HK1195051A - Preparation of chiral amides and amines - Google Patents

Description

Preparation of chiral amides and amines

The application is a divisional application with the name of 'preparation of chiral amide and amine' of Chinese invention patent application 200780013686.6(PCT/US2007/065659), 3 and 30 months of 2007 application date.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35u.s.c. § 119(e) to u.s. provisional patent application 60/787,837 filed 3/31/2006, which is incorporated herein by reference in its entirety for all purposes.

Technical Field

The present invention relates to processes suitable for the large-scale preparation of enantiomerically or diastereomerically enriched chiral amides and amines by these processes.

Background

Enantiomerically enriched chiral primary amines are commonly used as resolving agents for racemic acids, chiral auxiliaries for asymmetric syntheses and ligands for transition metal catalysts used in asymmetric catalysis. In addition, many drugs, such as sertraline, contain chiral amine moieties. Efficient methods for preparing these compounds are of great interest to the pharmaceutical industry. A particularly valuable process is the preparation of each enantiomer or diastereomer in enantiomeric or diastereomeric excess, if appropriate, from a prochiral or chiral starting material.

Enantiomerically enriched amines can be prepared by several methods. For example, Watanabe et al, Tetrahedron Asymm (1995) 6: 1531; denmark et al, j.am.chem.soc. (1987) 109: 2224; takahashi et al, chem.pharm.bull (1982) 30: 3160 reports the addition of organometallic reagents to imines or their derivatives; and mokhalalatiiet et al, Tetrahedron Lett, (1994) 35: 4267 discloses the addition of organometallic reagents to chiral oxazolidines. Despite the widespread use of some of these processes, they are almost impossible to produce amines on a large scale.

Other methods include optical resolution of individual enantiomers or diastereomers from mixtures. Resolution can be carried out by stereoselective biotransformation or by separation of diastereomeric salts by crystallization. The utility and applicability of resolution methods relying on selective recrystallization is often limited by the lack of suitable chiral auxiliary agents available. Furthermore, the resolution method of racemic mixture is 50% of maximum yield for each stereoisomer. Thus, resolving racemic mixtures is generally viewed as an inefficient process.

(WO 99/18065 to Johnson et al) has described the preparation of enantiomerically enriched amines by conversion of a precursor oxime to the corresponding enamide, followed by asymmetric hydrogenation and deprotection to the amine. However, this method cannot be universally applied to a wide range of substrates. In addition, many validated methods require a very large excess of metal reagent to convert effectively. The result is a large amount of solid metal waste, a characteristic which is undesirable for large scale production processes.

Thus, there is a need for a cost-effective, scalable process for converting oximes to the corresponding enamides that does not rely on metal reagents. The easy, high yield conversion of readily available oximes to the corresponding enamides without the use of metal reagents is a valuable step in the large scale synthesis of chiral amides and amines. The present invention satisfies this and other needs.

Brief description of the invention

The present invention provides an efficient and convenient method for converting oximes into the corresponding enamides. The process of the present invention achieves the desired conversion without the use of metal reagents. The process is suitable for large-scale synthesis of enamides, amides, amines and their derivatives.

Accordingly, in a first aspect, the present invention provides a process for converting an oxime to an enamide. The method comprises contacting an oxime with a phosphine and an acyl donor under conditions suitable to convert the oxime into an enamide. The process produces enamides in high yield and can be universally used for a wide range of oxime structures. Enamides are readily converted to the corresponding amines. In one exemplary pathway, as described in more detail herein, an enamide is reduced to the corresponding amide, followed by deacylation to the amine.

The process is particularly useful for the large-scale synthesis of biologically active substances, such as those having the 1,2,3, 4-tetrahydro-N-alkyl-1-naphthylamine or 1,2,3, 4-tetrahydro-1-naphthylamine substructure. Examples of biologically active compounds having this substructure include sertraline and analogs of sertraline, the trans-isomer of sertraline, norsertraline and analogs thereof. Sertraline, (1S,4S) -cis 4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydro-N-methyl-1-naphthylamineApproved by the U.S. food and drug administration for the treatment of depression, under the trade name(Pfizer Inc., NY, N.Y., USA). In human subjects, sertraline has been shown to be metabolized to (1S,4S) -cis 4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydro-1-naphthalenamine, also known as norsertraline or norsertraline.

Enamides provide convenient precursors for compounds containing 1,2,3, 4-tetrahydro-N-alkyl-1-naphthylamine or 1,2,3, 4-tetrahydro-1-naphthylamine substructures. Accordingly, in a second aspect, the present invention provides an oxime having the formula:

a process for converting to an enamide having the formula:

in the above formula, the symbol R⁴Represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. Symbol R⁵Represents H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. The method comprises contacting the oxime with a phosphine and an acyl donor under conditions suitable to convert the oxime into the enamide.

In a third aspect, the present invention provides a mixture comprising

In the above formula, Q^-Is an anion. The labels e and f are numbers independently selected from 0 to 1. The symbols x and y independently represent (R) or (S). In an exemplary embodiment, when x is (R), y is (R); when x is (S), y is (S). In another exemplary embodiment, when x is (S), y is (R).

The present invention provides a general and convenient method for converting oximes into enamides. In addition, the present invention provides a method for the stereoselective synthesis of sertraline and sertraline analogs, the trans-isomers of sertraline, norsertraline and analogs thereof. Other objects, advantages and embodiments of the invention are set forth in the detailed description that follows.

Detailed Description

Abbreviations

As used herein, "COD" refers to 1, 5-cyclooctadiene.

Definition of

When substituents are referred to by conventional formulae written from left to right, they also include chemically equivalent substituents written from right to left, e.g., -CH₂O-is also preferably intended to include-OCH₂-。

The term "alkyl" by itself or as part of another substituent, unless otherwise stated, refers to a straight or branched chain or cyclic hydrocarbon group or combinations thereof, which may be fully saturated, mono-or polyunsaturated, and may include mono-, di-and polyvalent groups, having the indicated number of carbon atoms (i.e., C.C.₁-C₁₀Meaning 1 to 10 carbons). Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs or isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is a group having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, ethenyl, 2-propenylButenyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butynyl and higher homologs and isomers. The term "alkyl" also preferably includes, unless otherwise indicated, derivatives of alkyl as defined in more detail below, such as "heteroalkyl". Alkyl groups limited to hydrocarbon groups are referred to as "homoalkyl groups". The term "alkyl," as used herein, refers to alkyl, alkenyl, and alkynyl moieties, each of which can be mono, di, or polyvalent. Alkyl groups are preferably substituted, for example by one or more of the "substituents of alkyl" described below.

The term "alkylene" by itself or as part of another substituent refers to a divalent radical derived from an alkane, such as, but not limited to, -CH₂CH₂CH₂CH₂Furthermore, those radicals which are referred to below as "heteroalkylene" are also included. Typically, alkyl (or alkylene) groups have 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, typically having 8 or fewer carbon atoms.

The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense to refer to those alkyl groups attached to the remainder of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively.

The term "heteroalkyl," by itself or in combination with other terms, means, unless otherwise stated, a stable straight or branched chain, or cycloalkyl group containing the indicated number of carbon atoms and at least one heteroatom selected from B, O, N, Si and S, where the heteroatom may be optionally oxidized and the nitrogen atom may optionally be tetravalent. One or more heteroatoms may be located at any internal position of the heteroalkyl group or at the end of the chain, e.g., the alkyl group is attached to the remainder of the molecule through its location. Examples of "heteroalkyl" include, but are not limited to, -CH₂-CH₂-O-CH₃、-CH₂-CH₂-NH-CH₃、-CH₂-CH₂-N(CH₃)-CH₃、-CH₂-S-CH₂-CH₃、-CH₂-CH₂、-S(O)-CH₃、-CH₂-CH₂-S(O)₂-CH₃、-CH=CH-O-CH₃、-Si(CH₃)₃、-CH₂-CH=N-OCH₃and-CH = CH-N (CH)₃)-CH₃. Two or more hetero atoms may be linked, e.g. -CH₂-NH-OCH₃and-CH₂-O-Si(CH₃)₃. Similarly, the term "heteroalkylene" by itself or as part of another substituent refers to a substituted or unsubstituted divalent heteroalkyl group, such as, but not limited to, -CH₂-CH₂-S-CH₂-CH₂-and-CH₂-S-CH₂-CH₂-NH-CH₂-. For heteroalkylene groups, heteroatoms can occupy one or both chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Furthermore, for groups that are linked to alkylene and heteroalkylene, the orientation in which the formula of the linker is written does not imply a position of the linker. For example of the formula-C (O)₂R' -represents-C (O)₂R '-, preferably-R' C (O)₂-。

The terms "cycloalkyl" and "heterocycloalkyl" by themselves or in combination with other terms, unless otherwise stated, refer to the ring type of "alkyl" and "heteroalkyl," respectively. Further, for heterocycloalkyl, a heteroatom may occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1,2,5, 6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

The term "halo" or "halogen" by itself or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine or iodine atom. Furthermore, terms such as "haloalkyl"Is meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C)₁-C₄) Alkyl "includes, but is not limited to, trifluoromethyl, 2,2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

Unless otherwise indicated, the term "aryl" refers to a polyunsaturated aromatic substituent, which may be monocyclic or polycyclic (preferably 1 to 3 rings, one or more of which is optionally cycloalkyl or heterocycloalkyl), which may be fused together or covalently linked. The term "heteroaryl" refers to an aryl (or ring) containing 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and one or more nitrogen atoms are optionally tetravalent. The heteroaryl group may be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, 2-furyl, 3-furyl, 2-thienyl, Purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalyl, 5-quinoxalyl, 3-quinolyl and 6-quinolyl. The substituents for each of the above aryl and heteroaryl ring systems are selected from the group consisting of the "substituents for aryl" described below.

For brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthioxy, aralkyl) preferably includes both homoaryl and heteroaryl rings as defined above. Thus, the term "aralkyl" optionally includes those groups in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like), including alkyl groups in which one carbon atom (e.g., methylene) is substituted with, for example, one oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl, and the like).

Alkyl and heteroalkyl (including generallyThose referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are generally referred to as "substituents of alkyl," which may be one or more selected from the following groups, including but not limited to: -OR ', = O, = NR ', = N-OR ', -NR ' R ", -SR ', -halogen, -SiR ' R" R ', -oc (O) R ', -c (O) R ', -CO₂R′、-CONR′R"、-OC(O)NR′R"、-NR"C(O)R′、-NR′-C(O)NR"R"′、-NR"C(O)₂R′、-NR-C(NR′R"R′")=NR""、-NR-C(NR′R")=NR′"、-S(O)R′、-S(O)₂R′、-S(O)₂NR′R"、-NRSO₂R', -CN and-NO₂And in amounts of from 0 to (2m '+ 1), where m' is the total number of carbon atoms in these groups. R ', R ", R'" and R "" are each preferably independently hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy, or aralkyl. When a compound of the invention includes more than one R group, for example, each R group is independently selected according to each R ', R ", R'" and R "" group when more than one of these groups is present. When R' and R "are attached to the same nitrogen atom, they may be combined with the nitrogen atom to form a 5-, 6-or 7-membered ring. For example, -NR' R "includes but is not limited to 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, those skilled in the art will recognize that the term "alkyl" includes groups having a carbon atom attached to a group other than hydrogen, such as haloalkyl (e.g., -CF)₃and-CH₂CF₃) And acyl (e.g., -C (O) CH)₃、-C(O)CF₃、-C(O)CH₂OCH₃Etc.).

Similar to the substituents described above for alkyl groups, the substituents for aryl and heteroaryl groups are generally referred to as "substituents for aryl". These substituents are selected, for example, from: halogen, -OR ', = O, = NR ', = N-OR ', -NR ' R ", -SR ', -SiR ' R ', -OC (O) R ', -C (O) R ', -CO₂R′、-CONR′R"、-OC(O)NR′R"、-NR"C(O)R′、-NR′-C(O)NR"R′"、-NR"C(O)₂R′、-NR-C(NR′R"R′")=NR""、-NR-C(NR′R")=NR′"、-S(O)R′、-S(O)₂R′、-S(O)₂NR′R"、-NRSO₂R', -CN and-NO₂、-R′、-N₃、-CH(Ph)₂Fluoro (C)₁-C₄) Alkoxy and fluoro (C)₁-C₄) Alkyl groups in an amount of 0 to the total number of open valencies on the aromatic ring system; and wherein R ', R ", R'" and R "" are preferably independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each R group is independently selected according to each R ', R ", R'" and R "" group when more than one of these groups is present.

Two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted by a group of the formula T-C (O) - (CRR')_q-U-, wherein T and U are independently-NR-, -O-, -CRR' -or a single bond, and q is an integer of 0 to 3. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be represented by the formula-A- (CH)₂)_rA substituent of-B-, wherein A and B are independently-CRR' -, -O-, -NR-, -S (O)₂-、-S(O)₂NR' -or a single bond, r is an integer of 1 to 4. One single bond of the new ring formed may be optionally substituted by a double bond. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally substituted by a group of formula- (CRR')_S-X-(CR"R′")_d-wherein S and d are independently integers from 0 to 3, X is-O-, -NR' -, -S (O)₂-or-S (O)₂NR' -. The substituents R, R ', R "and R'" are preferably independently selected from hydrogen or substituted or unsubstituted (C)₁-C₆) An alkyl group.

The term "heteroatom" as used herein includes oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

The symbol "R" is a general abbreviation that represents a substituent selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl.

The term "salt(s)" includes salts of the compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, neat or in a suitable inert solvent. Examples of base addition salts include sodium, potassium, calcium, ammonium, organic amines, or magnesium salts or similar salts. When the compounds of the present invention contain relatively acidic functional groups, acid addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, neat or in a suitable inert solvent. Examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and the like, as well as salts derived from relatively nontoxic organic acids such as acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine salts and the like, and salts of organic acids such as glucuronic acid or galacturonic acid and the like (see, Berge et al, Journal of Pharmaceutical Science, 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functional groups that can convert the compounds to base or acid addition salts. Also included are hydrates of the salts.

When the compound prepared by the process of the present invention is a medicament, it is preferred that the salt is a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts are those above and are well known in the art. See, e.g., Wermuth, C, PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE-A HANDBOOK, Verlag Helvetica Chimica acta (2002).

The compound in neutral form is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salts in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for purposes of this invention.

In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical means in an in vitro environment. For example, prodrugs can be slowly converted to compounds of the present invention when placed in a reservoir of a transdermal patch containing an appropriate enzyme or chemical agent.

The term "prodrug" as used herein, unless otherwise indicated, refers to a derivative of a compound that can hydrolyze, oxidize, or otherwise provide the compound under biological conditions (in vitro or in vivo). Examples of prodrugs include, but are not limited to, compounds comprising biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Other examples of prodrugs include those comprising NO, NO₂-ONO, or-ONO₂A moiety of a compound. The term "prodrug" is in accordance with the definitions herein, such that the prodrug does not include the parent compound of the prodrug. When used to describe the compounds of the present invention, the term "prodrug" may also be construed to exclude other compounds of the present invention.

As used herein, unless otherwise indicated, the terms "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide", and "biohydrolyzable phosphate" refer to carbamates, carbonates, ureides, and phosphates, respectively, of a compound that: 1) does not interfere with the biological activity of the compound, but may impart beneficial in vivo properties to the compound, such as absorption, duration of action, or onset of action; or 2) is biologically inactive, but is converted in vivo to a biologically active compound. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

The term "biohydrolyzable ester" as used herein, unless otherwise indicated, refers to an ester of a compound which: 1) does not interfere with the biological activity of the compound, but may impart beneficial in vivo properties to the compound, such as absorption, duration of action, or onset of action; or 2) is biologically inactive, but is converted in vivo to a biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkylamidoalkyl esters, and choline esters.

As used herein, unless otherwise indicated, the term "biohydrolyzable amide" refers to an amide of a compound that: 1) does not interfere with the biological activity of the compound, but may impart beneficial in vivo properties to the compound, such as absorption, duration of action, or onset of action; or 2) is biologically inactive, but is converted in vivo to a biologically active compound. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, alpha-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

Certain compounds of the present invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polymorphic or amorphous forms. In general, all physical forms are equivalent for the applications for which the invention is concerned and are intended to be included within the scope of the invention.

Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemic compounds, diastereomers, geometric isomers, and individual isomers are included within the scope of the invention.

As used herein, unless otherwise specified, a composition that is "substantially free of" a compound means that the composition contains less than about 20% by weight, more preferably less than about 10% by weight, even more preferably less than about 5% by weight, and most preferably less than about 3% by weight of the compound.

The term "substantially free of its cis stereoisomer" as used herein means that a mixture of compounds consists of a significantly greater portion of the trans stereoisomer than its optical antipode. In a preferred embodiment of the invention, the term "substantially free of its cis stereoisomer" means that the compound consists of at least about 90% by weight of the trans stereoisomer and about 10% by weight or less of the cis stereoisomer. In a more preferred embodiment of the invention, the term "substantially free of its cis stereoisomer" means that the compound consists of at least about 95% by weight of the trans stereoisomer and about 5% by weight or less of the cis stereoisomer. In an even more preferred embodiment of the present invention, the term "substantially free of its cis stereoisomer" means that the compound consists of at least about 99% by weight of the trans stereoisomer and about 1% by weight or less of the cis stereoisomer.

Racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein were taken from Maehr, j.chem.ed., 62: 114-120(1985): the solid and broken wedge lines are used to represent the absolute configuration of the chiral component; wavy lines mean that the bond it represents may have produced no stereochemistry; solid and broken bold lines are geometric descriptors, indicating that relative configurations are shown, but do not imply any absolute stereochemistry; and the wedge lines and the dashed or broken lines represent enantiomerically pure compounds for which the absolute configuration was not determined.

The terms "enantiomeric excess" and "diastereomeric excess" are used interchangeably herein. Reference to a compound having a single stereocenter is said to exist in "enantiomeric excess". Reference to a compound having at least two stereogenic centers is said to exist in "diastereomeric excess".

The compounds of the present invention may also contain any unnatural fraction of atomic isotopes at one or more of the atoms that constitute such compounds. For example, radioactive isotopes such as tritium (f)³H) Iodine 125 (1)¹²⁵I) Or carbon-14 (¹⁴C) To radiolabel these compounds. Any isotopic variation of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

Introduction to

The present invention provides a non-metal mediated process for converting an oxime to the corresponding enamide. Enamides are formed in high yield and purity, which makes them suitable as substrates for homogeneous asymmetric hydrogenation, a process that provides enantiomerically-enriched amides. The amide may be deacylated to form an enantiomerically-enriched amine. Either enantiomer of the amine can be obtained by this method. Ketones and aldehydes can thus be converted into enantiomerically-enriched chiral amines. The method can be used for large-scale production.

Method of producing a composite material

A. Conversion of oximes into enamides

In a first aspect, the present invention provides a method of converting an oxime to an enamide. The method comprises contacting an oxime with a phosphine and an acyl donor under conditions suitable to convert the oxime to an enamide. Exemplary conditions are as described herein.

In one embodiment, the oxime used in the process of the invention has the formula:

symbol R¹、R²And R³Represents independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycleThe radical of an alkyl group. R¹、R²And R³Are optionally linked to form a ring system selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In another exemplary embodiment, the oxime has the formula:

the symbol Ar represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. R⁴Is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. The symbol a is an integer of 1 to 4.

