WO2008097483A2 - Methods for preparing aryl-substituted ketophosphonates - Google Patents

Abstract

Methods are provided for the synthesis of aryl-substituted ketophosphonates of the Formula (I): wherein variables are as described herein. Such compounds are useful as reagents for olefination reactions, and as intermediates in the synthesis of certain biologically active agents.

Description

METHODS FOR PREPARING ARYL-SUBSTITUTED KETOPHOSPHONATES

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application 60/899,236, filed

February 2, 2007, and U.S. Provisional Application 60/950,285, filed July 17, 2007, which provisional applications are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates generally to methods for synthesizing aryl-substituted ketophosphonates, which are generally useful as biologically active molecules and as intermediates in organic syntheses.

BACKGROUND OF THE INVENTION

Aryl-substituted ketophosphonates are intermediates in the synthesis of a variety of compounds. For example, aryl-substituted ketophosphonates are reagents in the Horner- Wadsworth-Emmons (HWE) olefϊnation reaction {see, e.g., Maryanoff and Reitz (1989) Chem. Rev. 59:863-927), which is used in numerous synthetic protocols, including in the synthesis of certain biologically active molecules. Certain aryl-substituted ketophosphonates have also been reported to have bone anabolic activity {see, e.g., WO 2004/026245) or to function as thyroid receptor ligands {see, e.g., US 2006/0046980).

Existing methods for the synthesis of aryl-substituted ketophosphonates include the acylation of a benzoic acid ester (or chloride) with a lithiated phosphonate (Corey and Kwiatkowski (1966) J. Am. Chem. Soc. 55:5654), the reaction of a trialkyl phosphite with an α- haloacetophenone (often referred to as an Arbuzov or Michaelis-Arbuzov reaction), and the reaction of a dialkyl chlorophosphate with a dilithiated derivative of an α-bromo ketone (Sampson et al. (1986) J. Org. Chem. 51Α342-41). All of these reactions require extreme temperatures. Another such method involves the reaction of a lithiated chloromethylphosphonate with a benzaldehyde followed by treatment of the intermediate species with a second equivalent of base to afford the β-aryl-β-ketophosphonate (P. Savignac (1978) Synthesis 682-684). Only a limited number of substituted β-ketophosphonates can be prepared by the rearrangement of a vinylphosphate, and attempts to extend this methodology to vinylphosphates derived from acetophenones resulted in alkyne formation as a result of the more preferred phosphate elimination (Calogeropoulou et al. (1987) J. Org. Chem. 52:4185-90). Aryl-β-ketophosphonates have been synthesized from phosphonoacetic acids. In the one case, the dianion derived from diethylphosphonoacetic acid is allowed to react with benzoyl chlorides. The intermediate then undergoes a decarboxylation upon warming to yield, after aqueous workup, the desired β-aryl-β- ketophosphonate (D. Kim (1997) Bull. Korean Chem. Soc. 7S(3):339-41). A variation of this chemistry utilizes in situ prepared trimethylsilyl diethylphosphonoacetete (Kim et al. (1997) J. Chem. Soc, Perkin Trans. 7: 1361-63). Finally, indole substituted ketophosphonates have been prepared by reaction with diethylphosphonoacetic acid and acetic anhydride at 100 ⁰C (Slatt et al (2005) /. Heterocyclic Chem. ¥2:141-45).

These existing methods for aryl-substituted ketophosphonate synthesis suffer from significant disadvantages. In each case, the range of aromatic substrates is limited {e.g., many of these reactions require that the aromatic substrate already possess some acyl functionality). In addition, many require extreme temperatures and will not tolerate the presence of a variety of functionalities, such as unprotected alcohols and esters.

Accordingly, there is a need in the art for improved methods for synthesizing aryl- substituted ketophosphonates. The present invention fulfills this need, and provides further related advantages.

SUMMARY OF THE INVENTION

In certain aspects, the present invention provides methods for synthesizing aryl- substituted ketophosphonates of Formula I:

O O o

Λ l l ,^K1 M_Γ Y'^^V? Formula I

R₂ wherein: Ar is an optionally substituted aryl or heteroaryl moiety; preferably Ar is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, each of which is optionally substituted and each of which is preferably substituted with from 0 to 7 substituents independently chosen from:

(a) halogen, hydroxy, cyano, amino, nitro, -COOH, aminocarbonyl and aminosulfonyl; (b) C,-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, (C₃-C₈cycloalkyl)Co-C₄alkyl, C,-C₈haloalkyl, C₁-

C₈alkoxy, C_rC₈haloalkoxy, C_rC_galkylthio, Ci-C₈alkylsulfinylCo-C₄alkyl, C₂-C₈alkyl ether, Ci-C₈alkoxycarbonyl, Ci-C₈alkylsulfonylCo-C₄alkyl, mono- or di-(Ci- C₈alkyl)aminoCo-C₄alkyl, Ci-CsalkylsulfonylaminoCo-Qalkyl, mono- or di-(C_r C₈alkyl)aminosulfonylC₀-C₄alkyl, mono- or di-(CrC₈alkyl)aminocarbonylCo-C₄alkyl, phenylCo-C₄alkyl, (4- to 8-membered heterocycle)C₀-C₄alkyl and (4- to 8-membered heterocycle)Ci-C₄alkoxy; each of which is optionally substituted and each of which is preferably substituted with from 0 to 6 substituents independently chosen from R₃; (c) groups that are taken together to form a fused 5- or 6-membered carbocycle or heterocycle that is optionally substituted and is preferably substituted with from 0 to 3 substituents independently chosen from R₃; and

(d) groups that are taken together with a substituent of Y to form a fused, optionally substituted C₄-C₇cycloalkyl;

Y is C_rC₃alkylene or C₂-C₃alkylene ether, each of which is optionally substituted and is preferably substituted with from 0 to 2 substituents independently chosen from:

(a) halogen, hydroxy and amino;

(b) Ci-C₄alkyl, Ci-C₄alkanoyl, mono- or di-(Ci-C₄alkyl)amino and phenylCi-C₃alkyl, each of which is optionally substituted and each of which is preferably substituted with from 0 to

3 substituents independently chosen from R₃;

(c) groups that are taken together to form an optionally substituted C₃-C₆cycloalkyl; and

(d) groups that are taken together with a substituent of Ar to form a fused 4- to 7-membered cycloalkyl or heterocycloalkyl ring that is substituted with oxo; Ri and R₂ are independently chosen from optionally substituted C|-C₆alkyl, or Ri and R₂ are taken together to form an optionally substituted 4- to 7-membered heterocycloalkyl; preferably, Ri and R₂ are substituted with from 0 to 6 substituents independently chosen from R₃; and Each R₃ is independently chosen from oxo, halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl, -COOH, Ci-Cβalkyl, C|-C₆hydroxyalkyl, Ci-C₆haloalkyl, Q- C₆alkoxy, Ci-C₆haloalkoxy, C₂-C₆hydroxyalkoxy, C₂-C₆alkyl ether, Ci-C₆alkylthio, C_r

C^alkoxycarbonyl, Ci-C₆alkanoyl, Q-Cβalkanoyloxy, CVCβalkanone, mono- or di-(Cp C₆alkyl)amino, Ci-C₆alkylsulfonyl, mono- or di-(C₁-C₆alkyl)aminosulfonyl, and mono- or di- (C) -C₆alkyl)aminocarbonyl; the methods comprising the step of reacting: (a) Ar-H; with

(b) a di-alkoxy phosphoryl alkanoic acid of Formula II:

O O

JL _^ R-OR₁ Formula II

^{H0 Y} W in the presence of a perfluoroalkanoic anhydride (such as trifluoroacetic anhydride) and phosphoric acid.

These and other aspects of the present invention will become apparent upon reference to the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention provides compounds and methods useful for synthesizing aryl-substituted ketophosphonates of Formula I. TERMINOLOGY

Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise specified) all of the optical isomers and mixtures thereof are encompassed. In addition, compounds with carbon- carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. Where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms. Compound descriptions are intended to encompass compounds with all possible isotopes of atoms occurring in the compounds. Isotopes are those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include ¹¹C, ¹³C and ¹⁴C. Certain compounds are described herein using a general formula that includes variables (e.g., Ar, n, Ri). Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. In general, the variables may have any definition described herein that results in a stable compound.

The term "aryl-substituted ketophosphonate" refers to any compound that satisfies Formula I, or is a salt or hydrate of such a compound. Suitable salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids or phosphonate groups. Specific pharmaceutically acceptable anions for use in salt formation include, but are not limited to, acetate, 2-acetoxybenzoate, ascorbate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, carbonate, chloride, citrate, dihydrochloride, diphosphate, edetate, estolate (ethylsuccinate), formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, hydroxymaleate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methylbromide, methylnitrate, methylsulfate, mucate, nitrate, pamoate, pantothenate, phenylacetate, phosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfamate, sulfanilate, sulfate, sulfonates including besylate (benzenesulfonate), camsylate (camphorsulfonate), edisylate (ethane- 1,2-disulfonate), esylate (ethanesulfonate) 2-hydroxyethylsulfonate, mesylate (methanesulfonate), napsylate, triflate (trifluoromethanesulfonate) and tosylate (p-toluenesulfonate), tannate, tartrate, teoclate and triethiodide. Similarly, pharmaceutically acceptable cations for use in salt formation include, but are not limited to ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, and metals such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Those of ordinary skill in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein. In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, methanol, isopropanol or acetonitrile, is preferred.

As used herein, the term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon. Alkyl groups include groups having from 1 to 8 carbon atoms (Q-Cgalkyl), from 1 to 6 carbon atoms (Ci-Cβalkyl) and from 1 to 4 carbon atoms (Ci-C₄alkyl), such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-buty\, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2- hexyl, 3-hexyl and 3-methylpentyl. "C₀-C_nalkyl" refers to a single covalent bond (C₀) or an alkyl group having from 1 to n carbon atoms; for example "Co-C₄alkyl" refers to a single covalent bond or a Ci-C₄alkyl group. In some instances, one or more substituents of an alkyl group are specifically indicated. For example, "CrC₆hydroxyalkyl" refers to a C_rC₆alkyl group that has at least one hydroxy substituent. "Alkylene" refers to a divalent alkyl group, as defined above. C₀-C₄alkylene is a single covalent bond (Co) or an alkylene group having from 1 to 4 carbon atoms.

"Alkenyl" refers to straight or branched chain alkene groups, which comprise at least one unsaturated carbon-carbon double bond. Alkenyl groups include C₂-C₈alkenyl, C₂-C₆alkenyl and C₂-C₄alkenyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively, such as ethenyl, allyl or isopropenyl. "Alkynyl" refers to straight or branched chain alkyne groups, which have one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond. Alkynyl groups include C₂-C₈alkynyl, C₂-C₆alkynyl and C₂-C₄alkynyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.

A "cycloalkyl" is a group that comprises one or more rings, each of which is saturated and/or partially saturated, and each of which has only carbon ring members. Representative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and partially saturated variants of the foregoing, such as cyclohexenyl. Cycloalkyl groups do not comprise an aromatic ring or a heterocyclic ring. Certain cycloalkyl groups are C₃- Cgcycloalkyl, in which the cycloalkyl group contains a single ring having from 3 to 8 ring members, all of which are carbon. A "(C₃-Cgcycloalkyl)Co-C₄alkyl" is a C₃-C₈cycloalkyl group linked via a single covalent bond or a Ci-C₄alkylene group.

By "alkoxy," as used herein, is meant an alkyl group as described above attached via an oxygen bridge. Alkoxy groups include Ci-C₈alkoxy and Ci-C₆alkoxy groups, which have from 1 to 8 or from 1 to 6 carbon atoms, respectively. Methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, 5ec-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2- hexoxy, 3-hexoxy, and 3-methylpentoxy are representative alkoxy groups. "C₂- C₆hydroxyalkoxy" refers to a C₂-C₆alkoxy moiety that is substituted with one or more hydroxy groups.

Similarly, "alkylthio" refers to an alkyl group as described above attached via a sulfur bridge. Ci-Cgalkylthio has from 1 to 8 carbon atoms in the alkyl portion. The term "oxo," as used herein refers to an oxygen substituent of a carbon atom that results in the formation of a keto or aldehyde group (C=O). An oxo group that is a substituent of a nonaromatic carbon atom results in a conversion of -CH₂- to -C(=O)-.

The term "alkanoyl" refers to an acyl group (e.g., -(C=O)-alkyl), in which carbon atoms are in a linear or branched alkyl arrangement and where attachment is through the carbon of the keto group. Alkanoyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms. For example a C₂alkanoyl group is an acetyl group having the formula -(C=O)CH₃. Alkanoyl groups include, for example, C₂-

Cgalkanoyl, C₂-C₆alkanoyl and C₂-C₄alkanoyl groups, which have from 2 to 8, from 2 to 6 or from

2 to 4 carbon atoms, respectively. "C i alkanoyl" refers to -(C=O)H, which (along with C₂- Cgalkanoyl) is encompassed by the term "Ci -Cgalkanoyl."

