WO2011146610A2

WO2011146610A2 - An enantioselective synthesis of chiral amines for the production of rotigotine

Info

Publication number: WO2011146610A2
Application number: PCT/US2011/036990
Authority: WO
Inventors: Christopher James Cobley; Tamara Fanjul Solares
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2010-05-19
Filing date: 2011-05-18
Publication date: 2011-11-24
Also published as: WO2011146610A3

Abstract

Methods of preparing (S)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)propion amide compounds 4 from N-(3,4-dihydronaphthalen-2-yl)propionamide compounds 3: where the constituent variables are as defined.

Description

AN ENANTIOSELECTIVE SYNTHESIS OF CHIRAL AMINES FOR THE

PRODUCTION OF ROTIGOTINE

INTRODUCTION

The application relates to an improved process for the preparation of chiral substituted tetrahydronaphthalen-2-amine compounds as an intermediate in the manufacture of biologically active dopamine agonists.

Certain 2-aminotetralin compounds, such as those disclosed in Horn, US Patent No. 4,564,628, issued January 14, 1986 (the disclosure of which is hereby incorporated herein by reference in its entirety), are partial or full agonist (depending on the assay) at the D_{1 ;} D₂, D₃, D₄₂,D_4.4, D_4.7, and D₅ dopamine receptors. They are useful in treating dopamine-related disorders including, Parkinson's disease (PD), restless legs syndrome (RLS), and depression. Rotigotine or (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydro naphthalen-1 -ol hydrochloride was approved in Europe in 2006 and is today being sold in several European countries. In 2007, the Neupro patch, containing rotigotine, was approved by the Food and Drug Administration (FDA). The structure of rotigotine (1) is shown below.

1

Horn, US Patent No. 4,564,628 teaches that 2-(/V-propylamino)-5- methoxytetralin is useful as an intermediate in the preparation of these 2- aminotetralin compounds. Horn US Patent No. 4,657,925, issued April 14, 1987, (the disclosure of which is hereby incorporated herein by reference in its entirety) teaches that racemic 2-(/V-propylamino)-5-methoxytetralin can be resolved into its enantiomers before being converted to 6-[propyl(2-thiophen-2-ylethyl)amino]- 5,6,7,8-tetrahydronaphthalen-1 -ol and that the product formed from the (-)- enantiomer has a pharmacological activity which is 140 times the activity of the product formed from the (+)-enantiomer. It is desirable to provide 2-aminotetralin compounds and other such pharmaceuticals as (+)- or (-)-enantiomers. Various techniques have been used to resolve them or intermediates used in preparing them. For example, Gerding et al., Journal of High Resolution Chromatography & Chromatography Communications, Vol. 10, September 1987, pp. 523-525, teach 6-[propyl(2- thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1 -ol is resolved by (a) derivatization with (+)-glucuronic acid followed by separation in a non-chiral chromatographic system or by (b) crystallization with the chiral phosphoric acids of ten Hoeve et al., J. Org. Chem., 1985, Vol. 50, pp. 4508-4514, i.e., with certain rather exotic compounds, such as 4,-(2-chlorophenyl)-5,5-dimethyl-2-hydroxy- 1 ,3,2-dioxaphosphorinane 2-oxide, which are expensive and time-consuming to synthesize and resolve. Seiler et al., J. Med. Chem., 1986, Vol. 29, pp. 912-917, disclose that (-)-2-(/V-propylamino)-5-methoxytetralin can be obtained by the propylation and subsequent debenzylation of (-)-2-(/V-benzylamino)-5- methoxytetralin, a compound which McDermed er a/., J. Med. Chem., 1976, Vol. 19, No. 4, pp. 547-549, teach is prepared by reacting 5-methoxytetralone with benzylamine and resolving the resultant racemic 2-(/V-benzylamino)-5- methoxytetralin with (-)-mandelic acid. Manimaran et al. US Patent No. 4,968,837, issued November 6, 1990, (the disclosure of which is hereby incorporated herein by reference in its entirety) teach racemic 2-(/V-propylamino)- 5-methoxytetralin is resolved by treating it with a chiral diaroyltartaric acid in an organic solvent at an elevated temperature. Such classical resolution procedures of racemic amines have a maximum theoretical yield of 50%. Development of an efficient asymmetric synthesis would clearly lead to obvious cost and yield benefits.

