Related Art [0002] Several classes of therapeutically useful drugs, including local anesthetics such as lidocaine and bupivacaine, antiarrhythmics such as propafenone and amioclarone, and anticonvulsants such as lamotrigine, phenytoin and carbamazepine, have been shown to share a common mechanism of action by blocking or modulating Na+ channel activity (Catterall, W. A., Trends Pharmacol. Sci. 8 : 57-65 (1987) ). Each of these agents is believed to act by interfering with the rapid influx of Na+ ions.

[0003] Recently, other Na+ channel blockers such as BW619C89 and lifarizine have been shown to be neuroprotective in animal models of global and focal ischemia and are presently in clinical trials (Graham et al., J. Pharmacol. Exp. Ther. 269 : 854-859 (1994); Brown et al., British J. Pharmacol. 115 : 1425-1432 (1995)).

[0004] The neuroprotective activity of Na channel blockers is due to their effectiveness in decreasing extracellular glutamate concentration during ischemia by inhibiting the release of this excitotoxic amino acid neurotransmitter. Studies have shown that unlike glutamate receptor antagonists, Na+ channel blockers prevent hypoxic damage to mammalian white matter (Stys et al., J. Neurosci. 12 : 430-439 (1992)).

Thus, they may offer advantages for treating certain types of strokes or neuronal trauma where damage to white matter tracts is prominent.

[0005] Another example of clinical use of a Na channel blocker is riluzole. This drug has been shown to prolong survival in a subset of patients with ALS (Bensimm et al., New Engl. J. Med. 330 : 585-591 (1994) ) and has subsequently been approved by the FDA for the treatment of ALS. In addition to the above-mentioned clinical uses, carbamazepine, lidocaine and phenytoin are occasionally used to treat neuropathic pain, such as from trigeminal neurologia, diabetic neuropathy and other forms of nerve damage (Taylor and Meldrum, Trends Phannacol. Sci. 16 : 309-316 (1995)), and carbamazepine and lamotrigine have been used for the treatment of manic depression (Denicott et al., J. Clin. Psychiatry 55 : 70-76 (1994) ). Furthermore, based on a number of similiarities between chronic pain and tinnitus, (Moller, A. R., Am. J OtoL 18 : 577-585 (1997) ; Tonndorf, J., Hear.

Res. 28 : 271-275 (1987)) it has been proposed that tinnitus should be viewed as a form of chronic pain sensation (Simpson, J. J. and Davies, E. W., Trends Pharmacol. Sci. 20: 12-18 (1999) ). Indeed, lignocaine and carbamazepine have been shown to be efficacious in treating tinnitus (Majumdar, B. et al., Clin. Otolaryngol. 8 : 175-180 (1983) ; Donaldson, I., Laryngol. Otol. 95 : 947-951 (1981)).

[0006] It has been established that there are at least five to six sites on the voltage-sensitive Na+ channels which bind neurotoxins specifically (Catterall, W. A., Science 242 : 50-61 (1988) ). Studies have further revealed that therapeutic antiarrhythmics, anticonvulsants and local anesthetics whose actions are mediated by Na+ channels, exert their action by interacting with the intracellular side of the Na channel and allosterically inhibiting interaction with neurotoxin receptor site 2 (Catterall, W. A., Ann. Rev. Pharmacol. Toxicol. 10 : 15-43 (1980)).

[0007] 2-Aryl pyrimidine 4-carboxylic acid amides have been shown to block or modulate Na+ channel activity, and thus are useful for treating disorders responsive to the blockade of sodium channels (Hogenkamp, D. J. et al., U. S. Pat. Appl. Publ. No. 2002/0040025 Al).

The usual method of manufacturing this type of compound involves creation of the pyrimidine ring by cyclizing an aryl carboxamidine with methyl 2,2-dimethoxyethyl ketone, followed by oxidation of the methyl group at the 4-position of the pyrimidine ring to a carboxyl group and subsequent conversion to an amide to generate the pyrimidine 4-carboxylic acid amide. See, e. g., Burdeska, K. et al., Helv. Chim. Acta 64 : 113-152 (1981); Sakamoto, T. et al., Chem.

Pharm. Bull. 28 : 571-577 (1980). This oxidation is typically effected using selenium dioxide, whose toxicity presents problems for practicably carrying out the reaction on a commercial scale. Various permanganate-and chromium-based oxidations reported for use with pyridines yielded poor results when attempted on the corresponding pyrimidines. Committed to the aryl carboxamidine as a synthetic intermediate, a different approach was conceived, one in which the cyclization would yield a substituted pyrimidine with the carbon atom attached to C-4 of the pyrimidine ring already in the ultimate oxidation state.

[0008] Riley, T. A. et al. (J Heterocyclic Chem. 24 : 955-964 (1987)) reports the formation of ethyl 2- (P-D-ribofuranosyl) pyrimidine carboxylate from 2, 5-anhydro-D-allonamidine hydrochloride and ethyl 4-(dimethylamino)-2-oxo-3-butenoate in 41% yield. Such a yield prohibits economically carrying out the reaction on a commercial scale.