An "alkanone" is a ketone moiety in which carbon atoms are in a linear or branched alkyl arrangement. "C₃-C₆alkanone" refers to an alkanone having from 3 to 6 carbon atoms. A C₃alkanone group has the structure -CH₂-(C=O)-CH₃.

Similarly, "alkyl ether" refers to a linear or branched ether substituent (i.e., an alkyl group that is substituted with an alkoxy group). Alkyl ether groups include C₂-Cgalkyl ether, C₂-C₆alkyl ether and C₂-C₄alkyl ether groups, which have 2 to 8, 6 or 4 carbon atoms, respectively. A C₂alkyl ether has the structure -CH₂-O-CH₃.

"Alkylene ether" refers to a divalent alkyl ether group. "C₂-C₃alkylene ether" groups include, for example, -CH₂-O-CH₂-, -CH₂-O-CH₂-CH₂-, CH₂-CH₂-O-CH₂-, -CH₂-O- CH(CH₃)- and -CH(CH₃)-O-CH₂-.

The term "alkoxycarbonyl" refers to an alkoxy group attached through a keto (-(C=O)-) bridge (i.e., a group having the general structure -C(=O)-O-alkyl). Alkoxycarbonyl groups include Ci-Cg, Ci-C₆ and Ci-C₄alkoxycarbonyl groups, which have from 1 to 8, 6 or 4 carbon atoms, respectively, in the alkyl portion of the group (i.e., the carbon of the keto bridge is not included in the indicated number of carbon atoms). "Ci alkoxycarbonyl" refers to -C(=0)-O- CH₃; Qalkoxycarbonyl indicates -C(=O>-O-(CH₂)₂CH₃ or -C(=O)-O-(CH)(CH₃)₂.

"Alkanoyloxy," as used herein, refers to an alkanoyl group linked via an oxygen bridge (i.e., a group having the general structure -O-C(=O)-alkyl). Alkanoyloxy groups include C₂-C₈, C₂-C₆ and C₂-C₄alkanoyloxy groups, which have from 2 to 8, 6 or 4 carbon atoms, respectively. For example, "C₂alkanoyloxy" refers to -O-C(=O)-CH₃.

"Alkylsulfonyl" refers to groups of the formula -(SO₂)-alkyl, in which the sulfur atom is the point of attachment. Alkylsulfonyl groups include Ci-Cgalkylsulfonyl and C]-C₆alkylsulfonyl groups, which have from 1 to 8 or from 1 to 6 carbon atoms, respectively. "(Ci- C₈alkylsulfonyl)C₀-C₄alkyl" is a Ci-C₈alkylsulfonyl group that is linked via a single covalent bond or via a C_rC₄alkylene group.

"Alkylsulfinyl" refers to groups of the formula -(SO)-alkyl, in which the sulfur atom is the point of attachment. Alkylsulfinyl groups include Ci-Cgalkylsulfϊnyl and Ci-Csalkylsulfϊnyl groups, which have from 1 to 8 or from 1 to 6 carbon atoms, respectively.

The term "aminocarbonyl" refers to an amide group (i.e., -(C=O)NH₂)- The term "mono- or di-(Ci-Cgalkyl)aminocarbonyl" refers to groups of the formula -(C=O)-N(R)₂, in which the carbonyl is the point of attachment, one R is Cj-Cgalkyl and the other R is hydrogen or an independently chosen CpCgalkyl.

"Mono- or di-(Ci-C₈alkyl)aminocarbonylCo-C₄alkyl" is an aminocarbonyl group in which one or both of the hydrogen atoms is replaced with Q-Cgalkyl, and which is linked via a single covalent bond (i.e., mono- or di-(Ci-C₈alkyl)aminocarbonyl) or a Ci-C₄alkylene group (i.e., -(Ci- C₄alkyl)-(C=O)N(Ci-C₈alkyl)₂). If both hydrogen atoms are so replaced, the Q-Cgalkyl groups may be the same or different.

"Aminosulfonyl" refers to groups of the formula -(SO₂)-NH₂, in which the sulfur atom is the point of attachment. The term "mono- or di-(Ci-C₈alkyl)aminosulfonyl" refers to groups that satisfy the formula -(SO₂)-NR₂, in which the sulfur atom is the point of attachment, and in which one R is Ci-Cgalkyl and the other R is hydrogen or an independently chosen Ci-Cgalkyl. "Mono- or di-(Ci-Cgalkyl)aminosulfonylCo-C₄alkyl" is an aminosulfonyl group in which one or both of the hydrogen atoms is replaced with Q-Cgalkyl, and which is linked via a single covalent bond (i.e., mono- or di-(Ci-Cgalkyl)aminosulfonyl) or a Ci-C₄alkylene group (i.e., -(d- C₄alkyl)-( SO₂)N(Ci-C₈alkyl)₂). If both hydrogen atoms are so replaced, the Q-Cgalkyl groups may be the same or different. "Alkylamino" refers to a secondary or tertiary amine that has the general structure -NH- alkyl or -N(alkyl)(alkyl), wherein each alkyl is selected independently from alkyl, cycloalkyl and (cycloalkyl)alkyl groups. Such groups include, for example, mono- and di-(Ci-C₈alkyl)amino groups, in which each C_rC₈alkyl may be the same or different, as well as mono- and di-(C_r CβalkyOamino groups and mono- and di-(C]-C₄alkyl)amino groups. "Alkylaminoalkyl" refers to an alkylamino group linked via an alkylene group (i.e., a group having the general structure -alkylene-NH-alkyl or -alkylene-N(alkyl)(alkyl)) in which each alkyl is selected independently from alkyl, cycloalkyl and (cycloalkyl)alkyl groups. Alkylaminoalkyl groups include, for example, mono- and di-(Ci-C₈alkyl)aminoCi-C₄alkyl. "Mono- or di-(Ci-Cgalkyl)aminoCo-C₄alkyl" refers to a mono- or di-(Ci-Cgalkyl)amino group linked via a single covalent bond or a C]-C₄alkylene group. The following are representative alkylaminoalkyl groups:

It will be apparent that the definition of "alkyl" as used in the terms "alkylamino" and "alkylaminoalkyl" differs from the definition of "alkyl" used for all other alkyl-containing groups, in the inclusion of cycloalkyl and (cycloalkyl)alkyl groups (e.g., (C₃-C₇cycloalkyl)Co-C₆alkyl). The term "halogen" refers to fluorine, chlorine, bromine or iodine.

A "haloalkyl" is an alkyl group that is substituted with 1 or more independently chosen halogens (e.g., "Ci-C₈haloalkyl" groups have from 1 to 8 carbon atoms; "Ci-C₆haloalkyl" groups have from 1 to 6 carbon atoms). Examples of haloalkyl groups include, but are not limited to, mono-, di- or tri-fluoromethyl; mono-, di- or tri-chloromethyl; mono-, di-, tri-, tetra- or penta- fluoroethyl; mono-, di-, tri-, tetra- or penta-chloroethyl; and 1,2,2,2-tetrafluoro-l-trifluoromethyl- ethyl. Typical haloalkyl groups are trifluoromethyl and difluoromethyl. Similarly, the term "haloalkoxy" refers to a haloalkyl group as defined above attached via an oxygen bridge. "Ci- C₈haloalkoxy" groups have 1 to 8 carbon atoms.

A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH₂ is attached through the carbon atom.

A "carbocycle" or "carbocyclic group" comprises at least one ring formed entirely by carbon-carbon bonds (referred to herein as a carbocyclic ring), and does not contain a heterocycle. Unless otherwise specified, each ring within a carbocycle may be independently saturated, partially saturated or aromatic, and is optionally substituted as indicated. A carbocycle generally has from 1 to 3 fused, pendant or spiro rings; carbocycles within certain embodiments have one ring or two fused rings. Typically, each ring contains from 3 to 8 ring members (i.e., C₃-Cg); C₅- C₇ rings are recited in certain embodiments. Carbocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members. Certain carbocycles are C₆-Ci₀ (i.e., contain from 6 to 10 ring members, and one or two rings). Certain representative carbocycles are cycloalkyl as described above. Other carbocycles are aryl (i.e., contain at least one aromatic carbocyclic ring, with or without one or more additional aromatic and/or cycloalkyl rings). Such aryl carbocycles include, for example, phenyl, naphthyl (e.g., 1-naphthyl and 2-naphthyl), fluorenyl, indanyl and 1,2,3,4-tetrahydronaphthyl. In Formula I, the aryl moiety "Ar" is attached to the carbonyl via an aromatic ring carbon atom. Certain carbocycles recited herein are phenyl Co-C₄alkyl groups (i.e., groups in which a phenyl group is linked via a single covalent bond or a d-C₄alkylene group). Such groups include, for example, benzyl, 1 -phenyl -ethyl, 1 -phenyl -propyl and 2-phenyl-ethyl).

A "heterocycle" or "heterocyclic group" has from 1 to 3 fused, pendant or spiro rings, at least one of which is a heterocyclic ring (i.e., one or more ring atoms is a heteroatom independently chosen from O, S and N, with the remaining ring atoms being carbon). Additional rings, if present, may be heterocyclic or carbocyclic. Typically, a heterocyclic ring comprises 1, 2, 3 or 4 heteroatoms; within certain embodiments each heterocyclic ring has 1 or 2 heteroatoms per ring. Each heterocyclic ring generally contains from 4 to 8 ring members (rings having 5 or 6 ring members are recited in certain embodiments) and heterocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members. Certain heterocycles comprise a sulfur atom as a ring member; in certain embodiments, the sulfur atom is oxidized to SO or SO₂. Heterocycles may be optionally substituted with a variety of substituents, as indicated. Unless otherwise specified, a heterocycle may be a heterocycloalkyl group (i.e., each ring is saturated or partially saturated) or a heteroaryl group (i.e., at least one ring within the group is aromatic), such as a 5- to 10-membered heteroaryl (which may be monocyclic or bicyclic) or a 6-membered heteroaryl (e.g., pyridyl or pyrimidyl). N-linked heterocyclic groups are linked via a component nitrogen atom.

Heterocyclic groups include, for example, azepanyl, azocinyl, benzimidazolyl, benzimidazolinyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzothiazolyl, benztetrazolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, dihydroisoquinolinyl, dihydrotetrahydrofuranyl, 1 ,4-dioxa-8-aza-spiro[4.5]decyl, dithiazinyl, furanyl, furazanyl, imidazolinyl, imidazolidinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isothiazolyl, isoxazolyl, isoquinolinyl, moφholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, oxazolidinyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoimidazolyl, pyridooxazolyl, pyridothiazolyl, pyridyl, pyrimidyl, pyrrolidinyl, pyrrolidonyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiadiazinyl, thiadiazolyl, thiazolyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, thiophenyl, thiomoφholinyl and variants thereof in which the sulfur atom is oxidized, triazinyl, and any of the foregoing that are substituted with from 1 to 4 substituents as described above.

A "(4- to 8-membered heterocycle)Co-C₄alkyl" is a 4- to 8-membered heterocyclic group linked via a single covalent bond or Ci-C₄alkylene group. Similarly, a "(4- to 8-membered heterocycle)Co-C₄alkoxy" is a 4- to 8-membered heterocyclic group linked via an oxygen bridge or a C_rC₄alkoxy moiety.

A "substiruent," as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a ring substituent may be a moiety such as a halogen, alkyl group, haloalkyl group or other group that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member. Substituents of aromatic groups are generally covalently bonded to a ring carbon atom. The term "substitution" refers to replacing a hydrogen atom in a molecular structure with a substituent, such that the valence on the designated atom is not exceeded, and such that a chemically stable compound (i.e., a compound that can be isolated, characterized, and tested for biological activity) results from the substitution.

Groups that are "optionally substituted" are unsubstituted or are substituted by other than hydrogen at one or more available positions, typically 1, 2, 3, 4 or 5 positions, by one or more suitable groups (which may be the same or different). Optional substitution is also indicated by the phrase "substituted with from 0 to X substituents," where X is the maximum number of possible substituents. Certain optionally substituted groups are substituted with from 0 to 2, 3 or

4 independently selected substituents (i.e., are unsubstituted or substituted with up to the recited maximum number of substitutents). It will be apparent that optionally substituted groups may be substituted with any substituent(s), provided that the resulting compound is stable and is suitable for the synthetic reactions described herein. Preferred optional substituents are recited in certain embodiments.

SYNTHESIS OF ARYL-SUBSTITUTED KETOPHOSPHONATES

Starting materials for the methods provided herein are commercially available from suppliers such as Sigma-Aldrich Corp. (St. Louis, MO), or may be synthesized from commercially available precursors using well known protocols. The following Schemes illustrate certain embodiments of the present invention, and are intended to be exemplary only, and nonlimiting. It will be apparent that the methods provided herein may be combined with other methods known in the art to generate further embodiments. Each variable in the following schemes refers to any group consistent with the description of the compounds provided herein. Scheme I illustrates the synthesis of aryl-substituted ketophosphonates of Formula I.