SUMMARY

In one aspect, the application provides methods of preparing (S)-N- (1 ,2,3,4-tetrahydronaphthalen-2-yl)propionamide compounds 4 from Λ/-(3,4- dihydronaphthalen-2-yl)propionamide compounds 3:

wherein the constituent variables are as defined below.

DETAILED DESCRIPTION

One aspect of the application provides methods of preparing (S)-N- (1 ,2,3,4-tetrahydronaphthalen-2-yl)propionamide compounds 4 from Λ/-(3,4- dihydronaphthalen-2-yl)propionamide compounds 3:

wherein:

R², R³, and R are each independently H-, HO-, R^sC(O)-O-, or C C₆alkoxy-;

R is CrC₆alkyl, C₆-Ci₄aryl, or d-Cgheteroaryl; and with the provisos that at least one of R², R³, and R⁴ is H, that at least one of R², R³, and R⁴ is not H, and that R² and R⁴ are not both HO-, R⁵C(O)-O-, or C C₆alkoxy-; by reduction with an asymmetric catalyst in a solvent.

Another aspect of the application is a process wherein said R³ = R⁴ = H.

Another aspect of the application is a process wherein said R² = d- C₆alkoxy.

Another aspect of the application is a process wherein said R²

Another aspect of the application is a process wherein said reduction is done with hydrogen. Another aspect of the application is a process wherein said asymmetric catalyst is a rhodium, ruthenium, or iridium metal complex.

Another aspect of the application is a process wherein said asymmetric catalyst is a rhodium, ruthenium, or iridium metal complex of a phosphorus containing ligand.

Another aspect of the application is a process wherein said asymmetric catalyst is [(fl,fl)-Ph-BPE Rh (COD)]BF₄, [(F?)-PhanePhos Rh (COD)]BF₄, [{R,R)- Et-DuPhos Rh (COD)]BF₄, [(S,S)-Et-FerroTane Rh (COD)]BF₄, [RuCI₂(fl)- BINAP]₂.NEt₃, [RuCI₂(fl)-BINAP]₂.NEt₃, [(RuCI (f?)-BINAP)₂^-CI)₃][NH₂Me₂],

[(RuCI (Α)-Τ-ΒΙΝΑΡ)2(μ-ΟΙ)₃][ΝΗ₂Μθ2], [(RuCI(fl)-DM-BINAP)₂^-CI)₃][NH₂Me₂], [Ru(OAc)₂((f?)-DM-BINAP)], [Ru(( fl)-Et-DuPhos)(TFA)₂], [Ru((fl)-MeO- BIPHEP)(TFA)₂], or [(RuCI(fl)-T-BINAP)₂^-CI)₃][NH₂Me₂].

Another aspect of the application is a process wherein said asymmetric catalyst is [(RuCI(fl)-T-BINAP)₂^-CI)₃][NH₂Me₂]. Another aspect of the application is a process wherein said solvent is an alcohol solvent.

Another aspect of the application is a process wherein said the alcohol solvent is methanol.

The catalytic reduction reactions are usually heated above room temperature, typically in the range of about 25 °C to about 60 °C, in one embodiment from about 30 °C to about 50 °C. In another embodiment, the temperature is raised to at least about 25 °C, and in another embodiment, to at least about 30 °C. However the reaction can also be performed at temperatures as high as about 50 °C. The pressure is above atmospheric pressure, typically in the range from about 10 bar to about 100 bar. In one embodiment, the pressure is from about 10 bar to about 25 bar. Between about 2 and about 30 volumes of solvent, and in one embodiment, between 2 and 10 volumes of solvent are used per unit mass of substrate. The molar substrate/catalyst (S/C) ratio is between about 200 and about 10,000. In one embodiment, the (S/C) ratio is between 500 and 1 ,000. Alternative catalysts may be used for the reduction. These may _

-5- include different metals such as Ir, Pt, Pd, or Cu and different more selective ligands.

In one aspect, the application further comprises synthesis of the Λ/-(3,4- dihydronaphthalen-2-yl)propionamide compounds 3 from 3,4-dihydronaphthalen- 2(1 H)-one compounds 2:

by reaction with CH₃CH₂C(O)NH₂.

