WO2001044184A1

WO2001044184A1 - Synthesis of indole-containing spla2 inhibitors

Info

Publication number: WO2001044184A1
Application number: PCT/US2000/032444
Authority: WO
Inventors: Michael John Martinelli; Jason Scott Sawyer
Original assignee: Eli Lilly And Company
Priority date: 1999-12-16
Filing date: 2000-12-11
Publication date: 2001-06-21
Also published as: AU2050001A

Abstract

A method of making a compound include reacting a compound represented by formula (I), with a base, to form the compound of formula (II); and where R1 is H, R10 or -C(O)R10; R2 is R20 -OR20, -SR20, -NR20R20' or -C(O)R20;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(O)2R; provided that at least one of R4 and R5 is not H; each R, R10 and R20 is individually alkyl, alkenyl, alkynyl, aryl or heterocyclic radical; each R' and R20' is individually H, alkyl, alkenyl, alkynyl, aryl or heterocyclic radical; and W is a trisubstituted phosphorous. The method provides an alternative route to indole-3-glyoxylamide compounds.

Description

SYNTHESIS OF INDOLE-CONTAINING SP A2 INHIBITORS

This application claims benefit of priority from U.S. 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 lH-indole-3- glyoxylamide sPLA₂ inhibitors, including the methyl ester of ( (3- (2-amino-l, 2-dioxoethyl) -l-benzyl-2-ethyl-lH-indol-4- yl) oxy) acetic acid. The morpholino ester of this compound, ( (3- (2-amino-l , 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-l, 2-dioxoethyl) -1-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.

R

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 S0₂C1₂, 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 BrCH₂C0₂CH₃ and K₂C0₃ in acetone, to form the methyl ester of formula X. Next, the methyl ester is reacted with (C0C1)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 Cs₂C0₃ 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, =0, by the group =CR_xR_y. In the reaction, an ylide, W=CR_xR_y (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

and, formula (II) is

and where

Ri is selected from the group consisting of H, Rι₀ and -

C(O)R₁₀;

R₂ is selected from the group consisting of R₂₀ -OR₂₀, -SRo,

-NR₂₀R₂o'and -C(O)R₂₀; R₃, R₄, R₅, R_δ and R₇ are each individually selected from the group consisting of H, halogen, R, -OR, -SR, -NRR' , -C(0)R,

-C(0)OR, -S(0)R and -S(0)₂R; provided that at least one of

R₄ and R₅ is not H; each R, Rio and Ro 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 (X¹) is

wherein; where Ri, R₂, R₅, Rε and R₇ are described above;

Rs 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 -A_x-B_y-C_z-D- ; A is -0- -N(R_A)- and -C(R_AR_A' ) B is -0-, -S-, -N(RB)- and -C(R_BR_B')-; C is -0- , -S-, -N(Rc)- and -C(RcRc')-; and D is -C(R_DR_D')-; each R_A, R_B, R_c and R_D is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical, or any two of R_A, R_B, Rc and R_D together form a bond, or any two of R_A, R_B, Rc and R_D together with the atoms to which they are bonded for a ring; each R_A', R_B ' Rc ' and R_D ' is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical, or any two of R_A', R_B ' , R_c ' and R_D' together form a bond, or any two R_A' , R_B ' , R_c ' and R_D ' 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 R_i; R₃ , R₄ R5, Re , R7 and W are described above .

These and other aspects and features of the invention will become more fully understood in the detailed description . DETAI ED 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 (-NRR¹), 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, lH-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 :

Ri is H, Rio or -C(O)Rι₀;

R₂ is R₂₀ -OR20, -SR20, -NR20R20' or -C(O)R₂₀; R₃, R₄, R₅, R₆ and R₇ are each individually H, halogen, R, -

OR, -SR, -NRR', -C(0)R, -C(0)OR, -S(0)R or -S(0)₂R; provided that at least one of R₄ and R₅ is not H; each R, Rio and R₂o is individually alkyl, alkenyl, alkynyl, aryl or heterocyclic radical; and each R' and R₂o ' is individually H, alkyl, alkenyl, alkynyl, aryl or heterocyclic radical.