In an exemplary embodiment according to this aspect, R⁴Is a substituted or unsubstituted aryl group (e.g., phenyl). In another exemplary embodiment, R⁴Is phenyl substituted by at least one halogen atom.

In another exemplary embodiment, R⁴Having the formula:

wherein the symbol X¹And X²Represent independently selected halogen moieties. In a preferred embodiment, X¹And X²Respectively chlorine.

In another exemplary embodiment, the oxime has the formula:

wherein R is⁴Selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

In another exemplary embodiment, the oxime has the formula:

the preparation of oximes is well known in the art and a wide range of methods are known and readily practiced by those skilled in the art. Typically, preparing an oxime involves reacting a ketone or aldehyde with hydroxylamine (or an alkoxyamine) under one of a variety of conditions. See, e.g., Sandler and Kara, "ORGANIC FUNCTIONAL GROUP PREPARATIONS," Vol.3, pp372-381, Academic Press, New York, 1972.

In an exemplary embodiment, optically pure tetralone is converted to the corresponding oxime according to scheme 1.

Scheme 1

In scheme 1, optically pure tetralone 1 is treated with hydroxylamine hydrochloride and sodium acetate in methanol to afford the oxime 2. Compound 2 can be isolated or transferred to the next step as a solution in a suitable solvent. In another method, the ketone is converted to the corresponding oxime in an aromatic hydrocarbon solvent such as toluene.

According to the process of the present invention, oximes are converted into enamides. In an exemplary embodiment, the enamide has the formula:

wherein R is₁-R³As discussed above, R⁵Selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl.

In another exemplary embodiment, the enamide has the formula:

wherein R is⁴Selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. R⁵Selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl.

An exemplary enamide has the formula:

in an exemplary embodiment according to this aspect, C-4 of the ketone, oxime and enamide is in the (S) configuration.

In a preferred embodiment, the enamide has the formula:

c-4 has a configuration selected from the group consisting of (R) and (S), and in a preferred embodiment, C-4 is the (S) configuration. In another embodiment, the present process provides a mixture of enamides comprising the (S) and (R) enantiomers.

Acyl donors

Acyl donors of essentially any structure may be used in the present invention. An exemplary acyl donor has the formula:

Z-C(O)-R⁵

wherein Z is a leaving group. R⁵Is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl.

In an exemplary embodiment, the acyl donor is an anhydride, wherein Z has the formula:

R⁶-C(O)-O-

wherein R is⁶Is a member selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl.

In another exemplary embodiment, R⁵And R⁶Independently selected from substituted or unsubstituted C₁-C₄And (4) partial.

In another embodiment, the acyl donor is an anhydride, preferably acetic anhydride (Ac)₂O)。

In another exemplary embodiment, the acyl donor is a member selected from the group consisting of an acyl chloride (Z = Cl) and an activated ester such as N-hydroxysuccinimide ester.

The acyl donor can be present in any useful amount, which is selected to be within the ability of one skilled in the art. In an exemplary embodiment, the acyl donor is used in an amount of about 1 to about 3 equivalents, preferably about 1 to about 2 equivalents, and more preferably about 1 to about 1.5 equivalents, relative to the oxime substrate.

Phosphines

Phosphorus reagents of any structure, such as phosphines, may be used in the practice of the present invention. For example, typically, the phosphine has the formula:

P(Q)₃

wherein each Q is independently selected from the group consisting of H, substituted or unsubstituted alkyl, and substituted or unsubstituted aryl.

In an exemplary embodiment, each Q is independently selected from substituted or unsubstituted C₁-C₆A member of the group consisting of alkyl and substituted or unsubstituted phenyl. Current dextrorotatory phosphorus agents include, but are not limited to, biphenylphosphine (Ph)₂PH), triphenylphosphine (Ph)₃P), tri-n-butylphosphine (n-Bu)₃P), triethylphosphine (Et)₃P), tri-n-propylphosphine (n-Pr)₃P), 1, 2-Biphenylphosphinoethane (Ph)₂PCH₂CH₂PPh₂) Diethyl phosphite (Et)₂OP (O) H), triphenyl phosphite ((PhO)₃P), P-chlorodiphenylphosphine (Ph)₂PCl), methyl triphenyl bromide(MePh₃PBr) and benzyltriphenylphosphonium chloride(BnPh₃PCl)。

Phosphorus reagents such as phosphines may be incorporated into the reaction mixture in essentially any useful amount. The phosphorus reagent used in the exemplary reactions of the present invention is about 0.5 equivalents to about 5 equivalents, preferably about 1 equivalent to about 3 equivalents, and more preferably about 1.1 equivalents to about 2 equivalents, relative to the carbonyl-containing substrate.

Solvent(s)

In an exemplary embodiment, an oxime is contacted with a phosphorus reagent (e.g., a phosphine) and an acyl donor in the presence of an organic solvent. The solvent may be a protic or aprotic solvent. In a preferred embodiment, the solvent is an aprotic solvent. In a further preferred embodiment, the aprotic solvent is an aromatic solvent (e.g., toluene, xylene, and combinations thereof).

In an exemplary embodiment, wherein the oxime is compound 3, the solvent is preferably toluene.

B. Conversion of enamides to amides

In another aspect, the present invention provides a method of converting an enamide to an amide. The process comprises contacting an enamide with a hydrogenation catalyst and hydrogen or a hydrogen transfer agent under conditions suitable to hydrogenate the carbon-carbon double bond of the enamide, thereby converting the enamide to an amide.

The process of the present invention is not limited to practice with only enamides characterized by any particular structural element or relationship within any single structural group. The methods described herein can be broadly applied to a wide range of enamide structures. Exemplary reagents and reaction conditions for converting an enamide to an amide are described below.

Catalyst and process for preparing same

Reduction of the carbon-carbon double bond of the enamide by various methods such as hydrogen transfer using a hydrogen donor such as a secondary alcohol, particularly isopropanol, and hydrogenation; molecular hydrogen is used for the hydrogenation. Hydrogen transfer and hydrogenation processes require a catalyst or catalytic system to activate the reducing agent, i.e., alcohol or molecular hydrogen, respectively.

In selected embodiments of the invention, the enamide substrate is chiral or prochiral, and is reduced, hydrogen transferred or hydrogenated in a stereoselective manner. In this embodiment, it is generally preferred that the catalyst is a chiral catalyst. Also preferably, the chiral catalyst is a transition metal catalyst.

Chiral transition metal complex catalysts that can be used in catalyzing asymmetric hydrogenation reactions are disclosed in a number of reports. Among them, transition metal complexes of ruthenium, iridium, rhodium, palladium, nickel, etc., containing an optically active phosphine as a ligand, have been reported to show excellent properties as catalysts for asymmetric synthesis reactions, and some of them have been used in industry. See, e.g., ASYMMETRIC CATALYSIS IN ORGANIC SYNTHESIS, Ed., R.Noyori, Wiley & Sons (1994); and g.franci oa, etc., angle and chemie, int.ed., 39: 1428-1430(2000).

In a preferred embodiment, the metal in the catalyst is rhodium (Rh), ruthenium (Ru) or iridium (Ir).

In an exemplary embodiment, the catalyst used in the process is a complex of a chiral transition metal and a chiral phosphine ligand, including mono-and di-coordinated ligands. For example, preferred bidentate ligands include 1, 2-bis (2, 5-dimethylphosphino) ethane (MeBPE), P-1, 2-phenylenedi{ (2, 5-endo-dimethyl) -7-phosphobicyclo [2.2.1 { (2, 5-endo-dimethyl) } -H]Heptane } (MePennphos), 5, 6-bis (biphenylphosphino) bicyclo [2.2.1]Hept-2-ene (NorPhos) and 3, 4-bis (biphenylphosphino) N-benzylpyrrolidine (commercially available asD, sales).

In a preferred embodiment of the preparation of amides derived from tetralone, the chiral catalyst is (R, S, R, S) -MePennphos (COD) RhBF₄、(R,R)-MeBPE(COD)RhBF₄、(R,R)-NorPhos(COD)RhBF₄(Brunner et al, Angewandte Chemie91 (8): 655-6(1979)), or (R, R) -D(COD)RhBF₄(Nagel et al, Chemische Berichte119 (11): 3326-43 (1986)).

The catalyst may be present in the reaction mixture in any useful amount. It is within the ability of one skilled in the art to determine the structure of an appropriate catalyst and the effective amount of catalyst. In an exemplary embodiment, the catalyst is present in an amount of about 0.005mol% to about 1 mol%. Generally, it is preferred that the catalyst be present in an amount of from about 0.01mol% to about 0.5mol%, even more preferably from about 0.02mol% to about 0.2 mol%.

In an exemplary embodiment, the enamides are hydrogenated to the corresponding amides in the presence of about 0.02 to about 0.3mol%, preferably about 0.03 to about 0.2mol%, and even more preferably about 0.03 to about 0.1mol% of an Rh-MeBPE catalyst.

In another exemplary embodiment, the enamine is hydrogenated to the amide in the presence of from about 0.1 to about 1.0mol%, preferably from about 0.1 to about 0.5mol%, more preferably about 0.3mol% of an Rh-PennPhos catalyst.

In another exemplary embodiment, the (R, R) -NorPhos (COD) RhBF is present at about 0.005 to about 1.0mol%, preferably about 0.01 to about 0.5mol%, more preferably about 0.02 to about 0.1mol%₄The hydrogenation of the enamide to the amide is carried out in the presence of a catalyst.