The reactions with CH₃CH₂C(0)NH₂ are usually heated above room temperature, typically in the range of about 80 °C to about 140 °C, but in one embodiment from about 95 °C to about 115 °C. In another embodiment, the temperature is raised to at least about 115 °C, and in another embodiment, to at least about 110 °C. However the reaction can also be performed at temperatures as high as about 140 °C. The solvent is any solvent, which forms an immiscible azeotrope with water. In one embodiment, an aromatic hydrocarbon solvent that is capable of dissolving a solute to form a uniformly dispersed solution is used. Examples of an aromatic hydrocarbon solvent include, but are not limited to, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or mixtures thereof. Between about 2 volumes and about 15 volumes of solvent, an in one embodiment, between about 2 and about 7 volumes of solvent are used per unit mass of substrate. A strong acid, such as a sulfonic acid, should be used as a catalyst.

In one aspect, the application further comprises the step of reducing the N- (3,4-dihydronaphthalen-2-yl)propionamide compounds 4 to (S)-A/-(1 ,2,3,4- tetrahydronaphthalen-2-yl)-N-propylamine compounds 5:

by a suitable amide reducing agent.

The amide reduction reactions are usually heated above room temperature, typically in the range of about 30 °C to about 120 °C, and in one embodiment, about 40 °C to about 1 0 °C. In another embodiment, the temperature is raised to at least about 60 °C or in another embodiment, to least about 110 °C. However the reaction can also be performed at temperatures as high as about 120 °C. Between about 2 volumes and about 70 volumes of solvent, and in one embodiment, between about 2 and about 40 volumes of solvent are used per unit mass of substrate. Any solvent that is capable of dissolving a solute to form a uniformly dispersed solution is used but does not react with the reducing agent is used. In an embodiment, an aromatic hydrocarbon solvent such as toluene or an ether solvent such as THF or diethyl ether is used.

In one aspect, the application further comprises the step of acylating the (S)-/V-(1 ,2,3,4-tetrahydronaphthalen-2-yl)-N-propylamine compounds 5 to the (S)- /V-( ,2,3,4-tetrahydronaphthalen-2-yl)-/V-propyl-2-amide compounds 6:

by acylation with X-C(0)-CH₂)_n-R¹; wherein:

X is a leaving group; - -

R¹ is 3-hydroxyphenyl, 4-hydroxyphenyl, 3-pyridyl, 4-pyridyl, C₆H₅-CH(OH)-, (C₆H₅)2C(CN)-, 4-indolyl, 2-furanyl, 2-thiophenyl, 2-pyrrolyl, 3-furanyl, 3- thiophenyl, 3-pyrrolyl, or 4-imidiazolyl;

and n is 1 or 2.

In one aspect, the application further comprises the step of reducing the (S)-/V-(1 ,2,3,4-tetrahydronaphthalen-2-yl)-/V-propyl-2-amide compounds 6 to the (S)-6-(propyl(alkyl)amino)-5,6,7,8-tetrahydronaphthalene compounds 7:

by a suitable amide reducing agent.

In one aspect, the application optionally further comprises, when R₂≠ HO- or H, the step of hydrolyzing the (S)-6-(propyl(alkyl)amino)-5, 6,7,8- tetrahydronaphthalene compounds 7 to the (S)-6-(propyl(alkyl)amino)-5, 6,7,8- tetrahydronaphthalen-1 -ol compounds 8:

by a suitable hydrolyzing agent.

In one aspect, the application provides a method of preparing (S)-N-(5- methoxy-1 ,2,3,4-tetrahydronaphthalen-2-yl)propionamide (11 ):

11

from A/-(5-methoxy-3,4-< dihydronaphthalen-2-yl)propionamide (10):

comprising the step of reducing 10 with an asymmetric hydrogenating agent.

DEFINITIONS

The following definitions are used in connection with the compounds of the present application unless the context indicates otherwise. In general, the number of carbon atoms present in a given group is designated "C_x-C_y", where x and y are the lower and upper limits, respectively. For example, a group designated as "C-r C₆" contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.