Scheme I

^{0 0} R ^{0 0} R

Ar-H ₊ HO^ΛYΥ ¹ AΛY'Y ' ii *² i *

Within Scheme I, aryl-substituted ketophosphonate I is synthesized from aromatic moiety Ar-H and dialkylphosphonoalkanoic acid II, both of which are generally commercially available or readily prepared using well known procedures. Scheme II illustrates the preparation of various representative dialkylphosphonoalkanoic acids II using standard techniques. Scheme II

(82%)

O O aq NaOH (1.0 equiv) O O ► P_x-OEt

^EtO T OEt then HCI HO \ OEt Me

(>95%) Me

Ar is generally any aryl or heteroaryl group; typically Ar is a 5- to 10-membered aryl or heteroaryl, optionally substituted as described above. In certain embodiments, the reaction shown in Scheme I is an intramolecular reaction in which Ar is covalently linked to Y. If desired, reactive functional groups present on Ar may be protected (e.g., using standard techniques); however, in general, such protection is not required. The variable "Y" is Q-C₃alkylene that is optionally substituted as described above. Representative "Y" moieties include methylene that is optionally substituted with methyl. Representative R] and R₂ groups include, for example, Q- C₄alkyl and Q-C₄haloalkyl, such as methyl, ethyl, and halogenated methyl and ethyl groups.

Briefly, Ar-H is initially incubated with a perfluoroalkanoic anhydride (i.e., the anhydride of a perfluoroalkanoic carboxylic acid, e.g., trifluoroacetic anhydride (TFAA)), the dialkylphosphonoalkanoic acid II and phosphoric acid (e.g., 85 weight percent in water) to generate the aryl-substituted ketophosphonate I. In certain embodiments, one molar equivalent of Ar-H is incubated with at least one molar equivalent of the perfluoroalkanoic anhydride and at least one molar equivalent of II; the TFAA and II may be added simultaneously or sequentially in either order. At least 0.1 molar equivalent (with about 1 molar equivalent in certain embodiments) of phosphoric acid is typically used in this reaction - the phosphoric acid may be added before, after or simultaneously with the perfluoroalkanoic anhydride and II. In certain embodiments, the reaction is performed by first charging the reaction vessel with TFAA, then adding Ar-H, followed by II and then the phosphoric acid.

In certain embodiments, the minimum amount of the perfluoroalkanoic anhydride is determined by the amount of dialkylphosphonoalkanoic acid II (n) and the amount of phosphoric acid (x), according to the equation: moles of perfluoroalkanoic anhydride = n + 3x

By way of example, if 1.0 molar equivalent of II and 1.0 molar equivalent of H₃PO₄ are used, the minimum amount of the perfluoroalkanoic anhydride is preferably 4.0 molar equivalents. In certain embodiments, reactions are performed using 1.2 molar equivalents of II and H₃PO₄; in such cases, the amount of the perfluoroalkanoic anhydride is preferably at least 4.8 molar equivalents. In other embodiments, the reaction is performed using about 1 molar equivalent of II and 0.1 or 0.2 molar equivalents Of H₃PO₄. In such reactions, it is often convenient to use more the perfluoroalkanoic anhydride than the calculated minimum about (e.g., about 3 molar equivalents of the perfluoroalkanoic anhydride), with moderate heating (e.g., to about 50 ⁰C). Typically, the initial amount of the perfluoroalkanoic anhydride (i.e., the amount present at the start of the reaction) is at least one molar equivalent (e.g., from 1 to 10 molar equivalents, preferably from about 4 to about 5 molar equivalents), relative to the moles of dialkylphosponoalkanoic acid. In certain embodiments, the perfluoroalkanoic anhydride is added prior to II, and the reaction time in the presence of the perfluoroalkanoic anhydride and prior to the addition of II, is at least 10 minutes (e.g., 10-60 minutes). In certain embodiments, the reaction time prior to the addition of phosphoric acid (e.g., 0.1 - 10 molar equivalents, preferably 0.5-2 molar equivalents), is at least about 10 minutes (e.g., 10-60 minutes). Following the addition of phosphoric acid, the reaction is typically stirred (e.g., for 1 hour to 2 days, with 10-20 hours preferred for certain embodiments), resulting in the slow formation of aryl-substituted ketophosphonate I.

In certain embodiments, the H₃PO₄ is initially present (i.e., at the start of the reaction) in an amount ranging from 0.1 to 0.3 molar equivalents, relative to the initial amount of dialkylphosphonoalkanoic acid, and the perfluoroalkanoic anhydride is initially present in an amount ranging from 1.3 to 5 molar equivalents, relative to the initial amount of dialkylphosphonoalkanoic acid.

In other embodiments, the H₃PO₄ is initially present in an amount ranging from 1.0 to 1.5 molar equivalents, relative to the initial amount of dialkylphosphonoalkanoic acid, and the perfluoroalkanoic anhydride is initially present in an amount ranging from 4 to 5 molar equivalents, relative to the initial amount of dialkylphosphonoalkanoic acid. As noted above, such reactions are preferably performed with moderate heating.

Reactions may be performed in the presence or absence of organic solvent. Suitable solvents include, for example, nitromethane and acetonitrile. Within certain embodiments, such reactions are performed in the absence of solvent. Reaction temperatures may vary (e.g., below 80 ⁰C, from 0 to 72 ⁰C, preferably from 0 to 50 ⁰C, in certain embodiments from 0 to 40 ⁰C), with temperatures at or below room temperature (or below 25 ⁰C) preferred in certain situations.

Further purification of aryl-substituted ketophosphonate I may be achieved by standard methods. Within certain embodiments, such purification includes the steps of:

(i) adjusting the pH of the reaction mixture to a basic pH {e.g., by diluting the reaction mixture with water and adjusting to a pH ranging from about 7 to 9, preferably from about 8 to 9, with an aqueous solution of NaOH);

(ii) extracting the pH-adjusted reaction mixture with an organic solvent (e.g., an ethereal solvent such as methyl tertiary butyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran or dimethoxyethane; dichloromethane; toluene; or an alkyl acetate) to yield an organic phase and an aqueous phase;

(iii) extracting the organic phase with an aqueous solution of an inorganic base (e.g., NaOH, such as 1 N NaOH) to yield a second organic phase and a second aqueous phase;

(iv) adjusting the pH of the second aqueous phase to an acidic pH (e.g., with concentrated

HCl);

(v) extracting the pH-adjusted second aqueous phase with an organic solvent (e.g., an ethereal solvent, dichloromethane, toluene, or an alkyl acetate) to yield a third organic phase and a third aqueous phase; and

(vi) concentrating the third organic phase to yield the aryl-substituted ketophosphonate I.

The methods provided herein for synthesizing aryl-substituted ketophosphonates represent a substantial improvement over existing methods, which require that the aromatic substrate initially possess some acyl functionality, which is then further functionalized to provide the targeted ketophosphonate. This is not a prerequisite for the present methods. In addition, the present methods may be performed under mild conditions (e.g., at a temperature ranging from 0

⁰C to 40 ⁰C) and using starting materials with functionalities that may not be tolerated in other synthetic methods (e.g., unprotected alcohols, esters, etc.). These improvements provide clear advantages over previously described methods for the synthesis of aryl-substituted ketophosphonates.

Aryl-substituted ketophosphonates that may be synthesized using the methods provided herein generally satisfy Formula I. Within certain embodiments, the variable Ar is phenyl that is substituted with from 0 to 5 substituents independently chosen from (i) hydroxy, halogen and amino; and (ii) Ci-C₆alkyl, Ci-Cδhaloalkyl, Ci-C₆alkoxy, mono- or di-(Ci-C₆alkyl)amino and phenyl; each of which is further substituted with from 0 to 3 substituents independently chosen from oxo, hydroxy, halogen, amino, Ci-C₆alkyl, Ci-C₅haloalkyl, Ci-C₆alkylsulfonyl, C_r C₆alkylsulfonylamino, Ci-C₆alkylsulfonyloxy, C_rC₆alkoxycarbonyl and mono- or di-(C_r C₆alkyl)amino. Representative Ar moieties include, for example, phenyl that is fused to a 5- or 6- membered heterocycle, wherein each phenyl and heterocycle is substituted with from 0 to 3

substituents independently chosen from Ci-C₆alkyl, Ci-C₆alkoxy and phenyl; and

The variable Y, in certain embodiments, is methylene. Certain representative Ri and R₂ groups include methyl and ethyl. Representative aryl-substituted ketophosphonates that are prepared as described herein further satisfy one of the following formulas:

wherein m is an integer typically ranging from 2 to 6.

USE OF ARYL-SUBSTITUTED KETOPHOSPHONATES

Aryl-substituted ketophosphonates prepared as described herein may be used in a variety of subsequent reactions, including Horner-Wadsworth-Emmons (HWE) olefination reactions in which an α,β-unsaturated aryl-substituted ketone is formed by the reaction of a β-aryl-β- ketophosphonate with an aldehyde or ketone in the presence of base:

R^a = H, alkyl, halogen

Certain representative olefination reactions are provided as Examples herein. Olefins generated from aryl-substituted ketophosphonates find use, for example, in the synthesis of certain melanin concentrating hormone (MCH) receptor antagonists of the Formula:

in which Ar₁ and Ar₂ are independently chosen optionally substituted 6- to 10-membered aryl groups. The use of such MCH receptor antagonists is described, for example, in published US patent application US 2006/0009456 and in US Patent Number 6,953,801 , which are hereby incorporated by reference for their teaching of methods for using MCH receptor antagonists that satisfy the above formula.

Briefly, such MCH receptor antagonists are prepared from an aryl-substituted ketophosphonate as illustrated in Scheme III:

Scheme III

reductive cyclization acid RH

Within Scheme III, the protected intermediate 2 is readily prepared from 2-(piperazin-2- yl)ethanol. PGi and PG₂ are the same or different, and are independently hydrogen or any protecting group known in the art including benzyl, BOC and benzyloxycarbonyl, any of which may be optionally substituted. The addition of such groups to the piperazine ring of 2-(piperazin- 2-yl)ethanol may be achieved using standard techniques. The synthesis of 3 is conveniently performed by reacting a molar equivalent of each of I, 2, LiCl, and i-Pr₂NEt in aqueous CH₃CN at room temperature. Removal of CH₃CN (e.g., by distillation), extraction with i-PrOAc, washing the organic layer with base (e.g., IN aqueous NaOH), acid (e.g., 1 H aqueous HCl) and brine, and concentration of the aqueous layer yields 3.

The next step encompasses reductive cyclization and optional salt formation. If 3 is non- racemic, and PGi is CBz, the cyclization takes place without racemization. A suitable cyclization is a hydrogenation reaction, which may employ any of a variety of well known catalysts such as, but not limited to, Pd(OH)₂/C, Pd/C, Raney nickel and any of the known platinum catalysts. Suitable conditions include, for example, Pd(OH)₂/C, 50 psi H₂ for 1-5 hours. Alternatively, a catalytic transfer hydrogenation reaction may be used, typically employing a hydrogen donor such as ammonium formate and a palladium or nickel catalyst. The cyclized intermediate 4 may be used directly in the synthesis of 5 or 6 if desired, or it may be convenient to prepare a salt, using standard techniques, prior to subsequent reactions. Compound 5 is synthesized using any activated acid (e.g., X may be a halogen such as Cl, or a peptide coupling agent). In the preparation of 6, L is typically a halogen or other leaving group such as a sulfonate ester (e.g., triflate or mesylate), a boronic acid or a boronic acid ester.

The following Examples are offered by way of illustration and not by way of limitation. Unless otherwise specified, all reagents and solvent are of standard commercial grade and are used without further purification. Starting materials are available from commercial suppliers, such as Sigma-Aldrich (St. Louis, MO), or are synthesized using procedures that are known in the art.

EXAMPLES

NMR

¹H NMR spectra are obtained on either a Varian 300 (300 MHz) Mercury Plus or Varian 400

(400 MHz) Mercury Plus spectrometer as noted.

¹³C NMR spectra are obtained on a Varian 400 (100.6 MHz) Mercury Plus spectrometer as noted.

³¹P NMR spectra are obtained on a Varian 300 (121.5 MHz, Η-decoupled) Mercury Plus spectrometer with H₃PO₄ (δp = 0.00 ppm) as an external standard.

