[0064] The amphetamine obtained from several of the hydrogenolysis reactions of both types was analyzed by HPLC
and/or GLC and the results summarized in Table 7. The products of Experiments Experiment P and Experiment Q
25 were obtained by extraction into ether and drying of the extract to remove any water. The product obtained in Experi-
ments R, S, and U were shown by Karl Fischer analyses to contain water and is compensated for in the Weight-%
amphetamine analyses. The percent yield of amphetamine is calculated from the actual weight of the product isolated
and the percentage of amphetamine in the product as determined by GLC or HPLC weight-% analyses. The composition
of the product is the area-% analysis.
30
Table 7.
Crude and Actual Yields of Amphetamine from Both Reduction Methods
Experiment Reaction Size (mol) Crude Yield (g) Wt. % Amp. Calc. Yield Amp. (g) % Yield Amp.
35 B1 0.10 10.4 75.23 7.82 58.0
N1 0.05 6.75 83.7 4.34 64.2
T1 0.10 13.65 68.86 9.35 69.6
V1 0.05 7.00 63.02 4.41 66.1
40
Y1 0.10 14.66 73.32 10.70 79.3
M2 0.022 1.97 81.8 1.61 55.0
O2 0.025 2.48 81.8 1.61 55.0
45 P2 0.025 1.55* 96.16 1.44 42.8
Q2 0.10 2.82* 90.2 2.54 75.4
R2 0.05 6.03 71.52 4.31 63.9
S2 0.10 12.2 70.0 8.54 63.3
50
U2 0.205 40.83 60.18 24.57 88.8
1catalytic hydrogenation
2catalytic transfer hydrogenation
* product obtained in these reactions by extraction into ether and drying extract
55

[0065] Instead of having wt % amphetamine data, area % of amphetamine in product mixture was used to calculate
expected yield of amphetamine. In other reactions, the product obtained was not dry.

14
 EP 1 442 006 B1

[0066] All publications, patent applications, patents, and other references mentioned herein are incorporated by
reference in their entirety. Furthermore, unless otherwise defined, all technical and scientific terms used herein have
the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
[0067] As required, the above description includes the best mode presently contemplated for carrying out the inven-
5 tion. It will be noted that the invention has been described with reference to numerous specific embodiments and
examples; it is emphasized that these embodiments and examples are not to be construed as limiting the invention
but are made merely for the purpose of describing the general principles of the invention and illustrating the invention.
Therefore, although suitable methods, apparatus, and materials for the practice or testing of the present invention are
described above, other suitable methods, apparatus, and materials similar or equivalent to those described herein,
10 which are well known in the art or will hereinafter be developed, can also be used without departing from the spirit or
scope of the invention. As these various equivalents and substitutions will be recognized by those of ordinary skill in
the art in view of the foregoing disclosure, they are contemplated to be within the scope of the present invention as
defined by the appended claims. The appended claims solely define the scope of the invention.

15
Claims

1. A process for making compound of formula I

20

25

30 from a phenylpropanolamine salt of formula II

35

40

through the intermediate compound of formula III

45

50

55 wherein:

R1 is hydrogen or a C1-C8 alkyl group;

each R2 is independently a hydrogen, halogen, C1-C8 alkyl group, C1-C8 alkoxy groups, C1-C8 alkyl group

15
 EP 1 442 006 B1

substituted with 1 to 5 halogens, C1-C8 alkoxy groups substituted with 1 to 5 halogens, or both R2 together
when on adjacent carbons constitute a -O(CH2)xO- where
x is 1 to 4, thereby forming a ring structure fused with the phenyl group;
R3 is a C1-C8-alkyl group, a C1-C12-aralkyl group, C1-C12-alkaryl group, or a phenyl group, each optionally
5 substituted by 1 to 5 substituents selected from halogen, hydroxy, or C1-C6-alkyl; and
HX is an equivalent of an organic or inorganic acid,

the process comprising:

10 (a) acylating the phenylpropanolamine salt of formula II with an acylating agent in a solvent at elevated tem-
perature to make a reaction mixture containing an O-acylated phenylpropanolamine salt of formula III which
can be isolated by the addition of a crystallization solvent, or optionally this mixture can be used in the next
step; and
(b) hydrogenating the O-acylated phenylpropanolamine salt to make the compound of formula I in the presence
15 of a catalyst.

2. The process of claim 1, wherein the acylating agent is selected from the group consisting of: acetic anhydride,
acetyl chloride, propionic anhydride, propionyl chloride, butyric anhydride, and butyryl chloride.

20 3. The process of claim 1, wherein the acylating agent is a compound of formula R3C(O)X, wherein:

X is a halogen; and
R3 is a C1-C8-alkyl group, a C1-C12-aralkyl group, C1-C12-alkaryl group, or a phenyl group, each optionally
substituted by 1 to 5 substituents selected from halogen, hydroxy, or C1-C6-alkyl.
25
4. The process of claim 3, wherein R3 is a methyl group.

5. The process of claim 1, wherein the acylating agent is a compound of formula R3C(O)O(O)CR3', wherein:

30 R3 and R3' are independently a C1-C8-alkyl group, a C1-C12-aralkyl group, C1-C12-alkaryl group, or a phenyl
group, each optionally substituted by 1 to 5 substituents selected from halogen, hydroxy, or C1-C6-alkyl.