An "alcohol solvent" is an organic solvent containing a carbon bound to a hydroxy! group. "Alcohol solvents" include but are not limited to methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1 - propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1 -butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, and the like. __g_

"Alkoxy-" refers to the group R-O- where R is an alkyl group, as defined below. Exemplary CrC₆alkoxy- groups include but are not limited to methoxy, ethoxy, n-propoxy, 1 -propoxy, n-butoxy, and t-butoxy.

"Alkyl-" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. In the absence of any numerical designation, "alkyl-" is a chain (straight or branched) having 1 to 6 (inclusive) carbon atoms in it. Examples of d-C₆alkyl- groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec- butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. "Amide reducing agent" refers to a reagent which can reduce an amide to an amine. Such reagents are known in the art and are disclosed in, for example, in March, "Advanced Organic Chemistry - Reactions, Mechanisms and Structure", Third Edition, John Wiley & Sons, 1985, pages 1099-1100, Brown and Kxishnamurthy, Aldrichimica Acta 12:3 (1979) and references cited therein. Examples include lithium aluminum hydride, lithium triethyl borohydride, borane reagents (e.g., borane-tetrahydrofuran, borane-methyl sulfide, disiamylborane, and the like), aluminum hydride, DIBAL, lithium trimethoxy aluminum hydride, Red-AI™, Zn/silane, and triethyloxonium fluoroborate/sodium borohydride.

"Aryl-" refers to an aromatic hydrocarbon radical. Examples of an C₆- Ci₄aryl- group include, but are not limited to, phenyl, 1 -naphthyl, 2-naphthyl, 3- biphen-1 -yl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthenyl. In the absence of any numerical designation, "aryl-" is an aromatic hydrocarbon having 6 to 14 (inclusive) carbon atoms in it.

"Asymmetric catalyst" refers to a compound that promotes reactions and lead to the formation of large amounts of enantiomerically pure or enriched products. The precise nature of the asymmetric catalyst to be employed will ultimately be dependent upon the particular enantiomeric form of the product desired from the reaction. Selection of an appropriate asymmetric catalyst, and ascertainment of the precise amount thereof to be utilized in the procedure, will generally be made by the skilled worker on a trial and error basis. "Heteroaryl-" refers to 5-10-membered mono and bicyclic aromatic groups containing at least one heteroatom selected from oxygen, sulfur, and nitrogen. Examples of monocyclic CrCgheteroaryl- radicals include, but are not limited to, oxazinyl, thiazinyl, diazinyl, triazinyl, thiadiazoyl, tetrazinyl, imidazolyl, tetrazolyl, isoxazolyl, furanyl, furazanyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, pyrimidinyl, N-pyridyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl. Examples of bicyclic d- Cgheteroaryl- radicals include but are not limited to, benzimidazolyl, indolyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indazolyl, quinolinyl, quinazolinyl, purinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl, and indazolyl.

"Hydrolyzing agent" refers to a reagent capable of the rupture of a chemical bond between an oxygen atom and another non-hydrogen atom such as carbon by a reaction that involves liberation of an alcohol. Examples of such agents with ethers are HBr, HI, BBr₃, Lil, NaCN/DMSO and the like. Examples of such agents with esters are aqueous acid (e.g. H₂SO₄)/heat, aqueous NaOH, and the like.

"Leaving group" refers to an atom or group (charged or uncharged) that becomes detached from an atom in what is considered to be the residual or main part of the substrate in a specified reaction. For example, in the heterolytic solvolysis of benzyl bromide in acetic acid: the leaving group is bromide. In the reaction of N,N,N-trimethyl-1 -phenylmethanaminium ion with methanethiolate, the leaving group is trimethylamine. In the electrophilic nitration of benzene, it is H⁺. The term has meaning only in relation to a specified reaction. Examples of leaving groups include, for example, carboxylates (i.e. CH₃COO^", CF₃CO₂ ^", or (CH₃)₂CH₂COO^"), F^", water, CI^", Br^", Γ, N₃ ^", SCN^", trichloroacetimidate, thiopyridyl, tertiary amines (i.e. trimethylamine), phenoxides (i.e. o- nitrophenoxide), and sulfonates (/^'. e. tosylate, mesylate, or triflate).