ANALYTICAL LC/MS Mass spectroscopy in the following Examples is Electrospray MS, obtained in positive ion mode using a Waters ZMD II Mass Spectrometer (Waters Corp.; Milford, MA), equipped with a Waters 600 pump (Waters Corp.), Waters 996 photodiode array detector (Waters Corp.), and a Gilson 215 autosampler (Gilson, Inc.; Middleton, WI). MassLynx™ (Waters Corp.; Milford, MA) version 4.0 software with OpenLynx processing is used for data collection and analysis. MS conditions are: capillary voltage = 3.5 kV; cone voltage = 30 V, desolvation and source temperature = 25O⁰C and 100⁰C, respectively; mass range = 100-750 with a scan time of 0.75 seconds and an interscan delay of 0.15 seconds. LCMS conditions are as follows:

Column 4.6x30mm, XTerra MS Cl 8, 5μm or equivalent

UV 10 spectra/sec; 210 to 350nm scan range Extracted Wavelengths 220 and 254nm.

Flow rate 4.0 mL/min

Injection Volume 2-10μl

Standard Method:

Mobile phase A 95% Water, 5% Methanol with 0.05% Formic acid Mobile phase B 95% Methanol, 5% Water with 0.025% Formic acid

Gradient:

Time fmin) %B

0 5 0.01 5 2.0 100 3.50 100 3.51 5

Basic Method:

Mobile phase A: 95% Aqueous 1OmM Ammonium Formate, 5% Methanol

Mobile phase B: 95% Methanol, 5% Water with 0.025% Formic acid Gradient:

Time(min) %B 0 10

0.01 10 2.0 100 3.50 100 3.51 10

Analysis Time: 4 minutes.

Certain abbreviations used in the following Examples and elsewhere herein include

Ac acetyl aq aqueous

Bn benzyl

BOC teAt-butyloxycarbonyl

Bu butyl

Bz benzoyl

Cbz benzyloxycarbonyl

DCM dichloromethane

DMF dimethyl formamide eq equivalent(s)

Et ethyl h hour(s) i-Pr isopropyl

LCMS liquid chromatography-mass spectrometry min minute(s)

MTBE methyl tert-buty\ ether

NMR nuclear magnetic resonance rt room temperature

PG protecting group

TEMPO 2,2,6,6-tetramethyl-l -piperidinyloxy, free radical

TFAA trifluoracetic anhydride

THF tetrahydrofuran

TLC thin-layer chromatography

UV ultraviolet EXAMPLE 1. PREPARATION OF REPRESENTATIVE ARYL-SUBSTITUTED KETOPHOSPHONATES

This Example illustrates the synthesis of representative aryl-substituted ketophosphonates via the following method:

A 3-neck round bottom flask equipped with a mechanical stirrer and a thermocouple is charged with the aromatic substrate (1.0 eq). The flask is immersed in an ice/water bath, and TFAA (4.8 eq) is slowly added, maintaining the temperature below 25 ⁰C. After 10 min, diethylphosphonoacetic acid (1.2 eq) is added over a five minute period of time to the 20 ⁰C solution. The solution is stirred for a further 10 min, then phosphoric acid (85%, 1.2 eq) is added, a precipitate slowly forms, and the resulting mixture is stirred overnight.

The vessel is equipped with a distillation head and a heating mantel, and the volatiles are evaporated under reduced pressure (~30 mm Hg). Once distillation is complete the heating is discontinued, the flask is placed in an ice/water bath, and the residue is diluted with water (150 mL). Next, 10 N aq NaOH is slowly added until pH ~8 (by pH paper) is reached. The solution is then extracted twice with DCM. The combined DCM extracts are washed three times with 1 N aq NaOH. The combined NaOH washes are acidified to pH <2 with concentrated HCl and then extracted twice with DCM. The combined DCM extracts are washed with brine and evaporated to give the indicated ketophosphonate.

A. DIETHYL [2-(2,5-DIMETHOXYPHENYL)-2-OXOETHYL]PHOSPHONATE

Using the method described above, 1 ,4-dimethoxybenzene (8.00 g, 57.9 mmol), TFAA (38.6 mL, 278 mmol), diethylphosphonoacetic acid (11.76 mL, 69.5 mmol) and phosphoric acid (4.75 mL, 69.5 mmol) yields the title compound (12.71 g) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.26 (d, J = 1 Hz, IH), 7.07-7.03 (m, IH), 6.90 (d, J = 9.1 Hz, IH), 4.15-4.05 (m, 4H), 3.88 (s, 3H), 3.83 (d, J = 22.0 Hz, 2H), 3.78 (s, 3H), 1.27-1.23 (m, 6H). ¹³C NMR (100.6 MHz, CDCl₃) δ 193.15 (d, J = 7.6 Hz, 1C), 153.67, 153.52, 127.82, 121.42, 1 14.39, 1 13.33, 62.50 (d, J = 6.1 Hz, 1C), 56.32, 56.05, 42.00 (d, J = 130.5 Hz, 1C), 16.50 (d, J = 6.9 Hz, 1C). ³¹P NMR (121.5 MHz, CDCl₃) δ 22.47 (s). LCMS (Standard Method): 2.47 min; 317 (M+H)⁺. B. DIETHYL ^-O^-DIMETHOXYPHENYL^-OXOETHYLJPHOSPHONATE

Using the method described above, 1 ,2-dimethoxybenzene (8.00 g, 57.9 mmol), TFAA (38.6 mL, 278 mmol), diethylphosphonoacetic acid (11.76 mL, 69.5 mmol) and phosphoric acid (4.75 mL, 69.5 mmol) yields the title compound (8.24 g) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.64 (dd, J = 2.2, 8.5 Hz, IH), 7.55 (d, J = 2.2 Hz, IH), 6.89 (d, J = 8.5 Hz, IH), 4.18- 4.08 (m, 4H), 3.94 (s, 3H), 3.92 (s, 3H), 3.59 (d, J = 22.8 Hz, 2H), 1.28 (t, J = 7.0 Hz, 6H). ¹³C NMR (100.6 MHz, CDCl₃) δ 190.47 (d, J = 6.9Hz, 1C), 154.11 , 149.25, 129.91 , 124.68, 1 10.85, 1 10.17, 63.03 (d, J = 6.1 Hz, 2C), 56.34, 56.22, 38.31 (d, J = 130.5 Hz, 1C), 16.49 (2, J= 6.1 Hz, 2C). ³¹P NMR (121.5 MHz, CDCl₃) δ 21.71. LCMS (Standard Method): 2.28 min; 317 (M+H)⁺.

C. DIETHYL [2-(2-METHOXY-S-METHYLPHENYL)^-OXOETHYL]PHOSPHONATE

Using the method described above, 1 -methoxy-4-methylbenzene (1.26 mL, 10 mmol), TFAA (6.67 mL, 48 mmol), diethylphosphonoacetic acid (2.03 mL, 12 mmol) and phosphoric acid (0.82 mL, 12 mmol) yields 1.65 g of the title compound as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.50 (d, J = 2.2 Hz, IH), 7.29-7.25 (m, IH), 6.84 (d, J = 8.2 Hz, IH), 4.14-4.04 (m, 4H), 3.88 (s, 3H), 3.81 (d, J = 22 Hz, 2H), 2.28 (s, 3H), 1.24 (t, J = 7.2 Hz, 6H). ¹³C NMR (100.6 MHz, CDCl₃) δ 193.58 (d, J = 7.6 Hz, 1C), 157.00, 135.12, 131.35, 130.33, 111.77, 62.66 (d, J = 6.9 Hz, 1C), 55.88, 42.58 (d, J = 130.5 Hz, 1C), 20.42, 16.49 (d, J = 6.9 Hz, 1C). ³¹P NMR (121.5 MHz, CDCl₃) δ 22.73 (s). LCMS (Standard Method): 2.58 min; 301 (M+H)⁺.

EXAMPLE 2. PREPARATION OF ADDITIONAL REPRESENTATIVE ARYL-SUBSTITUTED KETOPHOSPHONATES

A. DIETHYL [2-(4-METHOXY-2,3-DIMETHYLPHENYL)-2-OXOETHYL]PHOSPHONATE

CH₃NO₂ A 50 mL round bottom flask is charged with diethylphosphonoacetic acid (0.98 g, 5.0 mmol), 2,3-dimethylanisole (0.68 g, 5.0 mmol), and nitromethane (10 mL) at rt. The solution is cooled to 0 ⁰C with stirring and then treated with TFAA (2.78 mL, 20.0 mmol) followed by 85% H₃PO₄ (0.58 g, 5.0 mmol). A deep pink-light purple color develops. The reaction mixture is allowed to gradually warm to rt and is stirred overnight. The reaction mixture is then diluted with water (40 mL) and extracted with EtOAc. The organic layer is washed with half-saturated aq NaHCO₃ (40 mL). The aqueous phase is still slightly acidic, so the organic phase is washed once more with half-saturated aq NaHCO₃ (40 mL). The aqueous layer is now slightly basic. The organic layer is finally washed with water (40 mL) and concentrated in vacuo to 1.47 g of a pale amber syrup. ¹H NMR analysis reveals a 14:1 ratio of para:ortho regioisomers. ¹H NMR (300 MHz, CDCl₃): δ 7.62 (d, J = 8.8 Hz, IH), 6.74 (d, J = 8.8 Hz, IH), 4.1 1 (pent, J = 7.1 Hz, 4H), 3.86 (s, 3H), 3.56 (d, J = 22.2 Hz, 2H), 2.40 (s, 3H), 2.16 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H) ppm. LCMS (Standard Method): 2.48 min; 315 (M+l), 337 (M+Na).

B. 2-{4-[(DlETHOXYPHOSPHORYL)ACETYL]-2,3-DIMETHYLPHENOXY} ETHYL BENZOATE

85% H₃PO₄ CH₃NO₂

A 500 mL round bottom flask equipped with a magnetic stir bar is charged with diethylphosphonoacetic acid (95%, 4.34 g, 21.0 mmol), nitromethane (40 mL), and 2-(2,3- dimethylphenoxy)ethyl benzoate (5.41 g, 20.0 mmol) at rt. The resulting solution is cooled to 0 ⁰C with stirring and treated with TFAA (1 1.1 mL, 80.0 mmol) followed by 85% H₃PO₄ (2.31 g, 20.0 mmol). The reaction mixture is allowed to slowly warm to rt and is then stirred at rt for 48 h. The dark purple reaction mixture is then concentrated in vacuo to remove the volatiles. The residue is diluted with water (50 mL), EtOAc, and saturated aq NaHCO₃ (50 mL) with stirring. The aqueous layer is still acidic, so additional saturated aq NaHCO₃ (25 mL) is added. The aqueous layer is slightly basic at this point. The mixture is stirred vigorously for 30 min and then extracted with EtOAc. The organic layer is washed with water (2 x 50 mL) and concentrated in vacuo to a syrup. ¹H NMR (300 MHz, CDCl₃): δ 8.05 (d, J = 7.2 Hz, 2H), 7.61 (d, J = 8.8 Hz, IH), 7.56 (d, J = 7.5 Hz, IH), 7.44 (t, J = 7.5 Hz, 2H), 6.77 (d, J = 8.8 Hz, IH), 4.71 (m, 2H), 4.34 (m, 2H), 4.1 1 (m, 4H), 3.55 (d, J = 22.6 Hz, 2H), 2.40 (s, 3H), 2.18 (s, 3H), 1.27 (t, J = 7.3 Hz, 6H) ppm. LCMS (Standard Method): 2.77 min; 449 (M+l), 471 (M+Na). C. DIMETHYL ^-^-^-HYDROXYETHOXY^.S-DIMETHYLPHENYL]^-

OXOETH YL} PHOSPHONATE

Step 1. Preparation of 2-(2,3-dimethylphenoxy)ethanol

2,3-Dimethylphenol (114.6 g, 0.938 mol) is added to DMF (anhydrous, 200 mL) under nitrogen followed by potassium carbonate (anhydrous, 19.4 g, 0.141 mol) and ethylene carbonate (86.7 g, 0.986 mol) at rt. The mixture is heated to 110-115 ⁰C. Carbon dioxide is released from the reaction mixture, and the bubbling continues for about 3 h. The reaction temperature is maintained at 115-120 ⁰C for an additional 14-16 h.

The reaction mixture is cooled to rt and poured into water (1.2 L) with efficient stirring. The precipitated solid is collected by filtration and rinsed with water four times. The wet solid is dried under nitrogen flow at 55 ⁰C in a vacuum oven until a constant weight is obtained. Yield: 128.5 g. ¹H NMR (300 MHz, CDCl₃): δ 7.05 (t, J = 8 Hz, IH), 6.81 (d, J = 7.4 Hz, IH), 6.72 (d, J = 8.3 Hz, IH), 4.07 (m, 2H), 3.98 (m, 2H), 2.28 (s, 3H), 2.17 (s, 3H), 2.05 (br t, IH) ppm. LCMS (Standard Method): 2.40 min; 167 (M+l), 189 (M+Na).

