(12) United States Patent (10) Patent No.: US 9.278,904 B2 Meckler Et Al

US009278904B2

(12) United States Patent (10) Patent No.: US 9.278,904 B2 Meckler et al. (45) Date of Patent: *Mar. 8, 2016

(54) SYNTHESIS OF CHIRAL AMPHETAMINE Crossland et al., A Facile Synthesis of Methanesulfonate Esters. DERIVATIVES BY STEREOSPECIFIC, Journal of Organic Chemistry. 1970, 35, 3195-3196.* REGIOSELECTIVE CUPRATE ADDITION Rydzewski, Real World Drug Discovery 2008, 42-43.* REACTION WITH AZRDINE L.A. Cates, et al., “Phosphorus-Nitrogen Compounds VI: Some PHOSPHORAMDATE COMPOUNDS Phenethylamine Derivatives,” Journal of Pharmaceutical Sciences, vol. 55, No. 12, Dec. 1966, pp. 1400-1405. (71) Applicant: Chemapotheca, LLC, Delmar, NY (US) T. Gajda, et al., “Synthesis of Primary sec-Alkylamines via Nucleophilic Ring-opening of N-Phosphorylated Aziridines.” Tetra (72) Inventors: Harold Meckler, Delmar, NY (US); hedron, vol. 53, No. 13, 1997, pp. 4935-4946. Brian Thomas Gregg, Altamont, NY K. Osowska-Pacewicka, et al., Reactions of N-Phosphorylated Aziridines with Dianions Derived from Ethyl Acetoacetate and 1,3- (US); Jie Yang, Rensselaer, NY (US) Diketones: New Route to Substituted Pyrrolines and Pyrrolidines, Synthetic Communications. An International Journal for Rapid (73) Assignee: Chemapotheca, LLC, Delmar, NY (US) Communication of Synthetic Organic Chemistry, vol. 28, No. 7. 1998, pp. 1127-1137. (*) Notice: Subject to any disclaimer, the term of this P. Giles, et al. "An Improved Process for the N-Alkylation of Indoles patent is extended or adjusted under 35 Using Chiral N-Protected 2-Methylaziridines.” Organic Process U.S.C. 154(b) by 0 days. Research & Development, vol. 7, No. 1, 2003, pp. 22-24. This patent is Subject to a terminal dis A. Poshkus, et al., “The Reaction of Neutral Esters of Trivalent claimer. Phosphorus Acids with Inorganic Acid Chlorides. I. The Reaction of Trialkyl Phosphites with Sulfuryl Chloride.” Journal of the American (21) Appl. No.: 14/189.630 Chemical Society, Contribution from the Research and Development Center of the Armstrong Cork Co., 1957, pp. 6127-6129. (22) Filed: Feb. 25, 2014 A. Borkovec, et al., Insect Chemosterilants. III. 1-Aziridinylphosphine Oxides, Journal of Medicinal Chemistry, vol. (65) Prior Publication Data 9, Jul. 1966, pp. 522-526. N. Stojanovska, et al., “A Review of Impurity Profiling and Synthetic US 2015/O183716 A1 Jul. 2, 2015 Route of Manufacture of Methylamphetamine, 3,4- methylenedioxymethylamphetamine, amphetamine, Related U.S. Application Data dimethylamphetamine and p-methoxyamphetamine.” Forensic Sci ence International, vol. 224, 2013, pp. 8-26. (60) Provisional application No. 61/922,729, filed on Dec. M. Sylla-lyarreta Veitia, et al., “Synthesis of Novel N-Protected 31, 2013. B3-Amino Nitriles: Study of Their Hydrolysis Involving a Nitrilase Catalyzed Step.” Tetrahedron. Asymmetry, vol. 20, No. 18, 2009, pp. (51) Int. Cl. 2O77-2089. CD7C 209/68 (2006.01) Zwierzak, Andrzej, Alkylation of Diethyl Phosphoramidates—A C07F 9/564 (2006.01) Simple Route from Primary to Secondary Amines, Angew Chem Intil CD7C 209/62 (2006.01) Ed Engl 16 (1977) No. 2 p. 107. C07F 9/24 (2006.01) WO 2015/130660 Int'l Search Report Zwierzak, Synthesis (52) U.S. Cl. Comm., Phosphor-amido-mercuration, pp. 918, Nov. 1982; CPC ...... C07C 209/62 (2013.01); C07F 9/2458 Zwierzak, Tetrahedron Letters, Synthesis of Primary sec (2013.01); C07F 9/2475 (2013.01); C07B Alkylamines, 53:13, 4935, 1997; and Li Xinyao, Synthesis, An 2200/07 (2013.01); C07F 9/564 (2013.01) Improved and Mild Wenker Synthesis of Aziridines, vol. 20, 3423, (58) Field of Classification Search 2010, abstract, scheme 2, Jun. 25, 2015, Chemapotheca. None WO 2015/130660 Int’l Written Opinion of 660 ISR, Jun. 25, 2015, See application file for complete search history. Chemapotheca. (Continued) (56) References Cited U.S. PATENT DOCUMENTS Primary Examiner — Rebecca Anderson Assistant Examiner — Po-Chih Chen 6,399,828 B1 6, 2002 Boswell (74) Attorney, Agent, or Firm — Todd L. Juneau 7,705,184 B2 4/2010 Buenger 8.487,134 B2 7, 2013 Meudt (57) ABSTRACT The invention includes processes for the synthesis of amphet FOREIGN PATENT DOCUMENTS amine, dexamphetamine, methamphetamine, derivatives of FR 5857 M 3, 1968 these, including their salts, and novel precursors and interme diates obtained thereby, by synthesizing aziridine phospho OTHER PUBLICATIONS ramidate compounds in specified solvents at specified tem CAPLUS printout of “Veitia et al., Synthesis of novel N-protected peratures, and then converting to a novel aryl or aryl-alkyl beta,3-amino nitriles: study of their hydrolysis involving a nitrilase phosphoramidate precursors using an organometallic com catalyzed step. Tetrahedron: Assymetry. 2009, 20, 2077-2089.” pound Such as a copper salt, where the novel aryl oraryl-alkyl Moore et al... An efficient and operationally convenient gerenal Syn phosphoramidate precursor is then easily converted to the thesis of tertiary amines by direct alkylation of secondary amines target compounds using known reactions. with alkyl halides in the presence of Huenig's base. Arkivoc. 2005, 287-292.* 20 Claims, No Drawings US 9.278,904 B2 Page 2