It is presently preferred that the catalyst used in the present invention provides amides from enamides in high yields, where the yield is at least 85%, preferably at least 90%, more preferably at least 95%. When the synthesis is on a larger scale of at least 300 grams, preferably at least 500 grams, more preferably at least 750 grams, even more preferably at least 1,000 grams, the catalyst that is generally preferred is one that provides a high yield of amide. When the reaction is carried out on a larger scale as described above, the preferred catalyst provides the amide in high yield as described above. An exemplary catalyst having these desirable properties is (R, R) -NorPhos (COD) RhBF₄。

Pressure of hydrogen gas

When the C-C double bond of the enamide is converted to the corresponding C-C single bond by hydrogenation, the hydrogen pressure in the reactor can be adjusted to optimize the reaction yield and stereoselectivity. The process of the invention can be carried out with any useful hydrogen pressure, and the skilled person will know how to adjust the hydrogen pressure to optimize the desired result.

In an exemplary embodiment, the enamide is hydrogenated to give the amide under a hydrogen pressure of about 2 to about 10bar, preferably about 4 to about 8bar, more preferably about 5 to about 6 bar.

Solvent(s)

The process of the invention is not limited to practice with any one solvent or any kind of solvent, such as protic, aprotic, aromatic or aliphatic solvents. The selection of an appropriate solvent for a particular reaction is within the ability of one skilled in the art.

In an exemplary embodiment, the enamide is converted to the amide in the presence of a protic solvent, an aprotic solvent, or a mixture thereof. In a preferred embodiment, the solvent is a protic solvent, which is an alcohol, more preferably C₁To C₄-an alcohol. In another preferred embodiment, the alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol or 2,2, 2-trifluoroethanol (CF)₃CH₂OH). In a presently preferred embodiment, the alcohol is isopropanol.

In another exemplary embodiment, the aprotic solvent is an aromatic solvent, a non-aromatic solvent, or a mixture thereof. Exemplary aromatic solvents for use in the present invention include toluene, benzene and xylene, and preferably less toxic aromatic solvents such as toluene and xylene. Exemplary non-aromatic solvents for use in the process of the invention include Tetrahydrofuran (THF), methylene Chloride (CH)₂Cl₂) Ethyl acetate (EtOAc) and acetonitrile (CH)₃CN)。

The solvent and substrate are present in essentially any useful ratio. In an exemplary embodiment, the solvent and substrate are present in an amount to provide a substrate solvent of from about 0.05M to about 0.5M, preferably from about 0.1M to about 0.3M, more preferably from about 0.12M to about 0.34M.

Amides of carboxylic acids

The amides formed by the process of the present invention have different structures and may include alkyl, heteroalkyl, aryl and heteroaryl substructures. In one exemplary embodiment, the amide has the formula:

wherein R is¹-R³And R⁵As discussed above.

As discussed previously, the process of the present invention can be used to prepare amides containing 1,2,3, 4-tetrahydro-N-alkyl-1-naphthylamine or 1,2,3, 4-tetrahydro-1-naphthylamine substructures. Thus, in one exemplary embodiment, the amide has the formula:

wherein R is⁴And R⁵As described above.

One exemplary amide is a trans-amide having the formula:

another exemplary amide has the formula:

in a preferred embodiment, the amide has the formula:

in each of the above amide formulae, C-1 and C-4 have a configuration independently selected from the group consisting of (R) and (S), and in a preferred embodiment, C-1 is the (R) configuration and C-4 is the (S) configuration.

Enantiomeric or diastereomeric excess

In a preferred embodiment, the process of the invention produces an enantiomeric excess (ee) of the desired enantiomer or diastereomeric excess (de) of the desired diastereomer in the range of from about 60% ee/de to about 99% ee/de, preferably from about 70% ee/de to about 99% ee/de, more preferably from about 80% ee/de to about 99% ee/de, still more preferably from about 90% ee/de to about 99% ee/de.

In another preferred embodiment, the present invention provides amides, in enantiomeric or diastereomeric excess of at least about 99%, preferably at least about 99.4%, more preferably at least about 99.8%. Amides substantially free of their optical antipodes can be obtained by the process of the invention.

When rhodium catalyst systems are used on the basis of chiral bidentate ligands, e.g. from 1, 2-bis (phosphine) ethane (BPE) ligands, P-1, 2-phenylenedi (7-phosphobicyclo [2.2.1 ]]Heptane) (Pennphos) ligand, 5, 6-bis (phosphino) bicyclo [2.2.1]Hept-2-ene (NorPhos) ligands or 3, 4-bis (phosphino) pyrrolidines (commercially available asD), it is surprising that the diastereomeric purity of the trans-amides produced from the corresponding enamides is particularly high.

In a preferred embodiment, when the amide comprises a 1,2,3, 4-tetrahydro-N-alkyl-1-naphthylamine or a 1,2,3, 4-tetrahydro-1-naphthylamine subunit, the process provides a (1R,4S) -trans amide substantially free of its cis isomer.

In an exemplary embodiment, the enamine is hydrogenated to a trans N-acetamide of about 80 to about 99% de, preferably at least 95% de, more preferably at least 99% de, using about 0.03 to about 0.05mol% Rh-Me-BPE catalyst in isopropanol at a hydrogen pressure of about 4 to about 6 bar.

In another exemplary embodiment, the enamine is hydrogenated to a trans N-acetamide in isopropanol using from about 0.2 to about 0.5mol% of a Rh-Pennphos catalyst at a hydrogen pressure of from about 4 to about 5bar to yield a trans N-acetamide in from about 80 to about 99% de, preferably at least 95% de, more preferably at least 99% de.

In another exemplary embodiment, about 0.01 to about 0.05mol% of (R, R) NorPhos (COD) RhBF is used in isopropanol₄A catalyst for the hydrogenation of an enamide under a hydrogen pressure of about 5 to about 8bar to give a trans N-acetamido amide in about 80-99% de, preferably at least 95% de, more preferably at least 99% de.

In a preferred embodiment, the hydrogenation is carried out at an enamide concentration of from about 0.1M to about 0.3M.

In another exemplary embodiment, the stereoisomer-enriched amide is purified or further concentrated by selective crystallization. In another exemplary embodiment, the amide is purified or concentrated to about 90 to about 99% ee/de enantiomerically or diastereomerically pure. In another exemplary embodiment, the amide is purified or concentrated to about 95 to about 99% ee/de enantiomerically or diastereomerically pure.

The hydrogenated or hydrogen transferred product may be subjected to enantiomeric or diastereomeric enrichment by methods known in the art, such as chiral chromatography, selective crystallization, and the like. It is generally preferred that concentration provides a product that is at least about 95% a single stereoisomer. More preferably at least about 97%, still more preferably at least about 99% is a single stereoisomer.

In a presently preferred embodiment, the enriched trans amide is purified or concentrated by selective crystallization to give the desired trans isomer at about 99% de.

C. Conversion of amides to amines

In another aspect, the invention provides a method of converting an amide formed from a corresponding enamide to an amine. In an exemplary embodiment, the method comprises contacting the amide with a deacylating agent under conditions suitable to deacylate the amide, thereby forming an amine.

In an exemplary embodiment, the amine has the formula:

or a salt thereof. The groups are the same as described above.

The amine may be of any desired structure, but is preferably a chiral amine. When the amine is chiral, the enantiomeric excess (ee) of the desired enantiomer or diastereomeric excess (de) of the desired diastereomer prepared by this method is from about 60% ee/de to about 99% ee/de, preferably from about 70% ee/de to about 99% ee/de, more preferably from about 80% ee/de to about 99% ee/de, still more preferably from about 90% ee/de to about 99% ee/de.

In another preferred embodiment, the present invention provides an amine, enantiomeric or diastereomeric excess of at least about 99%, preferably at least about 99.4%, more preferably at least about 99.8%. Amines substantially free of their optical antipodes can be obtained by the process of the invention.

In an exemplary embodiment, the amine comprises a 1,2,3, 4-tetrahydro-N-alkyl-1-naphthylamine or 1,2,3, 4-tetrahydro-1-naphthylamine substructure and has the formula:

or a salt thereof.

In a preferred embodiment, the amine is a trans amine having the formula:

or a salt thereof.

An exemplary amine has the formula:

wherein Q^-Is an anion. The symbol e is a number from 0 to 1. The notation may take fractional values indicating that the amine salt is a half salt.

In a preferred embodiment, the amine has the formula:

wherein Q^-And e are as described above.

C-1 and C-4 have a configuration independently selected from (R) and (S). Preferably, C-1 is in the (R) configuration and C-4 is in the (S) configuration.

In another preferred embodiment, the amine is in the trans configuration and is substantially free of cis isomer.

The amide may be deacylated by any suitable method. Many methods for deacylating amides to the corresponding amines are known in the art. In an exemplary embodiment, the deacylating agent is an enzyme. Exemplary enzymes for use in the method include those of the EC3.5.1 (e.g., amidases, aminoacylases) and EC3.4.19 classes.

In another embodiment, the deacylating agent is an acid or a base. The acid or base may be inorganic or organic. Mixtures of acids or mixtures of bases are also useful. When the deacylating agent is an acid, it is generally preferred to select the acid such that acid hydrolysis produces the amine form of the product. In an exemplary embodiment, the acid is hydrochloric acid (HCl).

Other deacylation conditions useful in the present invention include, but are not limited to, methanesulfonic acid/HBr, triphenyl phosphite/halogen (e.g., bromine, chlorine) complexes, and di-t-butyl heavy carbonate/lithium hydroxide sequences in alcoholic solvents.

In a preferred embodiment, the amide is deacylated by treatment with an activating agent such as trifluoromethanesulfonic anhydride, phosgene, preferably oxalyl chloride/pyridine. The reaction is stopped with an alcohol, preferably a diol, such as propylene glycol.

When the amide includes a 1,2,3, 4-tetrahydro-N-alkyl-1-naphthylamine or a 1,2,3, 4-tetrahydro-1-naphthylamine substructure, the deacylation conditions are preferably selected to minimize the formation of any dihydronaphthalene by-product.

