Provisional Application No. 60/171, 230, filed December 16, 1999, the entire content of which is incorporated by reference herein.

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)-l-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 SO2C12, followed by HC1, 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 (COC1) 2, followed by NH3 in CH2C12, 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.

SCHEME A

It would be useful to have alternative routes to this class of indole-3-glyoxylamides. In particular, it would be useful to have a new route involving fewer processing steps to form the 2, 4-disubstituted, and 2, 5-disubstituted indole nucleuses of these molecules. Improved processes would result in higher yield and reduced cost compared to the prior art.

The Wittig reaction is a classic method for forming carbon-carbon double bonds, by replacing a carbonyl oxygen, =O, by the group =CRxRy. In the reaction, an ylide, W=CRxRy (where W is a trisubstituted phosphorous), is reacted with the carbonyl. The ylide is itself formed by reaction of a trisubstituted phosphorous with an alkyl halide, to form an alkyl trisubstituted phosphorous halide, followed by deprotonation with a base. Typically, the ylide is not isolated, but rather is prepared in situ from the alkyl trisubstituted phosphorous halide. Although the Wittig reaction has been used to form indoles, it has not been used to form 2, 4-disubstituted indoles, nor 2, 5-disubstituted indoles. The present invention provides a novel method for synthesizing indole-3-glyoxylamides, using the Wittig reaction to form 2, 4-disubstituted indoles, or 2, 5- disubstituted indoles, which affords fewer processing steps and improved efficiency.

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

(n) and where Ri is selected from the group consisting of H, Rio and- C (O) Rio ; R2 is selected from the group consisting of R20 -OR20, -SR20, -NR2oR2o'and-C (O) 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, Rio and R20 is individually selected from the group consisting of alkyl, alkenyl, alkynyl, aryl and heterocyclic radical ; each R'and R20'is individually selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical ; and W is a trisubstituted phosphorous.

In another aspect, the present invention provides a method of making a compound, comprising reacting a compound represented by formula (I), with a base, 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

wherein ; where R1, R2, R5, R6 and R7 are described above ; R8 is selected from the group consisting of alkali metal, H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical ;

Rg 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, 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 of RA, Ra, Re and RD together with the atoms to which they are bonded for a ring ; each RA', RB', Ru'an 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 the formula (I), where formula (I) is described above.

In still another aspect, the present invention provides a compound of the formula (III) : where Rl, R3, R4 R5, R6, R7 and W are 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 (-O-), 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 HC1, 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) : (n)

where : Ri is H, Rio or-C (O) Rlo ; R2 is R2o-OR2o,-SR2o,-NR2oR20'or-C (O) R2o ; R3, R4, R5, R6 and R7 are each individually H, halogen, R,- OR,-SR,-NRR',-C (O) R,-C (0) OR,-S (O) R or-S (O) 2R ; provided that at least one of R4 and R5 is not H ; each R, Rio 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 C1-6 alkyl. Preferably, Ri is H, unsubstituted C1-6 alkyl, or aryl substituted Cl-6 alkyl, and more preferably R1 is H or benzyl. 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-OR, and more preferably R4 is-OCH3.

In a preferred embodiment the compound of formula (II) is compound G or M :

The method comprises reacting a compound of formula (I) with a base : where Rl, R2, R3, R4, R5, R6 and R7 are described above, and W is a trisubstituted phosphorous. Preferably wherein the compound of formula (I) further comprises X-, where X-is the anion of a strong acid, more preferably X is C1, 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 phosphine.

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. In a preferred embodiment, the compound of formula (I) is compound F or L :

In this reaction, the ylide is not isolated, but rather is formed in situ. In an alternate, but less preferred embodiment, the reacting includes the isolation of the ylide before forming of the compound of formula (II).

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 toluene. Preferably the reaction takes place at a temperature of 0 to 200° C.

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 R1, R2, R3, R4, R5, R6, R7, W and X are described above.