[00091 As described below, the present invention utilizes 4-alkoxy- 2-oxo-3-butenoic esters in the synthesis of 2-aryl pyrimidine 4-carboxylic acid amides. These compounds have been reported as useful as enzyme inhibitors and as educts for the synthesis of pyrimidines and benzodiazepines (Tietze, L.-F. et al., Synthesis, 274-77 (1988)).

[0010] Syntheses of 4-alkoxy-2-oxo-3-butenoic esters have been reported. See, e. g., Walkup, R. D. and Obeyesekere, N. U., Synthesis, 607-11 (1987) ; Tietze, L.-F., et al., Synthesis, 274-77 (1988); and Dujardin, G., et al., Synthesis, 763-70 (1998). The methods reported by Walkup and by Tietze involve reaction of a chlorooxoacetate with a vinyl ether, neat, at 0°C. The difficulties with this reaction include slow initiation of reaction, hard control of the exothermic process, and decomposition of the product. The hydrogen chloride produced during the reaction does not get neutralized. The method reported by Dujardin uses palladium acetate as a catalyst. The disadvantages of this procedure include the usage of an expensive catalyst, and reflux in a volatile solvent for an extended period of time, which could present safety issues in large-scale production.

[0011] The present invention provides a novel synthesis of 2-aryl pyrimidine 4-carboxylic acid amides. The present invention also provides a novel synthesis of 2-aryl 4-alkoxycarbonyl pyrimidines, which are thereafter converted to the corresponding 2-aryl pyrimidine 4-carboxylic acid amides by treatment with ammonia or an amine. The present invention also provides a novel method of preparing 4-substituted 2-oxo-3-butenoic esters.

SUMMARY OF THE INVENTION [0012] The present invention provides a method for synthesizing 2- aryl pyrimidine 4-carboxylic acid amides.

[0013] In particular, one aspect of the invention relates to a method for the preparation of 2-aryl pyrimidine 4-carboxylic acid amides comprising reacting an aryl carboxamidine with a 4-substituted 2-oxo- 3-butenyl amide.

[0014] In a second aspect, the invention relates to a method for the preparation of 2-aryl 4-alkoxycarbonyl pyrimidines comprising reacting an aryl carboxamidine with a 4-substituted 2-oxo-3-butenyl ester. The resulting alkoxycarbonyl pyrimidines are thereafter converted to the corresponding pyrimidine carboxylic acid amides by reaction with a suitable reagent, such as a solution of ammonia or an amine. Preferably, a polar protic solvent such as methanol or ethanol is employed.

[0015] In a further aspect, the invention relates to novel compounds useful in the method of the present invention, and to methods of making these novel compounds.

[0016] In a further aspect, the invention relates to a method for the preparation of 4-substituted 2-oxo-3-butenoic esters.

[0017] The method of the present invention proceeds in high yield and eliminates the need to employ toxic reagents such as selenium dioxide to oxidize the carbon atom attached to C-4 of the pyrimidine ring.

Thus, the method of the present invention is also suitable to large-scale employment.

Detailed Description Of The Invention [0018] In a first aspect, the invention relates to a method for the preparation of a compound of Formula IA : by reacting a compound of Formula II : with a compound selected from the group consisting of a compound of Formula IIIA and a compound of Formula IIA : wherein X is -O- or -S-; Y is-NRCRd where Rc and Rd are independently hydrogen, alkyl or aryl, or R° and Rd, together with the nitrogen atom to which they are attached, form a 3-12 membered aromatic or non-aromatic ring ; R1, R, R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino and cyano; Ruz is selected from the group consisting of alkyloxy, dialkylamino and -NRaRb where Ra and Rb taken together with the nitrogen atom to which they are attached form a 3-to 8-membered ring, which ring optionally contains 1 or 2 additional heteroatoms selected from the group consisting of N, O and S; and Z is-CHO or-C (H) (ORZ) (ORZ) where RZ and RZ are independently alkyl or aryl, or-ORZ and ORz', together with the carbon atom to which they are attached, form a 5-to 8-membered ring.

[0019] Preferred methods according to this first aspect of the present invention include those wherein X is-O-and wherein said compound selected from the group consisting of a compound of Formula IIIA and a compound of Formula IVA is a compound of Formula IIIA. l0020] Preferred methods according to this first aspect of the present invention also include those wherein R1 and R2 are independently selected from the group consisting of hydrogen, Cl-6 alkyl-, C2-6 alkenyl, 2-6 alkynyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxy, nitro, amino and cyano. More preferred include those wherein R1 and R2 are independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C1 6 haloalkyl and nitro.

Most preferred include those wherein Ri and R2 are independently selected from the group consisting of hydrogen, chloro and fluoro.

