BACKGROUND OF THE INVENTION The present invention provides a process for producing lH-indole-3-glyoxylamide compounds, including sPLA2 inhibitors, and intermediates useful in their synthesis.

Human non-pancreatic secretory phospholipase A2 (sPLA2) is believed to be a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids.

Compounds that inhibit sPLA2 release of fatty acids are valuable to treat conditions including septic shock, adult respiratory distress, pancreatitis, trauma, bronchial asthma, allergic rhinitis, and rheumatoid arthritis.

U. S. Patent No. 5, 654, 326 describes 1H-indole-3- glyoxylamide sPLA2 inhibitors, including the methyl ester of ( (3- (2-amino-1, 2-dioxoethyl)-l-benzyl-2-ethyl-lH-indol-4- yl) oxy) acetic acid. The morpholino ester of this compound, ( (3- (2-amino-1, 2-dioxoethyl)-l-benzyl-2-ethyl-lH- indol-4-yl) oxy) acetic acid mopholino-N-ethyl ester, acts as an ester type prodrug which is highly bioavailable upon oral administration. The acid form of this compound, ( (3- (2-amino-1, 2-dioxoethyl)-l-benzyl-2-ethyl-lH-indol-4-yl) oxy) acetic acid, and the sodium salt, sodium ( (3- (2-amino- 1, 2-dioxoethyl)-1-benzyl-2-ethyl-lH-indol-4-yl) oxy) acetate, are also active, and can be used to form the esters. The methyl ester, acid, morpholino ester, and sodium salt, have the formulas P, Q, R, and S, respectively.

The synthesis of this class of indole-3-glyoxylamides is described in U. S. Patent No. 5, 654, 326, as well as in Draheim et al., J. Med. Chem. 1996, 39, 5159-75. A current method of making these compounds is illustrated in Scheme A.

In this scheme, starting material of formula T is first

reacted with SO2Cl2, followed by HCl, and then NaOH and cyclohexanedione, to form the substituted cyclohexanetrione of formula U. The cyclohexanetrione of formula U is then reacted with benzylamine in toluene to form the bicycle of formula V. This bicycle is then aromatized with Pd/C in carbitol at 200° C, to give the alcohol of formula W, which is then alkylated with BrCH2CO2CH3 and K2CO3 in acetone, to form the methyl ester of formula X. Next, the methyl ester is reacted with (COCl) 2, followed by NH3 in CH2Cl2, to form the glyoxamide of formula P. The sodium salt of formula S can be prepared by saponification with NaOH in isopropanol.

Although not illustrated in the scheme, the acid form can easily be prepared from the sodium salt by protonation with an acid, and the morpholino ester can be prepared by esterification of the acid or the sodium salt using, for example, 4- (2-chloroethyl) morpholine hydrochloride with Cs2CO3 in dimethylformamide, heating overnight, working up the reaction with water, and extracting the product with ethyl acetate.

It would be useful to have alternative routes to this class of indole-3-glyoxylamides which provide fewer processing steps and improved efficiency. In particular, it would be useful to have a new route to form the 2, 4- disubstituted, and 2, 5-disubstituted indole nucleuses of these molecules using more cost effective processes.

Reductive cyclization has been used to form indoles.

In these reactions, 2- (l-alkenyl)-3-nitro substituted benzene ring is reduced under CO using a Pd (OAc) 2 catalyst, to form an indole, as described by Soderberg, B. C. and Shriver, J. A., J. Organic Chem., 1997, 62, 5838-45. This reference only describes the formation of two disubstituted indoles : 2, 3-dimethylindole ; and 3-methyl-6-methoxyindole.

Applicants have discovered an application of the above method to prepare indole-3-glyoxylamides having utility as sPLA2 inhibitors. Therefore, the present invention provides a novel method for synthesizing indole-3-glyoxylamides, using CO reductive cyclization to form 2, 4-disubstituted indoles, or 2, 5-disubstituted indoles.