The amine may be isolated or concentrated. One presently preferred method of separation or concentration includes at least one step of selective crystallization.

The amines are optionally N-alkylated or N-acylated to produce the corresponding N-alkyl or N-acyl derivatives.

In an exemplary embodiment, the present invention provides a process suitable for large scale preparation of trans 4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydro-1-naphthalenamine 5 and its salt forms. In an exemplary embodiment, the process comprises synthesizing an enamide, such as enamide 3, starting from optically pure (4S) -tetralone 1 via oxime 2, subjecting enamide 3 to catalytic asymmetric hydrogenation to give amide 4, and N-deacylation to give trans 4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydro-1-naphthylamine 5 or a salt thereof (scheme 2).

Scheme 2

In a preferred embodiment, the compound prepared by the route of scheme 2 is (1R,4S) -trans 4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydro-1-naphthalenamine. Even more preferably, the compound is prepared substantially free of its cis isomer.

Compounds according to formula 5 include stereoisomers of demethylsertraline. The N-methyl analog of 5 is a stereoisomer of sertraline.

The primary clinical application of sertraline is in the treatment of depression. Furthermore, U.S.4,981,870 discloses and claims the use of sertraline and related compounds in the treatment of psychosis, psoriasis, rheumatoid arthritis and inflammation.

(1R,4S) -trans 4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydro-1-naphthalenamine and (1S,4R) -trans 4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydro-1-naphthalenamine are useful for the treatment of CNS-related disorders modulated by monoamine activity (Jerussi et al U.S. 2004/0092605; incorporated by reference). Those CNS-related disorders include affective disorders (e.g., depression), anxiety disorders (e.g., OCD), behavioral disorders (e.g., ADD and ADHD), eating disorders, substance abuse disorders and sexual dysfunction. Potentially, these molecules produce fewer side effects than current therapeutic standards. These compounds may also be used for the prevention of migraine.

Composition IV

In another aspect, the present invention provides a mixture comprising:

wherein R is⁴Is a member selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. Q^-Is an anion. The symbols e and f independently represent numbers from 0 to 1. Thus, the above structure includes a half-salt.

The labels x and y are independently selected from (S) and (R). In one embodiment, when x is (S), y is (S); when x is (R), y is (R). In another embodiment, when x is (S), y is (R).

In an exemplary embodiment, R⁴Is a substituted or unsubstituted aryl group. One preferred aryl moiety is a substituted or unsubstituted phenyl moiety.

In another exemplary embodiment, the mixture comprises a compound having the formula:

wherein e, f, x and y are as described above.

The above-mentioned mixtures can be used in pharmaceutical preparations. It is generally recognized that stereoisomers of biologically active compounds may have different properties. For example, the beta-adrenergic blocker propranolol is known to be more than 100 times more potent in the S-enantiomer than in the R-enantiomer. However, efficacy is not the only consideration in the pharmaceutical field. Optical purity is also important because certain isomers are toxic in nature, rather than simply inert. Mixtures of diastereomers are effectively combined and the properties of each pure diastereomer are adjusted. Thus, in selected embodiments, the present invention provides mixtures of diastereomeric compounds a and B.

According to the invention, A or B may be the pure isomers or any mixture of A and B, and a therapeutically effective amount of A or B may also be administered to a human in need of treatment.

Disorders that may be treated by the compounds prepared by the process of the present invention include, but are not limited to, depression, major depressive disorder, bipolar disorder, long term fatigue disorder, seasonal affective disorder, agoraphobia, general anxiety disorder, phobic anxiety disorder, Obsessive Compulsive Disorder (OCD), panic disorder, acute stress disorder, social phobia, fibromyalgia, neuropathic pain, post-traumatic stress disorder, premenstrual syndrome, menopause, and andropause.

In addition to beneficial therapeutic effects, the compounds prepared by the methods of the present invention may provide additional benefits to avoid or reduce one or more side effects associated with conventional treatment of psychiatric disorders. These side effects include, for example, insomnia, breast pain, weight gain, extrapyramidal symptoms, elevated serum prolactin levels, and sexual dysfunction (including decreased libido, ejaculatory dysfunction, and anorgasmia).

The compounds (and mixtures thereof) prepared by the methods of the present invention are also effective in treating disruptive behavior disorders such as Attention Deficit Disorder (ADD) and attention deficit/hyperactivity disorder (ADHD) having, for example, DSM-IV-TR^TMThe art-accepted meanings are provided. These disorders are defined as affecting the behavior of a person, resulting in inappropriate behavior in learning and social environments. Although most occur in childhood, destructive behavioral disorders may also occur in adulthood.

The term "treating" when used in connection with the above disorders refers to ameliorating, preventing or alleviating the symptoms and/or effects associated with these disorders and includes prophylactic administration of a compound of formula a or B, mixtures thereof or pharmaceutically acceptable salts thereof, to substantially reduce the likelihood or severity of the disease.

Pure compounds and mixtures prepared by the process of the invention are also effective in the treatment of eating disorders. Eating disorders are defined as disorders of a person's appetite or eating habits or inappropriate bodily form appearance. Eating disorders include, but are not limited to, anorexia nervosa; bulimia nervosa, obesity, and cachexia.

The compounds and compositions of the present invention may be used to treat affective disorders, such as depression, for example dysthymic disorder or major depressive disorder; bipolar disorders such as bipolar I disorder, bipolar II disorder, and cyclothymic disorder; affective disorders due to general medical conditions with depressive and/or manic features; and substance-induced affective disorders.

Anxiety disorders such as acute stress disorder, agoraphobia without a history of panic disorder, general medical condition-induced anxiety disorder, general anxiety disorder, obsessive compulsive disorder, phobic disorder with agoraphobia, phobic disorder without open-field phobia, post-traumatic stress disorder, specific phobia, social phobia, and substance-induced anxiety disorder may be treated using the compounds and compositions of the present invention.

The compounds and mixtures prepared by the methods of the invention are also effective in treating brain dysfunction. The term brain dysfunction as used herein includes brain dysfunction associated with intellectual deficit, and may be exemplified by senile dementia, dementia of the alzheimer type, memory loss, amnestic/amnestic syndrome, epilepsy, disturbance of consciousness, coma, attentiveness reduction, language disorders, parkinson's disease and autism.

The compounds and mixtures are also useful in the treatment of schizophrenia and other psychotic disorders, such as stress, turbulence, delusional, residual or schizophrenic schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; shared mental disorder; psychotic disorder with delusions and/or hallucinations caused by general medical conditions.

The compounds of formulae a and B may also be effective in treating sexual dysfunction in both men and women. Such types of disorders include, for example, erectile dysfunction and orgasmic disorders associated with clitoral disorders.

The compounds and mixtures prepared by the methods of the present invention may also be used to treat substance abuse including, for example, cocaine, heroin, nicotine, alcohol, anxiolytic and hypnotic drugs, cannabis (indian cannabis), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrite addiction. Nicotine addiction includes all known forms of nicotine addiction, e.g., nicotine addiction resulting from cigarette, cigar and/or pipe smoking, andaddiction caused by tobacco chewing. In this regard, due to their activity as norepinephrine and dopamine uptake inhibitors, the compounds of the present invention may function to reduce nicotine-stimulated addiction. Bupropion (A), (B) and (C)GlaxoSmithKline, Research Triangle Park, n.c., USA) is a compound that is active at both norepinephrine and dopamine receptors and is currently used in the united states for smoking cessation therapy. However, as a benefit over the therapeutic activity of bupropion, the compounds of the present invention provide an additional 5-hydroxytryptamine energy component.

Pure compounds and mixtures prepared by the process of the invention are also effective in preventing migraine.

The compounds and mixtures prepared by the process of the invention may also be used to treat pain disorders including, for example, fibromyalgia, chronic pain, and neuropathic pain. The term "fibromyalgia" describes several diseases, all characterized by pain and stiffness of soft tissues including muscles, tendons and ligaments. Various alternative terms of fibromyalgia disease used in the past include systemic fibromyalgia, primary fibromyalgia syndrome, secondary fibromyalgia syndrome, localized fibromyalgia, and myofascial pain syndrome. Previously, these diseases were collectively referred to as fibrositis or fibromyositis syndrome. Neuropathic pain is thought to be caused by abnormal conditions of the nerve, spinal cord or brain, including but not limited to: burns and stinging sensations, hypersensitivity to contact and cold, phantom limb pain, post-herpetic neuralgia, and chronic pain syndromes (including, for example, sympathetically reflex dystrophy and causalgia).

The size of the prophylactic or therapeutic dose of a compound of formula a, B or mixtures thereof will vary with the nature and severity of the condition to be treated and the route of administration. The dosage and possibly the frequency of administration will also vary according to the age, weight and response of the individual patient. Generally, the total daily dose of the compounds of the present invention ranges from about 1 mg/day to about 500 mg/day, preferably from about 1 mg/day to about 200 mg/day, in a single dose or in multiple doses. It is also within the scope of the invention that the dosage of the compounds of the invention be less than 1 mg/day.

Any suitable route of administration may be used. For example, oral, rectal, intranasal, and parenteral (including subcutaneous, intramuscular, and intravenous) routes may be used. Dosage forms may include tablets, troches, dispersions, suspensions, solutions, capsules and patches.

The pharmaceutical compositions of the invention comprise as active ingredient a single compound of formula a or B or a mixture thereof, or a pharmaceutically acceptable salt of a or B, and a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients.

The pharmaceutically acceptable carrier may take a wide variety of forms depending on the desired route of administration, e.g., oral or parenteral (including intravenous). In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycerol, oils, alcohols, flavoring agents, preservatives and coloring agents in the case of oral liquid preparations including suspensions, elixirs, solutions. In the case of oral solid preparations such as powders, capsules and lozenges, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents may be used. Solid oral formulations are preferred over liquid formulations. Preferred solid oral formulations are tablets or capsules because of their ease of administration. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques. Oral and parenteral sustained release dosage forms may also be used.