The term "reacting" is intended to represent bringing the chemical reactants together under conditions such to cause the chemical reaction indicated to take place. Procedures used to perform the processes of the present application are described in Schemes 1 and 2 and are illustrated in the examples. Reasonable ^ variations of the described procedures are intended to be within the scope of the present application.

X is a leaving group;R¹ is 3-hydroxyphenyl, 4-hydroxyphenyl, 3-pyridyl, 4-pyridyl, C₆H₅-CH(OH)-, (C₆H₅)₂C(CN)-, 4-indolyl, 2-furanyl, 2-thiophenyl, 2-pyrrolyl, 3- furanyl, 3-thiophenyl, 3-pyrrolyl, or 4-imidiazolyl;and n is 1 or 2.

As shown in Scheme 1 , the overall combination of these steps provides an asymmetric route to chiral substituted tetrahydronaphthalen-2-amines 8. Scheme 2

13 12

As shown in Scheme 2, synthesis of rotigotine may be completed from (S)-5- methoxy-A/-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine (12) using the methods of Horn, US Patent No. 4,564,628.

EXAMPLES

DIBAL-H is diisobutylaluminum hydride, EtOAc is ethyl acetate, and EtOH is ethanol. The abbreviation %e.e. means the enantiomeric excess of a

substance, which is defined as the absolute difference between the mole fraction of each enantiomer. MeOH is methanol, NMR is nuclear magnetic resonance, OD-H is cellulose tris (3,5-dimethylphenylcarbamate) coated on 5μιτι silica-gel, PhMe is toluene, pTSA is p-toluenesulfonic acid mono hydrate, Red-AI™ is sodium bis(2-methoxyethoxy)aluminum or NaAIH₂(OC₂H₄OCH₃)₂ as a 65%- solution in toluene, Red-AI™ is a registered trademark of Sigma-Aldrich

Biotechnology LP and Sigma-Aldrich Co. [(fl)-PhanePhos Rh (COD)]BF₄ is (ft)-(- )-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane, [(f?,f?)-Ph-BPE Rh

(COD)]BF₄ is 1 ,2-bis[(2f?,5fl)-2,5-diphenylphospholano]ethane(1 ,5- cyclooctadiene)rhodium(l) tetrafluoroborate, SFC is Supercritical Fluid

Chromatography, and THF is tetrahydrofuran. [(S,S)-Et-FerroTane Rh (COD)]BF₄ - - is (-)-1 ,1 '-bis((2S₎4S)-2,4-diethylphosphotano)ferrocene(1 ,5-cyclooctadiene) rhodium(l) tetrafluoroborate. The following catalyst abbreviations were used:

(Λ)-ΒΙΝΑΡ (R)-DM-BINAP (^)-T-BINAP

( ?₍#)-Et-DuPhos ( ?)-MeO-BIPHEP

SYNTHETIC METHODS

The following methods outline the Examples of the present application.

Step 1 : Enamide formation

In a 250 ml_ round bottom flask fitted with Dean-Stark reflux apparatus, 5- methoxy-2-tetralone (9, 16.1 g, 91 mmol), propionamide (13.36 g, 182 mmol), and p-toluenesulfonic acid mono hydrate (0.87 g, 4.6 mmol) were dissolved in toluene (120 ml_). The mixture was heated at reflux overnight under a blanket of nitrogen during which time approximately 1.6 ml_ of water was collected in the trap. The dark orange reaction solution was allowed to cool to 60 °C and then added to a saturated aqueous NaHCO₃ solution (50 ml_). This caused an emulsion like solid to precipitate. Heating of this biphasic solution dissolved this solid and formed two clear distinct phases. The dark brown organic phase was collected, washed with brine (50 ml_), and then allowed to cool to room temperature. Crystallization was induced and the resulting suspension was stored in the freezer overnight. The solid produced was collected by filtration and recrystallized in toluene (50 ml_) to yield a pinkish colored microcrystalline solid. This was air dried for 1 hour after which ¹H NMR showed this to be the desired product. First crop = 9.6 g, 46% yield. ¹H NMR (CDCI₃): δ 1.21 (3H, CH₃, t, J³ 7.5 Hz), 2.32(2H, CH₂CH₃, q, J³ 7.5 Hz), 2.41 (2H, CH₂CH₂, t, J³ 8.5 Hz), 2.89 (2H, ArCH₂, tr, J³ 8.5 Hz), CH₃O 3.81 (3H, s), 6.6 (1 H, NH, br s), 6.65-6.71 (2H, Ar, m), 7.05-7.13 (2H, Ar and ArCH m) ¹³C NMR (CDCI₃): 5 9.6, 20.3, 27.2, 30.8, 55.4, 108.4, 119.2, 120.1 , 127.0, 135.0, 136.0, 155.9, 172.2.