SCHEME A

SUMMARY OF THE INVENTION In one aspect, the present invention is a method of making a compound, comprising : reacting a compound represented by formula (I), with CO and a catalyst, to form the compound of formula (II) ; wherein formula (I) is

and, formula (II) is

and where R2 is selected from the group consisting of R20,-OR20,-SR20, -NR2oR20'and-C (0) R20 ; R3, R4, R5, R6 and R7 are each individually selected from the group consisting of H, halogen, R,-OR,-SR,-NRR',-C (O) R, -C (O) OR,-S (O) R and-S (0) 2R ; provided that at least one of R4 and R5 is not H ;

each R and R20 is individually selected from the group consisting of alkyl, alkenyl, alkynyl, aryl and heterocyclic radical ; and each R'and R20'is individually selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical.

In another aspect, the present invention is a method of making a compound, comprising reacting a compound represented by formula (I), with CO and a catalyst, to form the compound of formula (II) ; and forming the compound of the formula (X) or (X') from the compound of formula (II) ; wherein formula (I) and formula (II) are as defined above, and formula (X) is

and formula (X') is where R2, R5, R6 and R7 are described above ;

R1 is selected from the group consisting of H, Rio and- C (O) Rlo ; Rlo is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl and heterocyclic radical ; R8 is selected from the group consisting of alkali metal, H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical ; R9 and Rg'are each individually selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical ; -L-is-AX-By-CZ-D- ; A is-O-,-S-,-N (RA)-and-C (RARA')- ; B is-0-,-S-,-N (RB)- and-C (RBRB')- ; C is-0-,-S-,-N (Rc)- and-C (RcRc')- ; and D is-C (RDRD')- ; each RA, RB, Ré and RD is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical, or any two of RA, RB, Ré and RD together form a bond, or any two of RA, RB, RC and RD together with the atoms to which they are bonded for a ring ; each RA', RBI/RC'and RD'is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical, or any two of RA'/RB', RC'and RD' together form a bond, or any two RA', RB', Ru'an RD' together with the atoms to which they are bonded for a ring ; and each x, y and z is either 0 or 1.

In yet another aspect, the present invention provides a compound of formula (I), where formula (I) is described above.

These and other aspects and features of the invention will become more fully understood in the detailed description.

DETAILED DESCRIPTION OF THE INVENTION Definitions "Alkyl" (or alkyl-or alk-) refers to a substituted or unsubstituted, straight, branched or cyclic hydrocarbon chain, preferably containing of from 1 to 20 carbon atoms.

More preferred alkyl groups are lower alkyl groups, i. e., alkyl groups containing from 1 to 6 carbon atoms. Preferred cycloalkyls have from 3 to 10, preferably 3-6, carbon atoms in their ring structure. Suitable examples of unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, iso-butyl, tert-butyl, sec-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, and the like."Alkylaryl"and"alkylheterocyclic"groups are alkyl groups covalently bonded to an aryl or heterocyclic group, respectively.

"Alkenyl"refers to a substituted or unsubstituted, straight, branched or cyclic, unsaturated hydrocarbon chain that contains at least one double bond, and preferably 2 to 20, more preferably 2 to 6, carbon atoms. Exemplary unsubstituted alkenyl groups include ethenyl (or vinyl) (- CH=CH2), 1-propenyl, 2-propenyl (or allyl) (-CH2-CH=CH2), 1, 3- butadienyl (-CH=CHCH=CH2), 1-butenyl (-CH=CHCH2CH3), hexenyl, pentenyl, 1, 3, 5-hexatrienyl, and the like. Preferred cycloalkenyl groups contain five to eight carbon atoms and at least one double bond. Examples of cycloalkenyl groups include cyclohexadienyl, cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, cyclooctatrienyl and the like.

"Alkoxy"refers to a substituted or unsubstituted,-0- alkyl group. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and the like.

"Alkynyl"refers to a substituted or unsubstituted, straight, branched or cyclic unsaturated hydrocarbon chain containing at least one triple bond, and preferably 2 to 20, more preferably 2 to 6, carbon atoms.

"Aryl"refers to any monovalent aromatic carbocyclic or heteroaromatic group, preferably of 3 to 10 carbon atoms.

The aryl group can be bicyclic (i. e. phenyl (or Ph)) or polycyclic (i. e. naphthyl) and can be unsubstituted or substituted. Preferred aryl groups include phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl, quinolinyl or isoquinolinyl.

