MXPA00009955A - Process for preparing 4-substituted-1h-indole-3-glyoxamides - Google Patents

Abstract

A process for preparing 1H-indole-3-glyoxamides useful for inhibiting SPLA2 and novel intermediates useful in the preparation of such compounds.

Description

PROCESS FOR PREPARING lH-IND? L-3-GLI? XAMIDAS- REPLACED IN POSITION 4 Description of the Invention This invention relates to a process for preparing certain lH-indol-3-glyoxamides useful for inhibiting the release of fatty acids mediated by sPLA2 for conditions such as septic shock and intermediates useful for the preparation of these compounds. Certain lH-indol-3-glyoxamides are known to be potent and selective inhibitors of mammalian sPLA2, useful for treating diseases such as septic shock, respiratory agony syndrome in adults, pancreatitis, trauma, bronchial asthma, allergic rhinitis , rheumatoid arthritis and diseases related and induced by sPLA2. For example, EPO Publication No. 0675110, discloses these compounds. Various patents and publications describe the processes for making these compounds by using the intermediates of the -hydroxy indole. Ref: 123641 The article, "Recherches en serie indolique, VI sur tryptamines substituees", by Marc Julia, Jean Igolen and Hanne Igolen, Bull. Soc. Chim. France, 1962, pp. 1060-1068 discloses certain indole-3-glyoxamides and their conversion to tryptane derivatives. The article, "2-Aryl-3-indoleglyoxylamides (FGIN-1): A New Class of Potent and Specific Ligands for the Mitochondrial DBI Receptor (MDR)" by E. Romeo, et al. , The Journal of Pharmacology and Experimental Therapeutics, Vol. 62, No. 3, (pp. 971-978) describes certain -aril-3-indolglycoxylamides have research applications in the central nervous systems of mammals. The summary, "Fragmentation of N-benzylindoles in Mass Spectro etry"; Chemical Abstracts, Vol. 67, 1967, 73028h, reports certain phenols included with benzyl including those that have glyoxylamide groups in position 3 of the indole nucleus. In the patent of E. U. A. No. 3,4 9,363 describes the trifluoromethyl groups having glyoxylamide groups in the 3-position of the indole nucleus.

U.S. Patent No. 3,351,630 describes the 3-indolyl acetic acid compounds substituted by alpha and their inclusive preparation of the glyoxylamide intermediates. U.S. Patent No. 2,825,734 describes the preparation of 3- (2-amino-1-hydroxyethyl) indoles using 3-indolglyoxylamide intermediates such as l-phenethyl-2-ethyl-6-carboxy-N-propyl-3. indolglyoxylamide (see, Example 30). U.A. Patent No. 4,397,850 prepares isoxazolyl m-lalamines by using glyoxylamide indoles as intermediates. The Patent of E. U. A. No. 3, 801, 594 discloses analgesics that are prepared by using 3-indolglyoxylamide intermediates. The article, "No. 565.- Inhibitors of enzymes, XII.-Preparation of (propargylamino-2 ethyl) -3 índols" by A. Alemahny, E. Fernández Alvarez, O. Nieto Lopey and M. E. Rubio Herraez; Bulletin of the Societe Chimique De France, 1974, No. 12, pp. 2883-2888, describes various indolyl-3-glyoxamides which are substituted by hydrogen in the 6-membered ring of the indole nucleus.