Step 2: Hydrogenation of enamide

The reaction was performed in a 50 ml_ Parr pressure vessel fitted with a glass liner, magnetic stirrer, injection port, bursting disk, pressure relief valve, and pressure gauge. The glass liner was charged with substrate (1.0 g, 4.32 mmol) and [(RuCI (R)-T-BINAP)₂^-CI)₃][NH₂Me₂] (15 mg, 8.64.10^"3 mmol), the vessel sealed and flushed five times with nitrogen (25 bar). MeOH (10 ml_, anhydrous and deoxygenated) was added to the vessel via the injection port and the system flushed three times with hydrogen (25 bar). The vessel was charged with hydrogen (25 bar), heated to 30 °C, and stirred (1 ,000 rpm) for 18 hours. The stirring was reduced to 500 rpm and the vessel allowed to cool to room temperature, vented to atmosphere, flushed once with nitrogen (25 bar) and opened. An aliquot of the reaction mixture was analyzed by SFC and ¹H NMR spectroscopy. This showed the reaction had gone to completion with an e.e. of 91%. The reaction mixture was reduced to dryness and recrystallized from hot ethyl acetate to yield white crystals of >98 %e.e. ¹H NMR (CDCI₃): δ 1.14 (3H,

CH₃, t, J³ 8.0 Hz), 1.72-1.81 (1 H, CHHCHN, m), 1.99-2.02 ( H, CHHCHN, m),

2.17 (2H, CH₂CO, q, J³ 8.0 Hz), 2.63 (1 H, CHHCHN, dd, J² 16.0 Hz, J³ 8.0 Hz), 2.69-2.82 (2H, CH₂, m), 3.09 (1 H, CHHCHN, dd, J²20.0 Hz, J³8.0 Hz), 3.81 (3H, OCH₃, s), 4.23-4.31 (1 H, C -/N, m), 5.61 (1 H, NH, br s), 6.67 (2H, Ar, d, J³8.0 Hz), 7.10 (1 H, Ar, t, J³ 8.0 Hz). SFC conditions: OD-H column, 250x4.6 mm x 5 μιτι, MeOH/C0₂ (90:10), 230nm, 4.15 min (S enantiomer), 5.13 min (enamide), 6.04 min (R enantiomer).

Step 3: Reduction of amide

Reaction with Red-AI

11 12

The crude amide product from the hydrogenation step (0.43 mmol) was dissolved in toluene (7 mL) and Red-AI™ 65% in toluene (0.26 mL, 0.86 mmol, 2.2 equiv.) was added under inert atmosphere at room temperature. The reaction was heated at reflux for 2 hours and then water (8 mL) was added. The aqueous layer was further extracted with toluene and the combined organic layers were washed with water, brine, NH₄CI aqueous solution and water again. The organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to give a brown oil (95% conversion).

Reaction with

11 ¹²

The crude amide product from the hydrogenation step (0.43 mmol) was dissolved in THF (4 mL) and L1AIH4 (23 mg, 0.61 mmol, 1.4 equiv.) was added as a solid under inert atmosphere at room temperature. The reaction was heated at reflux for 16 hours and then water (0.1 mL), NaOH 24% (0.1 mL), and water (0.4 mL) were added. The reaction mixture was stirred for 1 hour and then filtered.

The volatiles were removed in vacuo and the crude was dissolved in dichloromethane (5 mL). Water (5 mL) was added and the product was extracted. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give a brown oil (0.052 g, 55% isolated yield, 89% conversion).