"Amino"refers to an unsubstituted or substituted-NRR' group. The amine can be primary (-NH2), secondary (-NHR) or tertiary (-NRR'), depending on the number of substituents (R or R'). Examples of substituted amino groups include methylamino, dimethylamino, ethylamino, diethylamino, 2- propylamino, 1-propylamino, di (n-propyl) amino, di (iso- propyl) amino, methyl-n-propylamino, t-butylamino, anilino, and the like.

"Halogen" (or halo-) refers to fluorine, chlorine, iodine or bromine. The preferred halogen is fluorine or chlorine.

"Heterocyclic radical"refers to a stable, saturated, partially unsaturated, or aromatic ring, preferably containing 5 to 10, more preferably 5 or 6, atoms. The ring can be substituted 1 or more times (preferably 1, 2, 3, 4 or 5 times) with a substituent. The ring can be mono-, bi-or polycyclic. The heterocyclic group consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The heteroatoms can be protected or unprotected. Examples of useful heterocyclic groups include substituted or unsubstituted, protected or unprotected acridine, benzathiazoline, benzimidazole, benzofuran, benzothiophene,

benzthiazole, benzothiophenyl, carbazole, cinnoline, furan, imidazole, 1H-indazole, indole, isoindole, isoquinoline, isothiazole, morpholine, oxazole (i. e. 1, 2, 3-oxadiazole), phenazine, phenothiazine, phenoxazine, phthalazine, piperazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, thiazole, 1, 3, 4-thiadiazole, thiophene, 1, 3, 5-triazines, triazole (i. e. 1, 2, 3-triazole), and the like.

"Substituted"means that the moiety contains at least one, preferably 1-3 substituent (s). Suitable substituents include hydrogen (H) and hydroxyl (-OH), amino (-NH2), oxy (-0-), carbonyl (-CO-), thiol, alkyl, alkenyl, alkynyl, alkoxy, halo, nitrile, nitro, aryl and heterocyclic groups.

These substituents can optionally be further substituted with 1-3 substituents. Examples of substituted substituents include carboxamide, alkylmercapto, alkylsulphonyl, alkylamino, dialkylamino, carboxylate, alkoxycarbonyl, alkylaryl, aralkyl, alkylheterocyclic, and the like.

"Strong acid"means acids, which when added to water, are virtually completely ionized. Examples include HCl, HBr, HI, HN03, HSbF6, HC104 and HPF6.

All other acronyms and abbreviations have the corresponding meaning as published in journals relative to the art of chemistry.

A method of making a compound of formula (II) : The present invention provides a method of making a compound of formula (II) :

where ; R2 is R20 -OR20, -SR20, -NR20R20' or -C (O) Rza ; R3, R4, R5, R6 and R7 are each individually H, halogen, R,-OR,-SR,-NRR',-C (O) R,-C (O) OR,-S (O) R or-S (0) 2R ; provided that at least one of R4 and R5 is not H ; each R and R20 is individually alkyl, alkenyl, alkynyl, aryl or heterocyclic radical ; and each R'and R20'is individually H, alkyl, alkenyl, alkynyl, aryl or heterocyclic radical.

Preferably R is unsubstituted C16 alkyl. Preferably R2 is F or unsubstituted C1-6 alkyl, and more preferably R2 is ethyl. Preferably R3, R5 R6 and R7 are each H, F, R or-OR, and more preferably R3, R5, R6 and R7 are each H. Preferably R4 is halogen or -OR20, and more preferably R4 is-OCH3 or- OCH2C (O) OCH3.

In a preferred embodiment the compound of formula (II) is compound E or J :

The method comprises reacting a compound of formula (I), with CO and a catalyst : where R2, R3, R4, R5, R6 and R7 are described above, and the following moiety indicates that R2 may be either E, Z or a mixture thereof, with reference to R3. In a preferred embodiment, the compound of formula (I) is compound D or H : The reaction may be carried out in a solvent. Any solvent may be used, so long as it does not interfere with the reaction. Preferably the solvent is a hydrocarbon, halogenated hydrocarbon, ether, nitrile, sulfoxide, formamide or amine, and more preferably the solvent is acetonitrile or triethylamine. Preferably the reaction takes place at a temperature of 0 to 200° C.

