WO2011063268A2

WO2011063268A2 - Novel synthetic methods

Info

Publication number: WO2011063268A2
Application number: PCT/US2010/057484
Authority: WO
Inventors: Daw-Long Albert Kwok; William Kiesman; Michael Humora; Xiongwei Cai; Adam Littke; Hexi Chang
Original assignee: Biogen Idec Ma Inc
Priority date: 2009-11-19
Filing date: 2010-11-19
Publication date: 2011-05-26
Also published as: WO2011063268A3

Abstract

Described herein are xanthine-containing compounds and processes for their synthesis.

Description

NOVEL SYNTHETIC METHODS

CLAIM OF PRIORITY

This application claims priority from U.S. S.N. 61/262,812, filed November 19, 2009, which is incorporated herein by reference in its entirety.

TECHNICAL FIELD OF THE INVENTION

The invention relates to methods of making optionally bridged cycloalkyl containing xanthines which can be used, e.g., as adenosine receptor modulators. The invention also relates to intermediate compounds encompassed by these methods and methods of producing those intermediates. The method also includes purification techniques via certain intermediate synthetic routes.

BACKGROUND OF THE INVENTION

Adenosine receptors, which can be located, for example, in the nervous tissues, heart and kidney are capable of modulating the release of neurotransmitters, heart rate and renal hemodynamics. Adenosine modulators have been examined clinically for indications associated with these phenomena.

There are many examples of potent adenosine modulators. Of specific interest are Adenosine Ai antagonists and Adenosine A_2a antagonists. A number of specific compounds have been identified as potent Adenosine A₁ or A_2a antagonists. An interesting group of these modulators include 8-cycloalkyl substituted, including bridged 8-cycloalkyl derivatives, xanthine derivatives which have been previously described. See U.S. Patent No. 6,649,600 and 7,125,565. One particular derivative of interest is 3-[4-(2,6-dioxo-l,3-dipropyl-2,3,6,7-tetrahydro-lH-purin-8-yl)- bicyclo[2.2.2]oct-l-yl]propionic acid also referred to as compound (9) herein, which exhibits strong activity, both experimentally and clinically. While there are usable synthetic approaches to access 3-[4-(2,6-dioxo-l,3-dipropyl-2,3,6,7-tetrahydro-lH- purin-8-yl)-bicyclo[2.2.2]oct-l-yl]propionic acid, these approaches are generally linear. Thus, a need remains for a straightforward convergent approach which would allow access to large quantities in good yield. SUMMARY OF INVENTION

The inventors have discovered novel compounds novel methods of making xanthine containing compounds. In addition, the inventors have also discovered novel compounds, which can be used, e.g., as intermediates in the methods described herein. These methods, compounds and their compositions are described herein.

In one aspect, the invention is directed to a compound, pharmaceutically acceptable salt or prodrug selected from formula (I):

wherein

n, p, q, R¹, R², R³, R⁴, and M are as defined below.

In another aspect, the present invention is directed to a compound, pharmaceutically acceptable salt or prodrug selected from formula (V):

wherein

n, p, q, R¹, R³, R⁴, and ^ are as defined below.

In another aspect, the present invention is directed to a method of converting a compound of formula (IV):

to a compound of formula (V)

wherein n, p, q, R¹, R³ and R⁴ are as described for formula (V), the method comprising treating the compound of formula (IV) with a nitrile source and a base.

to a compound of formula (la):

wherein n, p, q, R¹, R³, R⁴ and M are as described for formula I, the method comprising treating the compound of formula (IV) with a source of bisulfite.

In another aspect, the present invention is directed to a method of purifying a compound of formula (IV):

the method comprising converting said compound of formula (IV) to a compound of formula (la);

and subsequently converting the compound of formula (la) to a compound of formula

(IV);

wherein n, p, q, R¹, R³, R⁴ and M are as described for formula (I).

In another aspect, the present invention is directed to a method of converting a compound of formula (V):

to a compound of formula (

wherein q, n, p, X¹, X², R¹, R³, R⁴, R⁵, R⁶ and ^ are as defined below; the method comprising converting a compound of formula (V) to an activated acid or activated acid intermediate and coupling with a compound of formula (VIII):

wherein X¹, X², R³, R⁴, R⁵ and R⁶ are as described for formula (X). In another aspect, the present invention is directed to a method of converting a compound of formula (X):

to a compound of formula (VII):

wherein q, n, p,

are as defined below; the method comprising cyclizing the pyrimidine ring and the amide carbonyl by dehydration to form the fused 5-membered ring of formula (VII), and hydro lyzing the nitrile to form the carboxylic acid or carboxylic ester of formula (VII).

In another aspect, the present invention is directed to a method of making a compound of formula (VII):

wherein q, n, p, X 1 , X 2 , R 3 , R 4 , R 5 , R 6 , R V and as defined below;

the method comprising purifying a compound of formula (IV):

by converting a compound of formula (IV) to a compound of formula la:

subsequently converting the compound of formula (la) to a compound of formula

(IV);

the method further comprising converting the compound of formula (IV) to a compound of formula (XI):

by treating the compound of formula (IV) with a ethyl ester source and a base; the method comprising converting a compound of formula (XI) to an activated activated acid intermediate and coupling with a compound of formula (VIII):

II),

wherein X¹, X², R³, R⁴, R⁵ and R⁶ are as described for formula (VII) to provide a compound of formula (X

the method further comprising converting the compound of formula (Xa) to a compound of formula (VII) via cyclizing pyrimidine and amide carbonyl by dehydration to form the fused 5-membered ring of formula (VII), and hydro lyzing the ethyl ester to form the carboxylic acid or carboxylic ester of formula (VII).

In another aspect, the present invention is directed to a method of purifying a compound of formula (VII), the method comprising providing a solution of a compound of formula (VII) and causing the compound of formula (VII) to precipitate from the solution.

In another aspect, the present invention is directed to a method of storing a compound of formula (la):

wherein n, p, q, R¹, R³, R⁴ and M are as described for formula (I), the method comprising storing the compound in a container.

In one embodiment, the compound is stored at or above 0°C. In another embodiment, the compound is stored at or above room temperature. In yet another embodiment, the compound is stored at or below 0°C. In some embodiments, the compound is stored in an anhydrous environment.

Definitions

Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March 's Advanced Organic Chemistry, 5^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

The term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine or iodine.

The term "haloalkyl" refers to an alkyl group that may have any number of hydrogens available on the group replaced with a halogen atom. Representative haloalkyl groups include but are not limited to: -CH₂C1, -CH₂C1CF₃, -CHBr₂ or -CF₃. The term "fluoroalkyl" refers to an alkyl group that may have any number of hydrogens available on the group replaced with a fluorine atom. Representative fluoroalkyl groups include but are not limited to: -CH₂F, -CH₂FCF₃, -CHF₂ or -CF₃. The term "haloalkoxy" refers to an alkoxy group that may have any number of hydrogen atoms available on the alkyl group replaced with a halogen atom.

Representative haloalkoxy groups include but are not limited to: -OCH₂Cl, - OCH₂CICF₃, -OCHBr₂ or -OCF₃. The term "fluoroalkoxy" refers to an alkoxy group that may have any number of hydrogens available on the group replaced with a fluorine atom. Representative fluoroalkoxy groups include but are not limited to: - OCH₂F, -OCH₂FCF₃, -OCHF₂ or -OCF₃.