[0021] Preferred methods according to this first aspect of the present invention also include those wherein R3 and R4 are independently selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyl. More preferred include those wherein R3 and R4 are independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl and Cl-6 haloalkyl. More preferred still include those wherein R3 and R4 are independently selected from the group consisting of hydrogen, chloro and fluoro. Most preferred include those wherein R3 and R4 are hydrogen.

[0022] Preferred methods according to this first aspect of the present invention also include those wherein Ru ils selected from the group consisting of C14 alkyloxy, di (C1-4 alkyl) amino, pyrrolidine, piperidine, piperazine and morpholine. More preferred include those wherein Rw is selected from the group consisting of methoxy, ethoxy, dimethylamino, and diethylamino. Most preferred include those wherein Ru ils ethoxy or dimethylamino.

[0023] Preferred methods according to this first aspect of the present invention also include those wherein RZ and RZ have the same value.

More preferred include those wherein RZ and RZ have the same value, and the value is of g alkyl.

[0024] Preferred methods according to this first aspect of the present invention also include those wherein Rc and Rd are independently hydrogen or Ci-6 alkyl. More preferred include those wherein R° and Ra are hydrogen.

[0025] Preferred methods according to this first aspect of the present invention also include those wherein the reaction is carried out in a polar solvent. Suitable solvents include dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), isopropyl acetate, dimethylsulfoxide (DMSO) and ethers. More preferred solvents include ethers. Suitable ethers include dioxane, glyme and diglyme.

[0026] Preferred methods according to this first aspect of the present invention also include those wherein the reaction is carried out at a temperature between about 25°C and about 175°C. More preferred include those wherein the reaction is carried out at a temperature between about 85°C and about 115°C.

[0027] Preferred methods according to this first aspect of the present invention also include those wherein said compound selected from the group consisting of a compound of Formula IIIA and a compound of Formula IVA is [0028] Specific examples of amides that can be prepared using this first aspect of the present invention include: 2- [4- (4-chlora-2-fluorophenoxy) phenyl] pyrimidine-4-carboxamide.

[0029] In a second aspect, the invention relates to a method for the preparation of a compound of Formula IB : by reacting a compound of Formula II : with a compound selected from the group consisting of a compound of Formula IIIB and a compound of Formula IVB : wherein X is -O- or -S-; Rl, R2, R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino and cyano; Rlo is alkyl or optionally-substituted aryl; Ru ils selected from the group consisting of alkyloxy, dialkylamino and -NRaRb where Ra and Rb taken together with the nitrogen atom to which they are attached form a 3-to 8-membered ring, which ring optionally contains 1 or 2 additional heteroatoms selected from the group consisting of N, O and S; and Z is-CHO or-C (H) (ORZ) (ORZ) where RZ and RZ are independently alkyl or aryl, or -ORz and ORz', together with the carbon atom to which they are attached, form a 5-to 8-membered ring.

[0030] Preferred methods according to this second aspect of the present invention include those wherein X is-O-and wherein said compound selected from the group consisting of a compound of Formula IIIB and a compound of Formula IVB is a compound of Formula IIIB.

[0031] Preferred methods according to this second aspect of the present invention also include those wherein Rl and R2 are as preferred in the first aspect, described above.

[0032] Preferred methods according to this second aspect of the present invention also include those wherein R3 and R4 are as preferred in the first aspect, described above.

[0033] Preferred methods according to this second aspect of the present invention also include those wherein Ru ils as preferred in the first aspect, described above.

[0034] Preferred methods according to this second aspect of the present invention also include those wherein RZ and RZ are as preferred in the first aspect, described above.

[0035] Preferred methods according to this second aspect of the present invention also include those wherein the reaction is carried out in a solvent as preferred in the first aspect, described above.

[0036] Preferred methods according to this second aspect of the present invention also include those wherein the reaction is carried out in a temperature range as preferred in the first aspect, described above.

[0037] Preferred methods according to this second aspect of the present invention also include those wherein Rlo is C1_6 alkyl. More preferred include those wherein Rlo is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

Most preferred include those wherein Rlo is ethyl.

[0038] Preferred methods according to this second aspect of the present invention also include those wherein said compound selected from the group consisting of a compound of Formula IIlB and a compound of Formula IVB is [0039] Specific examples of esters that can be prepared using this second aspect of the present invention include: ethyl 2- [4- (4-chloro-2-fluorophenoxy) phenyl] pyrimidine-4- carboxylate.

[0040] Esters of Formula IB can be converted to the corresponding amides of Formula L4 : wherein Y is-NRCRd where R° and Rd are independently hydrogen, alkyl or aryl, or R° and Rd, together with the nitrogen atom to which they are attached, form a 3-12 membered aromatic or non-aromatic ring. For example, treatment of IB where Rlo is-OCH2CH3 with methanolic ammonia produces IA where Y is-NH2. Specific examples of amides that can be prepared using the present invention include: 2- [4- (4-chloro-2-fluorophenoxy)-phenyl]-pyrimidine-4-carboxamide.