A catalyst is included in the reaction. The catalyst causes the reaction to proceed at a rate that allows for a reasonable yield (at least 1 wt. %) in a reasonable time period (24 hours or less). A preferred catalyst comprises

palladium. More preferably, the catalyst further comprises phosphorous. This type of catalyst is usually made in situ, by mixing together a palladium salt (such as Pd (OAc) 2) with a trisubstituted phosphorus in the reaction solvent (such as acetonitrile). The catalyst could also be prepared separately, optionally isolated and then added to the reaction, but this is less preferred.

The trisubstituted phosphorus preferably is PRllRl2Rl3, and where Rll, R12 and R13 are each independently selected from the group consisting of alkyl and aryl. Most preferably, Rll, R12 and R13 are all phenyl.

The reacting is with CO as well as the catalyst.

Preferably, the CO is present as a gas at a partial pressure of 0. 1 to 100 atm. More preferrably the CO is present as a gas at a partial pressure of 0. 5 to 8 atm.

The formation of the compound of formula (II) by the method of the invention is the indole forming reaction of an overall method for making indole-3-glyoxylamides. This includes the formation of compounds of formula (I), as illustrated in the following Synthetic Schemes, where R2, R3, R4, R5, R6 and R7, are described above ; Ri is selected from the group consisting of H, Rio and -C (O) Rlo ; Rlo is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl and heterocyclic radical ; W is a trisubstituted phosphorus, and X is the anion of a strong acid.

Preferably, Ri is H, unsubstituted C16 alkyl, and aryl substituted C16 alkyl, and most preferably Ri is benzyl.

More preferably X is Cl, Br or I, and most preferably X is Br. Preferably W is PRllRl2Rl3, where Rll, R12 and R13 are each independently alkyl or aryl, and more preferably W is triphenyl phosphorous.

SYNTHETIC SCHEMES

In the Synthetic Schemes, the synthesis starts with compounds of formula (VI) or (III). Compounds of formula (V) are formed by halogenation of the compounds of formula (VI), for example by, bromination with N-bromosuccinamide (NBS). The compounds of formula (IV) may be made by

reaction of the compounds of formula (V), with a trisubstituted phosphorus, for example with triphenyl phosphine. The compounds of formula (I) can be formed from the compounds of formula (IV) by reaction with a base, such as triethylamine, and the appropriate aldehyde (R2-CH=O), such as propionaldehyde ; alternatively, the compounds of formula (I) can be formed by reaction of the compounds of formula (III) with the appropriate ylide (R2-CH=W, where W is a trisubstituted phosphorus, for example triphenyl phosphine). Although not illustrated in the scheme, the ylide can be made in situ, by reacting a tertiary phosphonium halide with a base, for example propyltriphenylphosphonium bromide with n-butyllithium.

Whenever used, preferably the base is a metal alkoxide, alkyl, alkoxidealkyl, alkoxidearyl, alkylaryl, alkoxide halide, alkylhalide, or arylhalide. Preferably, the metal is an alkali metal, alkaline earth metal, or aluminum.

As described above, the compounds of formula (II) may be formed from the compounds of formula (I) by reaction with CO and a catalyst Finally, the compounds of formula (VII) can be made from the compounds of formula (II) by alkylation, for example by reaction with benzyl chloride and NaH in DMF.

The compound of formula (II) can be used to make indole-3-glyoxylamide compounds of formula (X) or (X') :

where R1, R2, R5, R6 and R7 are described above ; R8 is an alkali metal, H, alkyl, alkenyl, alkynyl, aryl or heterocyclic radical ; R9 and Rg'are each individually H, alkyl, alkenyl, alkynyl, aryl or heterocyclic radical ;-L- is-AX-By-Cz-D-; A is-O-,-S-,-N (RA)- and -C(RARA')-; B is- O-, -S-, -N (RB)- and -C(RBRB')-; C is-O-,-S-,-N (RC)- and - C (RcRc')- ; and D is-C (RDRD')-; each RA, RB, Ré and RD is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical, or any two of RA, RB, RC and RD together form a bond, or any two of RA, RB, R and RD together with the atoms to which they are bonded for a ring ; each RA', RB', RC'and RD'is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical, or any two of RA', RB', Ru'an RD' together form a bond, or any two RA'/RB', RC'and RD' together with the atoms to which they are bonded for a ring ; and each x, y and z is either 0 or 1.