The term "alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci- C₁₂ alkyl indicates that the group may have from 1 to 12 carbon atoms in it. The terms "arylalkyl" or "aralkyl" refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group. Examples of "arylalkyl" or "aralkyl" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.

The term "alkylene" refers to a divalent alkyl, e.g., -CH₂-, -CH₂CH₂-, and -

The term "alkenyl" refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and having one or more double bonds. Examples of alkenyl groups include, but are not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent. The term "alkynyl" refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and characterized in having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.

The terms "alkylamino" and "dialkylamino" refer to -NH(alkyl) and - NH(alkyl)₂ radicals respectively. The term "aralkylamino" refers to a -NH(aralkyl) radical. The term alkylaminoalkyl refers to a (alkyl)NH-alkyl- radical; the term dialkylaminoalkyl refers to a (alkyl^N-alkyl- radical. The term "alkoxy" refers to an -O-alkyl radical. The term "mercapto" refers to an SH radical. The term

"thioalkoxy" refers to an -S-alkyl radical. The term thioaryloxy refers to an -S-aryl radical. The term "aryl" refers to an aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system, wherein any ring atom capable of substitution can be substituted, e.g., by one or more substituents. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, and anthracenyl.

The term "cycloalkyl" as employed herein includes saturated cyclic, bicyclic, tricyclic,or poly cyclic hydrocarbon groups having 3 to 12 carbons. Any ring atom can be substituted, e.g., by one or more atoms or functional groups. The cycloalkyl groups can comprise fused rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.

The term "heterocyclyl" refers to a nonaromatic 3-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, Si, P or S, e.g., carbon atoms and 1-3, 1-6, or 1- 9 heteroatoms of N, O, Si, P or S if monocyclic, bicyclic, or tricyclic, respectively. The heteroatom may optionally be the point of attachment of the heterocyclyl substituent. Any ring atom optionally can be substituted. The heterocyclyl groups can comprise fused rings. Fused rings are rings that share a common carbon atom. Examples of heterocyclyl include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino, pyrrolinyl, pyrimidinyl, quinolinyl, and pyrrolidinyl.

The term "heterocyclylalkyl", as used herein, refers to an alkyl group substituted with a heterocycle group.

The term "cycloalkenyl" refers to partially unsaturated, nonaromatic, cyclic, bicyclic, tricyclic, or poly eye lie hydrocarbon groups having 5 to 12 carbons, preferably 5 to 8 carbons. The unsaturated carbon may optionally be the point of attachment of the cycloalkenyl substituent. Any ring atom optionally can be substituted. The cycloalkenyl groups can comprise fused rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkenyl moieties include, but are not limited to, cyclohexenyl, cyclohexadienyl, or norbornenyl. The term "heterocycloalkenyl" refers to a cycloalkenyl that contains at least one heteroatom selected from the group consisting of O, N, Si, P or S. The unsaturated carbon or the heteroatom may optionally be the point of attachment of the heterocycloalkenyl substituent. Any ring atom optionally can be substituted. The heterocycloalkenyl groups can comprise fused rings that share a common carbon atom. Examples of heterocycloalkenyl include but are not limited to

tetrahydropyridyl and dihydropyranyl.

The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, Si, P or S. Any ring atom optionally can be substituted.

The term "heteroarylalkyl" or the term "heteroaralkyl" refers to an alkyl substituted with a heteroaryl.

The term "oxo" refers to an oxygen atom, which forms a carbonyl when attached to carbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfone when attached to sulfur.

The term "acyl" refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which optionally may be further substituted.

The term "pharmaceutically acceptable salt" refers to those compounds derived from pharmaceutically acceptable inorganic and organic acids and bases, depending on the particular substances founds on the compound(s). Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate,

benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metalsuch as sodium, alkaline earth metal such as magnesium, ammonium and N-(alkyl)₄ ⁺ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. Salt forms of the compounds of any of the formulae herein can be amino acid salts of carboxy groups, such as for example, L-arginine, -lysine, - histidine salts.

The term "prodrug" refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. For instance, prodrugs for carboxylic acid analogs of the invention include a variety of esters. In an exemplary embodiment, the pharmaceutical compositions of the invention include a carboxylic acid ester. In another exemplary embodiment, the prodrug is suitable for treatment/prevention of those diseases and conditions that require the drug molecule to cross the blood brain barrier. In a preferred embodiment, the prodrug enters the brain, where it is converted into the active form of the drug molecule. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

The term "substituent" refers to a group attached to an alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl, or heteroaryl group at any atom of that group. Suitable substituents include, without limitation, straight or branched chain alkyl, cycloalkyl, haloalkyl such as CF₃, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl,

heterocycloalkenyl, alkoxy, haloalkoxy such as OCF₃, halo, hydroxy, carboxy, carboxylate, cyano, nitro, amino, alkyl amino, S0₃H, sulfate, phosphate,

methylenedioxy such as -0-CH₂-0- wherein oxygens are attached to vicinal atoms, ethylenedioxy, oxo, thioxo such as C=S, imino, S(0)_nalkyl, S(0)_n aryl, S(0)_n heteroaryl, S(0)_n heterocyclyl, i.e., wherein n is an integer between 0 and 2, an amine, an ester, and a sulfonamide. In one aspect, the substituent on a group is independent from any other substituent or any subset of the aforementioned substituents. In another aspect, a substituent may itself be substituted with any one of the above substituents.

DETAILED DESCRIPTION

Embodiments of the Invention:

In one aspect, the invention is directed to a compound selected from formula

(I):

wherein

n, p and q, each independently, is an integer from 0-3;

R¹ is selected from hydrogen, hydroxyl, Ci_₈ alkyl with 0-3 occurrences Ci_8 alkoxy substituted with 0-3 occurrences of R³, and -N(R⁴)₂;

R² is selected from hydrogen, Ci_₈ alkyl, and Ci_₈ alkoxy;

each R³ is independently for each occurrence selected from hydrogen, hydroxyl, halogen, Ci_₈ alkyl, Ci_₈ alkenyl, Ci_₈ alkoxy, Ci_₈ alkenoxy, Ci. ^■8 haloalkyl, Ci_₈ haloalkoxy, -N(R⁴)₂, cyano and nitro;

each R⁴ is independently for each occurrence selected from hydrogen, C 1-8 alkyl with 0-3 occurrences of R³, Ci_₈ alkoxy substituted with 0-3 occurrences of R³, and aralkyl substituted with 0-3 occurrences of R³; and

M is a metal cation.

In certain embodiments, n is 2, p is 1 , and/or q is 1.

In certain embodiments, the compound is selected from the following formula:

In certain embodiments, R¹ is Ci_g alkoxy with 0 occurrences of R³, e.g., methoxy.

In certain embodiments, R² is hydrogen.

In certain embodiments, M has a charge of +1. In some embodiments, M⁺ is Na⁺.

In another aspect, the present invention is directed to a compound selected from formula (V):

wherein

n, p and q, each independently, is an integer from 0-3;

R¹ is selected from hydrogen, hydroxyl, Ci_g alkyl with 0-3 occurrences of R³, Ci_8 alkoxy substituted with 0-3 occurrences of R³, and -N(R⁴)₂; and

each R³ is independently for each occurrence selected from hydroxyl, halogen, Ci_8 alkyl, Ci_g alkenyl, Ci_g alkoxy, Ci_g alkenoxy, Ci_g haloalkyl, Ci_g haloalkoxy, - N(R⁴)₂, cyano and nitro;

represents a single or double bond.