(56) References Cited Funel and Abele, Diels Alder Reactions Part 1, Angewandte Reviews, Angew. Chem Int2013 vol. 52, 1-44, 2013. OTHER PUBLICATIONS Funel and Abele, Diels Alder Reactions Part3. Angewandte Reviews, Angew. Chem Int2013 vol. 52, 1-44, 2013. WO 2015-130661 Int'l Search Report Zwierzak, Synthesis Funel and Abele, Diels Alder Reactions Part 2, Angewandte Reviews, Comm., Phosphor-amido-mercuration, pp. 918, Nov. 1982; Aeseng, Angew. Chem Int2013 vol. 52, 1-44, 2013. PhD Thesis, Asymmetric Synthesis of 2-Substituted-Aminotetralins, Funel and Abele, Diels Alder Reactions Part 4. Angewandte Reviews, Norway Univ SciTech, Nov. 2010, Scheme 1.4; and Li Xinyao, Angew. Chem Int2013 vol. 52, 1-44, 2013. Synthesis, An Improved and Mild Wenker Synthesis of Aziridines, Stephens, Substituted Aziridines, Prep and Properties, JChem Engin, vol. 20, 3423, 2010, abstract, scheme 2, Jun. 25, 2015, vol. 8, No. 4, pp. 625-626, Oct. 1963. Chemapotheca. Stephens, Relative rates of Reaction and Direction of Ring Opening, WO 2015/130661 Int’l Written Opinion of 661 ISR, Jun. 29, 2015, J Chem Engin, vol. 14, No. 1, pp. 114-115, Jan. 1969. Chemapotheca. Hata, Fragmentation Reaction of Ylide, JACS vol. 98-19, pp. 6033 Kojima, Scifinder CAS Registry 1485-13-8 for 2-methyl-3-phenyl 6036, Sep. 1976. aziridine, Kojima 1959 et al. Jessing, Aziridines in Synthesis, Baran Lab Jan. 2007. Streuff AZiridines—Overview and Recent Advancements, Hassner, A.; Galle, J. E.; “Ring Opening of Aziridine Phosphonates. Stoltzgroup Literature Seminar, Jan. 26, 2009. Correlation of Structure, Nuclear Magnetic Resonance Spectra and Allen and Ely, Synthetic Methods for Amphetamines, Crime Scene Reactivity”.J. Org. Chem., 1976, 41, 2273-2276. magazine, p. 15-25 Spring 2011. Stromberg, Comparative GC Analysis, J. Chromatography 106 Mekenyan, Scifinder 2010: 1165579 ACS, Aziridine Use of (1975) 335-342, amphet sulfate. Genotoxicity Information . . . . Chem Res Tox vol. 23 Issue 10 pp. Lambrechts, Profiling of Impurities in Illicit Amphetamine, 1986 J 1519-1540, 2010. Chromatography vol. 369 (1976) pp. 365-377 HPLC impurities. Sakurai, Scifinder 2000-630740 ACS, Aziridine Recommendation of Allen, Methamphetamines from Ephedrine, J Forensic Sci vol. 32. Occupational exposure limits, J Occup Health, vol. 42, Issue 4, pp. No. 4, Jul. 1987, pp. 953-962. 213-228, 2000. Milstein, Friedel Crafts Reactions of Htree Member Heterocycles, J Koleva, Scifinder 2011-1058228 ACS, Modelling of Acute Oral . . . Het Chem vol. 5, pp. 339-241, Mar. 1968. aziridine toxicity, Toxicology In Vitro, vol. 25, Issue 7, pp. 1281 Hassner, Regiospecificity: A Useful Terminology, JOC vol. 33, No. 7 1293, 2011. pp. 2684-2686 Jul. 1968. Lambrechts, Leuckart-specific impurities in amphetamine, Bulletin Todd, Aneurin, A Synthesis of Thiochrome, J Chem Soc 1936, pp. on Narcotics, UNODC Everywhere, pp. 47-57, Jan. 1, 1984. 1601-1605. D'Ambra, Scifinder Search Results for D'Ambra patents (allergy Hider, Prep of Evidence in Amphet Prosecutions, J. Forensic Scipp. drugs, regioselectivity) Accession 2002-52000, from TS-79 1960s. US20020007068, 1999. Anandasankar, Scifinder 7763-71-5, referring to WO 2011 130726, Rege et al. Drug Metabolism and Disposition, vol. 30 No. 12, pp. priority to US 2011-32804, and 2010-61325236, 2010. 1337-1343, Irreversible Inhibition of CYP2D6 by (-) Osowska-Pacewicka, N-Phosphorylated Aziridines—new reagents Chloroephedrine (impurity), 2002. for electrophilic amination, Polish JChem 68-6 pp. 1263-1264 1994. Emea Committee for Medical Products, Grignard Solvents Commit Pramanik. An Efficient Scalable Process for BenZphetamine HCI, tee, Feb. 10, 2005, pp. 1-7. JACSJ Org Process Res Dev 2014 vol. 18 pp. 495-500. FDA CDER. Guidance for Industry, (genotox guidance) Dec. 2008. Snodin, Potentially Mutagenic Impurities, J Org Process Res Dev Skinner, Methamphetamine Synthesis via Hydriodic . . . . Forensic 2014, vol. 18, pp. 836-839 Racemic. Sci Int'l, 48 (1990) 123-134, red phos method. Raman, Regulatory Expectations Towards Genotoxic, J.Org Process Anderson, Development of a Harmonized Method for Profiling . . . . Res Dev 2014 vol. 18 pp. 834-835. Forensic Sci Int’l 169 (2007) pp. 50-63, GC method. Teasdale, Regulatory Highlights, J Org Process Res Dev 2014 vol. Power, An Unusual Presentation of Customs Seizure, Forensic Sci 18, 458-472. Int’l 234 (2014) e10-e13. Jawahar, Direct Stereospecific Synthesis of Unprotected N—H and Barker, A Study of the Use of Ephedra, Forensic Sci Int’l 166 (2007) N-Me Aziridines from Olefins, Sciences 343, 61 pp. 61-65, 2014. 102-109. Koziara, A.; Oleiniczak, B., Osowska, K. Zwierzak, A. Humphrey, Keeping Afloat in a Sea of Impurities, Global Safety "Phosphoramidomercuration-Demercuration: A Simple Two-Step Assessment, AstraZeneca Jul. 6, 2007. Conversion of Alkenes into Alkanamines' Synthesis 1982, 918-920. EMEA Solvent (Grignard) impurities, ICH Topic Q3C (R4), pp. 1-22, 2010. * cited by examiner US 9,278,904 B2 1. 2 SYNTHESIS OF CHRAL AMPHETAMINE Additionally, the use of protecting groups and leaving DERIVATIVES BY STEREOSPECIFIC, groups is well known. However, it has been discovered that REGIOSELECTIVE CUPRATE ADDITION there is significant variation among the various protecting REACTION WITH AZRDINE groups. Specifically, where a carbonyl is used as a protecting PHOSPHORAMDATE COMPOUNDS group, the reaction must be kept at below -10 degrees Celsius or the carbonyl will react with the Grignard reagent. Where a CROSS-REFERENCE TO RELATED Sulfonyl is used as a protecting group, it is impossible to APPLICATIONS remove the protecting group without destroying the mol ecule. None. 10 Accordingly, there is a need for synthetic processes and useful compounds for the manufacture of amphetamine and STATEMENT REGARDING FEDERALLY its derivatives which have high chemical yield, high selectiv SPONSORED RESEARCH ity, low cost, lower toxicity and are less dangerous to handle. No federal government funds were used in the research or 15 BRIEF SUMMARY OF THE INVENTION development of this invention. The present invention addresses one or more of the short NAMES OF PARTIES TO AJOINT RESEARCH comings of the prior art by providing processes for the Syn AGREEMENT thesis of amphetamine, dexamphetamine, methamphet amine, derivatives of these, including their salts, and novel None. precursors and intermediates obtained thereby, by synthesiz ing aziridine phosphoramidate compounds in specified sol REFERENCE TO ASEQUENCE LISTING vents at specified temperatures, and then converting to a novel aryl or aryl-alkyl phosphoramidate precursors using a modi None. 25 fied organometallic compound Such as a organocopper reagent, where the novel aryl or aryl-alkyl phosphoramidate BACKGROUND precursor is then easily converted to the target compounds using known reactions, e.g. acidification, methylation of the 1. Field of the Invention nitrogen followed by dephosphorylation, etc. This is invention is related to processes for synthesis of 30 In one preferred aspect the invention provides a synthetic amphetamine derivatives and novel intermediates thereby. pathway to amphetamine derivatives using an aziridine based 2. Background of the Invention process with an organometallic compound by heating the The commercial importance of amphetamine derivatives reactants in a first step, and then adding as a second step the has led to the development of numerous synthetic methods for Grignard reagent in a dosage controlled fashion. In a pre their synthesis and their derivatization. One problem with 35 ferred embodiment, the reaction is heated to above 40 degrees amphetamine synthesis is that amphetamines have a stereo C., preferably above about 45 degrees C., and more prefer defined amine center, which can be subject to racemization. ably above about 48 degrees C. In one embodiment, the Accordingly, only stereospecific methods are useful. How temperature is maintained from 48-51 deg. C. for about 30 ever, Stereospecific methods do not provide the economic minutes and then brought to room temperature. requirements of high yields, high selectivity and low process 40 In another preferred embodiment, the invention provides a costs. Typically Such reactions involve a coupling agent, Such process of making the dexamphetamine, said process com as Grignard or organolithium reagents. Conventional teach prising: ing requires that the use such organometallics requires that providing a compound of Formula 5: the reaction temperature be maintained at a cold temperature, Such as an ice bath at less than 10 degrees Celsius. 45 Another problem with amphetamine synthesis is that the intermediates are toxic as well as flammable. This requires special handling such as double-walled drums and safety accommodations to protect manufacturing personnel. HC The prior art in U.S. Pat. No. 6,399,828 teaches the pro 50 duction of amphetamine using various methods. In one approach norephedrine is refluxed with hydrogen iodide and wherein R is alkyl or aryl; and red phosphorous. In another approach norephedrine is chlo deprotecting the compound of Formula 5 under acidic con rinated using thionyl chloride and then catalytically hydroge ditions effective to produce dexamphetamine of Formula 1: nated. In U.S. Pat. No. 7,705,184, amphetamine synthesis is 55 disclosed using hydrogenation of a chlorinated phenylpro panolamine. AZiridine chemistry, and specifically aziridine phosphoramidates are not taught in the amphetamine synthe sis prior art. Zwierzak et al. disclose a method of reacting N-phospho 60 rylated aziridines with copper-modified Grignard reagents as a new route to substituted pyrrolines and pyrrolidines. How In preferred aspects, the dexamphetamine process com ever, Zwierzak etal discloses this method as being regiospe prises wherein the acidic conditions are aqueous hydrochlo cific, which it is not. Int’l J. for Rapid Commun. of Syn. Org. ric, Sulfuric or phosphoric acids. Chem., 28:7, 1127-1137 (1998). Accordingly, where the prior 65 In preferred aspects, the dexamphetamine process com art contained an erroneous teaching, it was surprising to dis prises wherein the aqueous acid water content is in an amount cover otherwise. Of 50% to 90% US 9,278,904 B2 3 4 In preferred aspects, the dexamphetamine process com providing a compound of Formula 2: prises wherein the R-methyl, ethyl, isopropyl or phenyl. In preferred aspects, the dexamphetamine process com prises wherein said providing a compound of Formula 5 comprises: 5 providing a compound of Formula 4: He1\-1 OH wherein R is alkyl or aryl; and 10 reacting the compound of Formula 2 with methanesulfonyl N chloride and a base under conditions effective to produce a w compound of Formula 3. HC s In preferred aspects, the dexamphetamine process com prises a compound of Formula 2 wherein the R-methyl, ethyl, 15 isopropyl or phenyl. wherein R is alkyl or aryland In preferred aspects, the dexamphetamine process com reacting the compound of Formula 4 with phenylmagne prises wherein said providing a compound of Formula 2 sium halide and a copper halide catalyst under Solvent and comprises: temperature conditions effective to produce a compound of providing a compound of Formula 1: Formula 5 in a purity Substantially free of any regioisomeric impurities. In preferred aspects, the dexamphetamine process com prises wherein the regioisomeric purity of Formula 5 is >99% and the regioisomer is >0.1%. In preferred aspects, the dexamphetamine process com 25 prises wherein the R-methyl, ethyl, isopropyl or phenyl. and In preferred aspects, the dexamphetamine process com reacting the compound of Formula II with the appropriate prises wherein the copper halide catalyst is CuCl, CuCl, CuBr or Copper nanoparticles. 30 In preferred aspects, the dexamphetamine process com | prises wherein the solvent is an organic ether. P-Cl In preferred aspects, the dexamphetamine process com RO prises wherein the solvent is tetrahydrofuran or 2-methyltet OR rahydrofuran. 35 wherein R-alkyl or aryl In preferred aspects, the dexamphetamine process com under conditions effective to produce a compound of For prises wherein said treating is carried out at a temperature of mula 2. from about -10° C. to about 70° C. In preferred aspects, the dexamphetamine process involv In preferred aspects, the dexamphetamine process com 40 ing Formula 2 comprises wherein the R-methyl, ethyl, iso prises wherein said treating is carried out at a temperature of propyl or phenyl. from about 30° C. to about 60° C. In another preferred embodiment, the invention provides a In preferred aspects, the dexamphetamine process com process of making the dex-N-methylamphetamine, said pro prises wherein said providing a compound of Formula 4 cess comprising: comprises: 45 providing a compound of Formula 8: providing a compound of Formula 3: (EtO)2(OPN Me

50 H3C 1N1 OMS and deprotecting the compound of Formula 8 under acidic con wherein R is alkyl or aryl; and 55 ditions effective to produce dex-N-methylamphetamine of reacting the compound of Formula 3 with the base under Formula 9: conditions effective to produce a compound of Formula 4.