6. The process of claim 5, wherein R3 and R3' are methyl groups.

35 7. The process of claim 1, wherein HX is selected from the group consisting of:

hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric
acid, formic acid, acetic acid, propionic acid, benzoic acid, tartaric acid, succinic acid, oxalic acid, aspartic
acid, saccharic acid, and malic acid.
40
8. The process of claim 1, wherein HX is a carboxylic acid, dicarboxylic acid, or tricarboxylic acid.

9. The process of claim 1, wherein the compound of formula I is amphetamine.

45 10. The process of claim 9, wherein the amphetamine is d,l-amphetamine.

11. The process of claim 9, wherein the amphetamine is S-(+)-amphetamine.

12. The process of claim 9, wherein the amphetamine is R-(-)-amphetamine.

50
13. The process of claim 1, wherein the compound of formula I is methamphetamine.

14. The process of claim 13, wherein the methamphetamine is S-(+)-methamphetamine.

55 15. The process of claim 13, wherein the methamphetamine is R-(-)-methamphetamine.

16. The process of claim 1, wherein acetic acid, propionic acid, or butyric acid is added to the phenylpropanolamine
salt as solvent before or at the same time as the acylating agent.

16
 EP 1 442 006 B1

17. The process of claim 1, wherein the hydrogenation step (b) is performed using catalytic hydrogenation.

18. The process of claim 17, wherein the catalytic hydrogenation is performed using a precious metal catalyst.

5 19. The process of claim 18, wherein the precious metal catalyst is selected from the group consisting of: platinum,
palladium, ruthenium, osmium, iridium, rhodium, and mixtures thereof.

20. The process of claim 19, wherein the precious metal catalyst is in the form of a finely divided or high surface area
metal or alloy.
10
21. The process of claim 19, wherein the precious metal catalyst is obtained by converting a precursor compound into
the active catalyst before or during hydrogenation.

22. The process of claim 19, wherein the precious metal catalyst is distributed on an inorganic support.
15
23. The process of claim 22, wherein the inorganic support is selected from the group consisting of: carbon, activated
carbon, metal oxides, metal carbonates, and metal sulfates.

24. The process of claim 18, wherein the precious metal catalyst is palladium on carbon.
20
25. The process of claim 1, wherein the hydrogenation step (b) is performed using catalytic transfer hydrogenation
with a hydrogenation agent.

26. The process of claim 25, wherein the catalytic transfer hydrogenation is performed using a precious metal catalyst.
25
27. The process of claim 26, wherein the precious metal catalyst is selected from the group consisting of: platinum,
palladium, ruthenium, osmium, iridium, rhodium, and mixtures thereof.

28. The process of claim 27, wherein the precious metal catalyst is in the form of a finely divided or high surface area
30 metal or alloy.

29. The process of claim 28, wherein the precious metal catalyst is obtained by converting a precursor compound into
the active catalyst before or during hydrogenation.

35 30. The process of claim 27, wherein the precious metal catalyst is palladium on carbon.

31. The process of claim 25, wherein the hydrogenation agent is selected from the group consisting of ammonium
formate, formic acid, ammonium or metal salts of hypophosphite.

40 32. The process of claim 26, wherein the hydrogenation agent is selected from the group consisting of ammonium
formate, formic acid, ammonium or metal salts of hypophosphite.

33. The process of claim 1, wherein the acylated phenylpropanolamine salt obtained from step (a) is isolated before
step (b) is performed.
45
34. The process of claim 33, wherein the acylated phenylpropanolamine salt obtained from step (a) is isolated by
adding a crystallization solvent to the reaction mixture containing the acylated phenylpropanolamine salt.

35. The process of claim 34, wherein the crystallization solvent is selected from the group consisting of: pentane,
50 hexane, heptane, octane, methyl tert-butyl ether, methyl isobutyl ketone, ethanol, propanol, isopropanol, butanol,
and mixtures thereof.

36. The process of claim 35, wherein the crystallization solvent is heptane.

55 37. The process of claim 1, wherein the acylated phenylpropanolamine salt obtained from step (a) is not isolated before
step (b) is performed.

38. The process of claim 1, wherein the carbon bearing the amino group in the phenylpropanolamine salt has the

17
 EP 1 442 006 B1

racemic configuration.

39. The process of claim 1, wherein the carbon bearing the amino group in the phenylpropanolamine salt has the S
configuration.
5
40. The process of claim 1, wherein the phenylpropanolamine salt is selected from the group consisting of: 1R,2S-(-)-
norephedrine, 1S,2S-(+)-norpseudoephedrine, 1R,2S-(-)-ephedrine, and 1S,2S-(+)-pseudoephedrine.

41. The process of claim 1, wherein the compound of formula 1 is S-(+)-methamphetamine and the phenylpropa-
10 nolamine salt is selected from the group consisting of: 1R,2S-(-)-ephedrine and 1S,2S-(+)-pseudoephedrine.

42. The process of claim 1, wherein the amount of acylating agent used is between about 1.0 equivalents and 3.0
equivalents based on the amount of phenylpropanolamine salt.