In certain embodiments, n is 2, p is 1 , and /or q is 1. In certain embodiments, R¹ is hydroxyl or Ci_8 alkoxy substituted with 0-3 occurrences of R³. In some embodiments, R¹ is hydroxyl. In some embodiments, R¹ is Ci_8 alkoxy substituted with 0 occurrences of R³, e.g., methoxy.

In certain embodiments, is a single bond. In some embodiments, is a double bond. In some embodiments, the double bond contains an E geometry. In some embodiments, the double bond contains a Z geometry.

to a compound of formula (V)

In certain embodiments, n is 2, p is 1 , and/or q is 1.

In certain embodiments, the compound of formula (IV) is selected from the following:

In certain embodiments, R¹ is hydroxyl or Ci_8 alkoxy substituted with 0-3 occurrences of R³. In some embodiments, R¹ is hydroxyl. In some embodiments, R¹ is Ci_8 alkoxy substituted with 0 occurrences of R³, e.g., methoxy. In certain embodiments, formula (IV) is converted to formula (V) via treatment with acetonitrile and a base. In some embodiments, the base is sodium hydroxide. In some embodiments, the mixture is heated.

In certain embodiments, the method further comprises an ester hydrolysis step. In some embodiments, the ester hydrolysis step is carried out in the presence of an acid, such as for example, HC1 or aqueous HC1. In some embodiments, the ester hydrolysis step is heated. In some embodiments, the ester hydrolysis step is carried out in the presence of a base. In some embodiments, the base is sodium hydroxide, e.g., lM NaOH.

In certain embodiments, the method further comprises a reduction reaction on the product from the ester hydrolysis step. In some embodiments, the reduction step is carried out using H₂ and a Pd/C catalyst.

In certain embodiments, formula (IV) is converted to formula (V) via treatment with a cyanomethylphosphonate and a base. In some embodiments, the cyanomethylphosphonate is diethyl cyanomethylphosphonate. In some embodiments, the base is sodium t-butoxide. In some embodiments, the conversion of formula (IV) to formula (V) further comprises a solvent. In some embodiments, the solvent is THF.

to a compound of formula (la

wherein n, p, q, R¹, R³, R⁴ and M are as described for formula (I), the method comprising treating the compound of formula (IV) with a source of bisulfite. In certain embodiments, n is 2, p is 1, and/or q is 1.

In certain embodiments, the compound of formula (IV) is selected from the following formula:

In certain embodiments, R¹ is Ci_g alkoxy substituted with 0 occurrences of R³, e.g., methoxy.

In certain embodiments, the source of bisulfite is a bisulfite salt. In some embodiments, the bisulfite salt is sodium bisulfite. In some embodiments, the bisulfite salt is an aqueous mixture, e.g., 39% aqueous sodium bisulfite.

and subsequently converting the compound of formula (la) back to a compound of formula (IV);

wherein n, p, q, R¹, R³ and R⁴ are as described for formula (I).

In certain embodiments, n is 2, p is 1, and/or q is 1.

In certain embodiments, the compound of formula (IV) is converted to a compound of formula (la) by mixing the compound of formula (IV) with a source of bisulfite. In some embodiments, the source of bisulfite is a bisulfite salt. In some embodiments, the source of bisulfite is sodium bisulfite. In some embodiments, the bisulfite salt is an aqueous mixture, e.g., 39% aqueous sodium bisulfite.

In certain embodiments, the compound of formula (la) is converted to a compound of formula (IV) via treatment with acid, such as for example, sulfuric acid. In some embodiments, the method of converting a compound of formula (la) to a compound of formula (IV) further comprises a solvent. In some embodiments, the solvent is acetic acid. In some embodiments, the method of converting a compound of formula (la) to a compound of formula (IV) further comprises heat, e.g., 100°C.

to a compound of formula (X):

wherein

n, p and q, each independently, is an integer from 0-3;

X¹ and X², each independently, is S or O;

R¹ is selected from hydrogen, hydroxyl, Ci_g alkyl with 0-3 occurrences of R³, Ci_8 alkoxy substituted with 0-3 occurrences of R³ and -N(R⁴)₂;

each R³ is independently for each occurrence selected from hydrogen, hydroxyl, halogen, Ci_g alkyl, Ci_g alkenyl, Ci_g alkoxy, Ci_g alkenoxy, Ci_g haloalkyl, Ci_g haloalkoxy, -N(R⁴)₂, cyano and nitro;

each R⁴ is independently for each occurrence selected from hydrogen, Ci_g alkyl with 0-3 occurrences of R³, Ci_₈ alkoxy substituted with 0-3 occurrences of R³, and aralkyl substituted with 0-3 occurrences of R³;

R⁵ and R⁶, each independently, is hydrogen or Ci_₄ alkyl substituted with 0-3 occurrences of R³; and

represents a single or double bond;

the method comprising converting a compound of formula (V) to an activated acid or activated acid intermediate and coupling with a compound of formula (VIII):

wherein X¹, X², R³, R⁴, R⁵ and R⁶ are as described for formula (X).

In certain embodiments, n is 2, p is 1, and/or q is 1. In certain embodiments, the compound of formula (V) is selected from the following formula:

In certain embodiments, X¹ is O and/or X² is O.

In certain embodiments, R⁵ is Ci_₄ alkyl substituted with 0-3 occurrences of R³. In some embodiments, R⁵ is Ci_₄ alkyl substituted with 0 occurrences of R³, e.g., n-propyl.

In certain embodiments, R⁶ is Ci_₄ alkyl substituted with 0-3 occurrences of R³. In some embodiments, R⁶ is Ci_₄ alkyl substituted with 0 occurrences of R³, e.g., n-propyl.

In certain embodiments, the method optionally further comprises hydrolysis of an ester of a compound of formula (V). In some embodiments, the optional ester hydrolysis of the formula (V) compound is carried out in the presence of an acid. In some embodiments, the acid is HCl, e.g., 12M HCl (aq.). In some embodiments, the optional ester hydrolysis of the formula (V) compound is carried out in the presence of a base, such as for example, 1M NaOH.

In certain embodiments, the method optionally further comprises a reduction of the olefin of a compound of formula (V). In some embodiments, the optional olefin reduction of the formula (V) compound is carried out using a catalyst, e.g., Pd/C in the presence of H² at atmospheric pressure or higher. In certain

embodiments, activated acid of formula (V) is an acid chloride. In some

embodiments, converting the compound of (V) to an acid chloride is carried out by treating a compound of formula (V) with SOCl₂. In some embodiments, converting the compound of (V) an acid chloride is carried out at 0°C. In some embodiments, the activated acid intermediate of formula V is produced by treating with a coupling reagent, such as for example, DCC. In certain embodiments, the coupling of the activated acid or activated acid intermediate of formula (V) to the compound of formula (VIII) is carried out in the presence of a solvent wherein the solvent is MeTHF or a like solvent. In some embodiments, the coupling of the activated acid or activated acid intermediate for formula (V) further comprises a base. In some embodiments, the base is

triethylamine.