In preferred aspects, the dexamphetamine process involv ing Formula 3 comprises a compound of Formula 3 wherein the R-methyl, ethyl, isopropyl or phenyl. 60 In preferred aspects, the dexamphetamine process com prises wherein the base is potassium hydroxide or potassium carbonate. In preferred aspects, the dexamphetamine process com 65 In preferred aspects, the dex-N-methylamphetamine pro prises wherein said providing a compound of Formula 3 cess comprises wherein the acidic conditions are aqueous comprises: hydrochloric, Sulfuric or phosphoric acids. US 9,278,904 B2 5 6 In preferred aspects, the dex-N-methylamphetamine pro In another preferred embodiment, the invention provides a cess comprises wherein the aqueous acid water content is in compound of the formula: an amount of 50% to 90%

In preferred aspects, the dex-N-methylamphetamine pro (RO)2(OPN cess comprises wherein said providing a compound of For H mula 8 comprises:

(EtO)2(OPN Me 10 prepared according to one or more processes herein, in a regioisomeric purity of >1700:1 wherein: R is alkyl or aryl In preferred aspects, the invention further comprises a 15 compound of the formula: and reacting the compound of Formula 5b with a methyl alky

lating agent and a base (RO)2(OPN H In another preferred embodiment, the invention provides a process of making the dex-N-ethylamphetamine, said pro cess comprising: HC providing a compound of Formula 10: wherein the alkyl group is selected from the group consist ing of methyl, ethyl or isopropyl 25 In preferred aspects, the invention further comprises a -E compound of the formula:

30 (RO)2(OPN H s and HC deprotecting the compound of Formula 10 under acidic conditions effective to produce dex-N-ethylamphetamine of 35 wherein the aryl group is phenyl. Formula 11: In another preferred embodiment, the invention provides a compound of the formula:

40 N HC In preferred aspects, the dex-N-ethylamphetamine process 45 comprises wherein the acidic conditions are aqueous hydro wherein: R is alkyl or aryl chloric, Sulfuric or phosphoric acids. In preferred aspects, the invention further comprises a In preferred aspects, the dex-N-ethylamphetamine process compound of the formula: comprises wherein the aqueous acid water content is in an amount of 50% to 90% 50 N In preferred aspects, the dex-N-ethylamphetamine process comprises wherein said providing a compound of Formula 10 comprises: 55 wherein the alkyl group is selected from the group consist ing of methyl, ethyl or isopropyl. (EtO)2(OPN-Et In preferred aspects, the invention further comprises a compound of the formula:

60

N A and 65 HC reacting the compound of Formula 5b with a ethyl alkylat ing agent and a base wherein the aryl group is phenyl. US 9,278,904 B2 7 8 In yet another preferred embodiment, there is provided a R may also be in certain preferred embodiments any process for the synthesis of amphetamine derivatives com C2-C10 straight or branched chain alkenyl or C1-C10 alkoxy, prising the step of performing a stereo-specific cuprate addi unsubstituted or optionally substituted with moieties listed tion reaction upon an aziridine phosphoramidate compound above. to obtain a chiral aryl oraryl-alkyl phosphoramidate amphet Copper nanoparticles means particles having an average amine precursor. diameter of about 1 nm-100 nm. In yet another preferred embodiment, there is provided a Alkyl Phosphonic Acid Protecting group means any group process for solvent extraction of compounds 5a-d from a attached to the aziridine nitrogen having one or more alkyl mixture of compounds 5a-d and 6a-d, comprising the step of groups attached to a phosphorous atom thereby having the performing a solvent extraction using a mixture of two or formula P O—(OR), where R1 and R2 can be the same or more solvents wherein at least one of the two or more solvents different, and include without limitation any alkyl, alkoxy or is THF. aryl group as defined herein, and including any and all equiva lents thereof. DETAILED DESCRIPTION OF THE INVENTION 15 Solvents, as used and exemplified herein, are not intended to be limiting and may include without limitation solvents Accordingly, the present invention relates to processes for selected from Ligroine, Pentane, Hexane, Heptane, Octane, the synthesis of amphetamine, dexamphetamine, metham Cyclopentane, Cyclohexane, Cycloheptane, Cyclooctane, phetamine, derivatives of these, including their salts, and Dichloromethane, Chloroform, Carbon tetrachloride, 1,2- novel precursors and intermediates obtained thereby, by Syn Dichloroethane, 1.1.2.2-Tetrachloroethane, Methylacetate, thesizing aziridine phosphoramidate compounds in specified Ethylacetate, Propylacetate. Butylacetate, Dimethylforma Solvents at specified temperatures, and then converting to a mide, Diethylformamide, Dimethylacetamide, Diethylaceta novel aryl or aryl-alkyl phosphoramidate precursor using an mide, Diethylether, Diisopropylether, 20 methyl tert-Butyl organometallic compound Such as a copper salt, where the ether, THF, Dioxane, Acetonitrile, Sulfolane, DMSO, HMPT, novel aryl or aryl-alkyl phosphoramidate precursor is then 25 NMP or mixtures of these solvents. Preferred solvents are easily converted to the target compounds using known reac Dichloromethane, Chloroform, Ethyl acetate, Propyl acetate, tions, e.g. acid dephosphorylation, methylation of the nitro Butyl acetate, Dimethylformamide, Diethylformamide, Dim gen followed by acid dephosphorylation, etc. ethylacetamide, Diethylacetamide, Diisopropylether, methyl Alkyl means any C1-C10 straight or branched chain alkyl, tert-Butyl ether, THF, Dioxane, Acetonitrile or mixtures of wherein said alkyl, is optionally substituted with C1-C6 alkyl, 30 these. Especially preferred solvents are Dichloromethane, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbo Chloroform, Ethyl acetate. Butyl acetate, Dimethylforma nyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, mide, Dimethylacetamide, methyl tert-Butyl ether, THF, alkylamino, aminoalkyl, Sulfhydryl, thioalkyl, or Sulfonyl. Dioxane, Acetonitrile or mixtures of these. Aryl means any alicyclic or aromatic, mono-, bi- or tricy The term, regioselective or regioselectivity, means without clic, carbo- or heterocyclic ring, wherein the ring is either 35 limitation, by way of explanation, the preference of one direc unsubstituted or substituted with one or more substituent(s) tion of chemical bond making or breaking over all other independently selected from the group including, but not possible directions. It can often apply to which of many limited to, alkylamino, amido, amino, aminoalkyl, azo, ben possible positions a reagent will affect, such as which proton Zyloxy, C1-C9 straight or branched chain alkyl, C1-C9 40 a strong base will abstract from an organic molecule, or where alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain on a substituted benzene ring a further substituent will add. alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, Because of the preference for the formation of one product carboxy, cyano, diazo, ester, formanilido, halo, haloalkyl, over another, the reaction is selective. This reaction is regi hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, oselective because it selectively generates one constitutional phenoxy, Sulfhydryl, Sulfonylsulfoxy, thio, thioalkyl, thiocar 45 isomer rather than the other. bonyl, thiocyano, thioester, thioformamido, trifluoromethyl, The term, stereoselective or stereoselectivity, means with and carboxylic and heterocyclic moieties, including alicyclic out limitation, by way of explanation, the property of a chemi and aromatic structures; wherein the individual ring size is cal reaction in which a single reactant forms an unequal 5-8 members; wherein said heterocyclic ring contains 1-6 mixture of stereoisomers during the non-stereospecific cre heteroatom(s) independently selected from the group consist 50 ation of a new stereocenter or during the non-stereospecific ing of O, N, and S; and wherein said aromatic or tertiary alkyl transformation of a pre-existing one. The selectivity arises amine is optionally oxidized. Useful carbo- and heterocyclic from differences in steric effects and electronic effects in the rings include without limitation phenyl, benzyl, naphthyl, mechanistic pathways leading to the different products. indenyl, aZulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, The literature teaches that the product from the cuprate indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benz 55 addition to the aziridine phosphoramidate is regiospecific which has been discovered, is not the case. In fact, the crude imidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropy product is of acceptable purity to proceed with. Further, it has ranyl, pyridyl, pyrrolyl pyrrolidinyl, pyridinyl, pyrimidinyl, also been discovered that, where the process generates 3-5% purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, of 6 (a,b,c or d) in the crude product, that it could not be quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzox 60 removed later in the synthetic sequence. It was also found that azolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triaz if you used a single solvent (5b crystallizes from heptane or olyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazi petroleum ether), then you did not remove the corresponding nyl, trithianyl, indolizinyl, pyrazolyl pyrazolinyl, 6b. It is required to leave a residue of the reaction solvent pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, (THF) in the mixture to separate the 5b from 6b. Interestingly, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pte 65 it has been discovered that a ratio of specific solvents yielded ridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, the most preferred embodiment. This ratio comprises about 7 and phenoxazinyl. part heptane and 1 part THF for 5b, and the other versions of US 9,278,904 B2 10 5 (a, c ord) needed other solvent mixtures, but the common -continued item was that it was required to leave a residue of THF in the O mixture. RON 4. 2) 1.15 eqMsCl Experimental Introduction: M YNH - 1.10Y ed Et3N - Unless otherwise noted, reagents and solvents were used as 5 RO E received from commercial Suppliers. He1\-1OH NMR Spectra: Proton nuclear magnetic resonance spectra were obtained 2a-d O on a Bruker AV 300 or a Bruker AV 500 spectrometer at 300 10 ROM MHz and 500 MHz, respectively. Spectra are given in ppm (8) PS and coupling constants, J. are reported in Hertz. Tetrameth Ro? NH 3)4.0 eq KOH (3M) Hs ylsilane was used as an internal standard for proton spectra. O. A 5-10°C. 2h HPLC Analyses (Achiral): He-1N1 S{ then 40°C. 6h Analyses were obtained on a Varian Prostar 210 HPLC 15 M NCH, system using a Prevail C18 column (53x7 mm, Alltech) with O PDA detection at 208-210 nm and solvent gradient program 3a-d Method A. HPLC Method A: poor, 2O N

Time Flow A (min) (mL/min) % A % B

O.O 2.O 95.0 S.O 1O.O 2.O S.O 95.0 11.5 2.O S.O 95.0 11.6 2.O 95.0 S.O 13.0 2.O 95.0 S.O

A = Water with 0.05% wiw Trifluoroacetic Acid B = Acetonitrile with 0.05% wiw Trifluoroacetic Acid 30 HPLC Analyses (Chiral): Preparation of Analyses were obtained on a Varian Prostar 210 HPLC (S)-dimethyl(2-methylaziridin-1-yl)phosphonate (4a) system using a CR(-) CrownPak (150x4 mm, 5um, Diacil Lot #CRMOCB-OK005) with PDA detection at 210-215 nm. 35 and isocratic solvent system Method B. HPLC Method B NH i. 1.15 eqCIP(O)(OMe) s 1.25 eq EtN Flow rate: 0.7 mL/min OH -> Run time: 35 min 40 He1\1 Temp: ambient 1 Mobile phase: 90% water pH=1.5 (perchloric acid): 10% P(O)(OMe), ii. 1.15 eqMsCl Methanol HN 1.10 eq Et3N -e- GC (FID): 45 r OH Analyses were obtained on a Varian CP 3800 GC using a He1\-1 Supleco (Cat #24048) SPB-530x0.320; 0.25um column. 2a Column temperature initial: 50° C. 1 P(O)(OMe) 50 HN iii. 4.0 eq KOH (3M) Column temperature final: 275° C. E He Ramp profile: 20.0 deg/min OMS 5-10° C. 2h He1\-1 then Injector temperature: 250° C. 40° C. 6 Detector temperature: 250° C. 3a P(O)(OMe) Carrier Gas/flow rate: Helium, 2 mL/min 55 Referring now to the following synthetic schemes, Scheme 1 provides: A CH