Exemplary formulations are well known to those skilled in the art, and methods for preparing them may be found in any standard textbook OF the pharmaceutical sciences, such as Remington, THE SCIENCE and PRACTIICE OF PHARMACY, 21st Ed., Lippincott.

Thus, as shown herein, the invention is illustrated by the following aspects and embodiments.

A process for converting an oxime to an enamide. The method comprises the following steps: (a) contacting an oxime with a phosphine and an acyl donor under conditions suitable to convert the oxime into an enamide.

The method according to the previous paragraph, wherein the oxime has the formula:

wherein R is¹、R²And R³Is a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl. R¹、R²And R³Are optionally linked to form a ring system selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

The method according to any preceding paragraph, wherein the oxime has the formula:

wherein Ar is a member selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. R⁴Is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl; and, the label a is an integer selected from 1 to 4.

The process according to any of the preceding paragraphs, wherein R is⁴Is a substituted or unsubstituted aryl group.

The process according to any of the preceding paragraphs, wherein R is⁴Is a substituted or unsubstituted phenyl group.

A method according to any preceding paragraphProcess in which R⁴Is phenyl substituted by at least one halogen.

The process according to any of the preceding paragraphs, wherein R is⁴Having the formula:

wherein X¹And X²Are independently selected halogen moieties.

The method according to any of the preceding paragraphs, wherein X¹And X²Respectively chlorine.

The method according to any preceding paragraph, wherein Ar is substituted or unsubstituted phenyl.

The method according to any preceding paragraph, wherein the oxime has the formula:

the method according to any preceding paragraph, wherein the acyl donor has the formula: Z-C (O) -R⁵Wherein Z is a leaving group. R⁵Is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl.

The method according to any preceding paragraph, wherein Z has the formula:

R⁶-C(O)-O-

wherein R is⁶Is a member selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl.

According to any of the preceding claimsThe method of paragraph wherein R⁵And R⁶Are all independently selected from substituted or unsubstituted C₁-C₄And (4) partial.

The process according to any preceding paragraph, wherein the phosphine has the formula:

P(Q)₃

wherein each Q is a member independently selected from H, substituted or unsubstituted alkyl, and substituted or unsubstituted aryl.

The method according to any preceding paragraph, wherein each Q is independently selected from substituted or unsubstituted C₁-C₆A member of an alkyl group.

The method according to any preceding paragraph, wherein the contacting is in a solution comprising an aprotic solvent.

The process according to any preceding paragraph, wherein the aprotic solvent is an aromatic solvent.

The process according to any one of the preceding paragraphs, wherein the aprotic aromatic solvent is selected from the group consisting of toluene, xylene, and combinations thereof.

The method according to any preceding paragraph, wherein the enamide has the formula:

the method according to any preceding paragraph, wherein C-4 has a configuration selected from R, S and mixtures thereof.

The method according to any preceding paragraph, wherein C-4 is in the S configuration.

The method according to any of the preceding paragraphs, further comprising: (b) contacting the enamide formed in step (a) with a hydrogenation catalyst and hydrogen or a hydrogen transfer agent under conditions suitable to hydrogenate the carbon-carbon double bond of the enamide, thereby converting the enamide to an amide.

The process according to any preceding paragraph, wherein the catalyst is a chiral catalyst.

The process according to any preceding paragraph, wherein the chiral catalyst is a complex of a transition metal and a chiral phosphine ligand.

The process according to any preceding paragraph, wherein the amide is a racemic or chiral amide.

The method according to any preceding paragraph, wherein the amide has the formula:

the method according to any one of the preceding paragraphs, wherein C-1 and C-4 have a configuration independently selected from R and S.

The method according to any preceding paragraph, wherein C-1 is in the R configuration; and C-4 is in the S configuration.

The method according to any of the preceding paragraphs, further comprising: (c) reacting an amide with a deacylating agent in a suitable deamidating-HNC (O) R⁵Under conditions such that an amine is formed.

The method according to any of the preceding paragraphs, comprising: (d) isolating the amine.

The method according to any one of the preceding paragraphs, wherein the separating comprises selective crystallization.

The method according to any preceding paragraph, wherein the amine has the formula:

wherein Q^-Is an anion; and e is 0 to 1.

A method according to any preceding claim, wherein C-1 and C-4 have a configuration independently selected from R and S.

A process according to any preceding claim, wherein C-1 is in the R configuration; and C-4 is in the S configuration.

An oxime having the formula

A process for converting to an enamide having the formula:

wherein R is⁴Selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. R⁵Selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl. The method comprises the following steps: (a) contacting an oxime with a phosphine and an acyl donor under conditions suitable to convert the oxime into an enamide.

The method according to the preceding paragraph, wherein C-4 is in the S configuration.

The process according to the preceding paragraph, wherein the phosphine is a trialkylphosphine.

The method according to the preceding paragraph, wherein the oxime, acyl donor and phosphine are dissolved in an aromatic solvent.

The method according to the preceding paragraph, wherein the acyl donor is an alkyl anhydride.

The method according to the preceding paragraph, comprising: (b) contacting the enamide formed in step (a) with a chiral hydrogenation catalyst and hydrogen under conditions suitable to hydrogenate the carbon-carbon double bond attached to the c (o) of the enamide, thereby converting the enamide to an amide having the formula:

wherein C-1 has a configuration selected from R and S.

The process according to the preceding paragraph, wherein the chiral catalyst comprises rhodium complexed with a chiral phosphine ligand.

The method according to the preceding paragraph, further comprising: (c) reacting an amide with a deacylating agent in a suitable deamidating-HNC (O) R⁵Under conditions such that an amine having the formula:

wherein Q^-Is an anion; and the flag e is 0 or 1.

The method according to the preceding paragraph, wherein the deacylating agent is an enzyme.

The method according to the preceding paragraph, wherein the deacylating agent is an acid.

A mixture, comprising:

wherein R is⁴Is a member selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; q^-Is an anion; the labels e and f are numbers independently selected from 0 to 1; and x and y are selected from R and S such that when x is R, y is R, and when x is S, y is S.

The mixture according to the preceding paragraph, wherein A is present in the mixture in diastereomeric excess of at least 90% relative to B.

The mixture according to the preceding paragraph, wherein A is present in the mixture in diastereomeric excess of at least 98% relative to B.

The mixture according to the preceding paragraph, wherein x and y are R.

The mixture according to the preceding paragraph, wherein x and y are S.

Mixtures according to the preceding paragraph, wherein R⁴Is a substituted or unsubstituted phenyl group.

A pharmaceutical formulation comprising a mixture according to the preceding paragraph.

The following examples are provided to illustrate selected embodiments of the present invention and should not be construed as limiting the scope thereof.

Examples

Example 1:synthesis of N- ((S) -4- (3, 4-dichlorophenyl) -3, 4-dihydronaphthalen-1-yl) acetamide (3)

1.1. Synthesis of oxime 2

A suspension formed from a mixture of (S) -tetralone 1(56.0g, 0.192mol), hydroxylamine hydrochloride (14.7g, 0.212mol) and sodium acetate (17.4g, 0.212mol) in methanol (168mL) was placed in N₂Heated to reflux at atmospheric pressure for 1 to 5 hours. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was diluted with toluene (400mL) and 200mL of water. The organic layer was separated and washed with 200mL of water. The organic layer was concentrated and dried to give crude solid oxime 2(58.9g, 100%) m.p.117-120 ℃.

¹H NMR(400MHz，CDCl₃)δ(ppm)9.17(br，1H，OH)，7.98(m，1H)，7.36(d，1H，J=8.0Hz)，7.29(m，2H)，7.20(d，1H，J=2.4Hz)，6.91(m，2H)，4.11(dd，1H，J=7.2Hz，4.4Hz)，2.82(m，2H)，2.21(m，1H)，2.08(m，1H)。¹³C NMR(100MHz，CDCl₃)δ154.94，144.41，140.40，132.83，130.92，130.82，130.68，130.64，129.98，129.38，128.12，127.64，124.48，44.52，29.51，21.27。

1.2. Synthesis of enamides 3

A solution of crude oxime 2(59g, 0.193mol) in toluene (500mL) was dissolved in N₂Rinsing for 30 minutes. Et was added₃P (25g, 0.212 mol). After stirring for 10 minutes, acetic anhydride (21.6g, 20mL, 0.212mol) was added. The reaction mixture was refluxed for 8 to 13 hours. The progress of the reaction was monitored by HPLC. The reaction mixture was cooled to room temperature. 6N NaOH (aq) (86mL, 0.516mol) and 1.0M (n-Bu) were added₄NOH in methanol (1.0 mL). The hydrolysis is completed in about 2 to 4 hours. The organic layer was separated and diluted with EtOAc (300mL) and 2-BuOH (30 mL). The diluted organic solution was washed with 1% hoac (aq) solution (300mL) and DI water (3x300mL) and concentrated in vacuo to a slurry of about 350 mL. The slurry was diluted with heptane (100mL) and 2-BuOH (4mL) and heated to reflux to form a clear solution. Heptane (50 to 200mL) was added slowly until a cloudy solution formed. The suspension was slowly cooled to room temperature. The product was filtered off, washed with 30% toluene and 70% heptane (3X100mL) solution and dried in a vacuum oven to give 56.9g of a white solid (enamide 3, 89% yield), m.p.167-168 ℃.

