BACKGROUND OF THE INVENTION Oxazoles pervade many areas of synthetic organic chemistry, and found in many natural products and pharmaceuticals [For reviews on oxazole chemistry, see: I. J. Turchi et al., Chem. Rev., 1975, pp. 389-437 (1975); Oxazoles, I. J. Turchi, ed., Wiley-Interscience, New York, 1986; and Heterocyclic Compounds Vol. 5, R. C.

Elderfield, ed.; Wiley, New York, 1957]. Of particular importance in the synthesis of oxazoles for therapeutic agents is the linking of the oxazole moiety to the remainder of the molecule.

Oxazoles moieties may be linked to the remainder of a more complex molecule in one of three ways. Connections of the 2-substitutued are usually prepared by reaction of a 2-substituted oxazole possessing a leaving group (Lv) at C-2 with a nucleophile (Nu) [R. Gompper et al. Chem. Ber., 92, pp. 1928-1931 (1959)].

For the preparation of oxazoles of the 4- substituted type, an?-halo ketone is reacted with ammonium formate in formic acid. For example, 4-phenyl oxazole has been prepared from phenacyl bromide in this fashion [H. Bredereck et al., Chem. Ber., 87, pp. 700, 706 (1954)].

There are a few known methods for the preparation of 5-substituted oxazoles. These include dehydration of an N-phenacyl-formamide [Bachstez, Chem.

Ber., 47, p. 3165 (1914)] and condensation of an a-amino ketone with <BR> <BR> triethylorthoformate [N. P. Demchenko et al., J. Gen. _ Chem. USSR (Engl. Transl.), 32, pp. 1192-1193 (1962) These two methods are less than desirable because in certain syntheses, the immediate precursors to the 5- substituted oxazoles are difficult to produce.

A third process for the preparation of 5-aryl- oxazoles employs a reaction between an isonitrile and an aldehyde [A. M. van Leusen, Tetrahedron Lett., pp. 2369- 2372 (1972)]. This is the method set forth in PCT publication WO 97/40028 for the synthesis of intermediates useful in the production of IMPDH inhibitors. An example of this method uses p- toluenesulfonylmethyl isocyanide ("TosMIC"). Although this reagent yields the desired intermediate nitro- oxazole in good yield and with less synthetic difficulty, TosMIC is relatively expensive. Thus this process is less than desirable for the production of commercial quantities of the ultimate product containing the 5- substituted oxazole.

Thus, there is still a need for producing an oxazole of the 5-substituted variety in good yield, without synthetic difficulty and at a reasonable cost.

SUMMARY OF THE INVENTION The present invention fills this need by providing a new method for the production of oxazoles of the 5-substituted type which are useful as intermediates in the production of molecules containing such moieties.

The method involves the reaction of a compound of the formula: with NH4CO2R and RC02H at a temperature of between about 80°C and 160°C to produce a compound of the formula:

Y is Cl-Clo straight or branched alkyl or a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms independently selected from N, O, or S, and wherein Y may contain up to 4 independent, non-electrophilic substituents; X is selected from Cl, Br or I; R is selected from hydrogen or C1-C4 straight or branched alkyl; and R'is hydrogen or Cl-Cl0 straight or branched alkyl.

The method of this invention is particularly useful in the synthesis of a class of IMPDH inhibitors containing an oxazole moiety that is linked to the rest of the molecule via its 5-position. Such IMPDH inhibitors are described in detail in WO 97/40028 and WO 98/40381, the disclosures of which are herein incorporated by reference.

The present invention also provides novel compounds that are precursors of and used in the present method of synthesizing the 5-substituted oxazole moieties of this invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions The following definitions are used throughout the application.

The term"substituted"refers to the replacement of one or more hydrogen radicals in a given

structure with a radical selected from a specified group.

When more than one hydrogen radical may be replaced with a substituent selected from the same specified group, the substituents may be either the same or different at every position.

The term"monocyclic or bicyclic ring system consisting of 5 to 6 members per ring"refers to 5 or 6 member monocyclic rings and 8,9 and 10 membered bicyclic ring structures, wherein each bond in each ring may be possess any degree of saturation that is chemically feasible. When such structures contain substituents, those substituents may be at any position of the ring system, unless otherwise specified.

As specified, such ring systems may optionally comprise up to 4 heteroatoms selected from N, O or S.

Those heteroatoms may replace any carbon atoms in these ring systems as long as the resulting compound is chemically stable.