15 43. The process of claim 42, wherein the amount of acylating agent used is between about 1.1 equivalents and 2.5
equivalents based on the amount of phenylpropanolamine salt.

44. The process of claim 43, wherein the amount of acylating agent used is between about 1.1 equivalents and 2.0
equivalents based on the amount of phenylpropanolamine salt.
20
45. The process of claim 44, wherein the amount of acylating agent used is between about 1.2 equivalents and 1.5
equivalents based on the amount of phenylpropanolamine salt.

46. The process of claim 1, wherein the temperature of the reaction mixture of step (a) is between 50°C and 100°C.
25
47. The process of claim 46, wherein the temperature of the reaction mixture of step (a) is between 60°C and 90°C.

48. The process of claim 47, wherein the temperature of the reaction mixture of step (a) is between 70°C and 85°C.

30 49. The process of claim 1, wherein the phenylpropanolamine salt is made from phenylpropanolamine free base.

50. The process of claim 1, wherein the phenylpropanolamine salt is a salt of phenylpropylamine and an acid selected
from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,
phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, benzoic acid, tartaric acid, succinic acid, oxalic
35 acid, malic acid, aspartic acid, and saccharic acid.

51. The process of claim 1, wherein the phenylpropanolamine salt is a salt of phenylpropylamine and an acid selected
from the group consisting of carboxylic acid, dicarboxylic acid, and tricarboxylic acid.

40 52. The process of claim 1, wherein the phenylpropanolamine salt is a salt of phenylpropylamine and hydrochloric acid.

53. A process for making compound of formula I

45

50

from an O-acylated phenylpropanolamine salt of formula III

55

18
 EP 1 442 006 B1

10

wherein:

R1 is hydrogen or a C1-C8 alkyl group;

15 each R2 is independently a hydrogen, halogen, C1-C8 alkyl group, C1-C8 alkoxy groups, C1-C8 alkyl group
substituted with 1 to 5 halogens, C1-C8 alkoxy groups substituted with 1 to 5 halogens, or both R2 together
constitute a -O(CH2)xO- where x is 1 to 4, thereby forming a ring structure fused with the phenyl group;
R3 is a C1-C8-alkyl group, a C1-C12-aralkyl group, C1-C12-alkaryl group, or a phenyl group, each optionally
substituted by 1 to 5 substituents selected from halogen, hydroxy, or C1-C6-alkyl; and
20 HX is an equivalent of an organic or inorganic acid,

the process comprising: hydrogenating the O-acylated phenylpropanolamine salt to make the compound of formula
I.

25
Patentansprüche

1. Verfahren zur Herstellung einer Verbindung der Formel I

30

35

aus einem Phenylpropanolaminsalz der Formel II

40

45

50
über die Zwischenprodukt-Verbindung der Formel III

55

19
 EP 1 442 006 B1

10
worin:

R1 Wasserstoff oder eine C1-C8-Alkylgruppe ist;

jedes R2 unabhängig Wasserstoff, Halogen, eine C1-C8-Alkylgruppe, C1-C8-Alkoxygruppen, eine C1-C8-Al-
15 kylgruppe, die mit 1 bis 5 Halogenen substituiert ist, C1-C8-Alkoxygruppen ist, die mit 1 bis 5 Halogenen sub-
stituiert sind, oder beide R2 zusammen, wenn sie an benachbarten Kohlenstoffen vorliegen, -O(CH2)xO- dar-
stellen, worin x für 1 bis 4 steht, wodurch eine Ringstruktur gebildet wird, die mit der Phenylgruppe kondensiert
ist;
R3 eine C1-C8-Alkylgruppe, eine C1-C12-Aralkylgruppe, eine C1-C12-Alkarylgruppe oder eine Phenylgruppe
20 ist, wobei jede gegebenenfalls mit 1 bis 5 Substituenten substituiert ist, die aus Halogen, Hydroxy oder C1-C6-
Alkyl ausgewählt sind; und
HX ein Äquivalent einer organischen oder anorganischen Säure ist,

wobei das Verfahren umfasst:

25
(a) Acylieren des Phenylpropanolaminsalzes der Formel II mit einem Acylierungsmittel in einem Lösungsmittel
bei erhöhter Temperatur, um eine Reaktionsmischung herzustellen, die ein O-acyliertes Phenylpropanolamin-
salz der Formel III enthält, welches durch die Zugabe eines Kristallisationslösungsmittels isoliert werden kann,
oder diese Mischung kann gegebenenfalls im nächsten Schritt verwendet werden; und
30 (b) Hydrieren des O-acylierten Phenylpropanolaminsalzes in Anwesenheit eines Katalysators, um die Verbin-
dung der Formel I herzustellen.

2. Verfahren nach Anspruch 1, in dem das Acylierungsmittel ausgewählt ist aus der Gruppe bestehend aus: Acetan-
hydrid, Acetylchlorid, Propionsäureanhydrid, Propionylchlorid, Buttersäureanhydrid und Butyrylchlorid.
35
3. Verfahren nach Anspruch 1, in dem das Acylierungsmittel eine Verbindung der Formel R3C(O)X ist, worin:

X ein Halogen ist; und

R3 eine C1-C8-Alkylgruppe, eine C1-C12-Aralkylgruppe, eine C1-C12-Alkarylgruppe oder eine Phenylgruppe
40 ist, wobei jede gegebenenfalls mit 1 bis 5 Substituenten substituiert ist, die aus Halogen, Hydroxy oder C1-C6-
Alkyl ausgewählt sind.