In another aspect, the present invention is directed to a method of converting a compound of formula (X):

(X),

to a compound of formula (VII)

wherein

n, p and q, each independently, is an integer from 0-3;

X¹ and X², each independently, is S or O;

R³ and R⁴ are as defined for formula (I);

R⁵, R⁶ and R⁷, each independently, is hydrogen or Ci_₄ alkyl substituted with 0-3 occurrences of R³; and represents a single or double bond;

the method comprising cyclizing the pyrimidine ring and the amide carbonyl by dehydration to form the fused 5-membered ring of formula (VII), and hydro lyzing the nitrile to form the carboxylic acid or carboxylic ester of formula (VII).

In certain embodiments, represents a single bond while in other embodiments, it represents a double bond.

In certain embodiments, the method further comprises reducing the double bond of formula (VII).

In certain embodiments, n is 2, p is 1 , and/or q is 1.

In certain embodiments, the compound of formula (X) is the following formula:

wherein R³, R⁴, R⁵, R⁶, X¹, X² and ^ are as described for formula (X). In certain embodiments, X¹ is O and/or X² is O.

In certain embodiments, R⁶ is Ci_₄ alkyl substituted with 0-3 occurrences of R³. In some embodiments, R⁶ is Ci_₄ alkyl substituted with 0 occurrences of R³, e.g., n-propyl. In some embodiments, R⁷ is hydrogen.

In certain embodiments, the nitrile hydrolysis and the 5-membered ring formation is carried out in the same reaction. In some embodiments, the nitrile hydrolysis and the 5-membered ring formation is carried out in separate reactions. In certain embodiments, the nitrile hydrolysis is carried out in the presence of base. In some embodiments, the base is potassium hydroxide, e.g., 1.5M KOH. In some embodiments, the nitrile hydrolysis further comprises a solvent. In some embodiments, the solvent is isopropyl alcohol. In some embodiments, the nitrile hydrolysis further comprises heating the reaction mixture, e.g., heating to reflux.

In certain embodiments, the formation of the 5-membered ring system is carried in the presence of an acid. In some embodiments, the acid is HC1, e.g., concentrated HC1 or 12M HC1 (aq.). In some embodiments, the nitrile hydrolysis further comprises heating the reaction, e.g., heating to 90°C.

In certain embodiments, the formation of the 5-membered ring system is carried out in the presence of base. In some embodiments, the base is potassium hydroxide. In some embodiments, the formation of the 5-membered ring system further comprises a solvent. In some embodiments, the solvent is isopropyl alcohol. In some embodiments, the formation of the 5-membered ring system further comprises heating the reaction mixture, e.g., heating to reflux.

In certain embodiments, the method further comprises esterifying the free carboxylic acid.

(VII),

wherein

n, p and q, each independently, is an integer from 0-3;

X¹ and X², each independently, is S or O;

R³ and R⁴ are as defined for formula (I); R⁵, R⁶ and R⁷, each independently, is hydrogen or Ci_₄ alkyl substituted with 0-3 occurrences of R³; and

represents a single or double bond

the method comprising purifying a compound of formula (IV):

by converting a compound of formula (IV) to a compound of formula (la)

subsequently converting the compound of formula (la) back to a compound of formula (IV);

by treating the compound of formula (IV) with a ethyl ester source and a base; the method comprising converting a compound of formula (XI) to an activated acid or activated acid intermediate and coupling with a compound of formula (VIII):

wherein X¹, X², R³, R⁴, R⁵ and R⁶ are as described for formula (VII) to provide a compound of formula (Xa):

In certain embodiments, n is 2, p is 1 , and/or q is 1.

In certain embodiments, X¹ is O and/or X² is O.

In certain embodiments, R⁵ is Ci_₄ alkyl substituted with 0-3 occurrences of

R³. In some embodiments, R⁵ is Ci_₄ alkyl substituted with 0 occurrences of R³, e.g., n-propyl.

In certain embodiments, R⁶ is Ci_₄ alkyl substituted with 0-3 occurrences of

R³. In some embodiments, R⁶ is Ci_₄ alkyl substituted with 0 occurrences of R³, e.g., n-propyl. In some embodiments, R⁷ is hydrogen.

In certain embodiments, the compound of formula (IV) is converted to a compound of formula (la) by treating a compound of formula (IV) with a source of bisulfite, such as for example, a bisulfite salt like sodium bisulfite. In some embodiments, the sodium bisulfite is an aqueous mixture, e.g., 39% aqueous sodium bisulfite. In certain embodiments, the compound of formula (la) is converted back to a compound of formula (IV) by treating a compound of formula (la) with acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the conversion of a compound of formula (la) to a compound of formula (IV) further comprises a solvent. In some embodiments, the solvent is acetic acid. In some embodiments, the conversion of a compound of formula (la) to a compound of formula (IV) further comprises heat, e.g., 100°C.

In certain embodiments, the compound of formula (IV) is converted to a compound of formula (XI) by utilizing a phosphonoacetate as the ethyl ester source. In some embodiments, the phosphonoacetate is triethylphosphonoacetate. In some embodiments, the base for converting a compound of formula (IV) to a compound of formula (XI) is triethylamine. In some embodiments, the reaction with

triethylphosphonoacetate further comprises a solvent, e.g., acetonitrile. In some embodiments, the reaction with triethylphosphonoacetate further comprises magnesium chloride.

In certain embodiments, the purified compound of formula (IV) has a purity of 50%. In certain embodiments, the purified compound of formula (IV) has a purity of 60%. In certain embodiments, the purified compound of formula (IV) has a purity of 70%. In certain embodiments, the purified compound of formula (IV) has a purity of 75%. In certain embodiments, the purified compound of formula (IV) has a purity of 80%. In certain embodiments, the purified compound of formula (IV) has a purity of 85%. In certain embodiments, the purified compound of formula (IV) has a purity of 90%. In certain embodiments, the purified compound of formula (IV) has a purity of 95%. In certain embodiments, the purified compound of formula (IV) has a purity of 97%. In certain embodiments, the purified compound of formula (IV) has a purity of 99%. In certain embodiments, the purified compound of formula (IV) has a purity of 99.9%.

In certain embodiments, the method optionally further comprises a reduction of the olefin of a compound of formula (XI). In some embodiments, the reduction is carried out by hydrogenation of the olefin of formula (XI). In some embodiments, the hydrogenation is carried out under H². In some embodiments, the hydrogenation further comprises a catalyst, e.g., Pd/C.

In certain embodiments, an activated acid of formula (XI) is an acid chloride. In some embodiments, an acid chloride of formula (XII) is produced by treating a compound of formula (XI) with SOCl₂. In some embodiments, the treatment with SOCl₂ is carried out at 0°C.

In certain embodiments, the activated acid intermediate of formula (V) is produced by treating with a coupling reagent. In some embodiments, the coupling reagent is DCC.

In certain embodiments, the coupling of an activated acid or activated acid intermediate of formula (XI) to the compound of formula (VIII) is carried out in a solvent. In some embodiments, the solvent is MeTHF. In some embodiments, the coupling of an activated acid or activated acid intermediate of formula (XI) to a compound of formula (VIII) further comprises a base. In some embodiments, the base is triethylamine.

In certain embodiments, a compound of formula (Xa) is converted to a compound of formula (VII) by formation of the 5-membered ring and the ethyl ester hydrolysis in separate reaction steps.

In certain embodiments, a compound of formula (Xa) is converted to a compound of formula (VII) by formation of the 5-membered ring and ethyl ester hydrolysis in the same reaction step.

In certain embodiments, the formation of the 5-membered ring system is carried in the presence of an acid. In some embodiments, the acid is HC1.