[0041] In a further aspect, the invention relates to the compound 4-dimethylamino-2-oxo-but-3-enoic acid amide and its preparation.

This compound is useful as a reagent in the first aspect of the present invention (Formula IIIA : Y=NH2, RW=dimethylamino).

[0042] 4-Dimethylamino-2-oxo-but-3-enoic acid amide can be produced by reacting ethyl pyruvate with ammonia, then reacting the product of this reaction with N, N-dimethylformamide dimethylacetal.

This reaction is believed to proceed through an intermediate pyruvamide. Alternatively, 4-dimethylamino-2-oxo-but-3-enoic acid amide can be produced by reacting ethyl pyruvate with N, N-dimethylformamide dimethylacetal, then reacting the product of this reaction with ammonia. In either case, the ammonia can be provided as a gas or in solution.

[0043] In a further aspect, the invention relates to the preparation of compounds of Formula K : wherein R'and R"are independently selected from the group consisting of alkyl, alkenyl, alkynyl and haloalkyl.

[0044] According to the present invention, compounds of Formula V are prepared by reacting a compound of Formula VI: with a compound of Formula VII: in the presence of a base, and in a suitable solvent, wherein R'and R" are defined as above, and Hal is chloro or bromo.

[0045] Suitable values of R'and R"include C14 alkyl, C24 alkenyl, 2-4 alkynyl and CI-4 haloalkyl. R'is preferably C1_4 alkyl, more preferably ethyl. R"is preferably 1-4 alkyl, more preferably ethyl.

[0046] Suitable bases according to this aspect of the present invention include amines, preferably tertiary amines. One preferred base is triethylamine.

[0047] Suitable solvents according to this aspect of the present invention are aprotic solvents, such as ethyl acetate. Preferred solvents are ethers, such as diethyl ether and 1, 4-dioxane.

[0048] Formula V includes compounds of FormulaIIIB in which Rl () is alkyl and Rw is alkyloxy. Preferably, compounds of Formula IIIB in which Rlo is alkyl and Rw is alkyloxy, useful in the second aspect of the present invention, are prepared according to this further aspect of the present invention.

[00491 The term"alkyl"as employed herein by itself or as part of another group refers to both straight and branched chain radicals of up to 12 carbons, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like.

[0050] The term"alkenyl"is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is otherwise limited, wherein there is at least one double bond between two of the carbon atoms in the chain, including, but not limited to, ethenyl, I-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2- butenyl, and the like. Preferably, the alkenyl chain is 2 to 10 carbon atoms in length, more preferably 2 to 8 carbon atoms in length, most preferably 2 to 4 carbon atoms in length.

[0051] In all instances herein where there is an alkenyl moiety as a substituent group, the unsaturated linkage, i. e. , the vinylene linkage, is preferably not directly attached to a nitrogen, oxygen or sulfur moiety.

[0052] The term"alkynyl"is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is otherwise limited, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the like. Preferably, the alkynyl chain is 2 to 10 carbon atoms in length, more preferably 2 to 8 carbon atoms in length, most preferably 2 to 4 carbon atoms in length.

[0053] The term"alkoxy"or"alkyloxy"as employed herein by itself or as part of another group refers to a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is otherwise limited, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Preferably the alkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length.

[0054] The term"halogen"or"halo"as employed herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine, with chlorine being preferred.

[0055] The term"dialkylamine"or"dialkylamino"as employed herein by itself or as part of another group refers to an amino group substituted with two alkyl groups, each independently having from 1 to 6 carbon atoms.

[0056] The term"aryl"as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 14 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.

[0057] The term"heteroatom"is used herein to mean an oxygen atom ("O"), a sulfur atom ("S") or a nitrogen atom ("N"). It will be recognized that when the heteroatom is nitrogen, it may form an- NReRf moiety, wherein Re and Rf are independently hydrogen or Cl_8 alkyl, or together with the nitrogen to which they are attached form a saturated or unsaturated 5-, 6-, or 7-membered ring.

[0058] The term"substituted, "as used herein, means that one or more hydrogens of the designated moiety are replaced with a selection from the indicated group, provided that no atom's normal valency is exceeded, and that the substitution results in a stable compound. When a substituent is keto (i. e., =O), then 2 hydrogens attached to an atom of the moiety are replaced.

[0059] Optional substituents on Rl° when Rlo is optionally-substituted aryl include alkyl, alkenyl, alkynyl, halo, haloalkyl, hydroxyalkyl, phenyl, alkylphenyl, halophenyl, alkoxyphenyl, nitro, hydroxy, amino and cyano. More useful substituents on Rl° when Rl° is optionally- substituted aryl include Cl 6 alkyl, C2 6 alkenyl, 2-6 alkynyl, halo, halo (Cl 6) alkyl, hydroxy (Ci-6) alkyl, phenyl, (Cl-6 alkyl) phenyl, halophenyl, (C1-6 alkoxy) phenyl, nitro, hydroxy, amino and cyano.