4. Verfahren nach Anspruch 3, in dem R3 eine Methylgruppe ist.

45 5. Verfahren nach Anspruch 1, in dem das Acylierungsmittel eine Verbindung der Formel R3C(O)O(O)CR3' ist, worin:

R3 und R3' unabhängig eine C1-C8-Alkylgruppe, eine C1-C12-Aralkylgruppe, eine C1-C12-Alkarylgruppe oder
eine Phenylgruppe sind, wobei jede gegebenenfalls mit 1 bis 5 Substituenten substituiert ist, die aus Halogen,
Hydroxy oder C1-C6-Alkyl ausgewählt sind.
50
6. Verfahren nach Anspruch 5, in dem R3 und R3' Methylgruppen sind.

7. Verfahren nach Anspruch 1, in dem HX ausgewählt ist aus der Gruppe bestehend aus: Fluorwasserstoffsäure,
Chlorwasserstoffsäure, Bromwasserstoffsäure, lodwasserstoffsäure, Schwefelsäure, Phosphorsäure, Salpeter-
55 säure, Ameisensäure, Essigsäure, Propionsäure, Benzoesäure, Weinsäure, Bernsteinsäure, Oxalsäure, Aspa-
raginsäure, Zuckersäure und Äpfelsäure.

8. Verfahren nach Anspruch 1, in dem HX eine Carbonsäure, Dicarbonsäure oder Tricarbonsäure ist.

20
 EP 1 442 006 B1

9. Verfahren nach Anspruch 1, in dem die Verbindung der Formel I Amphetamin ist.

10. Verfahren nach Anspruch 9, in dem das Amphetamin d,l-Amphetamin ist.

5 11. Verfahren nach Anspruch 9, in dem das Amphetamin S-(+)-Amphetamin ist.

12. Verfahren nach Anspruch 9, in dem das Amphetamin R-(-)-Amphetamin ist.

13. Verfahren nach Anspruch 1, in dem die Verbindung der Formel I Methamphetamin ist.
10
14. Verfahren nach Anspruch 13, in dem das Methamphetamin S-(+)-Methamphetamin ist.

15. Verfahren nach Anspruch 13, in dem das Methamphetamin R-(-)-Methamphetamin ist.

15 16. Verfahren nach Anspruch 1, in dem vor oder gleichzeitig mit dem Acylierungsmittel Essigsäure, Propionsäure oder
Buttersäure als Lösungsmittel zu dem Phenylpropanolaminsalz gegeben wird.

17. Verfahren nach Anspruch 1, in dem der Hydrierschritt (b) unter Anwendung von katalytischer Hydrierung durch-
geführt wird.
20
18. Verfahren nach Anspruch 17, in dem die katalytische Hydrierung unter Verwendung eines Edelmetall-Katalysators
durchgeführt wird.

19. Verfahren nach Anspruch 18, in dem der Edelmetall-Katalysator ausgewählt ist aus der Gruppe bestehend aus:
25 Platin, Palladium, Ruthenium, Osmium, Iridium, Rhodium und deren Mischungen.

20. Verfahren nach Anspruch 19, in dem der Edelmetall-Katalysator in Form eines fein zerteilten Metalls oder einer
fein zerteilten Legierung oder eines Metalls oder einer Legierung mit hoher Oberfläche vorliegt.

30 21. Verfahren nach Anspruch 19, in dem der Edelmetall-Katalysator durch Überführen einer Vorstufen-Verbindung in
den aktiven Katalysator vor oder während der Hydrierung erhalten wird.

22. Verfahren nach Anspruch 19, in dem der Edelmetall-Katalysator auf einem anorganischen Träger verteilt ist.

35 23. Verfahren nach Anspruch 22, in dem der anorganische Träger ausgewählt ist aus der Gruppe bestehend aus:
Kohlenstoff, aktiviertem Kohlenstoff, Metalloxiden, Metallcarbonaten und Metallsulfaten.

24. Verfahren nach Anspruch 18, in dem der Edelmetall-Katalysator Palladium auf Kohlenstoff ist.

40 25. Verfahren nach Anspruch 1, in dem der Hydrierschritt (b) unter Verwendung von katalytischer Transferhydrierung
mit einem Hydriermittel durchgeführt wird.

26. Verfahren nach Anspruch 25, in dem die katalytische Transferhydrierung unter Verwendung eines Edelmetall-
Katalysators durchgeführt wird.
45
27. Verfahren nach Anspruch 26, in dem der Edelmetall-Katalysator ausgewählt ist aus der Gruppe bestehend aus:
Platin, Palladium, Ruthenium, Osmium, Iridium, Rhodium und deren Mischungen.

28. Verfahren nach Anspruch 27, in dem der Edelmetall-Katalysator in Form eines fein zerteilten Metalls oder einer
50 fein zerteilten Legierung oder eines Metalls oder einer Legierung mit hoher Oberfläche vorliegt.