Reaction with BH₃ THF:

12

11

The crude amide product from the hydrogenation step (0.43 mmol) was dissolved in THF (7 mL) and BH₃ THF 1.0 M in THF (1.73 mL, 1.73 mmol, 4 equiv.) was added under inert atmosphere at room temperature. The reaction was heated to reflux for 2 hours and then stirred at room temperature for 16 hours. HCI cone. (0.1 mL) in MeOH (0.7 mL) was added at 5 °C and the reaction mixture was refluxed for 2 hours. The volatiles were removed in vacuo, MeOH (5 mL) was added, and the crude was concentrated. Ethyl acetate (3 mL), water (2 mL) and NH₄OH 35% aqueous (to reach pH = 12) were added. The aqueous layer was extracted with ethyl acetate (7 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow oil (0.074 g, 78% isolated yield, 67% conversion).

Reaction with DIBAL-H:

11 12

The crude amide product from the hydrogenation step (0.43 mmol) was dissolved in THF (7 mL) and DIBAL-H 1.0 M in hexane (0.95 mL, 0.95 mmol, 2.2 equiv.) was added under inert atmosphere at room temperature. The reaction was heated at reflux for 5 hours and then water (5 mL) and ethyl acetate (5 mL) were added. The organic layer was extracted with water (2x5 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to give a brown oil (45 mg, 48 % isolated yield, 78% conversion). Ή NMR (CDCI₃): δ 0.94 (3H, CH₃, t, J³8.0 Hz), 1 .49-1 .60 (3H, CH₂ + CHH, m), 2.05-2.09 (1 H, CHH, m), 2.53-2.61 (2H, CH₂, m), 2.68 (2H, CH₂N, t, J³ 8.0 Hz), 2.36-2.93 (2H, CH₂, m), 2.99 (1 H, CHH, dd, J² 16.0 Hz, J³ 4.0 Hz), 3.81 (3H, OCH₃, s), 6.68 (1 H, Ar, d, J³8.0 Hz), 6.70 (1 H, Ar, d, J³8.0 Hz), 7.09 (1 H, Ar, t, J³8.0 Hz).

Table showing hydrogenation screening results

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the application described and claimed herein.

While particular embodiments of the present application have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

The structure depicted for the compounds within the present application are also meant to include all isomeric (e.g., enantiomeric or conformational) forms of the structures. For example, both the R and the S configurations at the stereogenic carbon are included in this invention. Therefore, single stereochemical isomers as well as enantiomeric and conformational mixtures of the present compound are within the scope of the invention. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention.

Claims

CLAIMS:

1 . A process for preparing (S)-A/-(1 ,2,3,4-tetrahydronaphthalen-2- yl)propionamide compounds 4 from A/-(3,4-dihydronaphthalen-2-yl)propionamide compounds 3:

3 4 wherein:

R², R³, and R⁴ are each independently H-, HO-, R⁵C(0)-0-, or C C₆alkoxy-; R⁵ is CrC₆alkyl, C₆-C₁₄aryl, or d-Cgheteroaryl; and with the provisos that at least one of R², R³, and R⁴ is H, that at least one of R², R³ and R⁴ is not H, and that R² and R⁴ are not both HO-, R⁵C(0)-0-, or C Cealkoxy-; comprising reduction with an asymmetric catalyst in a solvent.

2. The process of claim 1 , wherein R³ = R⁴ = H.

3. The process of claim 1 , wherein R² = CrC₆alkoxy.

4. The process of claim 3, wherein R² = CH₃0-.

5. The process of claim 1 , wherein reduction is done with hydrogen.

6. The process of claim 1 , wherein the asymmetric catalyst comprises a rhodium, ruthenium or iridium metal complex.

7. The process of claim 6, wherein asymmetric catalyst comprises a rhodium, ruthenium or iridium metal complex of a phosphorus containing ligand.