Preferably R8 is alkali metal, H, unsubstituted C1-6 alkyl or heterocyclic radical substituted C16 alkyl, and more preferably R8 is Na, H, methyl, or morpholino-N-ethyl.

Preferably R9 and Rg'are each individually H or C1-6 alkyl, and more preferably R9 and Rg'are both H. Preferably A is C (RARA')-, B is-C (RBRB')-, C is-C (RcRc')-, and most preferably-L-is-(CH2) 1-4--In a preferred embodiment the compounds of formula (X) are the compounds P, Q, R or S.

The compounds of formula (X) or (X') may be made from the compounds of formula (VII) by the schemes and reactions described in U. S. Patent No. 5, 654, 326 and in Draheim et al., J. Med. Chem. 1996, 39, 5159-75, or using some of the reaction described in Scheme A.

Novel intermediates The present invention provides the following novel intermediates : a compound of the formula (I) : where R2, R3, R4, R5, R6 and R7 are described above.

EXAMPLES The following examples and preparations are provided merely to further illustrate the invention. The scope of the invention is not construed as merely consisting of the following examples.

General. All reactions were run under a nitrogen atmosphere except where water was a solvent or reagent, and unless otherwise specified. Glassware was oven dried at 100 °C or flame dried with a torch. Commercially obtained reagents were used as received unless otherwise noted. Solvents were from freshly opened containers and were used without further drying, except tetrahydrofuran, which was dried and stored over 4A molecular sieves. Analyses were performed by the Physical Chemistry Research Department, MC625, at Eli Lilly.

All yields are corrected for chemical purity of both the limiting reagent and the product (i. e. Yield = (weight of product x purity/MW of product)/ (weight of limiting reagent x purity/MW of limiting reagent) x 100). If the purity of a product is not specified it is greater than 99%.

The following examples describe the synthesis of compound F as shown in Scheme I.

SCHEME I

Preparation of 2-hydroxy-6-nitrobenzaldehyde (compound A).

A solution of 2-methoxy-6-nitrobenzaldehyde (1. 5 g, 8. 3 mmol, M. C. Wani and M. E. Wall, Journal of Organic

Chemistry, 1969, 34, 1364-7) in methylene chloride (20 mL) was cooled to-20 °C and treated with boron tribromide (4. 2 g, 17 mmol). The mixture was allowed to warm to room temperature and stir for 3 h. The reaction was quenched carefully with methanol and diluted with methylene chloride.

The resulting solution was washed twice with water. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 800 mg (58%) of the title compound. MS ES-m/e 166 (p-1).

Preparation of 2-[(carbomethoxy) methoxy]-6-nitrobenzaldehyde (compound B). A solution of 2-hydroxy-6-nitrobenzaldehyde (700 mg, 4. 19 mmol) in N, N-dimethylformamide (10 mL) was treated carefully with 60% sodium hydride dispersion (200 mg) at room temperature. The mixture was stirred for 45 min then treated with methyl bromoacetate (591 mg, 4. 19 mmol).

The resulting mixture was stirred for 2 h at room temperature. The mixture was carefully quenched with water and diluted with ether. The organic layer was washed twice with water, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane to 50% ethyl acetate/50% hexane) of the residue provided 800 mg (80%) of the title product as a tan solid. 1H NMR (CDCl3) #10.43 (S, 1 H), 7.59 (t, J = 8 Hz, 1 H), 7. 51 (d, J = 8 Hz, 1 H), 7. 13 (d, J = 8 Hz, 1 H), 4. 79 (s, 2 H), 3. 81 (s, 3 H) ; MS ES-m/e 298 (p + CH3COO-) IR (CHC13, cm) 3029, 1761, 1537. Anal. Calcd for CloHgNO6 : C, 50. 22 ; H, 3. 79 ; N, 5. 86. Found : C, 48. 53 ; H, 3. 63 ; N, 5. 70.

Preparation of 2- (l-butenyl)-3- [(carbomethoxy) methoxy] nitrobenzene (compound D).