29. Verfahren nach Anspruch 28, in dem der Edelmetall-Katalysator durch Überführen einer Vorstufen-Verbindung in
den aktiven Katalysator vor oder während der Hydrierung erhalten wird.

55 30. Verfahren nach Anspruch 27, in dem der Edelmetall-Katalysator Palladium auf Kohlenstoff ist.

31. Verfahren nach Anspruch 25, in dem das Hydriermittel ausgewählt ist aus der Gruppe bestehend aus Ammoni-
umformiat, Ameisensäure, Ammonium- oder Metallsalzen von Hypophosphit.

21
 EP 1 442 006 B1

32. Verfahren nach Anspruch 26, in dem das Hydriermittel ausgewählt ist aus der Gruppe bestehend aus Ammoni-
umformiat, Ameisensäure, Ammonium- oder Metallsalzen von Hypophosphit.

33. Verfahren nach Anspruch 1, in dem das acylierte Phenylpropanolaminsalz, das aus Schritt (a) erhalten wird, isoliert
5 wird, bevor Schritt (b) durchgeführt wird.

34. Verfahren nach Anspruch 33, in dem das acetylierte Phenylpropanolaminsalz, das aus Schritt (a) erhalten wird,
durch Zugabe eines Kristallisationslösungsmittels zu der das acetylierte Phenylpropanolaminsalz enthaltenden
Reaktionsmischung isoliert wird.
10
35. Verfahren nach Anspruch 34, in dem das Kristallisationslösungsmittel ausgewählt ist aus der Gruppe bestehend
aus: Pentan, Hexan, Heptan, Octan, Methyl-tert.-butylether, Methylisobutylketon, Ethanol, Propanol, Isopropanol,
Butanol und deren Mischungen.

15 36. Verfahren nach Anspruch 35, in dem das Kristallisationslösungsmittel Heptan ist.

37. Verfahren nach Anspruch 1, in dem das acylierte Phenylpropanolaminsalz, das aus Schritt (a) erhalten wird, nicht
isoliert wird, bevor Schritt (b) durchgeführt wird.

20 38. Verfahren nach Anspruch 1, in dem der Kohlenstoff, der die Aminogruppe in dem Phenylpropanolaminsalz trägt,
die racemische Konfiguration aufweist.

39. Verfahren nach Anspruch 1, in dem der Kohlenstoff, der die Aminogruppe in dem Phenylpropanolaminsalz trägt,
die S-Konfiguration aufweist.
25
40. Verfahren nach Anspruch 1, in dem das Phenylpropanolaminsalz ausgewählt ist aus der Gruppe bestehend aus:
1R,2S-(-)Norephedrin, 1S,2S-(+)-Norpseudoephedrin, 1R,2S-(-)-Ephedrin und 1S,2S-(+)-Pseudoephedrin.

41. Verfahren nach Anspruch 1, in dem die Verbindung der Formel I S-(+)-Methamphetamin ist und das Phenylpro-
30 panolaminsalz ausgewählt ist aus der Gruppe bestehend aus: 1R,2S-(-)-Ephedrin und 1S,2S-(+)-Pseudoephedrin.

42. Verfahren nach Anspruch 1, in dem die verwendete Menge an Acylierungsmittel zwischen etwa 1,0 Äquivalenten
und 3,0 Äquivalenten, bezogen auf die Menge an Phenylpropanolaminsalz, liegt.

35 43. Verfahren nach Anspruch 42, in dem die verwendete Menge an Acylierungsmittel zwischen etwa 1,1 Äquivalenten
und 2,5 Äquivalenten, bezogen auf die Menge an Phenylpropanolaminsalz, liegt.

44. Verfahren nach Anspruch 43, in dem die verwendete Menge an Acylierungsmittel zwischen etwa 1,1 Äquivalenten
und 2,0 Äquivalenten, bezogen auf die Menge an Phenylpropanolaminsalz, liegt.
40
45. Verfahren nach Anspruch 44, in dem die verwendete Menge an Acylierungsmittel zwischen etwa 1,2 Äquivalenten
und 1,5 Äquivalenten, bezogen auf die Menge an Phenylpropanolaminsalz, liegt.

46. Verfahren nach Anspruch 1, in dem die Temperatur der Reaktionsmischung von Schritt (a) zwischen 50°C und
45 100°C beträgt.

47. Verfahren nach Anspruch 46, in dem die Temperatur der Reaktionsmischung von Schritt (a) zwischen 60°C und
90°C beträgt.

50 48. Verfahren nach Anspruch 47, in dem die Temperatur der Reaktionsmischung von Schritt (a) zwischen 70°C und
85°C beträgt.

49. Verfahren nach Anspruch 1, in dem das Phenylpropanolaminsalz aus freier Phenylpropanolamin-Base hergestellt
wird.
55
50. Verfahren nach Anspruch 1, in dem das Phenylpropanolaminsalz ein Salz von Phenylpropylamin und einer Säure
ist, die ausgewählt ist aus der Gruppe bestehend aus: Fluorwasserstoffsäure, Chlorwasserstoffsäure, Bromwas-
serstoffsäure, lodwasserstoffsäure, Schwefelsäure, Phosphorsäure, Salpetersäure, Ameisensäure, Essigsäure,

22
 EP 1 442 006 B1

Propionsäure, Benzoesäure, Weinsäure, Bernsteinsäure, Oxalsäure, Äpfelsäure, Asparaginsäure und Zuckersäu-

re.