Preferably R is unsubstituted Cι_₆ alkyl. Preferably,

Ri is H, unsubstituted Cι_₆ alkyl, or aryl substituted Cχ-₆ alkyl, and more preferably Ri is H or benzyl. Preferably R₂ is F or unsubstituted Cι_₆ alkyl, and more preferably R₂ is ethyl. Preferably R₃ , R₅, Re and R₇ are each H, F, R or -OR, and more preferably R₃, R₅, Rε 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 Ri , R₂, R₃ , R₄, R5, Rβ 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 Cl, Br or I , and most preferably X is Br . Preferably W is PRnRi₂Ri₃ where R_n, R₁₂ and Rι₃ 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 Ri , R , R₃, R₄, R₅, Re, 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, Re and R₇ are described above; Rs is an alkali metal, H, alkyl, alkenyl, alkynyl, aryl or heterocyclic radical; R₉ and R₉ ' are each individually H, alkyl, alkenyl, alkynyl, aryl or heterocyclic radical; -L- is -A_x-B_y-C_z-D-; A is -O- , -S-, -N(R_A)- and -C(R_AR_A')-; B is - 0-, -S-, -N(RB)- and -C(R_BR_B')-; C is -0- , -S-, -N(R_C)- and - C(R_cRc')-; and D is -C(R_DR_D')-; each R_A, R_B, R_c and R_D is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical, or any two of R_A,

R_B, R_c and R_D together form a bond, or any two of R_A, R_B, R_c and R_D together with the atoms to which they are bonded for a ring; each R_A', R_B'/ Rc ' and R_D ' is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical, or any two of R_A', R_B', R_c ' and R_D ' together form a bond, or any two R_A', R_B'/ Rc ' and R_D ' together with the atoms to which they are bonded for a ring; and each x, y and z is either 0 or 1.

Preferably Rs is alkali metal, H, unsubstituted C1-6 alkyl or heterocyclic radical substituted Cι_₆ alkyl, and more preferably Rs 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 R₉ ' are both H. Preferably A is C(R_AR_A' )-, B is -C(R_BR_B')-/ C is -C(RcRc')-, and most preferably -L- is -

(CH₂)i-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) :

where Ri, R₂ , R₃ , R₄ , R₅, Re , R7 and W are described above ; and

a compound of the formula (III) :

where Ri, R , R₄, R₅, R , 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

B C

D

G 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 tetrac loride (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. ^XH NMR (CDC1₃) δ7.52 (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 ^l ) 1534, 1354, 1275. Anal. Calcd for C₈H₈N0₃Br : 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. H NMR (CDC1₃) δ7.48 (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. ¹H NMR (CDC1₃) δ7.05 (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 - H₂0, 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. ^XH NMR (DMSO-d₆) 57.40-8.00 (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- methox (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) δlθ.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. H NMR (CDC1₃) δ7.89 (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, 4 th Edi tion by Jerry March, John Wiley & Sons (New York), 1992; and Advanced Organic Chemistry, Part B : Reactions and Synthesis, 3rd Edi tion by Francis A. Carey and Richard J. Sundberg, Plenum Press (New York), 1990.

SCHEME π

Preparation of 2- [N- (benzyl) amino] -6-methoxybenzyl alcohol (compound I) . 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 ) . 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.

Claims

1. A method of making a compound, comprising: reacting a compound of formula (I), with a base, to form the compound of formula (II); wherein formula (I) is

and, formula (II) is

and wherein;

Ri is selected from the group consisting of H, Rio and -C(0)Rιo;

R₂ is selected from the group consisting of R₂o - OR₂₀, -SR₂₀, -NR₂oR₂o'and -C(O)R₂₀; R₃ , R₄, R5, R and R₇ are each individually selected from the group consisting of H, halogen, R, -OR, - SR, -NRR', -C(0)R, -C(0)OR, -S(0)R and -S(0)₂R; provided that at least one of R₄ and R₅ is not H; each R, R₁₀ 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.

2. The method of Claim 1, wherein R₂ is selected from the group consisting of F and unsubstituted Cι_₆ alkyl.

3. The method of Claim 1, wherein R₃ , R₅, R₆ and R₇ are each individually selected from the group consisting of H, F, R and -OR.

4. The method of Claim 3, wherein each R is individually selected from the group consisting of unsubstituted C₁-₆ alkyl.

5. The method of Claim 1, wherein Ri is selected from the group consisting of H, unsubstituted Cι_₅ alkyl, and aryl substituted Cι_₆ alkyl.

6. The method of Claim 1, wherein R₄ is selected from the group consisting of halogen and -OR.

7. The method of Claim 1, wherein R₄ is OR, and each R is individually selected from the group consisting of unsubstituted Cι_₆ alkyl and aryl substituted C1-6 alkyl .