Propyltriphenylphosphonium bromide (1. 89 g, 4. 90 mmol) was

suspended in ether (15 mL) and cooled to-20 °C. To this suspension was added 1. 6 M n-butyllithium in hexane (3. 4 mL, 5. 4 mmol) dropwise over 2 minutes. The resulting orange mixture (containing compound C) was stirred at-20 °C for 2 h. A solution of 2- [ (carbomethoxy) methoxy]-6- nitrobenzaldehyde (1. 17 g, 4. 90 mmol) in tetrahydrofuran (5 mL) was added and the immediate formation of a precipitate was noted. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was filtered and the solids washed repeatedly with ether. The combined filtrates were washed once with water, dried (sodium sulfate), filtered, and concentrated in vacuo.

Chromatography (silica gel, 5% ethyl acetate/95% hexane to 30% ethyl acetate/70% hexane) of the residue provided 650 mg (50%) of the title product as an approximately 50 : 50 mixture of cis to trans isomers. MS ES+ m/e 283 (p + NH4+) ; IR -1 (CHC13, cm) 1761, 1530, 1361.

Preparation of 4-[(carbomethoxy) methoxy]-2-ethylindole (compound E). The reaction was set up and conducted according to the method of Soderber and Shriver : B. C.

Soderber and J. A. Shriver, Journal of Organic Chemistry, 1997, 62, 5838-45. A mixture 2- (l-butenyl)-3- [(carbomethoxy) methoxy] nitrobenzene (150 mg, 0. 566 mmol), palladium (II) acetate (7 mg, 0. 034 mmol), and triphenylphosphine (36 mg, 0. 14 mmol) in acetonitrile (5 mL) was placed in a pressure tube and purged with carbon monoxide for 30 min. The tube was then sealed and pressurized with carbon monoxide. The tube was evacuated and pressurized with carbon monoxide. This was repeated three times with the final pressure of carbon monoxide adjusted to 4 atm. The tube was immersed in an oil bath and maintained at 70 °C for 24 h. The tube was cooled to room temperature, evacuated, pressurized with air to 1 atm, and

unsealed. The reaction mixture was diluted with ether and washed twice with 1N hydrochloric acid solution. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 5% ethyl acetate/95% hexane to 20% ethyl acetate/80% hexane) of the residue provided 110 mg (83%) of the title product as an off-white solid. 1H NMR (CDCl3) #7.90 (bs, 1 H), 7.01 (m, 2 H), 6. 42 (m, 2H), 4, 78 (s, 2 H), 3. 81 (s, 3 H), 2. 78 (q, J = 8 Hz, 2 H), 1. 35 (t, J = 8 Hz, 3 H) ; MS ES-m/e 232 (p- 1 1) ; IR (CHC13, cm) 3473, 1760, 1507. Anal. Calcd for Cl3Hl5NO3 : C, 66. 94 ; H, 6. 48 ; N, 6. 00. Found : C, 65. 66 ; H, 6. 36 ; N, 5. 58.

Preparation of l-benzyl-4-[(carbomethoxy) methoxy]-2- ethylindole (compound F). A solution of 4- [(carbomethoxy) methoxy]-2-ethylindole (80 mg, 0. 34 mmol) in N, N-dimethylformamide (5 mL) was carefully treated with 60% sodium hydride dispersion (17 mg) at room temperature.

After stirring for 20 min, benzyl iodide (75 mg, 0. 34 mmol) was added and the resulting mixture stirred for 3 h. The mixture was diluted with ether and washed once with water.

The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo to provide 40 mg (36%) of the title product as an oil. 1H NMR (CDCl3) #6.75-7.05 (m, 7 H), 6.55 (s, 1 H), 6. 40 (d, J = 8 Hz), 5. 29 (s, 2 H), 4. 81 (s, 2 H), 3. 82 (s, 3 H), 2. 65 (q, J = 8 Hz, 2 H), 1. 30 (t, J = 8 Hz, 3 H) ; MS ES+ m/e 324 (p + 1).

The following examples describe the synthesis of compound J as shown in Scheme II.

SCHEME II

Preparation of 2-(1-butenyl)-3-nitroanisole (compound H).