51. Verfahren nach Anspruch 1, in dem das Phenylpropanolaminsalz ein Salz von Phenylpropylamin und einer Säure
5 ist, die ausgewählt ist aus der Gruppe bestehend aus Carbonsäure, Dicarbonsäure und Tricarbonsäure.

52. Verfahren nach Anspruch 1, in dem das Phenylpropanolaminsalz ein Salz von Phenylpropylamin und Chlorwas-
serstoffsäure ist.

10 53. Verfahren zur Herstellung einer Verbindung der Formel I

15

20
aus einem O-acylierten Phenylpropanolaminsalz der Formel III

25

30

worin:
35
R1 Wasserstoff oder eine C1-C8-Alkylgruppe ist;
jedes R2 unabhängig Wasserstoff, Halogen, eine C1-C8-Alkylgruppe, C1-C8-Alkoxygruppen, eine C1-C8-Al-
kylgruppe, die mit 1 bis 5 Halogenen substituiert ist, C1-C8-Alkoxygruppen ist, die mit 1 bis 5 Halogenen sub-
stituiert sind, oder beide R2 zusammen -O(CH2)xO- darstellen, worin x für 1 bis 4 steht, wodurch eine Ring-
40 struktur gebildet wird, die mit der Phenylgruppe kondensiert ist;
R3 eine C1-C8-Alkylgruppe, eine C1-C12-Aralkylgruppe, eine C1-C12-Alkarylgruppe oder eine Phenylgruppe
ist, wobei jede gegebenenfalls mit 1 bis 5 Substituenten substituiert ist, die aus Halogen, Hydroxy oder C1-C6-
Alkyl ausgewählt sind; und
HX ein Äquivalent einer organischen oder anorganischen Säure ist,
45
wobei das Verfahren umfasst: Hydrieren des O-acylierten Phenylpropanolaminsalzes, um eine Verbindung der
Formel I herzustellen.

50 Revendications

1. Procédé de préparation d'un composé de formule I

55

23
 EP 1 442 006 B1

10

à partir d'un sel de phénylpropanolamine de formule II

15

20

25 en passant par le composé intermédiaire de formule III

30

35

où:
40
R1 est un hydrogène ou un groupe alkyle en C1-C8;
chaque R2 est indépendamment un hydrogène, un halogène, un groupe alkyle en C1-C8, un groupe alcoxy
en C1-C8, un groupe alkyle en C1-C8 substitué par 1 à 5 halogènes, un groupe alcoxy en C1-C8 substitué par
1 à 5 halogènes, ou les deux R2 ensemble, lorsqu'ils se trouvent sur des atomes de carbone adjacents, cons-
45 tituent un groupe -O(CH2)xO- dans lequel x est 1 à 4, formant ainsi une structure cyclique condensée avec le
groupe phényle;
R3 est un groupe alkyle en C1-C8, un groupe aralkyle en C1-C12, un groupe alkaryle en C1-C12, ou un groupe
phényle, qui sont chacun éventuellement substitués par 1 à 5 substituants choisis parmi un halogène, un
hydroxy ou un alkyle en C1-C6; et
50 HX est un équivalent d'un acide organique ou inorganique,

le procédé comprenant:

(a) l'acylation du sel de phénylpropanolamine de formule II avec un agent d'acylation dans un solvant à tem-
55 pérature élevée pour préparer un mélange réactionnel contenant un sel de phénylpropanolamine O-acylé de
formule III qui peut être isolé par l'addition d'un solvant de cristallisation, ou ce mélange peut éventuellement
être utilisé dans l'étape suivante; et
(b) l'hydrogénation du sel de phénylpropanolamine O-acylé pour préparer le composé de formule I en présence

24
 EP 1 442 006 B1

d'un catalyseur.

2. Procédé selon la revendication 1, dans lequel l'agent d'acylation est choisi dans le groupe constitué par l'anhydride
acétique, le chlorure d'acétyle, l'anhydride propionique, le chlorure de propionyle, l'anhydride butyrique, et le chlo-
5 rure de butyryle.

3. Procédé selon la revendication 1, dans lequel l'agent d'acylation est un composé de formule R3C(O)X, dans la-
quelle:

10 X est un halogène; et
R3 est un groupe alkyle en C1-C8, un groupe aralkyle en C1-C12, un groupe alkaryle en C1-C12, ou un groupe
phényle, qui sont chacun éventuellement substitués par 1 à 5 substituants choisis parmi un halogène, un
hydroxy ou un alkyle en C1-C6.

15 4. Procédé selon la revendication 3, dans lequel R3 est un groupe méthyle.

5. Procédé selon la revendication 1, dans lequel l'agent d'acylation est un composé de formule R3C(O)O(O)CR3',
dans laquelle:

20 R3 et R3' sont indépendamment un groupe alkyle en C1-C8, un groupe aralkyle en C1-C12, un groupe alkaryle
en C1-C12, ou un groupe phényle, qui sont chacun éventuellement substitués par 1 à 5 substituants choisis
parmi un halogène, un hydroxy ou un alkyle en C1-C6.