In certain embodiments, the ester hydrolysis is carried out in the presence of base. In some embodiments, the base is potassium hydroxide. In some embodiments, the ester hydrolysis further comprises a solvent, e.g., 2-methyl THF. In some embodiments, the ester hydrolysis further comprises heating the reaction mixture, e.g., heating to 70°C.

In certain embodiments, the solution comprises acetic acid. In some embodiments, the solution comprises hot acetic acid. In some embodiments, the precipitation of the compound of formula (VII) is caused by adding water. In some embodiments, the precipitation of the compound of formula (VII) is caused by adding water to the solution and cooling the resulting solution, e.g., to 85°C, to 0°C, to -5°C.

Compounds of the invention

In synthetically guided efforts to identify methods of purifying key

intermediates in the synthetic process described herein, discovery of novel compounds has been achieved. Accordingly, described herein are compounds of formula (I),

wherein R¹, M, R² _, q, n and p are as described herein. The compounds can be useful, for example, to purify corresponding aldehydes such as compounds of formula (IV):

This method may be carried out by reacting an aldehyde, such as those aldehyde compounds described herein with a formula (I) compound. Conversion to a formula (I) compound is usually carried out via mixing with a source of bisulfite. The resulting compound is generally purified by filtration and washing with an appropriate solvent or a similar manner. Upon purification, the compound (I) intermediate can then easily be converted back to the aldehyde. Conversion back to the aldehyde can be accomplished in a number of ways, e.g., treatment with acid.

Also included in the present application are novel compounds of formula (V):

wherein R¹, q, n, p and— are as described herein. These compounds are novel intermediates discovered by the synthetic efforts toward a synthesis as described herein.

Methods of Making Compounds as Described Herein

The compounds of formula (I) described herein can be made using a variety of synthetic techniques.

Scheme 1.

Scheme 1 above is an exemplary synthetic sequence that depicts a

representative synthesis of compounds of formula I described herein. Aldehyde 19 is reacted with aqueous sodium bisulfite. The resulting heterogenous suspension was filtered and the filter cake was washed with MTBE and dried under vacuum. All variables depicted in scheme 1 above are as described herein.

The compound of formula (V) described herein can also be made using a variety of synthetic techniques.

Scheme 2.

Scheme 2 above is an exemplary synthetic sequence that depicts a

representative synthesis of compounds of formula (V) described herein. Aldehyde 19 is reacted with potassium hydroxide in an acetonitrile solvent. The resulting mixture is cooled and treated with cone, hydrochloric acid to produce a white precipitate. Upon filtration and drying target compound 21 is provided. All variable depicted in scheme 2 above are as described herein.

Compounds of formula (VII) can also be made using synthetic techniques described herein.

Scheme 3.

23 24

Scheme 3 above is an exemplary synthetic sequence that depicts a

representative synthesis of a compound of formula (VII) from a compound of formula (V) as described herein. Compound 21 is treated with SOCl₂ to form the

corresponding acid chloride (22). 22 is subsequently coupled with compound 25 under standard conditions to produce 23. Coupling product 23 is then treated with strong base, e.g., KOH and heat followed by strong acid, e.g., HC1 and heat to produce target compound 24. All variables depicted in scheme 3 above are as described herein. Scheme 4.

27 24

Scheme 4 above is an exemplary synthetic sequence that depicts a

representative synthesis of a compound of formula (VII) from a compound of formula (I) as described herein. Compound 20 is treated with triethylphosphonoacetate under standard Horner- Wadsworth-Emmons conditions to produce 26. Olefin 26 was then hydrogenated and treated with SOCl₂ to produce the acid chloride of 26 which when reacted with 25 under standard coupling conditions produced 27. Cyclization and hydrolysis of the ethyl ester can be carried out via treatment with strong base and acid to produce target compound 24. All variables depicted in scheme 4 above are as described herein.

Methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, any synthetic steps described herein may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies, i.e., protection and deprotection, useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. Reaction Mixtures

The present invention refers to compositions comprising a compound of formulas (I), (la), (IV), (V), (VII), (VIII), (X), (Xa) and (XI), including a reaction mixture, e.g., a reaction mixture that is present during a method or process described herein.

In certain embodiments, the methods described herein further comprise a solvent. In certain embodiments, the solvent is an organic solvent. In certain embodiments, the solvent is an aprotic solvent. Exemplary organic solvents include, but are not limited to, benzene, toluene, xylenes, methanol, ethanol, isopropanol, acetonitrile, acetone, ethyl acetate, ethyl ether, tetrahydrofuran, methylene chloride, dichloroethane and chloroform, or a mixture thereof. In certain embodiments, the solvent is acetonitrile. In certain embodiments, the solvent is methylene chloride. In certain embodiments, the solvent is tetrahydrofuran. In certain embodiments, the solvent is dichloroethane. In certain embodiments, the solvent is benzene.

In certain embodiments, the reaction is carried out below room temperature, e.g., a cooled reaction such as a reaction at a temperature of 0°C or lower. In certain embodiments, the reaction is carried out above room temperature, e.g., by heating. In certain embodiments, the reaction occurs under an inert atmosphere, e.g, an atmosphere of an inert gas such as nitrogen or argon. In certain embodiments, the reaction takes place under anhydrous conditions, e.g., conditions that are substantially free of water.

Described herein are compositions comprising a compound described herein, e.g., a compound of formulas (I), (la), (IV), (V), (VII), (VIII), (X), (Xa) and (XI). In some embodiments, the compounds described herein are in a composition comprising a solvent, e.g., as a mixture such as a solution or a heterogeneous mixture. The composition can be free of compounds that would react with or degrade a compound described herein e.g., the composition can be substantially free of water and/or substantially free of any reactive gases.

Pharmaceutical Compositions The present invention also features pharmaceutical compositions including any of the compounds described herein, either alone or in combination, together with a suitable excipient. In some preferred embodiments, the pharmaceutical composition is a composition that can be administered to a subject parenterally, e.g., a liquid composition such as a solution. In some embodiments, the composition is a solid composition, for example, a lyophilite, which can be further processed prior to administering the composition to a subject, for example, the solid composition can be further processed to form a liquid composition such as a solution.

Methods of Use

The compounds and compositions described herein, e.g., a compound or composition of formula (VII), can be administered to a subject who is suffering from a disorder where antagonizing the Ai adenosine receptor would be beneficial. For example, Ai adenosine receptor antagonists can be useful in the prevention and/or treatment of numerous diseases, including cardiac and circulatory disorders, degenerative disorders of the central nervous system, respiratory disorders, and many diseases for which diuretic treatment is suitable. In some preferred embodiments, a compound or composition described herein, for example, a composition including 3- [4-(2,6-dioxo-l ,3-dipropyl-2,3,6,7-tetrahydro-lH-purin-8-yl)-bicyclo[2.2.2]oct-l- yl]propionic acid is administered in the treatment of acute decompensated heart failure. In some preferred embodiments, a compound or composition described herein, for example, a composition including 3-[4-(2,6-dioxo-l,3-dipropyl-2,3,6,7- tetrahydro-lH-purin-8-yl)-bicyclo[2.2.2]oct-l-yl]propionic acid is administered in a subject having concomittant renal insufficiency. In some embodiments, the subject is being treated for both acute decompensated heart failure and concomittant renal insufficiency.

Incorporation by Reference

All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. EXAMPLES

Scheme 5.