SYNTHETIC SCHEMES

In the Synthetic Schemes, the synthesis starts with compounds of formula (VI) or (VII). Compounds of formula (V) are formed by halogenation of the compounds of formula

(VI), for example by reaction with HBr, or by halogenation of the compounds of formula (VII), for example by, bromination with N-bromosuccinamide (NBS). The compounds of formula (VIII) may be formed by acylation of the compounds of formula (VII), for example by reaction with propionyl chloride and triethylamine. The compounds of formula (III) can be formed from the compounds of formula (V) by reaction with a trisubstituted phosphorous, for example triphenyl phosphine. Although not illustrated in the scheme, it is also possible to form the compounds of formula (III) directly from the compounds of formula (VI) by reaction with the salt of a trisubstituted phosphorous and HX, for example with triphenylphosphine hydrobromide. The compounds of formula (IV) may be formed by acylation of the compounds of formula (V), for example by reaction with propionyl chloride and triethylamine, or by halogenation of the compounds of formula (VIII), for example by, bromination with N- bromosuccinamide (NBS). Finally, the compounds of formula (I) can be made from the compounds of formula (III) by acylation, for example by reaction with propionyl chloride and triethylamine, or from the compounds of formula (IV) by reaction with a trisubstituted phosphorous, for example triphenyl phosphine.

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

where Ri, 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, R 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', Ru'an 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', 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 C1-6 alkyl, and more preferably R8 is Na, H, methyl, or morpholino-N-ethyl.

Preferably R9 and R9'are each individually H or Cl-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 (II) 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) : (I)

where Rl, R2, R3, R4, R5, R6, R7 and W are described above ; and a compound of the formula (III) : where RI, R3, R4, R5, R6, R7 and W 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. 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 G as shown in Scheme I.

SCHEME I

Preparation of 2-nitro-6-methoxybenzyl bromide (compound B).

A mixture of 2-methyl-3-nitroanisole (compound A) (20. 0 g, 120 mmol), freshly recrystallized N-bromosuccinimide (25. 6 g, 144 mmol), and benzoyl peroxide (1. 45 g, 6. 00 mmol) in carbon tetrachloride (200 mL) was refluxed with infrared irradiation for 18 h. The mixture was cooled to room temperature, diluted with additional methylene chloride, and washed twice with water. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo to provide 29. 0 g (98%) of the title compound as yellow crystals. 1H NMR (CDC13) b7. 52 (d, J = 8 Hz, 1 H), 7. 42 (t, J = 8 Hz, 1 H), 7. 15 (d, J = 8 Hz, 1 H), 4. 82 (s, 2 H), 3. 98 (s, 3 H); MS FD m/e 247 (p + 1), 245 (p - 1); IR (CHCl3, cm 1) 1534, 1354, 1275. Anal. Calcd for C8H8NO3Br: C, 39.05; H, 3. 28 ; N, 5. 69. Found : C, 39. 28 ; H, 3. 24 ; N, 5. 54.

Preparation of 2-nitro-6-methoxybenzyl alcohol (compound C).

To a solution of sodium carbonate (8. 40 g, 79. 3 mmol) in water (600 mL) was added 2-nitro-6-methoxybenzyl bromide (15. 0 g, 61. 0 mmol). The resulting suspension was refluxed for 4 h. The mixture was cooled to room temperature and extracted twice with methylene chloride. The combined organic layers were dried (sodium sulfate), filtered, and concentrated in vacuo to provide 9. 4 g (84%) of the title product as a yellow solid. 1H NMR (CDC13) 67. 48 (d, J = 8 Hz, 1 H), 7. 41 (t, J = 8 Hz, 1 H), 7. 15 (d, J = 8 Hz, 1 H), 4. 79 (s, 2 H), 3. 92 (s, 3 H), 2. 58 (bs, 1 H,-OH).

Preparation of 2-amino-6-methoxybenzyl alcohol (compound D).

A solution of 2-nitro-6-methoxybenzyl alcohol (9. 00 g, 49. 2 mmol) and methanol (15 mL) in tetrahydrofuran (135 mL) was de-gassed thoroughly with nitrogen and treated with 10% palladium-on-carbon (1. 0 g). The resulting suspension was

hydrogenated at 45 psi for 4 h at room temperature. The mixture was de-gassed with nitrogen and filtered through diatomaceous earth. The resulting solution was concentrated in vacuo to provide 7. 5 g (100%) of the title product as an unstable red oil. H NMR (CDC13) 87. 05 (t, J = 8 Hz, 1 H), 6. 32 (d, J = 7 Hz, 1 H), 6. 29 (d, J = 8 Hz, 1 H), 4. 72 (s, 2 H), 3. 79 (s, 3 H), 3. 50 (bs, 2 H,-NH2) ; MS ES+ m/e 154 (p + 1, 50), 136 (p-H2O, 100).