Preferred subtituents on Rl° when Rl° is optionally-substituted aryl include phenyl.

[0060] By"stable compound"or"stable formula"is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.

[0061] When any variable occurs more than one time in any constituent or in any Formula, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

Scheme 1 [0062] Scheme 1 illustrates a first aspect of the present invention.

Substituents R1-R4, X, RW, Y and Z are defined as above. In this aspect, aryl carboxamidine 1 is reacted with either cyclization reagent 2 or cyclization reagent 3 to form 2-aryl-pyrimidine 4-carboxylic acid amide 4.

Scheme 2 [0063] Scheme 2 illustrates a second aspect of the present invention.

Substituents R1-R4, X, Ro, RW, Y and Z are defined as above. In this aspect, aryl carboxamidine 1 is reacted with either cyclization reagent 5 or cyclization reagent 6 to form 2-aryl-pyrimidine 4-carboxylic acid ester 7. This ester is further reacted with ammonia or an amine, usually in a polar solvent such as methanol, ethanol DMF or NMP, to form 2-aryl pyrimidine 4-carboxylic acid amide 4.

[0064] The following examples are illustrative, but not limiting, of the method of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered and obvious to those skilled in the art are within the spirit and scope of the invention.

EXAMPLES Example I 4- (4-Chloro-2-fluorophenoxy) benzamidine [0065] a) 4- (4-Chloro-2-fluorophenoxy) benzonitrile. A mixture of 4-fluorobenzonitrile (5.0 g, 41.3 mmol), 4-chloro-2-fluorophenol (4.7 mL, 44 mmol), and potassium carbonate (13.8 g, 99.8 mmol) in DMF (100 ml) was refluxed overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed twice with a 2N aqueous sodium hydroxide solution, washed with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give very light yellow solid. The weight of crude product was 7.56 g (74%). IH NMR (CDC13) : 6 7.61 (d, J = 8.1 Hz, 2H), 7.27 - 7. 07 (m, 3H), 6.98 (d, J = 8.7 Hz, 2H).

[0066] b) 4-(4-Chloro-2-fluorophenoxy)benzamidine. Hydrogen chloride gas was bubbled through a solution of 4- (4-chloro- 2-fluorophenoxy) benzonitrile (1.64 g, 6.64 mmol) in ethanol (100 mL) under N2 at 0 °C for 15 minutes. The solution was stoppered and stirred at room temperature for 24 hours and concentrated to dryness.

The residue was dissolved in ethanol (100 mL), ammonium carbonate (6.3 g, 65 mmol) was added and the resulting mixture was stirred at room temperature for 24 hours. The mixture was filtered and the filtrate was evaporated under reduced pressure to give a white solid, which was used without further purification. The weight of the crude product was 1. 48g (74%). 1H NMR (DMSO-d6) : 8 7.90 (d, J = 8.4, 2H), 7.40-7. 25 (m, 3H), 7. 18 (d, J = 8. 4,2H).

Example 2 2-4- (4-Chloro-2-fluorophenoxy)-phenylJ-pyrimidine- 4-carboxylic acid ethyl ester [0067] A mixture of 4- (4-chloro-2-fluorophenoxy) benzamidine hydrogen chloride (50 g, 0. 166 mol ; Example 1) in 1,4-dioxane (250 mL) were charged in a round bottom flask and refluxed under nitrogen for 1 h. Ethyl 4-ethoxy-2-oxo-3-butenoate (IIIB : Rl° is ethyl, Rw is ethoxy) (150.75 g, 22.66 wt % in dioxane, 0.198 mol) was added via a syringe over 30 min. The resultant mixture was allowed to reflux for an additional 3.5 h. The mixture was allowed to cool to room temperature, and was filtered to remove solid. The filtrate was concentrated to give a crude oil, which was crystallized from ethanol (150 mL). The product was obtained as a dark yellow solid (46.05 g, 74. 3 %). 1H NMR (CDC13) : 8 9.1 (d, J= 4. 9 Hz, 1H), 8. 63 (d, J= 9.2 Hz, 2H), 7.92 (d, J= 4.98 Hz, 1H), 7.36 (m, 1H), 7. 27-7. 17 (m, 4H), 4.64-4. 60 (quart, J= 6.97 Hz, 2H), 1.60-1. 57 (t, J= 6.97 Hz, 3H).

Example 3 2- [4-(4-Chloro-2-fluorophenoxy)-phenyl]-pyrimidine- 4-carboxylic acid amide [0068] A round bottom (RB) flask equipped with an agitator was nitrogen purged to remove oxygen. Added to the flask was 5.6 liters of N-methyl-2-pyrrolidone (NMP). Next, 1.2 kg (3.2 moles, 95% purity) 2- [4- (4-chloro-2-fluoro-phenoxy)-phenyl] pyrimidine-4-carboxylic acid ethyl ester (crude ethyl ester, Example 2) was added and dissolved. Under a nitrogen atmosphere, 230 g of activated powdered carbon was then added, and the solution was heated to 80-100°C, and held for approximately 1 hour to decolorize the solution. The carbon was then removed by filtration, and washed with 230 mL NMP to recover product trapped on the carbon.