2 3 4

Example 1. Preparation of Intermediate 4

Preparation of Nitrile 2 from Aldehyde 1:

Method A.

1 (29.4 g, 0.150 mol) and KOH (19.8 g, 0.300 mol) were placed in a round-bottom flask followed by addition of Acetonitrile (300 mL). The mixture was heated at reflux overnight and formed a cloudy suspension. To the reaction mixture was added water (300 mL). A clear solution is formed. The solution was subsequently heated at 65 °C for 3 h, and then stirred at rt overnight. The mixture was cooled with ice bath and added HCI (12N, 30 mL) to pH 2. White precipitates form in the mixture. The solid was collected by filtration and washed with water. The filtration cake was dried in a vacuum oven at 50 °C overnight to yield the crude product 3 (21 g) in 68% yield. Method B.

1 (9.81 g, 0.0500 mol) was dissolved in THF (100 mL). Diethyl cyanomethyl- phosphonate (8.90 mL, 0.0550 mol) was added. The mixture was cooled with an ice bath. Sodium tert-butoxide (5.28 g, 0.0550 mol) was added slowly. After 10 min, the suspension became a clear solution. After 2 h, aq NaOH (1M, 50 mL) was added. The mixture was stirred at room temperature overnight. To the reaction mixture was added water (100 mL) and MTBE (100 mL). The aqueous layer was separated and washed with MTBE (100 mL) cooled with ice batch and acidified with HCI (2M, 50 mL). The precipitate was collected by filtration and dried in a vacuum oven at 50 °C overnight to yield the product (3) as white solid (7.92 g) in 72.2% yield.

Preparation of Intermediate 4 from Olefin 3: 3 (1 g, 0.005 mol) was dissolved in THF (10 mL) which was followed by addition of Pd/C (10%, 0.4 g). The mixture was stirred under hydrogen (1 atm) overnight. The resulting reaction mixture was filtered through a pad of celite. Crystals formed in the mother liquid during the filtration. To the filtrate was added acetone and EtOAc. The solution was evaporated. The formed crystal was collected and dried in a vacuum oven at 30 °C for 48 h to yield the product (4).

Scheme 6.

6

Example 2. Preparation of Target Compound 9

Preparation of Acid Chloride 5:

4 (41.4 g, 0.200 mol) was dissolved in MeTHF (160 mL) followed by addition of DMF (1.6 mL). The mixture was cooled with an ice-bath. Thionyl chloride (16.0 mL, 0.220 mol) was subsequently added. The mixture was stirred at rt until the reaction was complete as determined by GC-FID analysis.

Preparation of 7 from Acid Chloride 5:

6 (57.8 g, 0.220 mol) was suspended in MeTHF (150 mL) which was followed by the addition of triethylamine (83.6 mL, 0.600 mol). The resulting suspension is cooled to 0 °C. Acid chloride 5 was then added. The mixture was stirred and warmed to rt. When the reaction was complete as determined by HPLC-UV analysis, water (300 mL) was added. The organic layer was separated and washed with HCI solution (1M, 300 mL) and aqueous Na₂C0₃ solution (0.5 M, 300 mL) sequentially. The organic layer was concentrated in vacuo at 36 °C to yield crude 7 as an oil, which was used in the next step without further purification. Preparation of Acid 8 from 7:

To crude 7 was added isopropyl alcohol (160 mL) and KOH aqueous solution (1.50 M, 400 mL). The reaction mixture was heated at reflux until the reaction was complete as determined by HPLC-UV analysis. The mixture was then cooled via an ice-bath. HC1 (12N, 55 mL) was added to adjust the reaction mixture to pH 2-3. The isopropyl alcohol was removed in vacuo at 36 °C. The mixture was stirred at room temperature for over 48 h and precipitants were formed from the mixture. The resulting solids were collected by filtration and dried in a vacuum oven at 50 °C overnight to yield 78 g of acid 7 as a yellow powder, 78 g, in a yield of 94% over 3 steps from intermediate 4.

Preparation of Target Compound 9 from Acid 8:

Method A.

To crude 8 (5.37 g, 0.0135 mol) was added concentrated hydrochloric acid (30 mL, 1 mol). The resulting reaction mixture was heated at 90 °C until the reaction was complete as determined by HPLC-UV analysis. To the mixture was added water. The resulting mixture was cooled to with an ice bath. The resulting precipitate was collected by filtration and dried in a vacuum oven at 50 °C to yield the crude product (9) as a yellow powder (4.80 g) in a yield of 85.4%.

Method B.

Crude 8 (27.1 g, 0.0682 mol) was suspended in isopropyl alcohol (50 mL) followed by addition of KOH aqueous solution (1.5 M, 135 mL, 0.202 mol). The resulting clear solution was heated at reflux until the reaction was complete as determined by HPLC-UV analysis. When the reaction was complete, the mixture was cooled with an ice-bath. HC1 (6M, 40 mL) was added and the mixture was concentrated in vacuo at 36 °C to remove the isopropyl alcohol. To the mixture was added water followed by cooling with an ice-bath. The resulting mixture was allowed to warm to room temperature stirred overnight. Precipitates formed from the mixture and the resulting solid was collected by filtration. The solid was then dried in a vacuum oven at 50 °C overnight to yield the crude product (9) as a yellow powder (30.6 g) in a yield of 108%.

Preparation of Target Compound 9 from 7: 7 (166 mg, 0.4 mmol) was added to 1 mL of solvent in a 20 mL scintillation vial containing a Teflon-coated stirring bar. A solution of 1.5M KOH (4 to 7 equivalents - 1.6 mmol to 2.8 mmol) was subsequently added and the vial was sealed and heated at 120 °C for 18 hours. The resulting mixture was diluted with water followed by addition of aq HC1 (12 N) until a pH 2 was reached. The mixture was stirred at room temperature for an additional 1 h. Precipitates formed in the mixture and the resulting solid was collected by filtration, and dried in a vacuum oven at 70 °C for 24 h. The obtained yield ranged from 104-207%. These unusually high yields were due to contamination of the crude product with diethylene glycol. The crude product may be recrystallized as set forth in Example 4 below.

Scheme 7.

10 11 12 13 14 15

Example 3. Preparation of Intermediate 15

Preparation of Acid Chloride 11 from 10:

To 10.0 kg (1.0 eq) of 10 in 6 liters if dichloromethane was added a catalytic amount (0.01L) of DMF followed by addition of 6.88 kg (1.05 eq) of oxalyl chloride at approximately 20°C. After the reaction was complete, methylene chloride was removed and heptane was added followed by cooling to -5°C which produced a white slurry. The slurry was filtered and dried to give 9.5 kg of 11, 87%> molar yield.

Preparation of 13 from Acid Chloride 11:

9.4 Kg of 11 was dissolved in 9.4 liters of 2-MeTHF and subsequently added to a mixture of 0.94 kg of Pd/BaS0₄ and 5.18 Kg (1.05eq) of collidine in 49.4 liters of 2- MeTHF under nitrogen. The reaction was allowed to stir under hydrogen pressure at about 30°C. The mixture was then cooled to 20°C and filtered. The collidine was removed by washing the resulting mixture with acid, e.g., aqueous HC1. The organic layer was further washed with aqueous Na₂C0₃ followed by addition of 98 Kg of 39%> aqueous NaHS0₃ (9 eq) at about 20°C to convert 11 to crystalline 13. The heterogeneous mixture was filtered, washed with MTBE and dried in vacuo to give 9.77 Kg of 13 in 93% molar yield from 11.