Scheme 1 60 4a NH, 1) 1.15 eqCIP(O)(OR)2 A 500 mL, 3-neck flask equipped with an overhead -N-OH 1.25 eq Et3N mechanical stirrer and pressure equalizing addition funnel HC was charged with L-alaninol (12.5g, 166.4 mmol), triethy 1-alaninol 65 lamine (29 mL. 208 mmol. 1.25 equiv) and dichloromethane 1 (125 mL). The reaction solution was cooled to +2° C. and treated with dimethoxyphosphoryl chloride (20 mL, 183 US 9,278,904 B2 11 12 mmol. 1.10 equiv) over 40 minutes while maintaining an -continued internal temperature>+8°C. The reaction mixture was stirred P(O)(OEt) with ice bath cooling for 1 hour at which point the reaction was complete by TLC analysis (silica gel, 93:6:1 DCM/ N MeOH/NHOH and 6/3/1 CHC1/MeOH/NHOH: KMnO, stain). Additional triethylamine (25.5 mL, 182.5 mmol. 1.10 CH equiv) was added to the reaction mixture and methanesulfo nyl chloride (14.9 mL, 191 mol, 1.15 equiv) was added drop wise over 45 minutes while maintaining an internal tempera A 12 L 3-neck flask fitted with an overhead mechanical ture <+10°C. The resulting reaction mixture was stirred with 10 ice bath cooling for 1.0 hour after which time TLC analysis stirrer and 1 L pressure equalizing addition funnel was indicated the reaction was complete. Potassium hydroxide charged with L-alaninol (250.0 g, 3.33 mol), triethylamine solution (3 M, 220 mL, 650 mmol. 4.0 equiv) was slowly (578 mL, 4.16 mol, 1.25 equiv) and dichloromethane (2.5L). added to the stirred reaction mixture while maintaining an 15 The stirred solution was cooled to +2°C. and diethoxyphos internal temperature <+16° C. The reaction was continued phoryl chloride (531 mL, 3.661 mol, 1.10 equiv) was added with agitation for 6 hours, after which time the aqueous layer over 1.5 hour while maintaining an internal temperature <+8° was separated and discarded. Saturated NaHCO, solution (35 C. The reaction mixture was stirred an additional 1 hour at mL) was added and the biphasic mixture heated to 40-42°C. which point the reaction was complete by TLC analysis Distillation was started and a first fraction of 90 mL ofdichlo (silica gel plate, 93:6:1 dichloromethane/MeoH/NH-OH and romethane was collected. When the temperature reached 50° C., a second fraction was collected until the batch temperature 6/3/1 CHCl/MeOH/NHOH: KMnO, stain). Additional tri was 65° C. The mixture was heated at 65° C. for another 1 ethylamine (510 mL, 3.65 mol, 1.10 equiv) was added to the hour and then cooled to ambient temperature. Dichlo reaction mixture and methanesulfonyl chloride (297 mL, 3.82 romethane (90 mL) was added and the mixture stirred for 10 25 mol. 1.15 equiv) was added drop-wise over 1.5 hours while minutes before separation. The dichloromethane layer was maintaining an internal temperature <+10°C. The resulting concentrated under reduced pressure. The residue was dis reaction mixture was stirred for 1.5 hours at which time TLC Solved in heptanes (15 mL) and concentrated under reduced analysis (see above methods) indicated the reaction was com pressure to remove the residual water. This azeotropic drying plete. Potassium hydroxide solution (3 M solution, 4.40 L, 13 was repeated two more times. The resulting 4a was obtained 30 mol. 4.0 equiv) was slowly added to the stirred reaction mix as a light yellow liquid (20.9 g, 76% yield, 95.40% GC ture while maintaining an internal temperature <+16°C. The purity). A colorless sample was prepared by short path distil reaction was stirred for 6 hours, after which time the aqueous lation (80-85° C.(a) 15 mm Hg vacuum). Optical rotation c=1.00, ethanol, 25.0° C., +39.3°. "H NMR (300 MHz, layer was separated. Saturated NaHCO solution (700 mL) CDC1,) & 3.80 (s, 3H), 3.76 (s, 3H), 2.65-2.50 (m. 1H), 5 was added and the biphasic mixture was heated to 40-42°C. 2.42-2.31 (m. 1H), 1.92 (dt, J=3.6, 1.2 Hz, 1H), 1.28 (dd. Distillation was started and a first fraction of 1.8 L of dichlo J=5.4, 1.2 Hz, 3H). romethane was collected. When the batch temperature reached 50°C., a second fraction was collected until the batch temperature was 65°C. The mixture was heated at 65° C. for Preparation of 40 (S)-diethyl(2-methylaziridin-1-yl)phosphonate (4b) another 1 hour and then cooled to ambient temperature. Dichloromethane (1.8 L) was added and the mixture stirred for 10 minutes before separation. The organic layer was con centrated under reduced pressure and heptane (250 mL) was NH i. 1.15 eqCIP(O)(OEt) 45 added to the concentrate. The resulting mixture was concen 1.25 eq Et3N trated under reduced pressure. The resulting 4b was obtained as a light yellow liquid (518.5 g., 80.6% yield, 98.90% GC He1\-1 purity). A colorless sample was prepared by short path distil 1 lation at 66-67° C., 0.9 mm Hg. Optical rotation c=1.01, 50 ethanol, 22.5°C., +28.8°. "H NMR (300 MHz, CDC1) & 4.15 (dq, J=8.0, 7.1 Hz, 4H), 2.64-2.45 (m. 1H), 2.33 (ddd, J=17.9, P(O)(OEt), ii. 1.15 eq MsCl 5.9, 1.3 Hz, 1H), 1.91-1.81 (m, 1H), 1.34 (dt, J=7.1, 0.9 Hz, HN 1.10 eq EtN -e- 6H), 1.28 (dd, J=5.4, 1.4 Hz, 3H). : OH 55 He1\-1 Preparation of (S)-diisopropyl(2-methylaziridin-1-yl)phosphonate 2b (4c)

60 P(O)(OEt)2 HN iii. 4.0 eq KOH (3M) NH i. 1.15 eqCIP(O)(OiPr) -- OMS 5-10° C. 2h 1.25 eq EtN He1N1 then 40° C. 6 65 1 US 9,278,904 B2

-continued -continued P(O)(OiPr). ii. 1.15 eqMsCl P(O)(OPh) ii. 1.15 eqMsCl HN 1.10 eq Et3N HN 1.10 eq Et3N Her He He1\1 OH He1\1 OH 2c 2d P(O)(OiPr)2 HN iii. 4.0 eq KOH (3M) -- 10 OMS 5-10° C. 2h He1N1 then - P(O)(OPh)2 40° C. 6 HN iii. 4.0 eq KOH (3M) 3c E He P(O)(OiPr) OMS 5-10° C. 2h 15 He1\1 then 40° C. 6 A 3S CH3 4c P(O)(OPh) A 250 L, 3-neck flask fitted with an overhead mechanical stirrer and pressure equalizing addition funnel was charged A with L-alaninol (4.2g, 55.7 mmol), triethylamine (9.74 mL, CH3 69.68 mmol. 1.25 equiv) and dichloromethane (50 mL). The 25 stirred reaction solution was cooled to +2° C. and diisopro pylphosphoryl chloride (12.3 g. 61.3 mmol. 1.10 equiv) was added drop-wise over 1.3 hours maintaining an internal tem perature <+8°C. The reaction mixture was stirred at about 0° C. for 10 hours. At this point, the reaction was complete by 30 TLC analysis (silica gel, 93:6:1 DCM/MeOH/NHOH and 6/3/1 CHC1/MeoH/NHOH, KMnO, stain). Additional tri A 500 L 3-neck flask fitted with an overhead mechanical ethylamine (8.6 mL, 61.3 mmol. 1.10 equiv) was added to the stirrer and a pressure equalizing addition funnel was charged reaction mixture and methanesulfonyl chloride (4.96 mL, 35 L-alaninol (8.5g, 113 mmol), triethylamine (19.5 mL, 139.36 64.1 mmol. 1.15 equiv) was added over 1.5 hours maintaining mmol. 1.25 equiv) and dichloromethane (100 mL). The an internal temperature <+10°C. The resulting reaction mix stirred reaction mixture was cooled to +2°C. and treated with ture was stirred at about 0°C. for 1.5 hours after which time TLC analysis (see above) indicated the complete consump diphenylchlorophosphate (33.4 g. 124.3 mmol. 1.10 equiv) over 1 hour while maintaining an internal temperature <+8° tion of 2c and formation of 3c. Potassium hydroxide solution 40 (3 M solution, 74 mL, 222.9 mmol. 4.0 equiv) was slowly C. The reaction mixture was stirred for 10 hours at which added to the stirred reaction mixture while maintaining an point the reaction was complete by TLC analysis (silica gel. internal temperature <+16° C. The reaction was continued 93:6:1 DCM/MeOH/NHOH and 6/3/1 CHC1/MeOH/ with agitation for 6 hours, after which time the layers were NHOH, KMnO stain). Additional triethylamine (17.5 mL, separated. The organic layer was washed with 10% citric acid 45 123 mmol. 1.10 equiv) was added to the reaction mixture and solution (40 mL) and saturated NaCl solution (2x40 mL). The methanesulfonyl chloride (10 mL, 129.1 mmol. 1.15 equiv) organic layer was concentrated under reduced pressure and was added over 50 minutes while maintaining an internal the residue was distilled (bulb-to-bulb. 79-82°C. (a)3 mm Hg temperature <+10° C. The resulting reaction mixture was vacuum) to afford 4c as a clear colorless liquid (5.2g, 42.0% 50 stirred with ice bath cooling for 1.5 hours after which time yield, 97.0% GC AUC purity). Optical rotation c=1.01, etha TLC analysis (see above) indicated the reaction was com nol, 22.5°C.,+28.8°. "H NMR (300 MHz, CDC1) & 4.71 (m, plete. Potassium carbonate (61.5g, 445 mmol. 4.0 equiv) was 2H), 2.64-2.41 (m. 1H), 2.28 (ddd, J–17.6, 5.6, 1.3 Hz, 1H), added to the cooled, stirred reaction mixture while maintain 1.81 (dd, J=14.1, 4.9, 1.3 Hz, 1H), 1.34 (m, 12H), 1.22 (dd. ing an internal temperature <+1.6°C. The reaction mixture J=5.6, 1.2 Hz, 3H). 55 was stirred for 6 hours at ambient temperature. The solid was Preparation of filtered and the organic phase was washed with 10% citric (S)-diphenyl(2-methylaziridin-1-yl)phosphonate (4d) acid solution (40 mL) and saturated NaCl solution (2x40 mL). The organic Solution was concentrated under reduced 60 pressure and the residue was purified by column chromatog NH i. 1.15 eqCIP(O)(OPh) raphy. The resulting 4d was obtained as Viscous oil (9.8 g. 1.25 eq EtN 30.0% yield, 97.0% GC purity). Optical rotation c=1.00, He-1S-1 ethanol, 25.1° C., +34.8°.'HNMR (300 MHz, CDC1) & 4.71 65 (m. 2H), 2.64-2.41 (m, 1H), 2.28 (ddd, J=17.6, 5.6, 1.3 Hz, 1 1H), 1.81 (dd, J=14.1, 4.9, 1.3 Hz, 1H), 1.34 (m. 12H), 1.22 (dd, J=5.6, 1.2 Hz, 3H). US 9,278,904 B2 15 16 Referring now to the following synthetic scheme, Scheme organic phase washed with deionized water (10 mL) and the 2 provides: organic phase concentrated under reduced pressure to give an