Step 2. Preparation of dimethyl {2-[4-(2-hydroxyethoxy)-2,3-dimethylphenyl^"l-2- oxoethyl } phosphonate

85% H₃PO₄

A 250 mL round bottomed flask equipped with a magnetic stir bar is charged with 2-(2,3- dimethylphenoxy)ethanol (8.31 g, 50 mmol) and then placed in an ice-water bath. Next, TFAA (20.9 mL, 150 mmol) is slowly charged down the side of the flask, with stirring, over a 5 min period. A dark brown-purple solution is formed. After 10 min, dimethylphosphonoacetic acid (8.4 g, 50 mmol) is added neat over a 5 min period at 0 ⁰C. Next, 85% H₃PO₄ (1.15 g, 10 mmol) is added drop-wise. After the addition of only a few drops, a thick precipitate rapidly forms, and stirring with a magnetic stir bar is no longer possible. The remainder of the 85% H₃PO₄ is slowly added over a few minutes as the flask is manually swirled. Once the addition is complete, the reaction mixture is allowed to warm to rt. As the reaction mixture warms, the precipitate dissolves, and an easily stirred solution results. The reaction mixture is stirred at rt for 1 h, then at 50 °C for 6 h. At this point, heating is discontinued and the reaction mixture allowed to slowly cool to rt overnight. The purple reaction mixture is cooled to 0 ⁰C and diluted with water (125 mL). Next, 10 N aq NaOH (~33 mL total) is slowly added until pH ~10 (by pH paper) is reached. The resulting amber solution is then stirred at rt for 1 h before the pH is adjusted to ~8 (pH paper) by the careful addition of cone. HCl (< 0.5 mL). The solution is then extracted twice with DCM (150 mL, 50 mL). The combined DCM extracts are washed twice with 1 N aq NaOH (100 mL, 50 mL). The combined NaOH washes are acidified to pH <2 with concentrated HCl (-13-15 mL) and then extracted twice with fresh DCM (150 mL, 50 mL). The combined secondary DCM extracts are diluted with n-BuOAc (50 mL). The resulting solution is concentrated in vacuo at 30 ⁰C to remove the DCM. Within minutes, a white precipitate begins to form in the resulting n-BuOAc solution. The mixture is allowed to sit at rt for 1 h. The solid is collected by filtration, washed with a small amount of w-BuOAc, and dried on the filter under suction in the open air for 10 min. Yield: 10.9 g (69%) of a white solid. ¹H NMR indicates -100:1 ratio of dimethyl {2-[4-(2- hydroxyethoxy)-2,3-dimethylphenyl]-2-oxoethyl}phosphonate : dimethyl {2-[2-(2- hydroxyethoxy)-3,4-dimethylphenyl]-2-oxoethyl}phosphonate. A second crystallization is carried out as follows. The solid is re-dissolved in DCM (50-

75 mL). The solution is filtered to remove a small amount of insoluble material. It is then diluted «-BuOAc (40 mL) and concentrated in vacuo at 30 ⁰C, as before, to remove the DCM. As the last amounts of DCM are removed, a white solid begins to precipitate. After the DCM is removed, the H-BuOAc suspension is allowed to sit at rt for 2 h before it is filtered. The solid is washed with a small amount of π-BuOAc and dried under suction in the open air for 10 min. Yield: 10.5 g (96% recovery, 66% overall yield) of a white solid. Melting point 92-94 °C. ¹H NMR (300 MHz, CDCl₃): δ 7.60 (d, J = 8.8 Hz, IH), 6.75 (d, J = 8.5 Hz, I H), 4.13 (m, 2H), 4.01 (m, 2H), 3.77 (d, J = 1 1.0 Hz, 6H), 3.58 (d, J = 22.2 Hz, 2H), 2.42 (s, 3H), 2.20 (s, 3H), 2.05 (br, IH) ppm. ³¹P NMR (121 MHz, Η-decoupled, CDCl₃): δ 24.69 ppm. LCMS (Standard Method): 2.20 min; 317 (M+l).

D. PREPARATION OF DIMETHYL {2-[4-(4-HYDROXYBUTOXY)-2,3-DIMETHYLPHENYL]-2-

OXOETH YL} PHOSPHONATE

Step 1. Preparation of 4-(2.3-dimethylphenoxy^')butan-l-ol

Method 1 :

A 5 L, 3 -neck round bottom flask equipped with a mechanical stirrer and a thermocouple is charged with 2,3-dimethylphenol (144.0 g, 1.18 mol) followed by r-BuOK (1.0 M in THF, 1.65 L) with stirring at rt. The resulting solution is stirred for 30 min, and then 4-bromobutyl acetate (300.0 g, 1.54 mol) is added over 10 min, and the internal temperature rises to 35 °C. The solution is stirred overnight, water (500 mL) is added, and the mixture is transferred to a separatory funnel. The layers are separated, and the aqueous layer is extracted once with EtOAc (200 mL). The combined organics are washed with brine (150 mL) and evaporated giving 285 g (103%) of crude material as a yellow oil.

The residue is dissolved in THF (1000 mL) and water (250 mL). LiOH-H₂O (64.37 g, 1.53 mol) is added, and the mixture is rapidly stirred for 3 h at rt. The layers are separated, and the aqueous layer is extracted once with EtOAc (300 mL). The combined organics are washed with water (200 mL), and brine (200 mL) and evaporated to give the title compound (167.3 g, 73% yield) as a light yellow syrup.

Method 2:

A 5 L, three-necked round bottom flask equipped with an overhead stirrer and nitrogen inlet is charged with 2,3-dimethylphenol (125.0 g, 1.02 mol), powdered K₂CO₃ (212.13 g, 1.53 mol), and DMA (500 mL) at rt. Next, 4-bromobutyl acetate (238.75 g, 1.22 mol) is added at rt with stirring. The mixture is then heated to 65 ⁰C (internal). The progress of the reaction is monitored by LC-MS. After 22 h, >95% conversion is noted.

At this point, 2.0 M aq KOH (1.50 L) is added over a 15 min period to the reaction mixture at 65 ⁰C. The progress of the reaction is monitored by LC-MS. After 15 min, -95% conversion is noted. After 1 h, complete conversion to the alcohol is noted, and after 1.5 h, heating is discontinued. After cooling to rt, the reaction mixture is diluted MTBE (1.75 L) with stirring. The mixture is transferred to a separatory funnel, and the bottom aq DMA layer is drained. The MTBE layer is then washed with water (3 x 500 mL) and half saturated brine (500 mL). The MTBE layer is then concentrated in vacuo to 194.8 g of a golden colored liquid.

The crude product is purified by short path, high vacuum (1 Torr) distillation. One forerun fraction (2.90 g) is collected between 90-140 °C (oil bath: 170 ⁰C). 4-(2,3- dimethylphenoxy)butan-l-ol (189.90 g, 96% yield) is collected between 140-142 ⁰C (sand bath: 185 ⁰C) as a light orange liquid.

LCMS (Standard Method), of 4-(2,3-dimethylphenoxy)butyl acetate: 3.05 min, 259 (M+Na)⁺. LCMS (Standard Method), of 4-(2,3-dimethylphenoxy)butan-l -ol: 2.82 min, 195 (M+H)⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.04 (t, J = 7.9 Hz, 2 H), 6.78 (d, J = 7.7 Hz, 1 H), 6.70 (d, J = 8.2 Hz, 1 H), 3.99 (t, J = 5.9 Hz, 2 H), 3.70 (t, J = 6.3 Hz, 2 H), 2.27 (s, 3 H), 2.15 (s, 3 H), 1.93-1.76 (m, 4 H), 1.64 (bs, I H).

Step 2. Preparation of Dimethyl {2-[4-(4-hvdroxybutoxyV2.3-dimethylphenyl]-2- oxoethyl ) phosphonate

Method 1 :

A 5 L, 3 -neck round bottom flask equipped with a mechanical stirrer and a thermocouple is charged with 4-(2,3-dimethylphenoxy)butan-l-ol (552.0 g, 2.84 mol). The flask is immersed in an ice/water bath, and TFAA (2.98 kg, 14.21 mol) is slowly added, maintaining the temperature below 25 ⁰C. A light purple solution forms upon complete addition of the TFAA. After 10 min, dimethylphosphonoacetic acid (477.38 g, 2.84 mol) is added over a five min period; a mild exotherm is noted (8 ⁰C). The purple solution is stirred for a further 10 min, and then phosphoric acid (85%, 327.44 g, 2.84 mol) is added; another exotherm is noted (10 ⁰C). The resulting mixture is stirred overnight.

The vessel is equipped with a distillation head and a heating mantel, and the volatiles are evaporated under reduced pressure (~30 mm Hg). Once distillation is complete, the heating is discontinued, the flask is placed in an ice/water bath, and the residue is diluted with water (500 mL). Next, 10 N aq NaOH (-500 mL total) is slowly added until pH -10 (by pH paper) is reached. The resulting amber solution is then stirred at rt for 1 h before the pH is adjusted to -8 (pH paper) by the careful addition of cone. HCl. The solution is then extracted with DCM (2 x 500 mL). The combined DCM extracts are washed with 1 N aq NaOH (3 x 400 mL). The combined NaOH washes are acidified to pH <2 with cone. HCl and then extracted with DCM (3 x 300 mL). The combined DCM extracts are washed with brine (100 mL) and evaporated. The resulting oil is dissolved in H-BuOAc (600 mL), and the resulting solution concentrated in vacuo at 30 ⁰C until a white precipitate begins to appear. The flask is immediately removed from the rotary evaporator and allowed to sit at rt overnight. The solid is collected by filtration, washed with a small amount of H-BuOAc, and dried on the filter under suction in the open air for 3 h. Yield: 460 g (56%) of a white solid. Method 2:

85% H₃PO₄ 50 ⁰C

A 250 mL 3-necked flask equipped with a thermocouple, nitrogen inlet and magnetic stir bar is charged with TFAA (15.1 mL, 109 mmol) and cooled to 0 ⁰C. Next, 4-(2,3- dimethylphenoxy)butan-l-ol (7.05 g, 36.29 mmol) is slowly charged at a rate so as to maintain an internal temperature between 0 and 5 ⁰C. The resulting rose colored solution is stirred for 5 min, then dimethylphosphonoacetic acid (7.32 g, 43.5 mmol) is slowly added to the solution at 0 ⁰C, followed by 85% phosphoric acid (0.84 g, 7.3 mmol). The dark pink- rose colored solution is removed from the ice bath and allowed to warm to room temperature. The flask is immersed in an oil bath and heated to 50 ⁰C (internal) for 4 h. Heating is discontinued, and the reaction mixture is allowed to slowly cool to rt.

After 16 h, the reaction mixture is cooled to 0 ⁰C and slowly diluted with water (100 mL). Next, 10 M aq NaOH is slowly added to the cloudy mixture until pH 12 (pH paper) is reached. Approximately 23-25 mL of 10 M aq NaOH is required. The mixture is stirred at rt until LC-MS indicates complete hydrolysis of the TFA ester (~ 30 min; pH changes to ~10- 1 1). The pH is then adjusted to ~8 by the careful addition of cone. HCl. The mixture is then extracted twice with CH₂Cl₂ (1 x 150 mL, 1 x 50 mL).

The combined product-containing CH₂Cl₂ extracts are extracted thrice with 1.0 M aq NaOH (1 x 80 mL, 2 x 40 mL). The combined product-containing aqueous extracts are acidified to pH <2 with cone. HCl (-12-14 mL) and extracted twice with fresh CH₂Cl₂. The combined product-containing CH₂Cl₂ extracts are concentrated to a minimal volume and filtered (to remove NaCl). The filtrate is diluted with /J-BUOAC (60 mL), and the remaining CH₂Cl₂ is then removed in vacuo. The n-BuOAc solution is seeded at rt with dimethyl {2-[4- (4-hydroxybutoxy)-2,3-dirnethylphenyl]-2-oxoethyl}phosphonate (10 mg) with stirring. The product begins to precipitate immediately. The slurry is stirred at room temperature for 2 h and then filtered on a medium frit glass Buchner funnel. The solid is washed with a small amount of fresh n-BuOAc and dried on the filter funnel under suction and a flow of nitrogen. Yield: 7.18 g (57%) of a white solid.

¹H NMR indicates >98:2 ratio of dimethyl {2-[4-(4-hydroxybutoxy)-2,3-dimethylphenyl]-2- oxoethyl}phosphonate : dimethyl {2-[2-(4-hydroxybutoxy)-3,4-dimethylphenyl]-2- oxoethyl}phosphonate isomer. LCMS (Standard Method), of dimethyl {2-[4-(4-hydroxybutoxy)- 2,3-dimethylphenyl]-2-oxoethyl}phosphonate: 2.44 min, 345 (M+H)⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.59 (d, J = 8.6 Hz, 1 H), 6.72 (d, J= 8.6 Hz, 1 H), 4.04 (t, J= 6.2 Hz, 2 H), 3.75 (d, J = 11.3 Hz, 6 H), 3.73 (t, J = 6.3 Hz, 2 H), 3.56 (d, J = 22.5 Hz, 2 H), 2.40 (s, 3 H), 2.14 (s, 3 H), 1.94-1.88 (m, 2 H), 1.81-1.71 (m, 2 H), OH not observed.

