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Preparation of Amphetamines From Europäisches Patentamt *EP001442006B1* (19) European Patent Office 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 , 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). EP 1 442 006 B1 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)2OinR3CO2H, to form the corresponding
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