The article, "Indol-Umlagerung von 1-Diphenylamino-2, 3-dihydro-2, 3-pyrrolidonen" by Gert Kollenz and Christa Labes; Liebigs Ann. Chem., 1975, pp. 1979-1983, describes the 3-glyoxylamides substituted by phenyl. Several of these processes employ an intermediate of 4-hydroxy indole. For example, U.S. Patent No. 5,654,326, which is incorporated herein by reference in its entirety, discloses a process for preparing lH-indol-3-glyoxamide-substituted-4 derivatives which comprises reacting a 4-methoxyindole. appropriately substituted (prepared as described by Clark, RD et al., Synthesis, 1991, pp. 871-878, the descriptions of which are incorporated herein by reference) with sodium hydride in dimethylformamide at room temperature ( 20-25 ° C) and then undergo treatment with arylmethyl halide at room temperature to give 1-arylmethylindole which is O-demethylated using boron tribro in methylene chloride (Tsung-Ying Shem and Charles A. Winter , Adv. Druq Res., 1977, 12, 176, of which the description is incorporated for reference) to give 4-hydroxy indole. The alkylation of hydroxyindole is achieved with a alpha-b-oalkanoic acid ester in dimethylformamide using sodium hydride as a base. The conversion to glyoxamide is achieved by first reacting the ester of ° c- [(indol-4-yl) oxy] alkanoic acid with oxapyl chloride, then with ammonia, followed by hydrolysis with sodium hydroxide in methanol. The process for preparing the 1H-indol-3-glyoxamide-substituted-4 derivatives, as discussed above, has its utility. However, this process uses expensive reagents and environmentally hazardous organic solvents, produces byproducts containing furan and results in a relatively low production of the desired product. In an alternative preparation an appropriately substituted proprionylacetate is halogenated with sulfuryl chloride. The halogenated intermediate is hydrolyzed and decarboxylated upon treatment with hydrochloric acid and then reacted with an appropriately substituted cyclohexanedione. The treatment of the alkylated dione with an appropriate amine produces a 4-keto-indole which is oxidized by refluxing it in a boiling polar hydrocarbon solvent at high temperatures such as carbitol, in the presence of a catalyst, such as palladium on carbon, to prepare the 4-hydroxyindole which can then be alkylated and converted to the desired glyoxamide as described above. However, this process is limited by the high temperature oxidation that is required and also requires recovery with a precious metal catalyst. While the methods described above for preparing the 4-hydroxyindole intermediate are satisfactory, a more efficient transformation is desired. The present invention provides an improved process for preparing the lH-indole-3-glyoxamides. The process of the present invention can be carried out with inexpensive reagents, readily available, under milder conditions, which results in better overall production. In addition, the present process allows a transformation with a wider variety of substituents on an indole platform. Other objectives, characteristics and advantages of this invention will be apparent from a subsequent description and the appended claims. The present invention provides a process for preparing a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof; wherein: R1 is selected from the group consisting of C-j-C2o alkyl, - wherein: R10 is selected from the group consisting of halogen, C1-C10 alkyl; C1-C10 alkoxy, -S- (Ci-Cι alkyl) and (C 1 -C 10) haloalkyl and t is an integer from 0 to 5 inclusive of both; R2 is selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0- (C1-C2 alkyl), -s- (C1-C2 alkyl) aryl, aryloxy, and HET; R 4 is selected from the group consisting of -CO 2 H, -SO 3 H, and -P (0) (OH) 2 or a salt or a prodrug derived therefrom; Y R5 is selected from the group consisting of hydrogen, alkyl (C? -C6), alkoxy (C? ~ C6), haloalkoxy (C? -C6) haloalkyl (C2-C6) bromine, chlorine, fluorine, iodine and aryl; these processes comprise the steps of: a) halogenating a compound of formula X * uu, wherein R is alkyl (C? -C6), aryl or HET; with S02C12 to form a compound of formula IX b) hydrolyzing and decarboxylating a compound of the formula IX to form a compound of the formula VIII c) to alkylate a compound of the formula VII with a compound of formula VIII to form a compound of formula VI d) animating and dehydrating a compound of formula VI VI with an amine of the formula R1NH2 in the presence of a solvent forming an azeotrope with water to form a compound of the formula V e) oxidizing a compound of the formula V when heated with a base and a compound of the formula RSOX where R is -alkyl- (C? -C6) or aryl and X is ? alkoxy- (C? -C6), halogen or alkyl -C02- (C? -C6) to form a compound of the formula IV f) renting a compound of formula IV with an alkylating agent of the formula XCH2R4a wherein X is a residual group and R ** is -C02R1, -S03R < b, -i IO) (0R, b) 2, or -P IOI IOR1") H, wherein R4b is an acid protecting group, to form a compound of the formula I I I g) reacting a compound of formula III with oxalyl chloride and ammonia to form a compound of formula II h) optionally hydrolyzing a compound of the formula II to form a compound of the formula I; and i) optionally salifying a compound of the formula I.