6. Procédé selon la revendication 5, dans lequel R3 et R3' sont des groupes méthyle.
25
7. Procédé selon la revendication 1, dans lequel HX est choisi dans le groupe constitué par l'acide fluorhydrique,
l'acide chlorhydrique, l'acide bromhydrique, l'acide iodhydrique, l'acide sulfurique, l'acide phosphorique, l'acide
nitrique, l'acide formique, l'acide acétique, l'acide propionique, l'acide benzoïque, l'acide tartrique, l'acide succini-
que, l'acide oxalique, l'acide aspartique, l'acide saccharique et l'acide malique.
30
8. Procédé selon la revendication 1, dans lequel HX est un acide carboxylique, un acide dicarboxylique ou un acide
tricarboxylique.

9. Procédé selon la revendication 1, dans lequel le composé de formule I est une amphétamine.
35
10. Procédé selon la revendication 9, dans lequel l'amphétamine est la d,l-amphétamine.

11. Procédé selon la revendication 9, dans lequel l'amphétamine est la S-(+)-amphétamine.

40 12. Procédé selon la revendication 9, dans lequel l'amphétamine est la R-(-)-amphétamine.

13. Procédé selon la revendication 1, dans lequel le composé de formule I est une méthamphétamine.

14. Procédé selon la revendication 13, dans lequel la méthamphétamine est la S-(+)-méthamphétamine.
45
15. Procédé selon la revendication 13, dans lequel la méthamphétamine est la R-(-)-méthamphétamine.

16. Procédé selon la revendication 1, dans lequel on ajoute de l'acide acétique, de l'acide propionique ou de l'acide
butyrique comme solvant au sel de phénylpropanolamine avant ou en même temps que l'agent d'acylation.
50
17. Procédé selon la revendication 1, dans lequel l'étape d'hydrogénation (b) s'effectue par hydrogénation catalytique.

18. Procédé selon la revendication 17, dans lequel l'hydrogénation catalytique s'effectue à l'aide d'un catalyseur à
base de métal précieux.
55
19. Procédé selon la revendication 18, dans lequel le catalyseur à base de métal précieux est choisi dans le groupe
constitué par le platine, le palladium, le ruthénium, l'osmium, l'iridium, le rhodium, et leurs mélanges.

25
 EP 1 442 006 B1

20. Procédé selon la revendication 19, dans lequel le catalyseur à base de métal précieux est sous forme d'un métal
ou d'un alliage finement divisé ou de surface spécifique élevée.

21. Procédé selon la revendication 19, dans lequel le catalyseur à base de métal précieux est obtenu par conversion
5 d'un composé précurseur en le catalyseur actif avant ou pendant l'hydrogénation.

22. Procédé selon la revendication 19, dans lequel le catalyseur à base de métal précieux est distribué sur un support
inorganique.

10 23. Procédé selon la revendication 22, dans lequel le support inorganique est choisi dans le groupe constitué par le
carbone, le carbone activé, des oxydes métalliques, des carbonates métalliques et des sulfates métalliques.

24. Procédé selon la revendication 18, dans lequel le catalyseur à base de métal précieux est du palladium sur du
carbone.
15
25. Procédé selon la revendication 1, dans lequel l'étape d'hydrogénation (b) s'effectue par hydrogénation par transfert
catalytique avec un agent d'hydrogénation.

26. Procédé selon la revendication 25, dans lequel l'hydrogénation par transfert catalytique s'effectue à l'aide d'un
20 catalyseur à base de métal précieux.

27. Procédé selon la revendication 26, dans lequel le catalyseur à base de métal précieux est choisi dans le groupe
constitué par le platine, le palladium, le ruthénium, l'osmium, l'iridium, le rhodium, et leurs mélanges.

25 28. Procédé selon la revendication 27, dans lequel le catalyseur à base de métal précieux est sous forme d'un métal
ou d'un alliage finement divisé ou de surface spécifique élevée.

29. Procédé selon la revendication 28, dans lequel le catalyseur à base de métal précieux est obtenu par conversion
d'un composé précurseur en le catalyseur actif avant ou pendant l'hydrogénation.
30
30. Procédé selon la revendication 27, dans lequel le catalyseur à base de métal précieux est du palladium sur du
carbone.

31. Procédé selon la revendication 25, dans lequel l'agent d'hydrogénation est choisi dans le groupe constitué par le
35 formate d'ammonium, l'acide formique, des sels d'ammonium ou de métaux d'hypophosphite.

32. Procédé selon la revendication 26, dans lequel l'agent d'hydrogénation est choisi dans le groupe constitué par le
formate d'ammonium, l'acide formique, des sels d'ammonium ou de métaux d'hypophosphite.

40 33. Procédé selon la revendication 1, dans lequel le sel de phénylpropanolamine acylé obtenu par l'étape (a) est isolé
avant la mise en oeuvre de l'étape (b).

34. Procédé selon la revendication 33, dans lequel le sel de phénylpropanolamine acylé obtenu par l'étape (a) est
isolé par addition d'un solvant de cristallisation au mélange réactionnel contenant le sel de phénylpropanolamine
45 acylé.