Scheme 2

MgCl P(O)(OR) CuCl (RO)2(O)PN (0.78 mol%) NH O -- /N y HerTHF Heat s -- Bor 2 N 1. How H3C H

4a-d Typical ratio = >97:3

purify by crystallization

1)3N HC1/80° C. (RO)2(O)PN 2) IPAC extraction -e- 3) 50% NaOH solution 4) MTBE extraction HC 5) distillation 5a-d purified

The phosphoryl chlorides were either purchased or pre- 30 oil. The residue was dissolved in heptanes (50 mL) and the pared as per Posheus, Herweh, J. Am. Chem. Soc. 1957, 79, Solution was concentrated under reduced pressure. The resi 6127-6129. due was crystallized from methyl tert-butyl ether (1 g/3 mL), filtered and dried to give 5a as white needles (3.29 g; 60.2% Preparation of yield), with 99.89% GC purity containing 0.05% 6a. mp (S)-dimethyl(1-phenylpropan-2-yl)phosphoramidate 35 86-88° C. Optical rotation c=1.00, ethanol, 25.0°C., +29.7°. (5a) "H NMR (300 MHz, CDC1) & 7.32-7.17 (m, 5H), 3.66 (d. J=6.4 Hz, 3H), 3.50-3.83 (m, 1H), 2.71 (d. J=6.6 Hz, 2H), 2.45 (m. 1H), 1.15 (d. J=6.6 Hz, 3H). (O)(OMe)2 11 eph McI 40 N CuC (1 mol%) Preparation of Dexamphetamine (7) from 5a Her / \ THF HC 4a 45 80° C. (MeO)2(O)P H ii. 50% NaOH solution

H3C 5a

5a 50

A 100 mL 3-neck flask was charged with 4a (4.0g, 24.2 mmol), THF (25 mL) and CuCl (28 mg, 1 mol %) and the stirrer was started. The mixture was heated to 48°C. A pres- 55 sure equalizing addition funnel was charged with PhMgCl (2M in THF, 13 mL) and the solution was added slowly while maintaining an internal temperature between 48-51 °C. The A 50 mL flask was charged with 5a (4.80 g. 19.73 mmol) reaction was stirred at 48-51 °C. for an additional 30 minutes and 3 M HCl (15.0 mL) and the stirred reaction mixture was and then cooled to ambient temperature. The reaction was 60 heated to 80°C. for 1 hour, then cooled to room temperature. quenched by slow addition to a cooled (15°C.) solution of The reaction mixture was washed with isopropyl acetate saturated aqueous ammonium chloride in water (50/50V/V, 40 (2x20 mL) and the organic extracts were disposed. The aque mL) while maintaining the temperature below 20° C. Hep ous layer was treated with sodium hydroxide solution (50%, tanes (40 mL) was used to rinse the reactor and the rinse 12.0 mL) keeping the internal temperature below 25° C. Solution was transferred to the quenched reaction mixture. 65 Methyl tert-butyl ether (15 mL) was added and the reaction The mixture was agitated for 5 minutes, allowed to separate mixture was agitated for 5 minutes then allowed to separate. for 20 minutes then the aqueous phase was discarded. The The organic layer washed with water (10 mL) and concen US 9,278,904 B2 17 18 trated under reduced pressure to give 7 as a colorless oil (2.51 -continued g, 94.4% yield, >99.5% purity by GC and chiral HPLC). (EtO)2(OPN H Preparation of (S)-diethyl(1-phenylpropan-2-yl) phosphor-amidate (5b) P(O)(OEt) 1.06 eq PhMgCl N CuC (0.78 mol%) -e- A \ THF A 250 mL 3-necked flask was charged with 4b (10g, 51.8 10 How3 mmol), THF (50 mL) and copper nanopowder (65 mg, 2 mol %) and the stirred mixture was heated to 50° C. A pressure 4b equalizing addition funnel was charged with PhMgCl (2M in (EtO)2(OPS THF, 29 mL) and the reagent was added while maintaining an internal temperature of 50-52°C. The reaction was allowed to 15 stir at 50-52°C. for an additional 16 hours and then cooled to HC ambient temperature. The reaction was quenched by slow addition to a cooled (15° C.) solution of saturated aqueous ammonium chloride/water (50/50 V/V, 50 L) while maintain A 12 L. jacketed, bottom outlet flask was charged with 4b ing an internal temperature below 20° C. Heptanes (50 L) was (500g, 2.58 mol), THF (2.5 L) and CuC1 (2.0 g, 0.78 mol%) used to rinse the reactor and this rinse was transferred to the and the stirred mixture was heated to 46° C. A pressure quenched mixture. The mixture was agitated for 5 minutes, equalizing addition funnel was charged with PhMgCl (2M in allowed to separate and the aqueous phase was removed. The THF, 1.6 L) and the solution was added slowly while main organic phase washed with deionized water (50 mL) and the taining an internal temperature between 48-51 °C. After the 25 organic phase concentrated under reduced pressure to a Vol addition was complete, the reaction mixture was stirred at ume of about 15 mL. Heptanes (50 mL) were added and the 48-51° C. for an additional 30 minutes and then cooled to Solution was evaporated under reduced pressure Volume to a ambient temperature. The reaction was quenched by slow total volume of about 15 mL. The solution was slowly stirred addition to a cooled mixture of saturated aqueous ammonium for about 24 hours affording a white slurry which was cooled chloride solution and water (50/50V/V, 3.0 L) while maintain 30 to 5° C. for about 1.5 hours. The resulting crystalline solid ing an internal temperature below 20°C. The flask was rinsed was collected by filtration and washed with cold heptanes with heptanes (2.0 L) and the rinse was transferred to the (2x10 mL). After drying under reduced pressure at 35° C. for quenched reaction mixture. The biphasic mixture was stirred 48 hours, 5b was obtained as a white crystalline solid (8.6 g. for 5 minutes, allowed to separate for 20 minutes and then the 60.5% yield, 99.90% GC purity). aqueous phase was removed. The organic phase washed with 35 Alternate Preparation of (S)-diethyl(1-phenylpropan deionized water (500 mL) and the organic phase concentrated 2-yl)phosphoramidate (5b) Using Cu(II) Chloride under vacuum to a volume of about 1.0 L. Heptanes (1000 mL) was added and the solution Volume was adjusted by reduced pressure distillation to a total volume of about 1.5 L. 40 The stirrer was slowed and the crystallization was allowed to P(O)(OEt" 1.06 ea Pi,MgCl proceed for about 24 hours. The slurry was cooled to 5°C. for N CuC (1 mol%) about 1.5 hours. The resulting crystalline solid was collected Hs by vacuum filtration and washed with cold heptanes (2x200 A THF How3 mL). After drying under vacuum at 35° C. for 48 hours the 45 (S)-diethyl(1-phenylpropan-2-yl)phosphoramidate (5b) was 4b obtained as a white crystalline solid (565.0 g, 80.5% yield; 99.66% GC purity with 0.04% 6b present), mp. 64-65° C. (EtO)2(OPN Optical rotation c=1.10, ethanol, 22.5°C., +27.7°. "H NMR (300 MHz, CDC1,) & 7.36-7.08 (m, 5H), 4.14-3.85 (m, 3H), 3.85-3.66 (m. 1H), 3.58-3.32 (m, 1H), 2.81-2.61 (m, 2H), 50 2.38 (t, J=9.8 Hz, 1H), 1.38-1.18 (m, 6H), 1.15 (d. J=6.4 Hz, 3H). Alternate Preparation of A 250 mL 3-neck flask was charged with 4b (10 g, 51.8 (S)-diethyl(1-phenylpropan-2-yl)phosphoramidate 55 mol), THF (50 mL) and CuCl2 (70 mg, 1 mol%) after which (5b) using Cu nanoparticles time the mixture was heated to about 50° C. A pressure equalizing addition funnel was charged with PhMgCl (2M in THF, 29 mL) and the reagent was added slowly while main taining an internal temperature between 50-52°C. The reac P(O)(OEt), 1.06 eq PhMgCl 60 tion was allowed to stir at 50-52°C. for an additional 16 hours Cu nanopowder and then cooled to ambient temperature. The reaction was N (2.0 mol%) -- quenched by slow addition to a cooled (about 15°C.) solution THF of saturated aqueous ammonium chloride/water (50/50 V/v, How3 50 mL) while maintaining an internal temperature below 20° 65 C. Heptanes (50 mL) was used to rinse the reactor and was 4b transferred to the quench mixture, the mixture was agitated for 5 minutes, allowed to separate for 20 minutes then the US 9,278,904 B2 19 20 aqueous phase was removed. The organic phase washed with conducted under the established procedure afforded 5b in deionized water (50 mL) and the organic phase concentrated comparable isolated yield, GC purity and devoid of the regioi under reduced pressure to a volume of about 15 mL. Heptanes somer 6b. (50 mL) was added and the solution was concentrated under reduced pressure distillation to a total volume of about 15 mL. Alternate Preparation of (S)-diethyl(1-phenylpropan The solution was slowly stirred for 24 hours at ambient tem 2-yl)phosphoramidate (5b) in THF-toluene Mixture perature to afford a white slurry which was then cooled to 5° C. for about 1.5 hours. The resulting crystalline solid was collected by filtration and washed with cold heptanes (2x10 10 mL). After drying under vacuum at 35° C. for 48 h, 5b was P(O)(OEt obtained as a white crystalline solid (8.7 g. 60.0% yield, )(OEt)2 eq PhMgClin 99.90% GC purity). N THF CuC (1 mol%) / \ Toluene Alternate Preparation of 15 HCV (S)-diethyl(1-phenylpropan-2-yl)phosphoramidate 4b (5b) using CuBr (EtO)2(OPN