According to one embodiment, the invention provides a method for the production of an oxazole of the formula: comprising the step of reacting a compound of the formula: with NH4CO2R and RC02H at a temperature of between about 80°C and 160°C, wherein: Y is Cl-Cl0 straight or branched alkyl or a monocyclic or a bicyclic ring system consisting of 5 to 6

members per ring, wherein said ring system optionally comprises up to 4 heteroatoms independently selected from N, O, or S, and wherein Y may contain up to 4 independently selected, non-electrophilic substituents; X is selected from Cl, Br or I; and R is selected from hydrogen C1-C4 straight or branched alkyl; and R'is hydrogen or Cl-Cl0 straight or branched alkyl.

Those of skill in the art will be well aware that the presence of an electrophilic substituent on Y will interfere with the desired reaction by causing a side reaction. Electrophilic substituents include, for example, halogens, nitriles, esters, sulfonyl esters, ketones and aldehydes. Other electrophilic substituents that must not be present on Y are well known in the art.

According to one preferred embodiment, R is H or CH3. Even more preferred is when R is H.

According to another preferred embodiment, X is Br.

In yet another preferred embodiment, Y is phenyl optionally substituted at the 4-position with nitro and optionally substituted at the 2-position with methoxy.

In the most preferred embodiment, this method is used to produce a compound of the formula: reacting a compound of the formula: with NH4CO2H and HC02H at a temperature of between about 80°C and 120°C. Preferably, between about 4 to 10 ml HCO2H and between about 0.5 to 1.0 gram NH4CO2H are used per gram of The

reaction is typically quenched by the addition of between about 20 to 30 ml water per gram of used in the reaction.

The immediate precursor to the 5-substituted oxazole produced by the method of this invention,

may be synthesized by the route set forth in Scheme 1, below if it is not commercially available.

Scheme 1: Of course, it should be understood that if any of the above intermediate compounds are commercially available, the synthesis of may begin with that

intermediate and follow the subsequent steps set forth in Scheme 1.

In another embodiment, the invention provides a method of synthesizing a compound of the formula: comprising the steps of:

a) reacting a compound of the formula: with (CH3) 2-N-CH (OCH3) 2 in the presence of N, N-dimethylformamide ("DMF") and heat, followed by the addition of water to yield a compound of the formula: i Ila_ 02N OCH3 with HCl and \ nez b) reacting water to produce a compound of the formula:

O H 02N OCH3-and H / c) reacting 02N OCH3 with Br2 and acetic H I Ber acid to produce N OCHs Preferably, in step a), the amount of DMF used is between about 5 to 15 ml per gram of It also preferred that the amount of

(CH3) 2-N-CH (OCH3) 2 be between about 2.5 to 5.0 grams per

gram of « The temperature of the reaction in step a) is preferably between about 100 to 120°C. And the amount of water added upon completion of the reaction is preferably between about 6 to 30 ml per gram of In step b), it is preferred that the amount of HC1 and water be between about 2 to 5 ml of concentrated HCl and 4 to 8 ml of water, respectively, per gram of It is also preferred that step b) be carried out at a temperature of between about 15 to 35°C.

In step c) the preferred amount of acetic acid and bromine is between about 5 to 15 ml of acetic acid and between about 1.0 to 1.5 grams of bromine per gram of Preferably, step c) is carried out at a temperature of between about 18 to 35°C. It is further preferred that the reaction in step c) be quenched by the addition of between about 5 to 15 ml water per gram of

In addition, the invention provides the individual compounds produced in steps a), b) and c), above.

In another aspect of the present invention, the method for producing a 5-substituted oxazole is utilized in the synthesis of compounds which have IMPDH inhibitory activity. Such compounds have the formula: wherein: A is selected from (Cl-C6)-straight or branched alkyl, or (C2-C6)-straight or branched alkenyl or alkynyl; and A optionally comprises up to 2 substituents, wherein: the first of said substituents, if present, is selected from R1 or R3, and the second of said substituents, if present, is R1; each of B and B'is independently selected from a saturated, unsaturated or partially saturated monocyclic or bicyclic ring system optionally comprising up to 4