8. The method of Claim 1, wherein the compound of formula (I) further comprises

X^", and X is the anion of a strong acid.

9. The method of Claim 8, wherein W is selected from the group consisting PRnRιRι₃, where R_n, R₁₂ and R₁₃ are each independently selected from the group consisting of alkyl and aryl ; and

X is selected from the group consisting of Cl, Br and I .

10. The method of Claim 1, wherein at least one of R, Rio/ R₂0/ R' and R₂o ' is substituted with a substituent, and said substituent is hydroxyl, amino, oxy, carbonyl, thiol, alkyl, alkenyl, alkynyl, alkoxy, halo, nitrile, nitro, aryl, carboxamide, alkylmercapto, alkylsulphonyl, alkylamino, dialkylamino, carboxylate, alkoxycarbonyl, alkylaryl or aralkyl .

11. The method of Claim 1, wherein said base is selected from the group consisting of metal alkoxides, alkyls, aryls, alkoxyalkyls , alkoxyaryls, alkoyalylaryls , alkylaryls, alkoxide halides, alkylhalides, arylhalide, alkoxyalkylhalides , and alkylarylhalides , and wherein said metal is selected from the group consisting of alkali metals, alkaline earth metal, and aluminum.

12. A method of making a compound, according to any of Claims 1 to 11, comprising: reacting a compound of 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) is

formula (II) is

and, formula (X) is

formula (X' ) is

wherein;

Ri is selected from the group consisting of H, Rio and -C(O)Ri₀;

R₂ is selected from the group consisting of R₂o - OR₂₀, -SR₂₀, -NR₂₀R2o'and -C(O)R₂₀;

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

Re is selected from the group consisting of alkali metal, H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical ;

R₉ and R₉ ' are each individually selected from the group consisting H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical each R, Rio and R₂o is individually selected from the group consisting of alkyl, alkenyl, alkynyl, aryl and heterocyclic radical; each R' and Ro ' is individually selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical;

-L- is -A_x-B_v-C_z-D- A is -0- -N(R_A)- and

C(R_AR_A')-; B is -0-, -S-, -N(R_B)- and -C(R_BR_B')-; C is -0-, - S-, -N(R_C)- and -C(R_CR_C')-; and D is -C(R_DR_D')-; each R_A, R_B, R_c and R_D is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical, or any two of R_A, R_B, R_C and R_D together form a bond, or any two of R_A, R_B, R_c and R_D together with the atoms to which they are bonded for a ring; each R_A', R_B ' , Re ' and R_D ' is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical, or any two of R_A', R_B ' , R_c ' and R_D' together form a bond, or any two R_A ' , R_B'/ Re ' and R_D' together with the atoms to which they are bonded for a ring; and each x, y and z is either 0 or 1; and

W is a trisubstituted phosphorous.

13 The method of Claim 12, wherein -L- is -(CH₂)ι_₄-

14. A compound of the formula (I]

wherein; Ri is selected from the group consisting of H, R₁₀ and -C(0)Rιo;

R2 is selected from the group consisting of R₂o - OR₂₀, -SR20, -NR₂₀R2o'and -C(O)R₂₀;

R₃ , R₄, R5, Re and R₇ are each individually selected from the group consisting of H, halogen, R, -OR, - SR, -NRR', -C(0)R, -C(0)OR, -S(0)R and -S(0)₂R; provided that at least one of R₄ and R₅ is not H; each R, Rι₀ and R₂o is individually selected from the group consisting of alkyl, alkenyl, alkynyl, aryl and heterocyclic radical; each R' and R₂o ' is individually selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical; and

W is a trisubstituted phosphorous.

15. The compound of Claim 14, wherein R₂ is selected from the group consisting of F and unsubstituted Cι-₆ alkyl.

16. The compound of Claim 14 or 15, wherein R₃ , R₅, Re and R₇ are each individually selected from the group consisting of H, F, R and -OR.

17. The compound of Claim 14, 15 or 16, wherein each R is individually selected from the group consisting of unsubstituted C1-₆ alkyl .

18. The compound of Claim 14, 15, 16 or 17, wherein R₁ is selected from the group consisting of H, unsubstituted C₁-₆ alkyl, and aryl substituted Cι_₆ alkyl.