P(O)(OEt(O)(OEt)2 eq PhMgCl N CuBr (1 mol%) THF

25 A 250 mL 3-neck flask was charged with 4b (10 g, 51.8 mol), toluene (50 mL) and CuC1 (51 mg, 1 mol%) after which time the mixture was heated to about 50° C. A dropping addition funnel was charged with PhMgCl (2M in THF, 29 (EtO)2(OPN 30 mL) and the reagent was added slowly while maintaining an internal temperature between 48-52° C. The reaction was allowed to stir at 50-52°C. for an additional 16 hours and then cooled to ambient temperature. The reaction was quenched by slow addition to a cooled (15° C.) solution of saturated 35 aqueous ammonium chloride/water (50/50 V/V, 50 mL) while maintaining an internal temperature below 20° C. Heptanes (50 mL) was used to rinse the reactor and was transferred to the quench mixture, the mixture was agitated for 5 minutes, A 250 mL 3-neck flask was charged with 4 (10g, 51.8 mol), 40 allowed to separate for 20 minutes then the aqueous phase THF (50 mL) and CuBr (74.4 mg, 1 mol%) after which time was removed. The organic phase washed with deionized the mixture was heated to about 50° C. A pressure equalizing water (50 mL) and the organic phase concentrated under addition funnel was charged with PhMgCl (2M in THF, 29 reduced pressure to a volume of about 15 mL. Heptanes (50 mL) and the reagent was added slowly while maintaining an mL) was added and the solution Volume was adjusted by internal temperature between 48-52° C. The reaction was 45 reduced pressure to a total volume of about 15 mL. The allowed to stir at 50-52°C. for an additional 16 hours and then solution was slowly stirred for 24 hours at ambient tempera cooled to ambient temperature. The reaction was quenched ture to afford a white slurry which was then cooled to 5°C. for by slow addition to a cooled (about 15° C.) solution of satu about 1.5 hours. The resulting crystalline solid was collected rated aqueous ammonium chloride/water (50/50 V/V, 50 mL) by filtration and washed with cold heptanes (2x10 mL). After 50 drying under vacuum at 35° C. for 36 hours, 5b was obtained while maintaining an internal temperature below 20° C. Hep as a white crystalline solid (8.7 g. 62% yield, 99.92% GC tanes (50 mL) was used to rinse the reactor and was trans purity). ferred to the quench mixture. The mixture was stirred for 5 minutes, allowed to separate for 20 minutes then the aqueous phase was removed. The organic phase washed with deion 55 Alternate Preparation of (S)-diethyl(1-phenylpropan ized water (50 mL) and the organic phase concentrated under 2-yl)phosphoramidate (5b) in THF-methyl tert-butyl reduced pressure to a volume of about 15 mL. Heptanes (50 Ether Mixture mL) was added and the solution was adjusted by reduced pressure distillation to a total volume of about 15 mL. The solution was slowly stirred for 24 hours at ambient tempera 60 ture to afforda white slurry which was then cooled to 5°C. for P(O)(OEt(O)(OEt)2 eq PhMgClin about 1.5 hours. The resulting crystalline solid was collected N THF CuC (1 mol%) by filtration and washed with cold heptanes (2x10 mL). After -e-methyl tert-butyl ether drying under vacuum at 35°C. for 48 h, 5b was obtained as a white crystalline solid (9.1 g, 65% yield, 99.90% GC purity). 65 The use of other copper salts (CuF. Cu(OAc), Cu(acac), Cu(OMe) and Copper turnings) in conversion to 4b to 5b, US 9,278,904 B2 21 22 -continued for 5 minutes, allowed to separate for 20 minutes then the (EtO)2(OPN aqueous phase was removed. The organic phase washed with H deionized water (50 mL) and the organic phase concentrated s under reduced pressure to a volume of about 15 mL. Heptanes (50 mL) was added and the solution volume was adjusted by reduced pressure distillation to a total volume of about 15 mL. The solution was slowly stirred for 24 hours at ambient tem perature to afford a white slurry which was then cooled to 5° A 250 mL 3-neck flask was charged with 4 (10g, 51.8 mol), C. for about 1.5 hours. The resulting crystalline solid was methyl tert-butyl ether (50 mL) and CuC1 (51 mg, 1 mol%) 10 collected by filtration and washed with cold heptanes (2x10 after which time the mixture was heated to about 50° C. A mL). After drying under vacuum at 35° C. for 24 hours, 5b pressure equalizing addition funnel was charged with was obtained as a white crystalline solid (9.1 g, 65% yield, PhMgCl (2M in THF, 29 mL) and the reagent was added 99.89% GC purity). slowly while maintaining an internal temperature between 48-52°C. The reaction was allowed to stir at 50-52°C. for an 15 additional 16 hours and then cooled to ambient temperature. Preparation of Dexamphetamine (7) from 5b The reaction was quenched by slow addition to a cooled (15° C.) Solution of Saturated aqueous ammonium chloride/water (50/50V/V, 50 mL) while maintaining an internal temperature below 20°C. Heptanes (50 mL) was used to rinse the reactor ii. IPAc extraction and was transferred to the quench mixture. The mixture was -e- agitated for 5 minutes, allowed to separate for 20 minutes and iii. 50% NaOHSolution then the aqueous phase was removed. The organic phase iv. MitBE extraction washed with deionized water (50 mL) and the organic phase concentrated under reduced pressure to a volume of about 15 25 mL. Heptanes (50 mL) was added and the solution volume was adjusted by reduced pressure distillation to a total volume of about 15 mL. The solution was slowly stirred for 24 hours at ambient temperature to afford a white slurry which was then cooled to 5°C. for about 1.5 hours. The resulting crys 30 talline solid was collected by filtration and washed with cold heptanes (2x10 mL). After drying under vacuum at 35°C. for A 2 Ljacketed, bottom outlet valve flask was charged with 24 hours, 5b was obtained as a white crystalline solid (8.8 g. 5b (209 g, 0.770 mol) and 3 M hydrochloric acid (510 mL) 63% yield, 99.93% GC purity). and the reaction mixture was heated to 80° C. for 1.5 hours 35 and then cooled to room temperature. The orange Solution Alternate Preparation of (S)-diethyl(1-phenylpropan was extracted with isopropyl acetate (500 mL) and the 2-yl)phosphoramidate (5b) in THF-2 methyl THF organic extract layer was discarded. Sodium hydroxide solu Mixture tion (50%, 175 mL) was slowly added to the remaining aque ous layer, keeping the internal temperature below 25° C. 40 Methyl tert-butyl ether (200 mL) was added and the reaction mixture was agitated for 20 minutes then allowed to separate P(O)(OEt(O)(OEt)2 eq PhMgClin for 30 minutes. The aqueous layer was removed and the N THF CuC (1 mol%) organic layer washed with water (100 mL) and concentrated 2-MeTHF under reduced pressure to afford a light brown oil. This oil 45 was distilled (Distillation conditions: 1" wipe film still, T-65 90°C., vacuum-4-5 mmHg, wiper speed=490-520 rpm.) to give dexamphetamine (7) as a clear colorless oil (81 g, 78% (EtO)2(OPN yield; >99.8% pure by GC). Chiral HPLC analysis: 99.83% dextroampehtamine: 0.16% levoamphetamine: 99.67% ee. 50 Optical rotation c=2.0, methanol, 22.0° C., +29.2°. "H NMR (300 MHz, CDC1) & 7.36-7.26 (m, 2H), 723-7.13 (m, 3H), 3.26-3.03 (m, 1H), 2.72 (dd, J=13.2, 5.4 Hz, 1H), 2.53 (dd. J=13.2, 8.0 Hz, 1H), 1.20 (brs, 2H), 1.13 (d. J=6.3 Hz, 3H). A 250 mL 3-neck flask was charged with 4 (10g, 51.8 mol), 55 2-MeTHF (50 mL) and CuC1 (51 mg, 1 mol%) after which Preparation of (5)-diisopropyl(1-phenylpropan-2-yl) time the mixture was heated to about 50° C. A pressure phosphoramidate (5c) equalizing addition funnel was charged with PhMgCl (2M in THF, 29 mL) and the reagent was added slowly while main taining an internal temperature between 48-52°C. The reac 60 tion was allowed to stir at 50-52°C. for an additional 12 hours 992 11 ephMC and then cooled to ambient temperature. The reaction was CuCl (1 mol%) quenched by slow addition to a cooled (15°C.) solution of / \ THF saturated aqueous ammonium chloride/water (50/50 V/V, 50 mL) while maintaining an internal temperature below 20°C. 65 How' Heptanes (50 mL) was used to rinse the reactor and was 4c transferred to the quench mixture. The mixture was agitated US 9,278,904 B2 23 24 -continued Methyl tert-butyl ether (40 mL) was added and the reaction "n - P(O)(OiPr). mixture was agitated for 5 minutes then allowed to separate for 15 minutes. The aqueous layer was extracted with methyl tert-butyl ether (40 mL) and the combined organic layers were washed with water (10 mL) and concentrated under Sc reduced pressure to give 7 as a colorless oil (1.28 g. 80.3% yield, >98.7% purity by GC and chiral HPLC). A 100 mL jacketed flask equipped with an overhead stirrer was charged with 4c (5.0g, 22.6 mmol), THF (25 mL) and 10 Preparation of (S)-diphenyl(1-phenylpropan-2-yl) CuCl (23 mg, 1 mol%). The stirrer was started and the phosphoramidate (5d) mixture was heated to 48°C. A pressure equalizing addition funnel was charged with PhMgCl (2M in THF, 12.4 mL) and this solution was added while maintaining the internal tem perature of 48-51° C. The reaction was allowed to stir at 15 48-51° C. for 30 minutes after Grignard addition and then poor 1.1 eq PhMgCl cooled to 20°C. The reaction was quenched by slow addition N CuC (1 mol%) to a pre-cooled (15°C.) Solution of saturated aqueous ammo nium chloride solution in water (50/50 V/V, 40 mL) while How maintaining an internal temperature below 20° C. Heptanes (40 mL) was used to rinse the reactor and the rinse solution 4d was added to the quench mixture. The mixture was agitated (PhO)2(OPN for 5 minutes, allowed to separate for 20 minutes and then the aqueous phase was removed. The organic phase washed with deionized water (10 mL) and the organic phase concentrated 25 under reduced pressure. The residue was dissolved in hep tanes (50 mL) and the solution was concentrated to dryness under reduced pressure. The residue was purified by chroma tography (120 g Combiflash Gold column eluting with 100% A 100 mL jacketed flask was charged with 4d (5.0 g, 17.3 dichloromethane to 5% MeOH in dichloromethane over a 40 30 minute gradient). The appropriate fractions were concen mmol), THF (25 mL) and CuCl (21 mg, 1 mol %) and the trated to dryness under reduced pressure to give the desired stirred mixture was heated to 48°C. A pressure equalizing product as a slow crystallizing solid (4.4 g. 65%, 92% GC addition funnel was charged with PhMgCl (2M in THF, 8.7 purity). The GC analysis indicated the presence of 5% biphe mL) and the Solution was added slowly while maintaining a reaction temperature of 48-51 °C. The reaction was allowed nyl as well as -0.8% of 6c. A 1 g sample was removed and 35 crystallized from 1 volume cold heptanes at -15° C. The to stir at 48-51° C. for an additional 30 minutes and then resulting crystals of 5c (0.421 mg, 42% recovery) were found cooled to ambient temperature. The reaction was quenched to be 99.75% pure by GC analysis with 0.09% of 6c. The by slow addition to a cooled (15° C.) solution of saturated crystalline 5c melted when the sample reached room tem aqueous ammonium chloride/water mixture (50/50 V/V, 30 perature. Optical rotation c=1.10, ethanol, 22.5°C., +27.7°. 40 mL) while maintaining the batch temperature below 20° C. "H NMR (300 MHz, CDC1) & 7.32-7.17 (m, 5H), 4.59-441 Heptanes (30 mL) was used to rinse the reactor and was (m. 2H), 3.53-3.41 (m, 1H), 2.86-2.80 (m, 1H), 2.69-2.61 (m, transferred to the quench mixture. The mixture was agitated 1H), 2.36 (t, J=9.6 Hz, 1H), 1.32-1.26 (m, 12H), 1.08 (d. for 5 minutes and the aqueous layer was removed. The J=10.1 Hz, 3H). organic layer washed with deionized water (8 mL) and the 45 organic phase concentrated under reduced pressure to give an Preparation of Dexamphetamine (7) from 5c oil. This residue was dissolved in heptanes (30 mL) and the Solution was concentrated under reduced pressure to afford a residue. The residue was crystallized from ethanol (1 g/5 mL) H P(O)(OP to give 5d as a white solid (3.14 g. 50% yield, 99.65% GC N - "00") . NHClso c. 50 purity containing 0.05% of 6d), mp 102-103°C. (lit 101-102° -es ii. 50% NaOHSolution C.). Optical rotation c=1.00, ethanol, 25.0° C., +18.4°. H NMR (300 MHz, CDC1,) & 7.38-7.11 (m. 15H), 3.83-3.65 Sc (m. 1H), 3.00-2.89 (m, 1H), 2.86-2.78 (m, 1H), 2.73-2.62 (m, 1H), 1.15 (d. J=10.1 Hz, 3H). NH 55 Preparation of Dexamphetamine (7) from 5d