8. The process of claim 7, wherein the rhodium, ruthenium or iridium metal complex of a phosphorus containing ligand is [(f?,f?)-Ph-BPE Rh

(COD)]BF₄, [(f?)-PhanePhos Rh (COD)]BF₄, [(f?,fl)-Et-DuPhos Rh (COD)]BF₄, [(S,S)-Et-FerroTane Rh (COD)]BF₄, [RuCI₂(fl)-BINAP]₂.NEt₃, [RuCI₂(fl)- BINAP]₂.NEt₃, [(RuCI (Α)-ΒΙΝΑΡ)₂(μ-ΟΙ)₃][ΝΗ₂Μβ₂], [(RuCI (Α)-Τ-ΒΙΝΑΡ)₂(μ- CI)₃][NH₂Me₂], [(RuCI(fl)-DM-BINAP)₂^-CI)₃][NH₂Me₂], [Ru(OAc)₂((fl)-DM- BINAP)], [Ru((fl,fl)-Et-DuPhos)(TFA)₂], [Ru((fl)-MeO-BIPHEP)(TFA)₂], or

[(RuCI(fl)-T-BINAP)₂^-CI)₃][NH₂Me₂].

9. The process of claim 8, wherein the rhodium, ruthenium or iridium metal complex of a phosphorus containing ligand is [(RuCI(f?)-T-BINAP)₂^- CI)₃][NH₂Me₂].

10. The process of claim 1 , wherein the solvent is an alcohol solvent.

1 1 . The process of claim 10, wherein the alcohol solvent is methanol.

12. The process of claim 1 , further comprising synthesis of the Λ/-(3,4- dihydronaphthalen-2-yl)propionamide compounds 3 from 3,4-dihydronaphthalen- 2(1 H)-one compounds 2:

2 3

by reaction with CH₃CH₂C(O)NH₂.

13. The process of claim 1 , further comprising reducing the N-(3,4- dihydronaphthalen-2-yl)propionamide compounds 4 to (S)-/V-(1 ,2,3,4- tetrahydronaphthalen-2-yl)-N-propylamine compounds 5:

by a suitable amide reducing agent.

14. The process of claim 13, further comprising acylating the {S)-N- (1 ,2,3,4-tetrahydronaphthalen-2-yl)-N-propylamine compounds 5 to the {S)-N- (1 ,2,3,4-tetrahydronaphthalen-2-yl)-/V-propyl-2-amide compounds 6:

by acylation with X-C(0)-CH₂)_n-R¹ ; wherein:

X is a leaving group;

R¹ is 3-hydroxyphenyl, 4-hydroxyphenyl, 3-pyridyl, 4-pyridyl, C₆H₅-CH(OH)-, (C₆H₅)₂C(CN)-, 4-indolyl, 2-furanyl, 2-thiophenyl, 2-pyrrolyl, 3-furanyl, 3- thiophenyl, 3-pyrrolyl, or 4-imidiazolyl;

and n is 1 or 2.

15. The process of claim 14, further comprising reducing the {S)-N- (1 ,2,3,4-tetrahydronaphthalen-2-yl)-A/-propyl-2-amide compounds 6 to the (S)-6- (propyl(alkyl)amino)-5,6,7,8-tetrahydronaphthalene compounds 7:

by a suitable amide reducing agent.

16. The process of claim 15, further comprising, when R₂≠ HO- or H, hydrolyzing the (S)-6-(propyl(alkyl)amino)-5,6,7,8-tetrahydronaphthalene compounds 7 to the (S)-6-(propyl(alkyl)amino)-5,6,7,8-tetrahydronaphthalen-1 -ol compounds 8:

by a suitable hydrolyzing agent.

17. The process of claim 1 , wherein (S)-A/-(5-methoxy-1 ,2,3,4- tetrahydronaphthalen-2-yl)propionamide (11 ):

11

is prepared from /V-(5-methoxy-3,4-dihydronaphthalen-2-yl)propionamide (10):

10

comprising the step of reducing 10 with an asymmetric hydrogenating agent.

18. The process of claim 5, wherein the reduction is performed at above atmospheric pressure.

19. The process of claim 18, wherein the pressure is about 10 bar to about 100 bar.

20. The process of claim 1 , wherein molar substrate/catalyst ratio is about 200 to about 10,000.

21 . The process of claim 20, wherein molar substrate/catalyst ratio is about 500 to about 1 ,000.

22. The process of claim 1 , wherein the reduction is performed at a temperature about 25 °C to 60 °C.

23. The process of claim 22, wherein the reduction is performed at a temperature of at least about 30 °C.