D. PREPARATION OF DIETHYL [2-(2,5-DIMETHOXYPHENYL)-I -METHYL^-

OXOETHYL]PHOSPHONATE

85% H₃PO₄

A 50 mL round bottom flask equipped with a magnetic stir bar is charged with 1,4- dimethoxybenzene (1.38 g, 10.0 mmol) followed by TFAA (6.7 mL, 48.0 mmol). The suspension is cooled to 0 ⁰C with stirring. Next, 2-(diethylphosphono)propionic acid (2.52 g, 12.0 mmol) is slowly added, followed by 85% H₃PO₄ (1.38 g, 12.0 mmol). With the addition of the H₃PO₄, the starting 1 ,4-dimethoxybenzene dissolves, and a yellow color develops. The ice bath is removed, and the reaction mixture is stirred at rt. The color darkens to orange, and a precipitate forms. After 20 h, the brown-orange reaction mixture is cooled to O ⁰C and diluted with water (30 mL). Next, 10 N aq NaOH ( — 10-1 1 mL) is carefully added until pH -8-9 is reached. The mixture is stirred at rt for 15 min and then extracted twice with CH₂Cl₂. The combined extracts are washed with 20 mL of a 1 : 1 mixture of 1 N aq HCl and brine and then concentrated in vacuo to 2.71 g of a residue. This crude material is dissolved in MTBE (~25 mL) and extracted thrice with 1 N NaOH (1 x 40 mL, 2 x 20 mL). The combined aqueous extracts are acidified with cone. HCl, and the resulting mixture extracted twice with CH₂Cl₂. The combined extracts are concentrated in vacuo to 2.26 g of a pale yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 7.16 (d, J = 3.0 Hz, IH), 7.01 (dd, J = 9.1 , 3.3 Hz, IH), 6.88 (d, J = 8.8 Hz, IH), 4.48 (dd, J = 23.9, 7.1 Hz, IH), 4.13-3.96 (m, 4H), 3.86 (s, 3H), 3.78 (s, 3H), 1.50 (dd, J = 18.0, 7.0 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H) ppm. ³¹P NMR (121 MHz, CDCl₃) δ 25.85 ppm. LCMS (Standard Method): 2.56 min; 331 (M+l), 353 (M+Na).

F. ADDITIONAL ARYL-SUBSTITUTED KETOPHOSPHONATES

Using methods described above, the following additional aryl-substituted ketophosphonates are prepared:

Aryl-Substituted Ketophosphonate Characterization J = 7.2 Hz, 2H), 7.61 (d, J 7.44 (t, J = 7.5 Hz, 2H), 4.34 (m, 2H), 4.1 1 (m, 4H),

2.18 (s, 3H), 1.27 (t, J = Aryl-Substituted Ketophosphonate Characterization

7.3 Hz, 6H)

LCMS (Standard Method): 2.77 min; 449 (M+ 1), 471 (M+Na) 6.74 (d, J 3.58 (d, J = Hz, 6H) (M+Na) H), 6.75 (d, 6.0 Hz, 2 H), 2.41 (s, 3 H)₁

6.94 (d, J J = 22.8

(M+Na) 7.06 (dd, 3H), 3.84 (d, H) (M+Na) Hz, IH), (s, 3H), Hz, IH) (M+Na) Hz, IH), 7.47 4.18- Hz, 6H) (M+Na)

J = 1 1.3 Hz, 6H)

7.71 (d, J 3H), 3.80

7.29-7.25 3.88 (s, 3H), Hz, 6H) Hz, 1C), = 6.9 Hz, 1C), J = 6.9 Hz,

(300 MHz, CDCl₃): δ 7.42 (dd, J = 8.9, 3.2 Hz, IH), (m, IH), 6.91 (άά, J = 9.1 , 4.1 Hz, I H), 4.14-4.04 (m, (s, 3H), 3.81 (d, J = 22.3 Hz, 2H), 1.25 (t, J = 7.2 Hz, (121 MHz, CDCl₃) δ 21.77

tandard Method): 2.52 min; 305 (M+l), 327 (M+Na) Aryl-Substituted Ketophosphonate Characterization

¹H NMR (300 MHz, CDCl₃): δ 8.06 (d, J = 2.2 Hz, IH), 7.95 (dd, J = 8.6, 2.2 Hz, IH), 6.99 (d, J = 8.8 Hz, IH), 4.19-4.09 (m, 4H), 3.98 (s, 3H), 3.56 (d, J = 22.8 Hz, 2H), 1.29 (t, 7 = 7.1 Hz, 6H) 3¹P NMR (121 MHz, CDCl₃) δ 20.81 LCMS (Standard Method): 2.58 min; 321 (M+l), 343 (M+Na)

¹H NMR (300 MHz, CDCl₃): δ 7.90 (d, J = 8.2 Hz, 2H), 7.27 (d, 7

= 8.2 Hz, 2H), 4.19-4.10 (m, 4H), 3.63 (d, J = 22.8 Hz, 2H), 2.41

(s, 3H), 1.28 (t, 7 = 7.1 Hz, 6H)

³¹P NMR (121 MHz, CDCl₃) δ 21.71

LCMS (Standard Method): 2.53 min; 271 (M+l), 293 (M+Na)

¹H NMR (300 MHz, CDCl₃): δ 7.66 (dd, 7 = 8.5, 1.9 Hz, IH), 7.58

(d, 7 = 1.9 Hz, IH), 6.90 (d, 7 = 8.5 Hz, IH), 4.20-4.00 (m, 5H)₁

3.95 (s, 3H), 3.93 (s, 3H), 1.52 (dd, J = 18.1 , 7.1 Hz, 3H), 1.29 (t, 7

= 1.1 Hz, 3H), 1.22 (t, 7 = 7.0 Hz, 3H)

³¹P NMR (121 MHz, CDCl₃) δ 24.96

LCMS (Standard Method): 2.41 min; 331 (M+l ), 353 (M+Na)

¹H NMR (300 MHz, CDC13): δ 7.62 (d, J = 1.6 Hz, IH), 7.30 (d, 7

= 3.5 Hz, IH), 6.56 (dd, 7 = 3.6, 1.6 Hz, IH), 4.19-4.09 (m, 4H),

3.49 (d, 7 = 22.8 Hz, 2H), 1.28 (t, 7 = 7.1 Hz, 6H)

³¹P NMR (121 MHz, CDCl₃) δ 20.59

LCMS (Standard Method): 2.07 min; 247 (M+l), 269 (M+Na) (d, 7 = 8.8 Hz, IH), 6.72 (d, 7 3.85 (s, 3H), 2.33 (s, 3H), 2.16 3H), 1.28 (t, J = 7.0 Hz, 3H),

329 (M+l), 351 (M+Na) IH), 6.74 (d, (s, 3H), 3.57 (d, 7 =

(M+Na) IH), 4.18- 2.54 (s, 3H),

(M+Na) Hz, IH), 7.82 (m, 4H), 1.28 (t, J = 7.0

(M+Na) IH), 7.35 (dd, (m, 4H), Hz, 2H),

(M+Na) (d, 7 = 2.2 Hz, IH), 7.41 (dd, IH), 4.14-4.04 (m, 4H), 3.67 (s, 3H), 3.57 (s, 2H),

(M+l ), 381 (M+Na) Aryl-Substituted Ketophosphonate Characterization 6.82 (d, J 2H), 2.53 2 (M+Na) 6.87-6.79 1.48 (d, J =

23

¹H NMR (300 MHz, CDC13): δ 7.71 (d, J = 8.2 Hz, IH), 6.94-6.91

(m, 2H), 3.89 (s, 3H), 3.84 (d, J= 11.1 Hz, 3H), 3.80 (d, J= 1 1.0

24 Hz, 3H), 3.46-3.27 (m, 3H)

³¹P NMR (121 MHz, CDCl₃) δ 27.39

LCMS (Standard Method): 2.07 min; 271 (M+l), 293 (M+Na) 6.73 (d, J 2H), 3.55 (d, J= 7.2 Hz,

25 1.27 (t, J =

(M+Na) 6.74 (d, J λ ^{L3 Hz}' ^6H)' (t, J= 7.2

26 3H) (M+Na) 4.56 (t, (d, J =

27 (M+Na)

EXAMPLE 3. USE OF ARYL-SUBSTITUTED KETOPHOSPHONATES IN REPRESENTATIVE OLEFINATION REACTIONS

This Example illustrates the preparation of representative compounds of the formula:

A. DlBENZYL (2S)-2-(2-OXOETHYL)PIPERAZINE-l ,4-DICARBOXYLATE

Step 1. Preparation of dibenzyl (2S)-2-(2-hvdroxyethvQpiperazine-l .4-dicarboxylate

A 12 L, 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, and addition funnel is charged with a solution of 2-[(2S)-piperazin-2-yl]ethanol (101 g, 0.78 mol) in water (800 mL) followed by THF (1200 mL). The resulting mixture is cooled to 2 ⁰C with stirring. Next, benzyl chloroformate (95%, 295 g, 1.64 mol) is added dropwise via the addition funnel over a 1 h period, maintaining the internal temperature below 10 ⁰C. Next, a solution of sodium bicarbonate (164 g, 1.95 mol) in water (1.7 L) is added slowly over a 45 min period, maintaining the internal temperature below 9 ⁰C. The reaction mixture is stirred at 2-5 ⁰C for 3 h, whereupon the cooling bath is removed, and the reaction mixture is diluted with DCM (2 L). The resulting mixture is mixed well before the layers are allowed to separate. The aqueous layer is re- extracted once with DCM (200 mL), and the combined extracts are washed thrice with 500 mL portions of water. The DCM extract is concentrated in vacuo to 344 g of a yellow syrup, which contains low levels of benzyl alcohol and benzyl chloride. These impurities are removed azeotropically by dissolving the crude product in MeOH, diluting the resulting solution with water, then concentrating the entire mixture in vacuo. The crude product is used in the next step without further purification. ¹H NMR (300 MHz, CDCl₃): δ 7.49-7.26 (m, 10H), 5.28-5.02 (m, 4H), 4.56-4.25 (br, IH), 4.25-3.77 (br, 3H), 3.77-2.69 (br m, 5H), 1.94-1.49 (br m, 2H) ppm. LCMS (Standard Method): 2.80 min; 399 (M+l), 421 (M+Na).

Step 2. Preparation of dibenzyl (2S)-2-(2-oxoethyl)piperazine-l ,4-dicarboxylate

A stock solution of buffered bleach is prepared by dissolving sodium bicarbonate (6.25 g, 74.4 mmol) in NaOCl solution (6.0%, 461 g, 372 mmol). Separately, a 3 L, 3-necked round bottom flask equipped with an overhead stirrer, thermocouple, and addition funnel is charged with a solution of dibenzyl (2S)-2-(2-hydroxyethyl)piperazine-l , 4-dicarboxylate (98.8 g, 248 mmol) in DCM (510 mL) followed by a solution of KBr (2.95 g, 24.8 mmol) dissolved in water (50 rnL). The biphasic mixture is cooled to -5 ⁰C with stirring. Next, TEMPO (0.387 g, 2.48 mmol) is added to the reaction mixture. Once the TEMPO dissolves, a portion of the buffered bleach solution 280.4 g, 0.9 eq) is added via the addition funnel drop-wise with vigorous stirring, maintaining the internal temperature below 5 °C. Once the addition is complete, the progress of the reaction is checked by TLC and LCMS. Three additional portions of the buffered bleach solution (0.1 eq, 0.05 eq, and 0.025 eq) are added, and the progress of the reaction checked after each addition. The reaction is deemed complete when only a minimal amount (1-3%) of unreacted dibenzyl (2S)-2-(2-hydroxyethyl)piperazine-l,4-dicarboxylate can be detected. At this point, the reaction mixture is poured into a separatory funnel and the layers allowed to settle overnight. The bottom organic layer is drained, and the aqueous layer re-extracted with toluene. The initial DCM extract is washed with a solution of KI (0.823 g, 4.96 mmol) dissolved in 1.0 N aq HCl (200 mL). After the layers have separated, the bottom organic layer is drained, and the aqueous layer re-extracted with the toluene extract. The DCM extract is washed with 1.0 M aq Na₂S₂O₃. After the layers have separated, the bottom organic layer is drained, and the aqueous layer re-extracted with the toluene extract. The DCM extract is concentrated in vacuo at 35 ⁰C until most of the solvent is removed. The residue is combined with the toluene extract, and concentration is continued further to remove the remaining DCM. The resulting toluene solution is diluted with additional toluene (500 mL) and then washed once with half-saturated aq sodium bicarbonate (200 mL) and twice with water (2 x 200 mL). The organic layer is then concentrated in vacuo to an amber syrup that is used in subsequent reactions without further purification. ¹H NMR (300 MHz, CDCl₃): δ 9.80-9.45 (br, IH), 7.47-7.24 (m, 10H), 5.27-4.97 (m, 4H), 4.92-4.59 (br, IH), 4.27-3.83 (br m, 3H), 3.24-2.40 (br m, 5H) ppm. LCMS (Standard Method): 2.80 min; 397 (M+l), 451 (M+MeOH+Na).