19. The compound of Claim 14, 15, 16, 17 or 18, wherein R₄ is selected from the group consisting of halogen and -OR.

20. The compound of Claim 14, 15, 16, 17, 18 or 19, wherein R₄ is OR, and each R is individually selected from the group consisting of unsubstituted Cι_₆ alkyl and aryl substituted Cι_6 alkyl.

21. The compound of Claim 14, 15, 16, 17, 18, 19 or 20, wherein the compound of formula (I) further comprises X^~, and X^" is the anion of a strong acid.

22. The compound of any of Claims 14 to 21, wherein W is selected from the group consisting PRnRι₂Rι₃, where Rn, R₁₂ and R_i3 are each independently selected from the group consisting of alkyl and aryl; and X is selected from the group consisting of Cl, Br and I .

23. The compound of Claim 14, wherein at least one of R, Rio, R20 R' and R₂o ' is substituted with a substituent, and said substituent is hydroxyl, amino, oxy, carbonyl, thiol, alkyl, alkenyl, alkynyl, alkoxy, halo, nitrile, nitro, aryl, carboxamide, alkylmercapto, alkylsulphonyl, alkylamino, dialkylamino, carboxylate, alkoxycarbonyl, alkylaryl or aralkyl .

24 A compound of formula (III!

wherein;

Ri is selected from the group consisting of H, Rio and -C(O)Rι₀;

R₃ , R , R₅, R6 and R₇ are each individually selected from the group consisting of H, halogen, R, -OR, - SR, -NRR', -C(0)R, -C(0)OR, -S(0)R and -S(0)₂R; provided that at least one of R4 and R₅ is not H; each R and Rio is individually selected from the group consisting of alkyl, alkenyl, alkynyl, aryl and heterocyclic radical; each R' is individually selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and heterocyclic radical; and

W is a trisubstituted phosphorous.

25. The compound of Claim 24, wherein R₃ , R₅, R₆ and R₇ are each individually selected from the group consisting of H, F, R and -OR.

26. The compound of Claim 24 or 25, wherein each R is individually selected from the group consisting of unsubstituted Cι_₆ alkyl.

27. The compound of Claim 24, 25 or 26, wherein Ri is selected from the group consisting of H, unsubstituted Cι_₆ alkyl, and aryl substituted Cι_₆ alkyl.

28. The compound of Claim 24, 25, 26, or 27, wherein R is selected from the group consisting of halogen and -OR.

29. The compound of any of Claims 24 to 28, wherein R₄ is OR, and each R is individually selected from the group consisting of unsubstituted Cι_₆ alkyl and aryl substituted Cι-6 alkyl.

30. The compound of any of Claims 24 to 29, wherein the compound of formula (I) further comprises X^", and X^" is the anion of a strong acid.

31. The compound of any of Claims 14 to 30, wherein W is selected from the group consisting PRnRι₂Rι₃, where Rn, R₁₂ and Rι₃ are each independently selected from the group consisting of alkyl and aryl; and

X is selected from the group consisting of CI, Br and I.

32. The compound of any of Claims 14 to 31, wherein at least one of R, Rio, R20 R' and R₂o ' is substituted with a substituent, and said substituent is hydroxyl, amino, oxy, carbonyl, thiol, alkyl, alkenyl, alkynyl, alkoxy, halo, nitrile, nitro, aryl, carboxamide, alkylmercapto, alkylsulphonyl, alkylamino, dialkylamino, carboxylate, alkoxycarbonyl, alkylaryl or aralkyl .

33. The method of Claim 1, wherein the compound of the formula (X) or (X') is selected from the group consisting of

R and

34. The method of Claim 14, wherein the compound of the formula (X) or (X') is selected from the group consisting of

Q

R and

35. A method of making a compound of Claim 1, comprising: reacting a compound represented by formula F, with a base, to form the compound of formula G; wherein formula F is

and, formula G is

36. A method of making a compound of Claim 1, comprising : reacting a compound represented by formula L, with a base, to form the compound of formula M; wherein formula L is

and, formula M is

37. The method of Claim 1, wherein the compound of formula (I) is the compound of formula F, and the compound of formula (II) is the compound of formula G; wherein formula F is

and, formula G is

38. The method of Claim 1, wherein the compound of formula (I) is the compound of formula L, and the compound of formula (II) is the compound of formula M; wherein formula L is

and, formula M is

39. A compound of the formula F, L or E