Preparation of 2-amino-6-methoxy (triphenylphosphonium) benzyl bromide (compound E). A mixture of 2-amino-6-methoxybenzyl alcohol (1. 00 g, 6. 54 mmol) and triphenylphosphine hydrobromide (2. 47 g, 7. 19 mmol) in chloroform (10 mL) was refluxed for 1 h. The mixture was cooled to room temperature and diluted with ether. The resulting precipitate was collected via vacuum filtration to provide 2. 8 g (90%) of the title product as an off-white amorphous solid. 1H NMR (DMSO-d6) 87. 40-8. 00 (m, 15 H), 6. 90 (t, J = 8 Hz, 1 H), 6. 21 (d, J = 8 Hz, 1 H), 5. 98 (d, J = 8 Hz, 1 H), 4. 72 (s, 1 H), 4. 62 (s, 1 H), 3. 08 (s, 3 H) ; MS ES+ m/e 398 (p-Br).

Preparation of 2- [N- (propionyl) amino]-6- methoxy (triphenylphosphonium) benzyl bromide (compound F). A suspension of 2-amino-6-methoxy (triphenylphosphonium) benzyl bromide (2. 50 g, 5. 22 mmol) in toluene (15 mL) and methylene chloride (15 mL) was treated at room temperature with triethylamine (1. 44 mL, 10. 4 mmol) followed by propionyl chloride (0. 58 mL, 6. 26 mmol). The reaction mixture was stirred for 1 h and concentrated in vacuo to produce a tan mass. This material was dissolved in fresh methylene chloride and the resulting solution washed once with 15% sodium carbonate solution, once with 1 N hydrochloric acid,

and once with water. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo to provide 2. 0 g (72%) of the title product as a yellow solid. H NMR (CDC13) 810. 64 (s, 1 H,-NH), 7. 70 (m, 3 H), 7. 50-7. 65 (m, 12 H), 7. 15 (m, 2 H), 6. 27 (m, 1 H), 5. 46 (s, 1 H), 5. 42 (s, 1 H), 3. 27 (s, 3 H), 2. 32 (q, J = 8 Hz, 2 H), 0. 89 (t, J = 7 Hz, 3 H) ; MS ES+ m/e 454 (p-Br).

Preparation of 2-ethyl-4-methoxyindole (compound G). A suspension of 2- [N- (propionyl) amino]-6- methoxy (triphenylphosphonium) benzyl bromide (1. 50 g, 2. 81 mmol) in toluene (35 mL) was heated to reflux. Potassium tert-butoxide (346 mg, 3. 09 mmol) was added in 5 portions and the resulting mixture refluxed for 1 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, diluted with ether, and filtered.

The final filtrate was concentrated in vacuo.

Chromatography (silica gel, 5% ethyl acetate/95% hexane to 20% ethyl acetate/80% hexane) provided 200 mg (41%) of the title product as a colorless oil. 1H NMR (CDC13) 87. 89 (bs, 1 H), 7. 05 (t, J = 8 Hz, 1 H), 6. 94 (d, J = 8 Hz, 1 H), 6. 51 (d, J = 8 Hz, 1 H), 6. 35 (s, 1 H), 3. 95 (s, 3 H), 2. 77 (q, J = 7 Hz, 2 H), 1. 34 (t, J = 8 Hz, 3 H) ; MS ES+ m/e 176 (p+1).

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

Preparation of 2- [N- (benzyl) amino]-6-methoxybenzyl alcohol (compound 1). 2-Amino-6-methoxybenzyl alcohol is first reacted with benzaldehyde to give the imine, which is then reduced by sodium borohydride.

Preparation of 2- [N- (benzyl)-N- (propionyl) amino]-6- methoxybenzyl alcohol (compound J). 2- [N- (benzyl) amino]-6- methoxybenzyl alcohol is treated with triethylamine and propionyl chloride.

Preparation of 2- [N- (benzyl)-N- (propionyl) amino]-6- methoxy (triphenylphosphonium) benzyl bromide (compound L).

2- [N- (benzyl)-N- (propionyl) amino]-6-methoxybenzyl alcohol is reacted with triphenylphosphonium hydrobromide.

Preparation of N-benzyl-2-ethyl-4-methoxyindole (compound M). 2- [N- (benzyl)-N- (propionyl) amino]-6- methoxy (triphenylphosphonium) benzyl bromide is reacted with sodium methoxide to give the corresponding ylide, which cyclizes to the indole.

Preparation of N-benzyl-2-ethyl-4-hydroxyindole (compound N). Deprotonation of N-benzyl-2-ethyl-4-methoxyindole with boron tribromide, gives the corresponding alcohol.