heteroatoms selected from N, O, or S and wherein each of B and B'optionally comprises up to 3 substituents, wherein: the first of said substituents, if present, is selected from Rl, R2, R4 or R5, the second of said substituents, if present, is selected from R1 or R4, and the third of said substituents, if present, is Ri; and D is selected from C (O), C (S), or S (0) 2; wherein: each R1 is independently selected from 1,2- methylenedioxy, 1,2-ethylenedioxy, R6 or (CH2) n-Z; wherein n is 0,1 or 2; and Z is selected from halogen, CN, N02, CF3, OCF3, OH, SR6, S (O) R6, SO2R6, N (R6) 2, N (R6) R8, COOR6 or OR6; each R2 is independently selected from (C1-C4)- straight or branched alkyl, or (C2-C4)-straight or branched alkenyl or alkynyl; and each R2 optionally comprises up to 2 substituents, wherein: the first of said substituents, if present, is selected from R1, R4 or R5; and the second of said substituents, if present, is RI; R3 is selected from a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, or S, and wherein a CH2 adjacent to any of said N, 0, or S heteroatoms is optionally substituted with C (0); and each R3 optionally comprises up to 3 substituents, wherein: the first of said substituents, if present, is selected from Rl, R2, R4 or R5,

the second of said substituents, if present, is selected from Ri, or R4, and the third of said substituents, if present, is R1 ; each R4 is independently selected from OR5, OC (O) R6, OC (O) R5, OC (O) OR6, OC (O) OR5, OC (0) N (R6) 2, OP (0) (OR6) 2, SR6, S(O)R5,SO2R6,SO2R5,SO2N(R6)2,SO2NR5R6,SO3R6,SR5,S(O)R6, C (O) Rs, C (O) OR5, C (O) R6, C (O) OR6, NC (O) C (O) R6, NC (O) C (O) R5, NC (O) C (O) OR6, NC (O) C (O) N (R6) 2, C (0) N (R6) 2, C (0) N (OR6) R6, C (O) N (OR6) R5, C (NOR6) R6, C (NOR6) R5, N (R6) 2, NR6C (O) Ri, NR6C (O) R6, NR6C (O) R5, NR6C (O) OR6, NR6C (O) OR5, NR6C (0) N (R6) 2, NR6SO2R5,NR6SO2N(R6)2,NR6SO2NR5R6,NR6C(O)NR5R6,NR6SO2R6, N (OR6) R6, N (OR6) R5, P (0) (OR6) N (R6) 2, and P(O) (OR6) 2; each R5 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH2 adjacent to said N, 0 or S maybe substituted with C (O) ; and each R5 optionally comprises up to 3 substituents, each of which, if present, is Rl; each R6 is independently selected from H, (C1-C4)- straight or branched alkyl, or (C2-C4) straight or branched alkenyl; and each R6 optionally comprises a substituent that is R7; R7 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, or S, and wherein a CH2 adjacent to said N, 0 or S maybe substituted with C (0); and each R7 optionally comprises up to 2 substituents independently chosen from H, (C1-C4)-straight or branched alkyl, (C2-C4) straight or branched alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH2) n-Z;

wherein n is 0,1 or 2; and Z is selected from halogen, CN, N02, CF3, OCF3, OH, S (Cl-C4)-alkyl, SO (Cl-C4)-alkyl, S02 (Cl-C4)-alkyl, NH2, NH (Cl-C4)-alkyl, N ((C1-C4)-alkyl) 2, N ((Cl-C4)-alkYl) R8t COOH, C (O) O (C1-C4)-alkyl or O (Cl-C4)-alkyl; R8 is an amino protecting group; E is oxygen; G is hydrogen; and G'is selected from hydrogen or Cl-C4-straight or branched alkyl; wherein any carbon atom in any A, R2 or R6 is optionally replaced by O, S, SO, S02, NH, or N (C1-C4)- alkyl.

Methods for synthesizing the desired end- product compounds of formula I or II from the 5- substituted oxazole intermediate are set forth in detail in WO 97/40028, the disclosure of which is herein incorporated by reference.

More preferably, the method for producing a 5- substituted oxazole is used to synthesize a compound of the formula: VX-497.

According to another embodiment, the method for producing a 5-substituted oxazole is utilized in the synthesis of another class of compounds which have IMPDH inhibitory activity. Such compounds have the formula: (III), wherein:

A'is a saturated, unsaturated or partially saturated monocyclic or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, 0, and S wherein each A'optionally comprises up to 4 substituents independently selected from R21, R24 and R25; each R21 is halogen, CN, NO2, CF3, OCF3, OH, R23, OR23, 1,2-methylenedioxy, 1,2-ethylenedioxy, SR23, S (O) R23, S (02) R23, NH2, NHR23, N (R23) 2, NR23R29, COOH, or COOR23; each R23 is independently (Cl-C4)-straight or branched alkyl, or (C2-C4)-straight or branched alkenyl or alkynyl; each R24 is independently (Cl-C6)-straight or branched alkyl, or (C2-C6)-straight or branched alkenyl or alkynyl; and each R24 optionally comprises up to 2 substituents, wherein: the first of said substituents, if present, is R21, R25 or R28, and the second of said substituents, if present, is R1 ; each R25 is independently selected from OR26, OC (O) R27, OC (O) R26, OC (O) OR27, OC (O) OR26, OC (O) N (R27)2, SR27,SR26,S(O)R27,S(O)R26,SO2R27,SO2R26,OP(O)(OR27)2, S02N (R27) 2, S02NR26R27, S03R27, C (0) R26, C (0) OR26, C (O) R27, NC(O)C(O)R26,NC(O)C(O)OR27,C(O)OR27,NC(O)C(O)R27, NC (O) C (O) N (R27) 2, C (0) N (R27) 2, C (0) N (OR27) R27, C (O) N (OR27) R26 C (NOR27) R27, C (NOR27) R26, N (R27) 2, NR27C (0) R26, NR27C (0) R27, NR6C (O) R26, NR27C (O) OR27, NR27C (O) OR26, NR27C (O) N (R27) 2, NR27C(O)NR26R27,NR27SO2N(R27)2,NR27SO2R26,

NR27SO2NR26R27, N (OR27) R27, N (OR27) R26, P (0) (OR27) N (R27) 2, P (0) (OR27) 2, P (0) (N (R27) 2) 2, and P (0) (OR27) R27- R26 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, and S, and wherein a CH2 adjacent to any of said N, O, or S heteroatoms is optionally substituted with C (O); and each R26 optionally comprises up to 3 substituents, each substituent independently selected from R21; each R27 is independently H, (Cl-C4)-straight or branched alkyl, or (C2-C4) straight or branched alkenyl; and each R27 optionally comprises a substituent that is R28 ; R28 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, and S, and wherein a CH2 adjacent to said N, 0 or S maybe substituted with C (O); and each R28 optionally comprises up to 2 substituents independently chosen from H, (Cl-C4)-straight or branched alkyl, (C2-C4) straight or branched alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy and (CH2) n-R21; wherein n is 0,1 or 2; R29 is an amino protecting group; and wherein any carbon atom in any R23, R24 or R27 is optionally replaced by 0, S, SO, S02, NH, or N (C1-C4)- alkyl.

Methods for synthesizing the desired end- product compounds of formula III from the 5-substituted oxazole intermediate are set forth in detail in WO

98/40381, the disclosure of which is herein incorporated by reference.

According to another embodiment, the method for producing a 5-substituted oxazole is utilized in the synthesis of yet another class of compounds which have IMPDH inhibitory activity. Such compounds have the formula: wherein: R31 is (Cl-C6)-straight or branched alkyl, wherein up to 4 hydrogen atoms in said alkyl are optionally and independently replaced by R33; R32 is selected from hydrogen,-CF3,-(Cl-C6)-straight or branched alkyl,- (Cl-C6)-straight or branched alkyl-Ar, or-Ar; or wherein R31 and R32 are taken together to form a 3- tetrahydrofuranyl moiety that is substituted at the 5 position by-OR36 ; each R33 is independently selected from halo,-OR34, or-N (R3s) 2 ; R34 is selected from hydrogen,-(Cl-C6)-straight alkyl,- (Cl-C6)-straight alkyl-Ar,-C (O)- (Cl-C6)-straight or branched alkyl,-C (O)-Ar, or- (Cl-C6)-straight alkyl- CN; each R35 is independently selected from hydrogen, -(C1-C6)-straight or branched alkyl,- (Cl-C6)-straight or branched alkyl-Ar,-(Cl-C6)-straight alkyl-CN,-(C1-C6)-

straight alkyl-OH,- (Cl-C6)-straight alkyl-OR34,-C (O)- (C1- C6)-straight or branched alkyl,-C (O)-Ar,-S (O) 2- (Cl-C6) straight or branched alkyl, or-S (0) 2-Ar; or two R35 moieties, when bound to the same nitrogen atom, are taken together with said nitrogen atom to form a 3 to 7- membered heterocyclic ring, wherein said heterocyclic ring optionally contains 1 to 3 additional heteroatoms independently selected from N, 0, or S; R36 is selected from-C (O)-CH3,-CH2-C (O)-OH, -CH2-C (O)-O-tBu,-CH2-CN, or-CH2-C=CH; and Ar is selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4- thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5- triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, peridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl or other chemically feasible monocyclic, bicyclic or tricyclic ring systems, wherein each ring consists of 5 to 7 ring atoms and wherein each ring comprises 0 to 3 heteroatoms independently selected from N, 0 and S; wherein any Ar or heterocyclic ring is optionally substituted with 1 to 3 substituents independently selected from halo, hydroxy, nitro, cyano, amino, (C1-C4)-

straight or branched alkyl; O- (Cl-C4)-straight or branched alkyl, (C2-C4)-straight or branched alkenyl or alkynyl, or 0- (C2-C4)-straight or branched alkenyl or alkynyl; and any Ar or heterocyclic ring is optionally benzofused.