Preparation of Aldehyde 14 from 13:

Under nitrogen, to 11.4 Kg of 13 in 14.9 L of acetic acid was added 29.8 L of 2M H₂SO₄. The resulting mixture was slowly heated to 100°C and allowed to stir for one hour. Distillation of the acid solvents was carried out until the final volume was 3.5 liters, 3.5 x 11.4 liters. The mixture was then heated to 100°C until the reaction was complete. The mixture was cooled to room temperature and stirred for an additional 10 hours. The mixture was then cooled to 0°C for 3 hours. The resulting suspension is filtered and the filter cake is washed three times with cold water. The wet cake is dried at about 50°C until KF is < 0.1% to give 5.5 kg of 14, 90% molar yield.

Preparation of Ethyl Ester 15 from Aldehyde 14:

Under nitrogen, to a mixture of 5.04 kg (1.0 eq) of 14 and 3.56 kg (1.35 eq) of anhydrous MgCl₂ was slowly added 25.2 liters of acetonitrile and 7.44 kg (1.2 eq) of triethyl phosphonoacetate at 30°C. 8.12 Kg (2.9 eq) of triethylamine was then added slowly while maintaining the temperature below 50°C. The mixture was stirred at 50°C until the reaction was complete. After the reaction was complete, the batch was cooled to 40°C followed by addition of 11.1 liters of water and 6 N aqueous HCl until a pH of 2.0-2.5 was reached. Charge 14.1 liters of water at 40°C and the batch was cooled to about 5°C in 2 hours. The batch was held at 5°C for 3 hours and filtered. The wet cake was washed three times with 5 liters of cold water and dried at 50°C in vacuo to give 6.6 Kg of 14 in 95%> molar yield.

Scheme 8.

6

Example 4. Preparation of Target Compound 9

Preparation of Ester 16 from 15:

Under nitrogen, 6.28 kg of 15 in 75 liters of THF was added 0.63 kg of Pd/C (10% Pd loading, 60%> wet) at about 25°C. The nitrogen inlet was then replaced with hydrogen, from 1 bar to 3 bar. After completion of the reaction, the batch was filtered, washed 3 times with 13 liters of THF and concentrated to 16 liters in volume. This was followed by addition of 63 liters of cold water, 2 to 5°C, to afford a white precipitate. The suspension was kept at 2 to 5°C overnight and filtered. The wet cake was dried 50°C under vacuo to give 6.0 kg of 16, 95% molar yield.

Preparation of Acid Chloride 17 from 16:

Under nitrogen, to 5.53 kg of 16 in 28 liters of 2-methyl THF at 5°C was added 0.44 kg (0.2 eq) of triethylamine followed by 2.95 kg (1.14 eq) of thionyl chloride. The reaction mixture was warmed to 22°C and stirred until the reaction was complete. Preparation of Coupling Product 18 from Acid Chloride 17:

To a heterogeneous solution of 6.86 kg (1.2 eq) of 6 in 33 liters of 2-methyl THF at 5°C was added 8.1 kg (3.68 eq) of triethylamine while maintaining the temperature under 10°C. To the resulting reaction mixture, an acid chloride (17) solution was added slowly at about 10°C. The reaction mixture was then allowed to warm to room temperature. After the reaction was completed, 33 liters of water was added followed by addition of 6N HC1, about 1.6 liter, until a pH of 3.0 -3.5 was reached. The resulting layers were separated and the organic phase was washed with 18.8 liter of water and used crude. Preparation of Target Molecule 9 from Coupling Product 18:

To a solution of 18 in 2-methyl THF was slowly added 19.4 L of 4 N aqueous KOH while maintaining the temperature below 30°C. The solution was heated to and maintained at 70°C until the reaction was complete. The solution was then cooled to about 20°C and the layers separated. The aqueous layer was further washed by MTBE with the pH adjusted to 10.5 to 11.0 with 3N HC1. The aqueous layer was separated and pH adjusted to about 2.5 with HC1 to afford white precipitation. The heterogeneous mixture was stirred at 20°C for 2 hours then filtered, washed and dried at 50°C to give 8.6 kg of crude cake of target molecule 9.

Purification of Target Molecule 9:

8.13 kg of crude 9 was charged with 49 L of acetic acid and warmed to 95°C resulting in a solution. The warm solution was filtered through 0.2μ filter. To the filtered solution was slowly and added 9.8 L of water. The resulting mixture was cooled to 85°C and 9 L of water was added slowly over 15 minutes. The batch was maintained at 85°C for one hour and then cooled to 5°C over 4 hours. After cooling to 5°C the batch was maintained at 0-5°C for another 2 hours. The batch was filtered and washed with 8 L of AcOH/H₂0, 3: 1, at 0-5°C. The batch was further washed with 16 L of water. The resulting wet cake was dried at 115°C in vacuo to give 7.32 kg of purified 9 in 90% molar yield from coupling product 18.

Claims

CLAIMS What is claimed is:

1. A compound or pharmaceutically acceptable salt or prodrug thereof selected from formula (I):

wherein

n, p and q, each independently, is an integer from 0-3;

R¹ is selected from hydrogen, hydroxyl, Ci_g alkyl with 0-3 occurrences of R³, Ci_g alkoxy substituted with 0-3 occurrences of R³, and -N(R⁴)₂;

R² is selected from hydrogen, Ci_₈ alkyl, and Ci_₈ alkoxy;

each R³ is independently for each occurrence selected from hydrogen, hydroxyl, halogen, Ci_g alkyl, Ci_g alkenyl, Ci_g alkoxy, Ci_g alkenoxy, Ci_g haloalkyl,

haloalkoxy, -N(R⁴)₂, cyano and nitro;

each R⁴ is independently for each occurrence selected from hydrogen, Ci_g alkyl with

0-3 occurrences of R³, Ci_₈ alkoxy substituted with 0-3 occurrences of R³, and aralkyl substituted with 0-3 occurrences of R³; and

M is a metal cation.

2. The compound according to claim 1 , wherein p is 1 , q is 1 and n is 2.

3. The compound according to claim 1 , wherein R¹ is methoxy, R² is hydrogen and M⁺ is Na⁺.

4. A compound or pharmaceutically acceptable salt or prodrug thereof selected from formula (V):

wherein

n, p and q, each independently, is an integer from 0-3;

R¹ is selected from hydrogen, hydroxyl, Ci_g alkyl with 0-3 occurrences of R³, Ci_g alkoxy substituted with 0-3 occurrences of R³, and -N(R⁴)₂; and

each R³ is independently for each occurrence selected from hydroxyl, halogen, Ci_g alkyl, Ci_g alkenyl, Ci_g alkoxy, Ci_g alkenoxy, Ci_g haloalkyl, Ci_g haloalkoxy, -

N(R⁴)₂, cyano and nitro;

each R⁴ is independently for each occurrence selected from hydrogen, Ci_₈ alkyl with

0-3 occurrences of R³, Ci_g alkoxy substituted with 0-3 occurrences of R³, and aralkyl substituted with 0-3 occurrences of R³; and

represents a single or double bond.