[0069] The NMP/product filtrate/wash was added to a second RB flask that was nitrogen purged to remove oxygen. The flask was equipped with an agitator and gas dispersion tube. Under a nitrogen atmosphere, the NMP/product filtrate/wash was cooled to-20 to 0°C. Once the solution was cooled, 700-800 g anhydrous ammonia was charged via the gas dispersion tube to the ethyl ester, forming the 2- [4- (4-chloro-2- fluoro-phenoxyl)-phenyl] pyrimidine-4-carboxylic acid amide. The reaction was complete in approximately 2 hours, and then the reaction solution was heated to 80-100°C. In a separate 20-liter reaction flask, 11.5 liters of water were heated to 80-100°C under a nitrogen atmosphere. When both solutions were at 80-100°C, the NMP reaction solution was added to the water to precipitate the amide. The slurry was slowly cooled to 5-25°C, and the solids recovered by filtration.

The solids were washed with 1.1 liters of a 1: 2 NMP/water solution, followed by 2.3 liters of a water wash to remove residual filtrate. The solids were vacuum dried at 60-80°C with a slight nitrogen bleed into the dryer to remove residual solvents. The nitrogen disrupted the gas- solid diffusion layer at the solids surface. The yield was 683 g 2- [4- (4- chloro-2-fluoro-phenoxy) -phenyl] pyrimidine-4-carboxylic acid amide (65% yield). 1H NMR (DMSO-d6): 8 8.91 (d, J= 4.9 Hz, 1H), 8. 47- 8.42 (m, 3H), 7.81 (br, s, 1H), 7.69 (d, J= 4.9 Hz, 1H), 7.52 (m, 1H), 7.20-7. 14 (m, 2H), 6.96-6. 93 (d, J= 8. 8 Hz, 2H).

Examples 4A-D 2- [4-(4-Chloro-2-fluorophenoxy)-phenyl]-pyrimidine- 4-carboxylic acid amide [0070] 4A: A suspension of 2- [4- (4-chloro-2-fluorophenoxy)-phenyl]- pyrimidine-4-carboxylic acid methyl ester (5 g, 13.9 mmole) in 100 mL reagent grade denatured 200 proof alcohol (95 parts Formula 3A to 5 parts IPA) was stirred and heated to 60°C to dissolve the methyl ester. Ammonia gas was bubbled through a dispersion tube over a one- hour period to the reaction mixture while maintaining 55°C. After one hour, HPLC analysis indicated 6. 02 % area of ester remaining. The heat was turned off and the mixture slowly cooled to ambient temperature. At 30°C, the title product crystallized from the reaction.

The reaction mixture was stirred over the weekend. HPLC after 93 hours indicated that the esters were consumed. The precipitated product was filtered, washed with 3A reagent anhydrous EtOH (4 x 10 mL), air dried, and vacuum oven dried at 50°C to afford 4.19 g (91% yield) of the title product as a white solid. HPLC after isolation indicated 89.59 % area title product with 6.80 % area ethyl ester remaining. l0071] 4B: A suspension of 2- [4- (4-chloro-2-fluorophenoxy)- phenyl]-pyrimidine-4-carboxylic acid methyl ester (5 g, 13.9 mmole) in 100 mL EtOH (reagent anhydrous) was stirred and heated to 60°C to dissolve the methyl ester. Ammonia gas (21 g, 1.23 moles) was bubbled through a dispersion tube over a six-hour period to the reaction mixture while maintaining 60°C. After six hours, HPLC analysis indicated-17 % area of esters remained. The heat was turned off and the mixture slowly cooled to ambient temperature. The reaction mixture was stirred overnight. HPLC after 17.5 hours indicated that the esters were consumed. The precipitated product was filtered, washed with 3A reagent anhydrous EtOH (4 x 10 mL), air dried, and vacuum oven dried at 50°C to afford 3.91 g (82% yield) of the title compound as a white solid. HPLC after isolation indicated 96.15 % area title compound with 1.82 % area ethyl ester remaining.

[0072] 4C: A suspension of 2- [4- (4-chloro-2-fluorophenoxy)-phenyl]- pyrimidine-4-carboxylic acid methyl ester (5 g, 13.9 mmole) in 100 mL reagent grade denatured 200 proof alcohol (95 parts Formula 3A to 5 parts IPA) was stirred and heated to reflux to dissolve the methyl ester. Ammonia gas was bubbled through a dispersion tube over 0.5 hours to the reaction mixture while maintaining reflux. During the addition, the temperature dropped to 50°C and was brought back to reflux. Within one hour, the product began to precipitate from the mixture. The heat was turned off and the mixture slowly cooled to ambient temperature. The reaction mixture was stirred over the weekend. The precipitated product was filtered, washed with 3A reagent anhydrous EtOH (4 x 10 mL), air dried, and vacuum oven dried at 50°C to afford 3.95 g (82% yield) of the title compound as a white solid. HPLC after isolation indicated 72.22 % area title compound with 10.66 % area ethyl ester remaining.