35. Procédé selon la revendication 34, dans lequel le solvant de cristallisation est choisi dans le groupe constitué par
pentane, hexane, heptane, octane, méthyle tert-butyle éther, méthylisobutylcétone, éthanol, propanol, isopropa-
nol, butanol et leurs mélanges.
50
36. Procédé selon la revendication 35, dans lequel le solvant de cristallisation est de l'heptane.

37. Procédé selon la revendication 1, dans lequel le sel de phénylpropanolamine acylé obtenu par l'étape (a) n'est
pas isolé avant la mise en oeuvre de l'étape (b).
55
38. Procédé selon la revendication 1, dans lequel le carbone portant le groupe amino dans le sel de phénylpropano-
lamine a la configuration racémique.

26
 EP 1 442 006 B1

39. Procédé selon la revendication 1, dans lequel le carbone portant le groupe amino dans le sel de phénylpropano-
lamine a la configuration S.

40. Procédé selon la revendication 1, dans lequel le sel de phénylpropanolamine est choisi dans le groupe constitué
5 par la 1R,2S-(-)-noréphédrine, la 1S,2S-(+)-norpseudoéphédrine, la 1R,2S-(-)-éphédrine, et la 1S,2S-(+)-pseu-
doéphédrine.

41. Procédé selon la revendication 1, dans lequel le composé de formule I est la S-(+)-méthamphétamine et le sel de
phénylpropanolamine est choisi dans le groupe constitué par la 1R,2S-(-)-éphédrine et la 1S,2S-(+)-pseudoéphé-
10 drine.

42. Procédé selon la revendication 1, dans lequel la quantité d'agent d'acylation utilisée se situe entre environ 1,0
équivalent et 3,0 équivalents par rapport à la quantité de sel de phénylpropanolamine.

15 43. Procédé selon la revendication 42, dans lequel la quantité d'agent d'acylation utilisée se situe entre environ 1,1
équivalent et 2,5 équivalents par rapport à la quantité de sel de phénylpropanolamine.

44. Procédé selon la revendication 43, dans lequel la quantité d'agent d'acylation utilisée se situe entre environ 1,1
équivalent et 2,0 équivalents par rapport à la quantité de sel de phénylpropanolamine.
20
45. Procédé selon la revendication 44, dans lequel la quantité d'agent d'acylation utilisée se situe entre environ 1,2
équivalent et 1,5 équivalent par rapport à la quantité de sel de phénylpropanolamine.

46. Procédé selon la revendication 1, dans lequel la température du mélange réactionnel de l'étape (a) se situe entre
25 50°C et 100°C.

47. Procédé selon la revendication 46, dans lequel la température du mélange réactionnel de l'étape (a) se situe entre
60°C et 90°C.

30 48. Procédé selon la revendication 47, dans lequel la température du mélange réactionnel de l'étape (a) se situe entre
70°C et 85°C.

49. Procédé selon la revendication 1, dans lequel le sel de phénylpropanolamine est préparé à partir de la phényl-
propanolamine base libre.
35
50. Procédé selon la revendication 1, dans lequel le sel de phénylpropanolamine est un sel de phénylpropanolamine
et d'un acide choisi dans le groupe constitué par l'acide fluorhydrique, l'acide chlorhydrique, l'acide bromhydrique,
l'acide iodhydrique, l'acide sulfurique, l'acide phosphorique, l'acide nitrique, l'acide formique, l'acide acétique, l'aci-
de propionique, l'acide benzoïque, l'acide tartrique, l'acide succinique, l'acide oxalique, l'acide malique, l'acide
40 aspartique et l'acide saccharique.

51. Procédé selon la revendication 1, dans lequel le sel de phénylpropanolamine est un sel de phénylpropanolamine
et d'un acide choisi dans le groupe constitué par un acide carboxylique, un acide dicarboxylique et un acide tri-
carboxylique.
45
52. Procédé selon la revendication 1, dans lequel le sel de phénylpropanolamine est un sel de phénylpropanolamine
et d'acide chlorhydrique.

53. Procédé de préparation d'un composé de formule I

50

55

27
 EP 1 442 006 B1

10

à partir d'un sel de phénylpropanolamine O-acylé de formule III

15

20

25
où:

R1 est un hydrogène ou un groupe alkyle en C1-C8;

chaque R2 est indépendamment un hydrogène, un halogène, un groupe alkyle en C1-C8, un groupe alcoxy
30 en C1-C8, un groupe alkyle en C1-C8 substitué par 1 à 5 halogènes, un groupe alcoxy en C1-C8 substitué par
1 à 5 halogènes, ou les deux R2 ensemble constituent un groupe -O(CH2)xO- dans lequel x est 1 à 4, formant
ainsi une structure cyclique condensée avec le groupe phényle;
R3 est un groupe alkyle en C1-C8, un groupe aralkyle en C1-C12, un groupe alkaryle en C1-C12, ou un groupe
phényle, qui sont chacun éventuellement substitués par 1 à 5 substituants choisis parmi un halogène, un
35 hydroxy ou un alkyle en C1-C6; et
HX est un équivalent d'un acide organique ou inorganique,

le procédé comprenantl'hydrogénation du sel de phénylpropanolamine O-acylé pour préparer le composé de for-

mule I.
40

45

50

55

28