(S) -tetralone 1(50.Og, 0.172mol) was stirred in methanol (150mL) with hydroxylamine hydrochloride (13.1g, 0.189mol) and sodium acetate (15.5g, 0.189 mol). The resulting suspension was heated to reflux under an inert atmosphere for 2 to 6 hours and the progress was monitored by HPLC. Upon completion, the mixture was cooled to 25 ℃, diluted with toluene (300mL) and quenched with 1.7N NaOH (100 mL). The mixture was concentrated under reduced pressure in vacuo to remove the aqueous layer and the organic layer was rewashed with DI water (100 mL). Additional toluene (300mL) was charged to the vessel and water was removed by azeotropic distillation. At ambient temperature, n-Bu₃P (47.1mL, 0.183mol) was charged to the reactor followed by acetic anhydride (32.5mL, 0.344 mol). The reaction was heated to reflux and monitored by HPLC. After 20-24 hours, the reaction was cooled to ambient temperature and stopped with 6N NaOH (120 mL). The mixture was allowed to react for 2 to 6 hours, and then the aqueous layer was removed. The organic layer was washed with DI water (100 mL). Vacuum concentratingThe mixture was cooled to room temperature, diluted with isopropanol (50mL), and heptane was added to aid crystallization. After the initial addition of heptane (50mL), an additional 650mL was added. The slurry was aged, then filtered, washed (4x100mL heptane) and dried to give a light yellow solid (enamide 3, 44.1g, 77%).

¹H NMR(400MHz，CDCl₃) δ (ppm)7.35(d, 1H, J =8.4Hz), 7.26(m, 3H), 7.17(m, 1H), 7.05(dd, 1H, J =8.0, 1.6Hz), 7.00(br, 1H), 6.87(m, 0.82H, 82% NH rotamer), 6.80(br, 0.18H, 18% NH rotamer), 6.31(t, 0.82H, J =4.8Hz, 82% H rotamer), 5.91(br, 0.18H, 18% H rotamer), 4.12(br, 0.18H, 18% H rotamer), 4.03(t, 0.82H, J =8.0Hz, 82% H rotamer), 2.72(m, 1H), 2.61(ddd, 1H, J =16.8, 8.0, 4.8, 2.82H, 2.46 s, 2.46H, 17 Hz), 2.46% H (CH, 17H, 17 Hz), 2.17H, 18% H rotamer)₃Rotamers), 1.95(s, 0.54H, 18% CH)₃Rotamers). 100MHz¹³C NMR(CDCl₃)δ169.3，143.8，137.7，132.3，131.8，131.4，130.5，130.3，130.2，128.8，128.1，127.8，127.2，123.8，122.5，121.2，117.5，42.6，30.3，24.1。

Example 2:synthesis of N- ((1R,4S) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) acetamide (4)

The enamide 3(24g, 72mmol) was stirred in degassed isopropanol (200 mL). The resulting slurry is transferred to a suitable reactor. The contents of the reactor were flushed with nitrogen before the catalyst solution was added. Mixing (R, R) -MeB PE (COD) RhBF₄A solution of catalyst (20.1mg, 0.036mmol, 0.05mol%) in Isopropanol (IPA) (100mL) was added to the reactor. The contents were cooled to 0 ℃ and flushed 3 times with nitrogen. The reactor was then flushed with hydrogen and pressurized to 90 psig. The reaction was allowed to complete by stirring at 0 ℃ for 7.5 hours and the transition was monitored by hydrogen uptake. The contents were then warmed to room temperature and the hydrogen vented. After washing with nitrogen, the contents were discharged. The reaction mixture was heated to 50 ℃ and filtered through a celite pad. The clear orange solution was concentrated to-50% volume (150mL) anddiluted with toluene (5.9g, 5 wt%). The suspension was heated to 65 ℃ and water (14.7mL) was added dropwise to form a cloudy solution. The slurry was slowly cooled to-10 ℃ and aged for 30 minutes. The solid was filtered and washed with cold IPA (2x45 mL). The cake was dried under vacuum at 45 deg.C overnight to give 20.0g (83% yield) of trans-acetamide 4 (R-acetamide)>99%de)。.

¹H NMR(CDCl₃)400MHzδ7.34(dd，2H，J=7.9，2.4Hz)，7.23(t，1H，J=7.5Hz)，7.15(m，2H)，6.85(dd，1H，J=8.2，2.0Hz)，6.82(d，1H，J=7.7Hz)，5.72(d，1H，J=8.4Hz)，5.31(dd，1H，J=13.2，8.1Hz)，4.10(dd，1H，J=7.0，5.9Hz)，2.17(m，2H)，2.06(s，3H)，1.87(m，1H)，1.72(m，1H)；¹³C NMR(CDCl₃)100MHzδ169.7，146.9，138.8，137.7，132.6，130.8，130.6，130.5，130.3，128.4，128.3，127.9，127.4，47.9，44.9，30.5，28.4，23.8。

Example 3:synthesis of hydrochloride of (1R,4S) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydronaphthalen-1-amine (5)

A solution of trans-acetamide 4(9.0g, 26.9mmol), n-propanol (45mL) and 5M hydrochloric acid (45mL) was refluxed for about 48 hours (90-93 deg.C). During this time, the reaction temperature was maintained at ≥ 90 ℃ by timed collection of the distillate until the reaction temperature was >92 ℃. Additional n-propanol was added periodically to maintain the solution at the initial volume. After hydrolysis was complete, the solution was slowly cooled to 0 ℃ to produce a slurry, which was aged at 0 ℃ for 1 hour. The reaction mixture was filtered and washed with 1: the cake was washed with 1 methanol/water (20mL) and then with t-butyl methyl ether (20 mL). The wet cake was dried under vacuum at 45 to 50 ℃ to give 7.0g of the amine hydrochloride 5(80% yield).

¹U NMR(DMSO-d₆)δ1.81-1.93(m，2H)，2.12-2.21(m，1H)，2.28-2.36(m，1H)，4.28(t，1H，J=6.8)，4.59(br.s，1H)，6.84(d，1H，J=7.6)，7.05(dd，1H，J=8.4，1.6)，7.25(t，1H，J=7.6)，7.32(t，1H，J=7.6)，7.37(d，1H，J=1.6)，7.56(d，1H，J=8.4)，7.76(d，1H，J=7.2)，8.80(br.s，3H)；¹³C NMR(DMSO-d₆)147.4，138.9，133.6，131.0，130.5，130.4，130.1，129.0，128.9，128.4，128.2，126.8，47.9，43.1，27.8，25.2。

Example 4:in situ oxime formation/acylation

The oxime 2 is acylated in situ to give intermediate 2A, which is reductively acylated to give a mixture of acylated enamide 3 and diacylated analog 3A. The reaction is carried out in toluene or o-xylene at reflux. The mixture of 3 and 3A is then treated with an aqueous solution of a base such as sodium hydroxide or sodium carbonate, with or without a phase transfer catalyst (e.g., tetrabutylammonium hydrogen sulfate/hydroxide), to convert intermediate 3A to the desired enamide 3. Exemplary reaction conditions for converting oxime 2 to enamide 3 are shown in schemes 3a and 3 b.

Example 5:using (R, S, R, S) -MePenn PhOs (COD) RhBF₄Catalytic asymmetric hydrogenation of enamides 3 as catalysts

As shown in scheme 4, in the presence of a chiral catalyst, H₂And subjecting enamide 3 to a homogeneous catalytic asymmetric hydrogenation in the presence of a solvent. In this example, the catalyst was derived from the transition metal rhodium with a chiral phosphine ligand (1R,2S,4R,5S) -P, P-1, 2-phenylenedi { (2, 5-endo-dimethyl) -7-phosphobicyclo [2.2.1]Heptane } (R, S, R, S-mepinnphos). The hydrogenation is carried out at a substrate concentration of compound 3 of about 0.12M to about 0.24M.

Scheme 4

Example 6:using (R, R) -MeBPE Rh(COD)BF₄Catalytic asymmetric hydrogenation of enamides 3 as catalysts

As shown in scheme 5, in the presence of a chiral catalyst, H₂And subjecting enamide 3 to a homogeneous catalytic asymmetric hydrogenation in the presence of a solvent. In this example, the catalyst is derived from a complex of transition metal rhodium with a chiral phosphine ligand (R, R) -1, 2-bis (2, 5-dimethylphosphino) ethane (R, R-MeBPE). The hydrogenation is carried out at a concentration of substrate 3 of about 0.12M to about 0.24M.

Scheme 5

Example 7:(R,R)-Norphos(COD)RH-BF₄catalytic asymmetric hydrogenation

A slurry of (S) -vinylamide, N- ((S) -4- (3, 4-dichlorophenyl) -3, 4-dihydronaphthalen-1-yl) acetamide (60.4g, 0.18mol) in isopropanol (595.0g) was flushed with oxygen under a vacuum/nitrogen cycle. The homogeneous catalyst precursor (also referred to as "catalyst"), (R, R) -Norphos (COD) RH-BF₄Methanol (34.6mg, 0.025mol%, 0.53mL) was added to the solution to prepare a solution. After flushing the system several times with hydrogen, the vessel was filled with hydrogen at the desired reaction pressure (about 7 bar). The mixture was stirred at 25 ℃ and the progress of the reaction was monitored by hydrogen uptake. When the reaction was judged to be complete (hydrogen uptake and HPLC), the pressure was released and the system was flushed repeatedly with nitrogen. The pale yellow slurry was diluted with isopropanol (194.7g), dissolved by heating (65 ℃) and triturated filtered. The mixture was heated to reflux to dissolve all solids. The solution was slowly cooled to 60-65 ℃ during which time the product crystallized. The anti-solvent-water (262g) was added at about 60-65 deg.C, and the mixture was cooled to 0 deg.C for 2 hours and aged while maintaining that temperature. The light colored solid was filtered and then washed with cold isopropanol (2 × 61 g). The off-white solid was dried under reduced pressure at 50-55 ℃ to give 99% de of (1R,4S) -acetamide (56.6g, 93% yield).