5. The compound according to claim 4, wherein n is 2, p is 1 and q is 1.

6. The compound according to claim 4, wherein R¹ is hydroxyl or methoxy and is a double bond

7. The compound according to claim 6, wherein the double bond contains a Z geometry.

8. A method of converting a compound of formula (V):

to a compound of formula (X):

wherein

n, p and q, each independently, is an integer from 0-3;

X¹ and X², each independently, is S or O;

R¹ is selected from hydrogen, hydroxyl, Ci_₈ alkyl substituted with 0-3 occurrences of

R³, Ci_8 alkoxy substituted with 0-3 occurrences of R³ and -N(R⁴)₂;

0-3 occurrences of R³, Ci_g alkoxy substituted with 0-3 occurrences of R³, and aralkyl substituted with 0-3 occurrences of R³;

R⁵ and R⁶, each independently, is hydrogen or Ci_₄ alkyl substituted with 0-3

occurrences of R³; and

represents a single or double bond;

wherein X¹, X², R³, R⁴, R⁵ and R⁶ are as described for formula (X).

9. The method of claim 8, wherein n is 2, p is 1 and q is 1.

10. The method of claim 8, wherein X¹ is O and X² is O

11. The method of claim 8, wherein R⁵ and R⁶, each independently, is Ci_₄ alkyl substituted with 0 occurrences of R³.

12. The method of claim 8, optionally further comprising hydrolysis of an ester of a compound of formula (V).

13. The method of claim 12, wherein the optional ester hydrolysis of the formula (V) compound is carried out in the presence of HC1 or sodium hydroxide.

14. The method of claim 8, optionally further comprising a reduction of the olefin of a compound of formula (V) in the presence of a catalyst.

15. The method of claim 8, wherein the activated acid of formula (V) is an acid chloride produced by treating a compound of formula (V) with SOCl₂ at 0°C.

16. The method of claim 8, wherein the coupling of the activated acid or activated acid intermediate of formula (V) to the compound of formula (VIII) is carried out in a MeTHF solvent in the presence of triethylamine.

17. A method of converting a compound of formula (X):

to a compound of formula (VII)

wherein

n, p and q, each independently, is an integer from 0-3;

X¹ and X², each independently, is S or O;

each R³ is independently for each occurrence selected from hydrogen, hydroxyl, halogen, Ci_g alkyl, Ci_g alkenyl, Ci_g alkoxy, Ci_g alkenoxy, Ci_g haloalkyl, Ci_g haloalkoxy, -N(R⁴)₂, cyano and nitro; each R⁴ is independently for each occurrence selected from hydrogen, Ci_g alkyl with 0-3 occurrences of R³, Ci_g alkoxy substituted with 0-3 occurrences of R³, and aralkyl substituted with 0-3 occurrences of R³;

R⁵, R⁶, and R⁷, each independently, is hydrogen or Ci_₄ alkyl substituted with 0-3 occurrences of R³; and

represents a single or double bond;

the method comprising cyclizing the pyrimidine ring and the amide carbonyl by

dehydration to form the fused 5-membered ring of formula (VII), and hydrolyzing the nitrile to form the carboxylic acid or carboxylic ester of formula (VII).

18. The method of claim 17, wherein represents a double bond.

19. The method of claim 17, further comprising reducing the double bond of formula (VII).

20. The method of claim 17, wherein n is 2, p is 1 and q is 1.

21. The method of claim 17, wherein X¹ is O and X² is O.

22. The method of claim 17, wherein R⁵ and R⁶, each independently, is Ci_₄ alkyl substituted with 0 occurrences of R³.

23. The method of claim 17, wherein R⁷ is hydrogen.

24. The method of claim 17, wherein the nitrile hydrolysis and the 5-membered ring formation is carried out in the same reaction.

25. The method of claim 17, wherein the nitrile hydrolysis and the 5-membered ring formation is carried out in separate reactions.

26. The method of claim 17, wherein the nitrile hydrolysis is carried out in the presence of isopropyl alcohol, a potassium hydroxide base and heat.

27. The method of claim 17, wherein the formation of the 5-membered ring

system is carried in the presence of HC1 and heat.

28. The method of claim 17, wherein the formation of the 5-membered ring

system is carried out in the presence of and isopropyl alcohol solvent, a potassium hydroxide base and heat.

29. The method of claim 17, further comprising esterifying the free carboxylic acid.

30. A method of making a compound of formula (VII):

wherein

n, p and q, each independently, is an integer from 0-3;

X¹ and X², each independently, is S or O;

each R³ is independently for each occurrence selected from hydrogen, hydroxyl, halogen, Ci_₈ alkyl, Ci_₈ alkenyl, Ci_₈ alkoxy, Ci_₈ alkenoxy, Ci_₈ haloalkyl, Ci_₈ haloalkoxy, -N(R⁴)₂, cyano and nitro;

0-3 occurrences of R³, Ci_₈ alkoxy substituted with 0-3 occurrences of R³, and aralkyl substituted with 0-3 occurrences of R³;

R⁵, R⁶ and R⁷, each independently, is hydrogen or Ci_₄ alkyl substituted with 0-3 occurrences of R³; and

represents a single or double bond

the method comprising purifying a compound of formula (IV):

COR¹

CHO (IV),

by converting a compound of formula (IV) to a compound of formula (la):

the method further comprising converting the compound of formula (IV) to a

compound of formula (XI):

by treating the compound of formula (IV) with a ethyl ester source and a base;

the method comprising converting a compound of formula (XI) to an activated acid or activated acid intermediate and coupling with a compound of formula (VIII):

the method further comprising converting the compound of formula (Xa) to a

compound of formula (VII) via cyclizing pyrimidine and amide carbonyl by dehydration to form the fused 5-membered ring of formula (VII), and hydrolyz the ethyl ester to form the carboxylic acid or carboxylic ester of formula (VII).

31. The method of claim 30, wherein n is 2, p is 1 and q is 1.

32. The method of claim 30, wherein X¹ is O and X² is O.

33. The method of claim 30, wherein R⁵ and R⁶, each independently, is Ci_₄ alkyl substituted with 0 occurrences of R³.

34. The method of claim 30, wherein R⁷ is hydrogen.

35. The method of claim 30, wherein the compound of formula (IV) is converted to a compound of formula (la) by treating a compound of formula (IV) with an aqueous mixture of sodium bisulfite.

36. The method of claim 30, wherein the compound of formula (la) is converted back to a compound of formula (IV) by treating a compound of formula (la) with an acetic acid solvent, sulfuric acid and heat.

37. The method of claim 30, wherein the compound of formula (IV) is converted to a compound of formula (XI) by utilizing triethylphosphonoacetate as the ethyl ester source and triethylamine in the presence of a magnesium chloride and a solvent.

38. The method of claim 30, optionally further comprising a hydrogenation

reduction of the olefin of a compound of formula (XI) carried out under H² in the presence of a catalyst.

39. The method of claim 30, wherein an activated acid of formula (XI) is an acid chloride produced by treating a compound of formula (XI) with SOCl₂ at 0°C.

40. The method of claim 30, wherein a compound of formula (Xa) is converted to a compound of formula (VII) by formation of the 5-membered ring and the ethyl ester hydrolysis in separate reaction steps.

41. The method of claim 30, wherein a compound of formula (Xa) is converted to a compound of formula (VII) by formation of the 5-membered ring and ethyl ester hydrolysis in the same reaction step.

42. The method of claim 30, wherein the formation of the 5-membered ring

system is carried in the presence of HC1.

43. The method of claim 30, wherein the ester hydrolysis is carried out in the presence of potassium hydroxide, a solvent and heat.