60 A 50 mL flask was charged with 5c (3.54g, 11.82 mmol) (PhO)2(OP .3NHC180° C. and 3 M HCl (8.7 mL) and the stirred reaction mixture was Hip heated to 80°C. for 12 hours, then cooled to room tempera ii. 50% NaOH solution ture. The aqueous solution was washed with isopropyl acetate (2x20 mL) and the organic extract was discarded. The aque 65 ous layer was treated with sodium hydroxide solution (50%, 3.0 mL) keeping the internal temperature below 25° C. US 9,278,904 B2 25 26 -continued A 100 mL 3-neck flask was charged with 6 (1.0 g, 7.4 mmol), EtN (1.23 mL, 8.8 mmol), and dichloromethane (25 mL). The solution was cooled to 0-5° C. and a solution of chlorophosphate (8.15 mmol) in dichloromethane (5 mL) was added over 5 minutes. The reaction mixture was allowed to stiratambient temperature overnight. The reaction mixture A 50 mL flask was charged with 5d (7.24 g. 19.71 mmol) was then quenched by adding water (20 mL) and the organic and 3 M HCl (15.0 mL) and the stirred reaction mixture was 10 layer was separated. The organic extract was washed with 1N heated to 80°C. for 32 hours, at which point it was cooled to room temperature. The organic layer was washed with iso HCl solution (10 mL), saturated NaHCO solution (10 mL), propyl acetate (2x20 mL) and the organic extracts were dis and Saturated Sodium chloride solution (10 mL). The organic carded. The aqueous layer was treated with sodium hydroxide phase was concentrated to dryness to afford the desired prod solution (50%, 3.0 mL) keeping the internal temperature 15 uct, 6a-d. below 25°C. Methyl tert-butyl ether (40 mL) was added and the reaction mixture was agitated for 5 minutes and then 6a: 81% yield, colorless oil. 95.8% GC purity. 'H NMR separated. A second portion of methyl tert-butyl ether (40 (300 MHz, CDC1) 87.30-7.19 (m, 5H), 3.68 (d. J=11.1 Hz, mL) was added and the reaction mixture was agitated for 5 3H), 3.63 (d. J=11.1 Hz, 3H), 3.20-3.00 (m, 2H), 2.95-2.80 minutes. The combined organic extracts were washed with (m. 1H), 2.45 (s, br. 1H), 1.26 (d. J=6.9 Hz, 3H). water (10 mL) and concentrated under reduced pressure to give 7 as a colorless oil (2.05 g, 76.9% yield, >99% GC 6b: 85% yield, colorless oil. 97.47% GC purity "H NMR purity). (300 MHz, CDC1) & 7.32-7.19 (m, 5H), 4.04-3.91 (m, 4H), 3.20-3.95 (m, 2H), 2.92-2.80 (m. 1H), 2.45 (s, br. 1H), 1.26 Preparation of Impurities 6a-d 25 (d. J=6.9 Hz, 3H). NH O 6c: The residue was chromatographed on a 40 g Combi 2 | EtN + RO-P-C --> flash Gold column eluting with 100% heptanes to 100% ethyl DCM OR acetate over a 20 minute gradient. Combined clean fractions we concentrated to dryness to give the desired product as a 6 clear colorless oil in 42% yield, 97.3% purity GC. "H NMR (RO)2(O)P n NH (300 MHz, CDC1) & 7.37-7.10 (m, 5H), 4.61-4.44 (m, 2H), 3.20-2.91 (m, 2H), 2.90-2.78 (m, 1H), 2.41-2.28 (m, 1H), 35 1.35-1.16 (m, 15H). 6d: 91% yield, colorless oil. 95.16% GC purity. "H NMR 6a R = Et (300 MHz, CDC1) & 7.26-7.04 (m, 15H), 3.48 (s, br. 1H), 6b R = Me 3.35-3.22 (m. 1H), 3.03-2.90 (m, 2H), 1.21 (m, 3H). 6c R = Pr 40 6d R = Ph Referring now to the following Scheme, Scheme 3 pro vides synthetic routes to the ethyl and methyl derivatives.

Scheme 3 (EtO)2(O)P (EtO)2(O)P - Me

-- 1) KtB/THF 1)3N HC1/80° C. HC 2) MeI HC 2) IPAC extraction 5b 3) 50% NaOH solution 4) MTBE extraction 1) NaH/toluene 2) Bu4N' I 3) EtI

(EtO)2(O)P Y Et

1)3N HC1/80° C. 2) IPAC extraction 10 3) 50% NaOH solution 11 4) MTBE extraction Note: both compounds isolated as their respective HCl salts mp and optical rotation matched the literature values US 9,278,904 B2 27 28 Preparation of (S)-diethyl minutes. The aqueous layer was removed and the organic methyl(1-phenylpropan-2-yl)phosphoramidate (8) layer washed with water (10 mL), dried over anhydrous from 5b Sodium sulfate, filtered and concentrated under reduced pres sure to give a light brown oil. This oil was distilled (bulb-to bulb at 65-67° C. (a)0.6 mm Hg vacuum) to afford 9 as a colorless oil (0.19 g, 75% yield). This distillate was converted (EtO)2(OPN KOBu to the known HCl salt for analysis, mp 172-175°C. Optical -e- THF rotation c=1.00, water, 25.2°C., +16.3°. CHI 10 Preparation of (S)-diethyl ethyl(1-phenylpropan-2-yl)phosphoramidate (10) from 5b