Example 8:formation of oximes and enamides

Chiral (4S) -tetralone (100.0g, 0.34mol) was reacted with hydroxylamine hydrochloride (28.7g, 0.41mol) and sodium acetate (33.8g, 0.41mol) in toluene (1.37L) at 103 ℃ for about 2 hours. The water in the reaction mixture was removed by azeotropic distillation. The reaction was stopped at 25 ℃ with 2N sodium hydroxide (167.0 g). The aqueous phase was separated and the organic phase was washed 1 time with water (400.0 g). Toluene (700.0g) was added, and the resulting oxime-containing organic solution was dried by azeotropic distillation under reduced pressure to a desired reaction concentration. Triethylphosphine (89.0g, 0.38mol, 50wt% in toluene) was added followed by acetic anhydride (38.5g, 0.38mol) to give an oxime acetate intermediate. The reaction mixture was allowed to react at reflux (112-. The reaction mixture was cooled to 20-25 ℃ and a small amount of the by-product of the alkenimide was hydrolyzed (to vinyl amide) with 6N sodium hydroxide (210g) and the phase transfer agent tert-butylammonium hydroxide (5.0 g). The biphasic mixture was phase separated and the aqueous phase was purged. The organic phase was washed with 0.5% aqueous acetic acid (67 ℃, 600.0 g). The aqueous phase was removed and the organic phase was washed 1 time with water (67 ℃, 600.0g) to remove the inorganic salts. The organic phase was concentrated and the hot solution was polish filtered to remove additional inorganic salts. Heptane (150g) and 2-butanol (7.0g) were added and the slurry was heated to 100 ℃ to achieve dissolution. The solution was cooled to about 85 ℃ to start crystallization. To the slurry was added further heptane (190g) at 85 ℃ and the mixture was cooled to 0 ℃. The slurry was aged at 0 ℃ for 15 minutes, then filtered and washed 3 times with a solution consisting of heptane and toluene (125 g). The product was dried under vacuum at 35-45 ℃. 17.8g (89% yield) of (S) -vinylamide as a white crystalline solid were recovered.

The method according to this example can be used for a large number of substrates, the results of which are shown in Table 1.

TABLE-1: oximes and enamides thus prepared

Example 9:deprotection of amides

A solution of (1R,4S) -acetamide in anhydrous THF (212.7g, 239.3mL) was treated with anhydrous pyridine (8.7g, 8.9mL, 110 mmol). The resulting clear colorless solution was cooled to about 0 ℃. Oxalyl chloride (12.9g, 8.9mL, 101.6mmol) was added to the stirred solution, with careful control of CO and CO₂Exothermic and effervescent. Simultaneously with the addition of the activating reagent, a slurry is formed. The slurry was cooled with stirring for a short period of time (about 15 minutes) and then sampled for transformation characterization. When the reaction was complete, anhydrous propylene glycol was added to the reaction, resulting in a small exotherm. The reaction was heated to 25 ℃, during which time the color and consistency of the slurry changed. HPLC analysis of the second sample indicated the reaction was complete and 1-propanol (96.9g, 120.5mL) was then added. 6N HCl (128.0g, 120.0mL) was added. The mixture was heated to effect dissolution, and the resulting mixture was polish filtered. THF was removed by atmospheric distillation. After concentrating the mixture, it was slowly cooled to 3 ℃. The resulting light colored slurry was filtered to give an off-white cake. The cake was first washed with 17wt% n-PrOH in deionized water (72.6g, 75mL total) and then with cold mtBE (55.5g, 75 mL). The off-white wet cake was dried under vacuum at 45-50 ℃. The product recovered is of good purity (>99% purity, HPLC) as an off-white to white solid (24.8g, 84.1% yield).

All publications and patent documents cited in this application are herein incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent document were individually indicated. Although various references are cited herein, applicants do not admit that any particular reference is "prior art" to their invention.

Claims (51)

1. A method of converting an oxime to an enamide, the method comprising:

(a) contacting the oxime with a phosphine and an acyl donor under conditions suitable to convert the oxime into the enamide.

2. The method according to claim 1, wherein the oxime has the formula:

wherein

R¹、R²And R³Is a member independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl, R¹、R²And R³Are optionally linked to form a ring system selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

3. The method according to claim 1, wherein the oxime has the formula:

wherein

Ar is a member selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

R⁴is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl;

and a is an integer selected from 1 to 4.

4. A process according to claim 3, wherein R is⁴Is a substituted or unsubstituted aryl group.

5. The method according to claim 4, wherein R⁴Is a substituted or unsubstituted phenyl group.

6. The method according to claim 5, wherein R⁴Is phenyl substituted by at least one halogen.

7. The method according to claim 6, wherein R⁴Having the formula:

wherein

X¹And X²Are independently selected halogen moieties.

8. The method according to claim 7, wherein X¹And X²Each is chlorine.

9. A method according to claim 3 wherein Ar is substituted or unsubstituted phenyl.

10. The method according to claim 9, said oxime having the formula:

11. the method according to claim 1, wherein the acyl donor has the formula:

Z-C(O)-R⁵

wherein

Z is a leaving group; and

R⁵is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl.

12. The method according to claim 11, wherein Z has the formula:

R⁶-C(O)-O-

wherein

R⁶Is selected from substituted orOne member of unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl.

13. The method according to claim 12, wherein R⁵And R⁶Are all independently selected from substituted or unsubstituted C₁-C₄And (4) partial.

14. The process according to claim 1, wherein the phosphine has the formula:

P(Q)₃

wherein

Each Q is a member independently selected from H, substituted or unsubstituted alkyl, and substituted or unsubstituted aryl.

15. The method according to claim 14, wherein each Q is independently selected from substituted or unsubstituted C₁-C₆A member of an alkyl group.

16. The method according to claim 1, wherein said contacting is in a solution comprising an aprotic solvent.

17. The method according to claim 16, wherein the aprotic solvent is an aromatic solvent.

18. The process according to claim 17, wherein the aprotic aromatic solvent is selected from the group consisting of toluene, xylene, and combinations thereof.

19. The method according to claim 15, wherein the enamide has the formula:

20. the method of claim 19, wherein C-4 has a configuration selected from the group consisting of R, S and mixtures thereof.

21. The method according to claim 20, wherein C-4 is in the S configuration.

22. The method of claim 1, further comprising:

(b) contacting said enamide formed in step (a) with a hydrogenation catalyst and hydrogen or a hydrogen transfer agent under conditions suitable to hydrogenate the carbon-carbon double bond of said enamide, thereby converting said enamide to an amide.

23. The process according to claim 22, wherein the catalyst is a chiral catalyst.

24. The process according to claim 23, wherein the chiral catalyst is a complex of a transition metal and a chiral phosphine ligand.

25. The method according to claim 22, wherein the amide is a racemic or chiral amide.

26. The method according to claim 22, wherein the amide has the formula:

27. the method according to claim 26, wherein C-1 and C-4 have a configuration independently selected from R and S.

28. The method of claim 27, wherein

C-1 is the R configuration; and

c-4 is in the S configuration.

29. The method of claim 22, further comprising:

(c) reacting said amide with a deacylating agent in a solvent suitable for deacylating said amide-HNC (O) R⁵Under conditions such that an amine is formed.

30. The method of claim 29, further comprising:

(d) isolating the amine.

31. The method according to claim 30, wherein said separating comprises selective crystallization.

32. The method of claim 29, wherein the amine has the formula:

wherein

Q^-Is an anion; and

e is 0 to 1.

33. The method according to claim 32, wherein C-1 and C-4 have a configuration independently selected from R and S.

34. The method of claim 33, wherein

C-1 is the R configuration; and

c-4 is in the S configuration.

35. An oxime having the formula

A process for converting to an enamide having the formula:

wherein

R⁴Selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; and

R⁵selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl,

the method comprises the following steps:

(a) contacting the oxime with a phosphine and an acyl donor under conditions suitable to convert the oxime into the enamide.

36. The method according to claim 35, wherein C-4 is in the S configuration.

37. The method according to claim 34, wherein the phosphine is a trialkylphosphine.

38. The method according to claim 35, wherein said oxime, said acyl donor and said phosphine are dissolved in an aromatic solvent.

39. The method according to claim 35, wherein the acyl donor is an alkyl anhydride.

40. The method of claim 35, further comprising:

(b) contacting the enamide formed in step (a) with a chiral hydrogenation catalyst and hydrogen under conditions suitable to hydrogenate the carbon-carbon double bond attached to the c (o) of the enamide, thereby converting the enamide to an amide having the formula:

wherein

C-1 has a configuration selected from R and S.

41. The process according to claim 40, wherein the chiral catalyst comprises rhodium complexed with a chiral phosphine ligand.

42. The method of claim 40, further comprising:

(c) reacting said amide with a deacylating agent in a solvent suitable for deacylating said amide-HNC (O) R⁵Under conditions such that an amine having the formula:

wherein

Q^-Is an anion; and

e is 0 or 1.

43. The method according to claim 42, wherein the deacylating agent is an enzyme.

44. The method according to claim 42, wherein the deacylating agent is an acid.

45. A mixture, comprising:

wherein

R⁴Is a member selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

Q^-is an anion;

e and f are independently selected from the group consisting of numbers 0 to 1; and

x and y are selected from R and S such that when x is R, y is R, and when x is S, y is S.

46. The mixture according to claim 45, wherein A is present in said mixture in diastereomeric excess of at least 90% relative to B.

47. Mixture according to claim 46, in which A is present in said mixture in a diastereomeric excess of at least 98% relative to B

48. The mixture according to claim 45, wherein x and y are R.

49. The mixture according to claim 45, wherein x and y are S.

50. The mixture according to claim 45, wherein x is S and y is R.

51. A pharmaceutical formulation comprising a mixture according to claim 45 and a pharmaceutically acceptable carrier.