B. DIBENZYL (2S)-2-[(2E)-4-{4-[2-(BENZOYLOXY)ETHOXY]-2,3-DIMETHYLPHENYL} -4- OXOBUT-2-EN-1 -YL]PIPERAZINE-I ^-DICARBOXYLATE

2-{4-[(Diethoxyphosphoryl)acetyl]-2,3-dimethylphenoxy}ethyl benzoate (1.5 g, 3.34 mmol) is dissolved in THF (15 mL). The solution is cooled to 0 ⁰C under nitrogen, and then sodium hydride (60% dispersion in mineral oil, 147 mg, 3.68 mmol) is added in one portion. The mixture is stirred at rt, during which time hydrogen gas is released. After 30 min, the resulting yellow solution is cooled to 0 ⁰C and treated dropwise via cannula with a solution of dibenzyl (2S)-2-(2-oxoethyl)piperazine-l,4-dicarboxylate (1.33 g, 3.34 mmol) in THF (5 mL), followed by two 1 mL rinses. The reaction mixture is stirred at 0 ⁰C for 15 min and then at rt for 3 h. LCMS and TLC confirms complete consumption of starting dibenzyl (2S)-2-(2-oxoethyl)piperazine-l,4- dicarboxylate. The reaction mixture is diluted with water (30 mL) and extracted with EtOAc. The organic layer is washed with brine (30 mL) and concentrated in vacuo to 2.54 g of a syrup. The crude product is purified by flash chromatography on silica gel. Elution with 3:2 hexanes- EtOAc yields 1.80 g of a thick, colorless syrup. LCMS (Standard Method): 3.10 min; 691 (M+ 1), 713 (M+Na). ¹H NMR (300 MHz, CDCl₃): δ 8.05 (d, J = IA Hz, 2H), 7.60-7.54 (m, I H), 7.46- 7.41 (m, 2H), 7.37-7.17 (m, 1 IH), 6.70-6.43 (m, 3H), 5.14-5.09 (m, 4H), 4.72-4.68 (m, 2H), 4.36- 4.28 (m, 3H), 4.18-3.93 (m, 3H), 3.14-2.76 (m, 3H), 2.59-2.40 (m, 2H), 2.26 (br s, 3H), 2.17 (s, 3H).

C. DIBENZYL (2S)-2-{(2E)-4-[4-(2-HYDROXYETHOXY)-2,3-DIMETHYLPHENYL]-4-OXOBUT-2-EN- 1-YL} PIPERAZINE-M-DICARBOXYLATE

A l-L, 3-neck round bottom flask, equipped with an overhead stirrer and thermocouple, is charged with dimethyl {2-[4-(2-hydroxyethoxy)-2,3-dimethylphenyl]-2-oxoethyl}phosphonate (41.16 g, 130 mmol), CH₃CN (300 mL), LiCl (5.52 g, 130 mmol), dibenzyl (2S)-2-(2- oxoethyl)piperazine-l ,4-dicarboxylate (46.9 g in 75 mL CH₃CN, 1 18 mmol), and water (3.75 mL), at rt with stirring. The reaction mixture is cooled to 3 ⁰C (internal temp.) using a crushed ice-water bath. /-Pr₂NEt (22.7 mL, 130 mmol) is added stream-wise over ~15 seconds. The ice bath is removed, and the reaction mixture is stirred at rt. A thin precipitate forms.

The reaction is monitored by TLC and LCMS. After 30 min, the reaction appears to be nearly complete. After 1.5 h, no starting dibenzyl (2S)-2-(2-oxoethyl)piperazine-l ,4- dicarboxylate can be detected by TLC. The reaction mixture is stirred at rt for three days. After three days, CH₃CN is distilled off at 82 ⁰C and atmospheric pressure. Nearly 300 mL (-75% of the original amount) is removed over a 1 h period. After the resulting slurry cools to <50 ⁰C, it is diluted with water (200 mL). The mixture is transferred to a separatory funnel and extracted with /-PrOAc (700 mL). The layers are separated. The organic layer is washed with 1 N aq. NaOH (2 x 100 mL). No dimethyl {2-[4-(2-hydroxyethoxy)-2,3-dimethylphenyl]-2- oxoethyl}phosphonate can be detected in the organic layer by LCMS. The organic layer is washed with 1 N aq. HCl (100 mL) followed by brine (100 mL). The organic layer is concentrated in vacuo (on the rotavap) to a thick, foaming, amber syrup (69 g). LCMS (Standard Method): 2.97 min; 587 (M+l). ¹H NMR (300 MHz, CDCl₃): δ 7.47-7.12 (m, HH), 6.76-6.44 (m, 3H), 5.23-5.03 (m, 4H), 4.45-4.28 (m, IH), 4.20-3.92 (m, 7H), 3.14-2.82 (m, 2H), 2.60-2.40 (m, 2H), 2.27 (br s, 3H), 2.18 (s, 3H).

D. DlBENZYL (2S)-2-{4-[4-(4-HYDROXYBUTOXY)-2,3-DIMETHYLPHENYL]-4-OXOBUT-2-EN-l- YL} PIPERAZINE-1 ,4-DICARBOXYLATE

A 5 L, 3 -neck round bottom flask equipped with a mechanical stirrer and a thermocouple is charged with dimethyl {2-[4-(4-hydroxybutoxy)-2,3-dimethylphenyl]-2-oxoethyl}phosphonate (370.0 g, 1.07 mol), CH₃CN (2970 mL), water (30 mL), LiCl (45.36 g, 1.07 mol) and crude dibenzyl (2S)-2-(2-oxoethyl)piperazine-l,4-dicarboxylate (396.26 g, 1.0 mol) at rt. The resulting mixture is cooled to 1 -2 ⁰C with stirring by immersion of the flask in a crushed ice-water bath. Next, /-Pr₂NEt (186 mL, 1.07 mol) is poured into the reaction mixture in one portion; no exotherm is observed. Shortly after the addition is complete, the reaction mixture begins to get cloudy, and a precipitate begins to form. The progress of the reaction is monitored by removing aliquots of the reaction mixture and assaying them by TLC and LCMS. The ice bath is allowed to slowly expire, and after 3 h the internal temperature of the reaction mixture has risen to 19 ⁰C. At this point, no more dibenzyl (2S)-2-(2-oxoethyl)piperazine-l ,4-dicarboxylate can be detected by TLC. After a total of 3.5 h, the reaction mixture is filtered to remove the solids and then evaporated to dryness. The residue is dissolved in /-PrOAc (2 L) and then washed with aqueous NaOH solution (0.5 N, 3 x 400 mL) and brine (1 x 250 mL). The solution is treated with Darco KB-B (30.75 g (5% w/w theory)). The slurry is stirred for 1 h, filtered through Celite, and the filtrate concentrated in vacuo to give the title compound, 584.13 g (95 % yield) of an amber syrup. LCMS (Standard Method): 3.07 min, 615 (M+H)⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.44- 7.10 (m, 1 IH), 6.71-6.41 (m, 3H), 5.23-5.00 (m, 4H), 4.34 (br, IH), 4.17-3.88 (m, 3H), 4.00 (t, J = 6.1 Hz, 2H), 3.73 (t, J = 6.5 Hz, 2H), 3.17-2.81 (m, 3H), 2.60-2.42 (m, 2H), 2.27 (br s, 3H), 2.16 (s, 3H), 1.95-1.85 (m, 2H), 1.81-1.68 (m, 3H).

EXAMPLE 4. PREPARATION OF REPRESENTATIVE MCH RECEPTOR ANTAGONISTS

This Example illustrates the synthesis of 4-{2,3-dimethyl-4-[(6R)-2-{[2- (trifluoromethy^pyrimidin-S-ylJcarbonylJoctahydro^H-pyridofl .Σ-aJpyrazin-ό- yl]phenoxy}butan-l -ol, a representative MCH receptor antagonists of the Formula:

Step 1. Preparation of 4-{2,3-Dimethyl-4-[(6R.9aSVoctahvdro-2H-pyridorL2-alpyrazin-6- yl]phenoxy)butan-l -ol

Crude dibenzyl (2S)-2-{4-[4-(4-hydroxybutoxy)-2,3-dimethylphenyl]-4-oxobut-2-en-l - yl}piperazine-l ,4-dicarboxylate (1 18.3 g, ~190 mmol) is dissolved in MeOH (600 mL) at rt and treated with Darco KB-B (5.0 g). The resulting slurry is stirred at rt for 1 h and then filtered through a pad of Celite. MeOH is used to rinse the flask and wash the filter cake. A total of 1000 mL of MeOH is used for the carbon treatment and filtration.

A 2.25 L hand blown borosilicate Parr bottle is flushed with nitrogen and then charged with 20% Pd(OH)₂/C (23.66 g) followed by the dibenzyl (2S)-2-{4-[4-(4-hydroxybutoxy)-2,3- dimethylphenyl]-4-oxobut-2-en-l-yl}piperazine-l ,4-dicarboxylate-MeOH solution, and finally AcOH (34.7 g, 570 mmol). The resulting mixture is then shaken under an atmosphere of hydrogen. The initial pressure is 50 psi, and within 10 min the pressure drops to 5 psi. The bottle is repressurized to 50 psi. After 15 min, the pressure is 15 psi, and bottle is re-pressurized again to 50 psi. After 1 hour the pressure is at 30 psi. The pressure is released, and again charged to 50 psi. The flask is shaken overnight. The final pressure is 35 psi.

After a total of 16 h, the reaction is deemed complete as judged by LCMS. At this point, the reaction mixture is sparged with argon and then filtered through a pad of Celite. The bottle is rinsed and the pad washed with MeOH. The filtrate is then concentrated in vacuo to an orange syrup that discolors slightly upon sitting. This material is then partitioned between water (300 mL) and MTBE (600 mL). The resulting mixture is stirred vigorously as 10 N aq NaOH (80 mL) is slowly added, adjusting the pH to >12. The mixture is stirred vigorously for several minutes before being transferred to a separatory funnel using additional MTBE (150 mL). The mixture is shaken and allowed to settle. The layers are separated and the aqueous layer re-extracted once with MTBE (300 mL). The combined extracts are concentrated in vacuo to 44.8 g (-70%) of a pale yellow foamy syrup. LCMS (Standard Method): 2.09 min, 333 (M+H)⁺. ¹H NMR (300 MHz, CDCl₃): complex mixture of rotamers, δ 7.33 (d, J = 8.6 Hz, -0.8H), 6.84 (br s, -0.2H), 6.71 (d, J = 8.8 Hz, -0.8H), 6.57 (br, -0.2H), 3.95 (br t, J = 5.9 Hz, 2H), 3.69 (t, J= 6.2 Hz, 2H), 3.27 (br d, -0.8H), 3.01 (br s, -0.2H), 2.86-2.41 (m, 6H), 2.20 (s, Me), 2.16 (s, Me), 2.13-1.24 (m, 1 1H).

Step 2. Preparation of (^"2R,3R)-2,3-Dihydroxysuccinic acid 4-(2.3-dimethyl-4-lY6R,9aS)- octahvdro-2H-pyridof 1 ,2-a1pyrazin-6-yl1phenoxy> butan- 1 -ol (1 : 1 )

A 3 L, 3 -neck round bottom flask equipped with a mechanical stirrer and a thermocouple is placed in a heating mantle. The flask is then charged with a solution of crude 4-{2,3-dimethyl- 4-[(6R,9aS)-octahydro-2H-pyrido[l,2-a]pyrazin-6-yl]phenoxy}butan-l-ol (219.4 g, 0.660 mol) in a mixture of MeOH (1335 mL) and /-PrOAc (267 mL). The solution is heated to 60 °C with stirring. Solid L-tartaric acid (99.02 g, 0.660 mol) is added portionwise over 1 min to the rapidly stirring solution at 60 ⁰C. The L-tartaric acid dissolves quickly. Heating is discontinued, with precipitation starting when the internal temperature is 48 ⁰C, and stirring is maintained while the mixture is allowed to cool to room temperature over 3 hours. The slurry is then further cooled, with stirring, to 0 ⁰C in an ice-water bath. After 45 min, the solid is collected by filtration on a 3000 mL, medium porosity glass fritted Buchner filter funnel. The solid is washed with a small amount of 1 : 1 MeOH:/-PrOAc and allowed to dry at rt in the open air overnight. Yield: 228.36 g (72% recovery) of a white powder. LCMS (Standard Method): 2.09 min, 333 (M+H)⁺. ¹H NMR (300 MHz, DMSO-<4): complex mixture of rotamers, δ 7.21 (d, J = 8.5 Hz, -0.8H), 6.88 (br, -0.2H), 6.79 (d, J= 8.5 Hz, -0.8H), 6.66 (br, -0.2H), 3.90 (t, J= 6.3 Hz, 2H), 3.44 (t, J= 6.3 Hz, 2H), 3.32-3.28 (m, -0.8 Hz), 3.15-3.04 (m, -2.2H), 2.82-2.58 (m, ~3H), 2.45-2.30 (m, ~2H), 2.15 (s, Me), 2.08 (s, Me), 2.05 (br), 1.95-1.86 (m, ~1H), 1.78-1.19 (m, -10H).