15 (EtO)2(OPN NaH -e- toluene EI A 100 mL, 3 neck flask was charged with 5b (1.00 g, 3.68 BuNI mmol) and dry THF (40 mL). Stirring was started and once a solution was obtained, potassium tert-butoxide (0.455 g, 4.05 (EtO)2(OPE mmol. 1.1 eq) was added. The mixture was stirred at room temperature for 10 minutes followed by the addition of iodomethane (0.252 mL, 4.05 mmol. 1.1 eq). The reaction 25 was followed by TLC analysis (silica gel plates; 1:1 hexanes/ 10 ethyl acetate and 95:5 dichloromethane/methanol) and addi tional base and iodomethane was added until the reaction was complete. The reaction was quenched with NaCl solution (20 A 100 mL, 3-neck flask was charged with toluene (40 mL) mL) and extracted with ethyl acetate (40 mL). The organic and 5b (5.58 g. 20 mmol) and the mixture was stirred until a extract was dried with anhydrous sodium sulfate, filtered and 30 solution was obtained. To this solution was added sodium concentrated under reduced pressure. The residue was chro hydride (60% suspension in mineral oil, 0.880g, 22.0 mmol. matographed (40 g Combiflash column, 100% heptane to 1.1 eq) followed by tetrabutylammonium iodide (0.369 g, 1 100% ethyl acetate eluent) and appropriate fractions were mmol.) and iodoethane (2.41 mL, 30 mmol). The mixture was combined and evaporated to afford 8 as a colorless oil (0.511 heated to 80° C. for 4 hours. Additional portions of iodoet g, 48% yield). Optical rotation c=1.10, ethanol, 25.2°C., 35 hane (0.200 mL) and sodium hydride (0.100 g) were added +36.5°. "H NMR (300 MHz, CDC1) & 7.32-7.18 (m, 5H), which resulted in complete consumption of 5b. The reaction 4.1.0-3.85 (m, 2H), 3.81-3.79 (m, 2H), 3.62-3.44 (m, 1H), was cooled to room temperature, quenched with NaCl solu 2.87-2.73 (m, 1H), 2.72-2.90 (m, 1H), 2.55 (d. J=9.6 Hz, 3H), tion (20 mL). The layers were separated and the aqueous 1.24 (t, J=6.8 Hz, 3H), 1.18-1.05 (m, 6H). phase extracted with toluene (40 mL). The combined organic 40 phases were dried with anhydrous sodium sulfate, filtered and Preparation of d-N-methylamphetamine (9) from 8 concentrated to a brown oily residue. This residue was chro matographed (40 g Combiflash column, 100% heptane to 100% ethyl acetate eluent) and product fractions were com bined and evaporated under reduced pressure to give 10 as a (EtO)2(OPN Me 45 clear, pale yellow oil (3.78 g, 12.6 mmol. 63% yield). Optical

He rotation c=1.00, ethanol, 25.0° C., +35.6°. "H NMR (300 1)3N HC1/80° C. MHz, CDC1) & 7.31-7.10 (m, 5H), 4.08-3.62 (m, 5H), 3.11 2) iPAC extraction 2.88 (m, 3H), 2.76-2.67 (m, 1H), 1.32-1.21 (m, 6H), 1.20 3) 50% NaOH solution 1.10 (m, 6H). 4) MtBE extraction 50 Preparation of d-N-ethylamphetamine (11) from 10

55 (EtO)2(OPN 1 Et -e- 1)3N HC1/80° C. 2) iPAC extraction A 50 mL, 3-necked round bottomed flask was charged with H3C 3) 50% NaOH solution 8 (0.5g, 1.75 mmol) and 3 M HCl (25 mL) and the stirred 10 4) MtBE extraction reaction mixture was heated to 80°C. for 2.5 hours and then 60 cooled to room temperature. The orange solution was extracted with isopropyl acetate (25 mL) and the organic extract layer was discarded. Sodium hydroxide solution (50% Solution, 10 mL) was slowly added to the remaining aqueous layer, keeping the internal temperature below 25°C. Methyl 65 11 tert-butyl ether (20 mL) was added and the reaction mixture was agitated for 20 minutes then allowed to separate for 30 US 9,278,904 B2 29 30 A 50 mL round bottomed flask was charged with 10 (2.5g, wherein R is alkyl or aryland 8.3 mmol) and 3 M HCl (25 mL) and the stirred reaction reacting the compound of Formula 4 with phenylmagne mixture was heated to 80° C. for 3.25 hours and cooled to sium halide and a copper catalyst under Solvent and room temperature. The orange solution was extracted with temperature conditions effective to produce a compound isopropyl acetate (25 mL) and the organic extract layer was 5 of Formula 5 having a regioisomeric purity >99%, discarded. Sodium hydroxide solution (50% solution, 25 mL) wherein the solvent conditions comprise a crystallization was slowly added to the remaining aqueous layer, keeping the step requiring a mixture of two or more solvents, internal temperature below 25° C. Methyl tert-butyl ether (20 wherein one of the two or more solvents is residue THF. mL) was added and the reaction mixture was agitated for 20 2. The process according to claim 1 wherein the acidic minutes and allowed to separate for 30 minutes. The aqueous 10 layer was removed and the organic layer washed with water conditions are aqueous hydrochloric, Sulfuric or phosphoric (10 mL) and concentrated under reduced pressure to give a acids. brown oily residue. This residue was distilled (bulb-to-bulb. 3. The process according to claim 2 wherein the aqueous 105-106°C. (a) 14.0 mm Hg vacuum) to give 11 as a colorless acid water content is in an amount of 50% to 90%. oil (1.10 g, 81% yield). 15 4. The process according to claim 1 wherein R-methyl, Distillation: 105-106° C., 14.0 mm Hg. This oil was con ethyl, isopropyl or phenyl. verted to the known HCl salt for analysis, mp 154-156° C. 5. The process according to claim 1 wherein the copper Optical rotation c=2.00, water, 20.0° C., +17.1°. catalyst is CuC1, CuCl, CuBr CuF, Cu(OAc). Cu(acac), The references recited herein are incorporated herein in Cu(OMe), Copper turnings or Copper nanoparticles. their entirety, particularly as they relate to teaching the level 6. The process according to claim 1 wherein one of the of ordinary skill in this art and for any disclosure necessary mixture of two or more solvents is selected from the group for the commoner understanding of the subject matter of the consisting of heptanes, an organic ether, 2-methyltetrahydro claimed invention. It will be clear to a person of ordinary skill furan, and toluene. in the art that the above embodiments may be altered or that 7. The process according to claim 1 wherein said tempera insubstantial changes may be made without departing from 25 ture conditions range from 25°C. to 80° C. the scope of the invention. Accordingly, the scope of the 8. The process according to claim 1, wherein said provid invention is determined by the scope of the following claims ing a compound of Formula 4 comprises: providing a com and their equitable Equivalents. pound of Formula 3 What is claimed is: 30 1. A process of making dexamphetamine, said process (Formula 3) comprising: P(O)(OR): providing a compound of Formula 5 having a regioiso - 'I'- meric purity >99%: OMS 35 H3C 1N1

(Formula 5) (RO)2(O)PN H wherein R is alkyl or aryl; and reacting the compound of Formula 3 with a base under 40 conditions effective to produce a compound of Formula 4. 9. The process according to claim 8 wherein the R-methyl, wherein R is alkyl or aryl; and ethyl, isopropyl or phenyl. deprotecting the compound of Formula 5 under acidic con 10. The process according to claim 8, wherein the base is ditions effective to produce dexamphetamine of For 45 potassium hydroxide or potassium carbonate. mula 1: 11. The process according to claim 8, wherein the step of providing a compound of Formula 3 comprises the steps of providing a compound of Formula 2

(Formula 1) 50 (Formula 2) NH1 P(O)(OR)2

55 wherein the step of providing a compound of Formula 5 comprises the steps of providing a compound of For mula 4: wherein R is alkyl or aryl; and 60 reacting the compound of Formula 2 with methanesulfonyl (Formula 4) chloride and a base under conditions effective to pro P(O)(OR)2: duce a compound of Formula 3. 12. The process according to claim 11 wherein the ...A R-methyl, ethyl, isopropyl or phenyl. H.C. 65 13. The process according to claim 11, wherein said pro viding a compound of Formula 2 comprises: providing a compound of Formula 1 US 9,278,904 B2 31 32 wherein the step of providing a compound of Formula 5 (Formula 1) comprises the step of: NH2 providing a compound of formula 4: s OH: He1\-1 5 (Formula 4) and P(O)(OR)2: reacting the compound of Formula 1 with N 10 4 \ HC

PS-C Ro1 No. wherein R is ethyl; and 15 reacting the compound of Formula 4 with phenylmagne wherein R-alkyl or aryl sium halide and a copper catalyst under Solvent and under conditions effective to produce a compound of For temperature conditions effective to produce a compound mula 2. of Formula 5 having a regioisomeric purity >99%, 14. The process according to claim 13 wherein the 20 wherein the solvent conditions comprise a crystallization R-methyl, ethyl, isopropyl or phenyl. step requiring a mixture of two or more solvents, 15. The process according to claim 1 wherein said tem wherein one of the two or more solvent is residue THF. perature conditions range from 30° C. to 60° C. 18. A process of making dex-N-ethylamphetamine, said 16. The process according to claim 1 wherein said tem process comprising: perature conditions range from 40°C. to 52°C. 17. A process of making dex-N-methylamphetamine, said providing a compound of formula 10: process comprising: providing a compound of formula 8: (formula 10) 30 (RO)2(OPSE (formula 8) (RO)2(OPS Me

35 HC wherein R is ethyl; and deprotecting the compound of formula 10 under acidic wherein R is ethyl; and conditions effective to produce dex-N-ethylamphet deprotecting the compound of formula 8 under acidic con amine of formula 1 1: ditions effective to produce dex-N-methylamphetamine 40 of formula 9: E (formula 11) HN1 t (formula 9) 45 H3C

wherein the step of providing a compound of formula 8 wherein the step of providing a compound of formula 8 comprises the step of: comprises the step of: providing a compound of formula 5 having a regioisomeric providing a compound of formula 5 having a regioisomeric purity >99%: purity >99%: 55

(Formula 5)

(Formula 5) (RO)2(O)P (RO)2(O)P H YNH s 60 HC wherein R is ethyl; and wherein R is ethyl; and reacting the compound of Formula 5 with a methyl alky 65 reacting the compound of Formula 5 with an ethylalkylat lating agent and a base to produce the compound of ing agent and a base to produce the compound of For Formula 8: mula 8: US 9,278,904 B2 33 34 wherein the step of providing a compound of Formula 5 comprises the step of: providing a compound of formula 4:

(Formula 4) P(O)(OR)2: N How 10 wherein R is ethyl; and reacting the compound of Formula 4 with phenylmagne sium halide and a copper catalyst under solvent and 15 temperature conditions effective to produce a compound of Formula 5 having a regioisomeric purity >99%, wherein the solvent conditions comprise a crystallization step requiring a mixture of two or more solvents, wherein one of the two or more solvent is residue THF. 20 19. The process according to claim 17 wherein the acidic conditions are aqueous hydrochloric, Sulfuric or phosphoric acids. 20. The process according to claim 18, wherein the acidic conditions are aqueous hydrochloric, Sulfuric or phosphoric 25 acids.