Methods for synthesizing the desired end- product compounds of formula IV from the 5-substituted oxazole intermediate are analagous to those set forth in WO 97/40028.

In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.

EXAMPLE1 Synthesis of a 5-Aryl Oxazole The synthesis is outlined in Scheme 2, below.

Scheme 2:

As can be seen above, reaction of a 2-methyl-5- nitroanisole with N, N-dimethylformamide dimethyl acetal in DMF at 120°C gives A997-146, which was then hydrolyzed to aryl-acetaldehyde A997-154. An advantage of this hydrolysis is that it is performed in water without the need for organic solvent. Bromination of A997-154 is carried out in glacial acetic acid, then VRT-039536 is obtained by heating the a-bromo-aryl-acetaldehyde in formic acid in the presence of ammonium formate. More details of the synthesis are provided below.

Preparation of A997-146: A 5 L, 4-necked, round-bottomed flask was fitted with a heating mantle, thermocouple, overhead mechanical stirrer, nitrogen inlet, and a reflux condenser was vented to a mineral oil bubbler. The flask

was charged with 172.0 g (1.029 mol) of 2-methyl-5- nitroanisole, 1.250 L of N, N-dimethylformamide, and 331.9 g (2.785 mol) of N, N-dimethylformamide dimethyl acetal (DMFDMA). The mixture was heated to 120°C and monitored by TLC (Si02 3: 1 hexanes: EtOAc) until the 2-methyl-5- nitroanisole had been consumed (about 24 hours heating at 120 °C). The maroon mixture was cooled to ambient temperature, and 1.250 L of H20 was added slowly over 60 minutes producing a thick maroon precipitate. The solid was collected by vacuum filtration, and washed with water until the filtrate passing into the flask was colorless.

The maroon solid was dried, and 211.0 g of the desired enamine was obtained (92% yield).

Preparation of A997-154: A 5 L, 4-necked, round- bottomed flask was fitted with a thermocouple, overhead mechanical stirrer, and addition funnel. The flask was charged with 152.0 g (0.6847 mol) of A997-146, suspended in 600.0 mL of H20, and 100.0 mL of concentrated HCl was added dropwise over 15 minutes causing the maroon suspension to turn yellow-brown. After 60 minutes the suspension was cooled to 5°C, and the solid collected by vacuum filtration to give 118.0 g of the aryl- acetaldehyde (88% yield).

Preparation of A997-155: A 3 L, 4-necked, round- bottomed flask was fitted with a thermocouple, overhead mechanical stirrer, and addition funnel. The flask was charged with 118.0 g (0.6051 mol) of A997-154 suspended in 750.0 mL of glacial acetic acid. To this suspension was added 136.5 g (0.8531 mol) of Br2 dropwise over 60 minutes. The solution was then stirred for 12 hours at

which time 800.0 mL H20 was added followed by cooling of the suspension to 10°C. The resulting yellow solid was washed with H20, and collected by vacuum filtration to give 244.3 g of the?-bromo-aryl-acetaldehyde as a moist solid.

Preparation of VRT-039536: A 3 L, 4-necked, round- bottomed flask was fitted with a heating mantle, thermocouple, overhead mechanical stirrer, and reflux condenser. The flask was charged with the 244.3 g (0.8916 mol) of the moist A997-155, and suspended in 1.200 L of 96% formic acid. The suspension was cooled in an ice-water bath to 17°C, and 225.0 g (3.568 mol) of ammonium formate was added at a rate such that the solution temperature never exceeded 20°C. Once the ammonium formate was added, the cooling bath was replaced with a heating mantle and the mixture heated at 100°C for 2 hours. The resulting brown-red mixture was cooled to ambient temperature, and poured into 2.500 L of H2O. The pH of the solution was adjusted to pH-6 by addition of 6 M NaOH, and the solids were collected by vacuum filtration to give the nitro-oxazole as a brown-yellow powder.

While we have hereinbefore presented a number of embodiments of this invention, it is apparent that my basic construction can be altered to provide other embodiments which utilize the methods of this invention.

Therefore, it will be appreciated that the scope of this invention is to be defined by the claims appended hereto rather than the specific embodiments which have been presented hereinbefore by way of example.