Step 3. Preparation of 4-{2.3-dimethyl-4-[^"(6R^')-2-([2-(trifluoromethyl)pyrimidin-5- yllcarbonvUoctahvdro^H-pyridori ^-alpyrazin-ό-yliphenoxylbutan-l-ol

A 5 L, 3 -neck round bottom flask equipped with a mechanical stirrer and a thermocouple is charged with (2R,3R)-2,3-dihydroxysuccinic acid 4-{2,3-dimethyl-4-[(6R,9aS)-octahydro-2H- pyrido[l ,2-a]pyrazin-6-yl]phenoxy}butan-l-ol (l :l) (262.0 g, 0.54 mol) and THF (1.5 L). An aqueous solution OfNaHCO₃ (1 13 g, 1.34 mol, 2.5 equiv, 2 L) is added to the flask gradually with stirring. The flask is immersed in an ice-salt bath to maintain the internal temperature of the reaction below 5 ⁰C. Once the solution is cooled a solution of 2-(trifluoromethyl)pyrimidine-5- carbonyl chloride (115 g, 0.55 mol, 1.02 equiv) in anhydrous THF (700 mL) is added dropwise over 40 min, maintaining the temperature below 5 ⁰C. Stirring is continued 1 hr at 0-5 ⁰C. An additional amount of the 2-(trifluoromethyl)pyrimidine-5-carbonyl chloride (5.65 g, 0.026 mol, 0.05 equiv) in anhydrous THF (30 mL) is added dropwise over 15 min, and the suspension is stirred for 1 h. The reaction mixture is allowed to warm from 0 ⁰C to rt overnight without stirring. The next day, the reaction mixture is diluted with 1 L of THF and stirred for 30 min. The light-orange colored THF layer is separated and then stirred with Darco 12-20 mesh (13.0 g, 5% by weight) for 30 min. The resulting colorless suspension is filtered through a pad of Celite, and the filter cake is washed with THF (500 mL). The combined THF layers are evaporated under reduced pressure to afford the title compound as a cream-colored, foamy solid (240.0 g, 88% yield). LCMS (Standard Method): 2.30 min, 507 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃): complex mixture of rotamers, δ 8.96, 8.90 (s, s, 2H), 7.33 (br, -0.8H), 6.84 (br, -0.2H), 6.77-6.70 (m, -0.8H), 6.59 (br, -0.2H), 4.57-4.45 (m, IH), 3.99-3.96 (m, 2H), 3.75-3.70 (m, 2H), 3.44-2.45 (m, ~6H), 2.34-2.11 (m, ~6H), 2.05-1.32 (m, ~12H).

All publications, patent applications, patents, and other documents cited herein are incorporated by reference in their entirety.

From the foregoing description, it will be apparent that variations and modifications may be made to the invention described herein. Such embodiments are also within the scope of the following claims.

Claims

What is claimed is: L A method for preparing an aryl-substituted ketophosphonate of the Formula:

wherein:

Ar is an optionally substituted 6- to 10-membered aryl group or an optionally substituted 5- to 10- membered heteroaryl group; Y is optionally substituted Ci-C₃alkylene or optionally substituted C₂-C₃alkylene ether; and

Ri and R₂ are independently Ci-C₆alkyl or C_rC₆haloalkyl, or Ri and R₂ are taken together to form a 4- to 7-membered heterocycloalkyl; each of which alkyl and heterocycloalkyl is optionally substituted; the method comprising reacting: (a) Ar-H; with

(b) a di-alkoxy phosphoryl alkanoic acid of the formula:

in the presence of a perfluoroalkanoic anhydride and phosphoric acid; and thereby generating an aryl-substituted ketophosphonate of the Formula:

2. A method according to claim 1 , wherein:

Ar is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, each of which is substituted with from 0 to 7 substituents independently chosen from: (a) halogen, hydroxy, cyano, amino, nitro, -COOH, aminocarbonyl and aminosulfonyl; (b) Ci-Cgalkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, (C₃-C₈cycloalkyl)Co-C₄alkyl, Ci-C₈haloalkyl, C₁-

Qalkoxy, Q-Qhaloalkoxy, Ci-C₈alkylthio,

C₂-C₈alkyl ether, Ci-Csalkoxycarbonyl, Ci-CsalkylsulfonylQrGjalkyl, mono- or di-(C_r C₈alkyl)aminoCo-C₄alkyl, Ci-C₈alkylsulfonylaminoCo-C₄alkyl, mono- or di-(C]- C₈alkyl)aminosulfonylCo-C₄alkyl, mono- or di-(Ci-C₈alkyl)aminocarbonylCo-C₄alkyl, phenylC₀-C₄alkyl, (4- to 8-membered heterocycle)C₀-C₄alkyl and (4- to 8-membered heterocycle)C|-C₄alkoxy; each of which is optionally substituted and each of which is preferably substituted with from 0 to 6 substituents independently chosen from R₃; (c) groups that are taken together to form a fused 5- or 6-membered carbocycle or heterocycle that is substituted with from 0 to 3 substituents independently chosen from R₃; and (d) groups that are taken together with a substituent of Y to form a fused C₄-C₇cycloalkyl;

Y is Ci-C₃alkylene or C₂-C₃alkylene ether, each of which is substituted with from 0 to 2 substituents independently chosen from:

(a) halogen, hydroxy and amino;

(b) Ci-C₄alkyl, Ci-C₄alkanoyl, mono- or di-(Ci-C₄alkyl)amino and phenylCi-C₃alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from R₃;

(c) groups that are taken together to form a CrCβcycloalkyl; and

(d) groups that are taken together with a substituent of Ar to form a fused 4- to 7-membered cycloalkyl or heterocycloalkyl ring that is substituted with oxo;

Ri and R₂ are independently C|-C₆alkyl or Ci-Cβhaloalkyl, or Ri and R₂ are taken together to form a 4- to 7-membered heterocycloalkyl; each of which alkyl and heterocycloalkyl is substituted with from 0 to 6 substituents independently chosen from R₃; and

Each R₃ is independently chosen from oxo, halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl, -COOH, Ci-C₆alkyl, Ci-C₆hydroxyalkyl, Ci-C₆haloalkyl, Q- Cβalkoxy, Ci-C₆haloalkoxy, C₂-C₆hydroxyalkoxy, C₂-C₆alkyl ether, Q-Cβalkylthio, Q- C₆alkoxycarbonyl, Ci-C₆alkanoyl, Ci-C₆alkanoyloxy, C₃-C₆alkanone, mono- or di-(C₍-

C₆alkyl)amino, Q-Cβalkylsulfonyl, mono- or di-(Q-C₆alkyl)aminosulfonyl, and mono- or di- (C i -C₆alkyl)aminocarbonyl.

3. A method according to claim 1 or claim 2, wherein Ar is phenyl that is substituted with from 0 to 5 substituents independently chosen from: (i) hydroxy, halogen and amino; and

(ii) Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, mono- or di-(Ci-C₆alkyl)amino and phenyl; each of which is further substituted with from 0 to 3 substituents independently chosen from oxo, hydroxy, halogen, amino, C|-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkylsulfonyl, Q- C₆alkylsulfonylamino, Ci-C₆alkylsulfonyloxy, Q-Cβalkoxycarbonyl and mono- or di-(Q- C₆alkyl)amino.

4. A method according to claim 1 or claim 2, wherein Ar is phenyl that is fused to a 5- or 6-membered heterocycle, wherein each phenyl and heterocycle is substituted with from 0 to 3 substituents independently chosen from Q-Cβalkyl, Q-Cβalkoxy and phenyl.

5. A method according to claim 4, wherein Ar is

O

6. A method according to any one of claims 1-5, wherein Y is methylene.

7. A method according to any one of claims 1-6, wherein Ri and R.₂ are each independently Ci-C₄alkyl or Ci-C₄haloalkyl.

8. A method according to any one of claims 1, 6 or 7, wherein the aryl-substituted ketophosphonate satisfies the formula:

wherein m is an integer ranging from 2 to 6.

9. A method according to any one of claims 1-8, wherein the step of reacting is performed at a temperature that is below 80 ⁰C.

10. A method according to claim 9, wherein the step of reacting is performed for 10 minutes to two days at a temperature ranging from 0 ⁰C to 72 ⁰C.

11. A method according to claim 10, wherein the step of reacting is performed for 10 minutes to two days at a temperature that ranges from 0 to 40 ⁰C.

12. A method according to claim 1 1 , wherein the step of reacting is performed for 10 minutes to two days at a temperature that ranges from 0 to 25 ⁰C.

13. A method according to any one of claims 1 -12, wherein the perfluoroalkanoic anhydride is trifluoroacetic anhydride.

14. A method according to claim 13, wherein the trifluoroacetic anhydride is initially present in an amount ranging from 1 to 10 molar equivalents, relative to the initial amount of dialkylphosphonoalkanoic acid.

15. A method according to claim 14, wherein the trifluoroacetic anhydride is initially present in an amount ranging from 4 to 5 molar equivalents, relative to the initial amount of dialkylphosphonoalkanoic acid.

16. A method according any one of claims 1-15, wherein the H₃PO₄ is initially present in an amount ranging from 0.1 to 10 molar equivalents, relative to the initial amount of dialkylphosphonoalkanoic acid.

17. A method according to claim 16, wherein the H₃PO₄ is initially present in an amount ranging from 0.5 to 2 molar equivalents, relative to the amount of dialkylphosphonoalkanoic acid.

18. A method according to claim 16, wherein the H₃PO₄ is initially present in an amount ranging from 0.1 to 0.3 molar equivalents, relative to the initial amount of dialkylphosphonoalkanoic acid, and the TFAA is initially present in an amount ranging from 1.3 to 5 molar equivalents, relative to the initial amount of dialkylphosphonoalkanoic acid.

19. A method according to claim 18, wherein the H₃PO₄ is initially present in an amount ranging from 1.0 to 1.5 molar equivalents, relative to the initial amount of dialkylphosphonoalkanoic acid, and the TFAA is initially present in an amount ranging from 4 to 5 molar equivalents, relative to the initial amount of dialkylphosphonoalkanoic acid.

20. A method according to any one of claims 1-19, wherein the step of reacting is performed in the absence of organic solvent.

21. A method according to any one of claims 1 -20, wherein after the step of reacting the method further comprising the steps of: (i) adjusting the pH of the reaction mixture to a basic pH; (ii) extracting the pH-adjusted reaction mixture with an organic solvent to yield an organic phase and an aqueous phase; (iii) extracting the organic phase with an aqueous solution of an inorganic base to yield a second organic phase and a second aqueous phase; (iv) adjusting the pH of the second aqueous phase to an acidic pH; (v) extracting the pH-adjusted second aqueous phase with an organic solvent to yield a third organic phase and a third aqueous phase; and (vi) concentrating the third organic phase to yield the aryl-substituted ketophosphonate.

22. A method according to any one of claims 1-20, wherein after the step of reacting the method further comprising the steps of:

(i) diluting the reaction mixture with water;

(ii) adjusting the pH of the reaction mixture to a pH ranging from 7 to 9 with an aqueous solution of NaOH;

(iii) extracting the pH-adjusted reaction mixture with an organic solvent to yield an organic phase and an aqueous phase; (iv) extracting the organic phase with an aqueous solution of NaOH to yield a second organic phase and a second aqueous phase; (iv) adjusting the pH of the second aqueous phase to an acidic pH with concentrated HCl;

(v) extracting the pH-adjusted second aqueous phase with an organic solvent to yield a third organic phase and a third aqueous phase; and (vi) concentrating the third organic phase to yield the aryl-substituted ketophosphonate.

23. A method according to any one of claims 1-20, wherein after the step of reacting the method further comprising the steps of:

(i) diluting the reaction mixture with water;

(ii) adjusting the pH of the reaction mixture to a pH ranging from 8 to 9 with an aqueous solution ofNaOH;

(iii) extracting the pH-adjusted reaction mixture with an organic solvent selected from ethereal solvents, dichloromethane, toluene, and alkyl acetates to yield an organic phase and an aqueous phase; (iv) extracting the organic phase with IN NaOH to yield a second organic phase and a second aqueous phase;

(iv) adjusting the pH of the second aqueous phase to an acidic pH with concentrated HCl; (v) extracting the pH-adjusted second aqueous phase with an organic solvent selected from ethereal solvents, dichloromethane, toluene, and alkyl acetates to yield a third organic phase and a third aqueous phase; and (vi) concentrating the third organic phase to yield the aryl-substituted ketophosphonate.