[0073] 4D: A mixture of 2- [4- (4-chloro-2-fluorophenoxy)-phenyl]- pyrimidine-4-carboxylic acid methyl ester (1.0 g, 2. 78 mmole) and 10 mL NMP was stirred at 25°C to dissolve the methyl ester. Ammonia gas was bubbled through a dispersion tube over 5 hours to the reaction mixture while maintaining 25 ° C. Within 0.25 hours, a hydrolysis by- product began to form. The formed carboxylic acid by-product was reconsumed within 5 hours to form the title product. The heat was turned off and the mixture slowly cooled to ambient temperature. The reaction mixture was stirred overnight. After 22 hours, HPLC analysis indicated the starting reagent was completely consumed. The precipitated product was filtered, washed with 3A reagent anhydrous EtOH (4 x 10 mL), air dried, and vacuum oven dried at 50 ° C to afford 0.69 g (72%) of the title compound as a white solid. HPLC after isolation indicated 99.66 % area title compound with 0.34 % area ethyl ester.

Example 5 2- [4-(4-Chloro-2-fluorophenoxy)-phenyl]-pyrimidine- 4-carboxylic acid amide [0074] (a) 4-Dimethylamino-2-oxo-but-3-enoic acid ethyl ester. Ethyl pyruvate (11.6 g) and dimethyl formamide dimethylacetal (11.9 g) were mixed at room temperature. The mixture turned brownish. The mixture was heated to 80-85°C. Distillate appeared at 60-64°C. It was heated further to 90°C and a vacuum of about 60 mmHg was pulled to remove volatiles. The viscous residue oil was black-brown. The residue oil was purified through a short plug of silica gel column. The column was washed with ethanol and then with 90/10 methylene chloride/methanol. The desired fraction 2 was purified again through another short plug of silica gel column. The gel column was washed with 90/10 methylene chloride/methanol. Fraction 4 from the wash contained the title compound. The brown oil (0.9 g) was used in the next reaction.

[0075] (b) 2-4- (4-Chloro-2-fluorophefaoxy)-phenylJ-pyrimidine- 4-carboxylic acid amide. A mixture of 4- (4-chloro- 2-fluorophenoxy) benzamidine (265 mg, 1 mmole), 10 mL absolute (200 proof) EtOH, and sodium ethoxide (21 wt % in denatured EtOH ; 272 mg, 4 mmole) was stirred and heated to reflux. 4-Dimethylamino- 2-oxo-but-3-enoic acid ester (50: 50 mole % mixture of Me and Et esters; 246mg, 1. 5 mmole) dissolved in 5 mL absolute (200 proof) EtOH was added to the stirred/refluxed reaction mixture. HPLC analysis after 6 hours indicated 2.09 % area of amidine remained and 7.91 % area carboxylic acid by-product formed. The mixture was refluxed overnight to completely consume amidine. After 21 hours, HPLC analysis indicated 0 % area amidine, 12.75 % area carboxylic acid, and 84. 04 % area desired ethyl ester (with concurrent transesterfication of the methyl amine). Conc. sulfuric acid (1000 mg, 10 mmole) was added to the refluxing reaction mixture to convert the carboxylic acid to the desired ethyl ester. After 3 hours, HPLC analysis indicated that the carboxylic acid % area dropped from 12.75 % area to 4.14 % area. The reaction was cooled to ambient temperature and saturated with ammonia gas through a dispersion tube.

After 3 days, HPLC analysis indicated 10 % area ethyl ester still remained. The mixture was further saturated with ammonia gas for 5 minutes. HPLC analysis indicated 86. 47 % area for the title product and 4. 38 % area of ethyl ester.

Exanzples 6A-B 4-Dimethylamino-2-oxo-but-3-efzoic acid amide [0076] 6A : (a) 4-Dimethylamino-2-oxo-but-3-enoic acid ethyl ester.

A mixture of NN-dimethylformamide dimethylacetal (52.8 g, 0.455 mol) and ethyl pyruvate (55.4 g, 0.465 mol) was stirred while immersed on a water bath to maintain ambient 18-20°C for 1 hour. The reaction mixture darkened steadily to a thin, opaque brown-red/black.

TLC indicated the reaction was complete after 2 hours. Reaction was continued overnight. The reaction mixture was evaporated under high vacuum overnight at 30°C. This afforded-48. 6 g (62% yield) of the ethyl ester as a dark, viscous brown-black oil.