Propyltriphenylphosphonium bromide (2. 13 g, 5. 52 mmol) was suspended in ether (15 mL) and cooled to-20 °C. To this suspension was added 1. 6 M n-butyllithium in hexane (3. 80 mL, 6. 08 mmol) dropwise over 2 minutes. The resulting orange mixture (containing compound C) was stirred at-20 °C for 2 h. A solution of 2-methoxy-6-nitrobenzaldehyde (compound A) (1. 00 g, 5. 52 mmol, M. C. Wani and M. E. Wall, Journal of Organic Chemistry, 1969, 34, 1364-7) in tetrahydrofuran (5 mL) was added and the immediate formation of a precipitate was noted. The reaction mixture was allowed to warm to room temperature and stirred for 18 h.

The mixture was filtered and the solids washed repeatedly with ether. The combined filtrates were washed once with water, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, hexane to 10% ethyl acetate/90% hexane) of the residue provided 647 mg (57%) of the title product as an approximately 60 : 40 mixture of cis to trans isomers. MS FD m/e 207 (p) ; IR (CHC13, cm) 2968, 1529, 1361, 1265. Anal. Calcd for CllHl3NO3 : C, 63. 76 ; H, 6. 32 ; N, 6. 76. Found : C, 64. 21 ; H, 5. 90 ; N, 6. 78.

Preparation of 2-ethyl-4-methoxyindole (compound J). The reaction was set up and conducted according to the method of Soderber and Shriver : B. C. Soderber and J. A. Shriver, Journal of Organic Chemistry, 1997, 62, 5838-45. A mixture of 2- (l-butenyl)-3-nitroanisole (320 mg, 1. 55 mmol), palladium (II) acetate (20 mg, 0. 093 mmol), and triphenylphosphine (97 mg, 0. 37 mmol) in acetonitrile (6 mL) was placed in a pressure tube and purged with carbon monoxide for 30 min. The tube was then sealed and pressurized with carbon monoxide. The tube was evacuated and pressurized with carbon monoxide. This was repeated three times with the final pressure of carbon monoxide

adjusted to 4 atm. The tube was immersed in an oil bath and maintained at 70 °C for 24 h. The tube was cooled to room temperature, evacuated, pressurized with air to 1 atm, and unsealed. The reaction mixture was diluted with ether and washed twice with 1N hydrochloric acid solution. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, hexane to 10% ethyl acetate/90% hexane) of the residue provided 190 mg (85%) of the title product as an amber oil. 1H NMR (CDC13) 7. 90 (bs, 1 H), 7. 05 (t, J = 8 Hz, 1 H), 6. 94 (d, J = 8 Hz, 1 H), 6. 52 (d, J = 8 Hz, 1 H), 6. 34 (s, 1 H), 3. 96 (s, 3 H), 2. 78 (q, J = 8 Hz, 2 H), 1. 34 (t, J = 8 Hz, 3 H) ; -1 MS ES+ m/e 176 (p + 1) ; IR (CHC13, cm) 3473, 3007, 1507, 1247. Anal. Calcd for CllHl3NO : C, 75. 40 ; H, 7. 48 ; N, 7. 99.

Found : C, 75. 39 ; H, 7. 19 ; N, 7. 89.

The following prophetic examples describe the synthesis of compound F as shown in Scheme III. In this scheme, the preparation of compound E (from compound D) and compound F (from compound E) are identical the these same reactions as carried out in Scheme I, previously described, and therefore are not repeated here. The remaining individual reactions are of types well known to those of ordinary skill in the art, and are described in Organic Synthesis by Michael B.

Smith, McGraw-Hill, Inc. (New York), 1994 ; Advanced Organic Chemistry : Reactions, Mechanisms, and Structure, 4th Edition by Jerry March, John Wiley & Sons (New York), 1992 ; and Advanced Organic Chemistry, Part B : Reactions and Synthesis, 3rd Edition by Francis A. Carey and Richard J. Sundberg, Plenum Press (New York), 1990.

SCHEME in

Preparation of 2-[(carbomehthoxy) methoxy]-6-nitrotoluene (compound L). 2-hydroxy-6-nitrotoluene (compound K) is reacted with ethyl bromoacetate and potassium carbonate.

Preparation of 2- (l-butenyl)-3- [ (carbomethoxy) methoxy] nitrobenzene (compound D). 2- [ (carbomehthoxy) methoxy]-6-nitrotoluene is first brominated with N-bromosuccinimide. Next, the product of the bromination is reacted with triphenylphosphine. Finally, the resulting triphenylphosphonium bromide is reacted with propionaldehyde and triethylamine.