[0077] (b) 4-Dimethylamino-2-oxo-but-3-enoic acid amide. A mixture of 4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester (45.36 grams, 0.265 mol) and 7N ammonia (350 mL, over 10 equivalents) in methanol was stirred on a water bath to keep within 5°C of ambient temperature. TLC indicated the reaction was complete after 1 hour.

Reaction was continued at room temperature for two days. The mixture was rotary evaporated off to end the reaction. That resulted in 61.13 g of thick green-black paste, which reduced to 60.82 g after being swept with dry nitrogen. Suction-driven column chromatography, using a gradient elution of 99: 1-97 : 3 dichloromethane : MA [MA = methanol : concentrated ammonium hydroxide (9: 1) ], yielded 19.78 grams of yellow-orange granular solid from 60.24 grams of crude black paste. The solid was purified by trituration with acetone to afford 16 g (42% yield) the title compound as a pale orange-white solid. 1H NMR (400 MHz, CDCl3) 8 2.95 (s, 3 H), 3.18 (s, 3 H), 5.60 (bs, 1 H), 6.05 (d, 1 H), 7. 28 (bs, 1 H), 7.79 (d, 1 H).

[00781, 6B : A mixture of ethyl pyruvate (1.16 g, 10 mmole) and ammonia gas was bubbled through a dispersion tube over a 2 hour period to the reaction mixture while maintaining 25°C. N, N-Dimethyl- formamide dimethylacetal (1.47 g, 10 mmole) was added to the reaction mixture, and the mixture was stirred for an additional 2 hrs.

Completion of reaction was monitored by HPLC to afford product formation of 27.99 % area over 2 hours. The reaction was continued overnight. Ethyl acetate was added to reaction mixture to crystallize product. The product was dried under vacuum. The HPLC afforded 79. 81 % area for the title product. The reaction afforded an orange oil, which did not crystallize.

Example 7 2-4- (4- 'laloro-2-fluoroplaenoxy)-phenylJ-pyrimidine- 4-carboxylic acid amide [0079] (a) 4-Dimethylamino-2-oxo-but-3-enoic acid amide. A mixture of 4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester (32 mg, 0.20 mmole) and 10 mL 7 N ammonia in methanol was stirred overnight.

Formation of 4-dimethylamino-2-oxo-but-3-enoic acid amide was verified via GC-mass spectrum, m/z 142 (M+) with 61% of sample (area %).

[0080] (b) 2-4- (4-Chloro-2-fluorophenoxy)-phenylJ-pyrimidine- 4-carboxylic acid amide. A mixture of the 4-dimethylamino-2-oxo- but-3-enoic acid amide solution in 10 mL methanol from (a), 4- (4-chloro-2-fluorophenoxy) benzamidine (40 mg, 0.15 mmole) and sodium ethoxide (21 wt % in denatured EtOH ; 10.2 mg, 4 mmole) was stirred under reflux. HPLC analysis after 6 hours indicated 21.91 % area of the starting amidine remained and 57.89 % area formation of the title product.

Example 8 Formation of pyruvamide [0081] Ethyl pyruvate (1.16 g, 10 mmole) was dissolved in 10 mL absolute EtOH (200 proof). Ammonia gas was bubbled in through a dispersion tube with vigorous stirring. A precipitate soon ensued. The solid was filtered and washed with ethanol. HPLC analysis indicated a retention time of 1.020 minutes and the product was pyruvamide, as verified by the GC-mass spectrum, m/z 87 (M+) with 43 % of sample (area %). Ethyl acetate was added to the filtrate and a second precipitate formed. This solid was filtered and washed with cold ethyl acetate. This solid had a retention time of 0.886 minutes, GC-mass spectrum, m/z 112 (M+) with 70 % of sample (area %) unknown and m/z 87 (M+) with 13 % of sample (area %).

Example 9 Ethyl 4-etAIaxy-2-oxo-3-butenoate [0082] A three-necked round bottom flask was charged with 1,4-dioxane (6. 8mL), triethylamine (2. 96g, 0. 0293mol) and ethyl vinyl ether (7. 37 g, 0.102 mol). The resulting solution was warmed to 30°C under nitrogen. Ethyl chlorooxoacetate (2.73 g, 0.02 mol) was added via syringe over 5 min. , and the reaction was allowed to stir at 33-36°C for 2 h. The reaction mixture was cooled to room temperature, and filtered to remove solid. To the crude oil obtained by concentration was added water (15 mL). The resultant mixture was extracted with ethyl acetate (15 mL). The organic layer was dried over sodium sulfate and concentrated to the title compound as a light brown oil (3.02 g, 87. 8%). 1H NMR (CDC13) : 8 7. 86 (d, 1H, J=12. 6 Hz), 6.17 (d, 1H, J=12. 6 Hz), 4.30 (q, 2H, J 1. 7 Hz), 4.05 (q, 2H, J=7. 1 Hz), 1.36 (m, 6H).

[0083] Having now fully described this invention, it will be understood to those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any embodiment thereof. All patents and publications cited herein are fully incorporated by reference herein in their entirety.