In another embodiment of the invention, there is provided a process for preparing a compound of formula I comprising the steps of: a) oxidizing a compound of the formula V when heated with a base and a compound of the formula RSOX wherein R alkyl- (Ci-Cß) or aplo and X is alkoxy- (Ci-Cß), halo or alkylene-OC02- (C? -C6) for form a compound of formula IV b) renting a compound of formula IV with an alkylating agent of the formula XCH2R4a wherein X is a leaving group and R4a is -C02R4, -S03R4, P (0) (OR4) 2, or -P (0) (OR4b) H, wherein R4b is an acid protecting group, to form a compound of formula III c) reacting a compound of formula III with oxalyl chloride and ammonia to form a compound of formula II d) optionally hydrolyzing a compound of the formula II to form a compound of the formula I; and i) optionally salifying a compound of the formula I. The compounds of the invention employ certain defining terms as follows: As used herein, the term "alkyl" by itself or as part of another substitute means, unless otherwise defined, a monovalent radical of a straight or branched chain hydrocarbon such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, tert-butyl, n -pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl, nonyl, decyl, and so on. The term "(Ci-Cio) alkoxy", as used herein, denotes a group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n- pentoxyl, isopentoxy, neopentoxy, heptoxyl, hexoxyl, octoxyl, nonoxy, decoxyl and similar groups, attached to the rest of the molecule by an oxygen atom. The term "(C3-C4) cycloalkyl" includes the cyclopropyl and cyclobutyl group. The term "C3-C4 cycloalkenyl" includes a cyclopropenyl or cyclobutenyl ring having a double bond in the 1- or 2- position. The term "halogen" means fluorine, chlorine, bromine or iodine. The term "(C1-C10) alkyl halogen" means a (C1-C10) alkyl group, substituted from 1 to 3 halogen atoms, attached to the rest of the molecule by an alkyl group. The term (C 1 -C 10) haloalkyl includes the term haloalkyl (C 2 -C 6) The term "haloalkoxy (C 6 -C 6)" means a halogen-substituted alkoxy group whose group is attached to the rest of the molecule in the oxygen of the The term "aryl" means a group having the ring structure characteristic of benzene, pentalene, indene, naphthalene, azulene, heptalene, phenanthrene, anthracene, etc. The aryl group can be optionally substituted with one to three substituents selected from the group consisting of alkyl (Ci-Cd) (preferably methyl), (C 1 -C 6) alkoxy or halogen (preferably fluorine or chlorine). The term "aryloxy" means an aryl group attached to the rest of the molecule by an oxygen binder. The term "residual group" means a substitute with a pair of non-shared electrons that are removed from the substrate of a nucleophilic substitution reaction. The term "residual group" includes halogen, sulfonate, acetate and the like. The term HET includes pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, pyrazole, furan, thiophene, triazole, isothiazole, oxadiazole, thiadiazole, imidazole, triazole and tetrazole. The heterocyclic ring can be attached to the rest of the molecule by any carbon in the heterocyclic ring. The salts of the compounds of the formula I are a further aspect of the invention. In those cases where the compounds of the invention possess acidic groups optionally, various salts can be formed that are more water soluble and physiologically suitable than the initiator compound. Representative pharmaceutically acceptable salts include but are not limited to the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum, and the like. The salts are conveniently prepared from the free acid, by treating the acid, in a solution with a base, or by exposing the acid to an ion exchange resin. Included within the definition of pharmaceutically acceptable salts are the basic inorganic addition salts and the relatively non-toxic organic salts of the compounds of the present invention, for example, ammonia, quaternary ammonia, and amine cations, which are derived from nitrogenous bases. of sufficient basicity to form salts with the compounds of this invention (see, for example, SM Berge et al., "Pharmaceurical Salts" J. Phar. Sci., 66: 1-19 (1977)). The term "acid protecting group" is used herein as it is frequently used in synthetic organic chemistry, to refer to a group that it prevents an acidic group from participating in a reaction that is carried out in some other functional group of the molecule, and that can be removed when it is desired to do so. These groups are discussed by T. W. Greene in Chapter 5 of Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1981, which is incorporated herein in its entirety for reference. Examples of acidic protecting groups include those derived from the ester or amide of the acid group such as methyl, methoxymethyl, methyl-thiomethyl, tetrahydropyranyl, methoxyethoxymethyl, benzyloxymethyl, phenylaryl, ethyl, 2,2,2-trichloroethyl, 2-methylthioethyl, t -butyl, cyclopentyl, triphenyl triethyl, p-bromobenzyl, trimethylsilyl, N, N-dimethyl, pyrrolidinyl, piperidinyl or o-nitroanilide. A preferred acid protecting group is methyl. Prodrugs are derivatives of the compounds of the invention that have chemically or metabolically cleavable groups and that are converted, by solvolysis or under physiological conditions, to the compounds of the invention which are pharmaceutically active in vivo. The derivatives of the compounds of this invention they have activity both in their acid and base-derived forms, but the acid-derived form commonly offers advantages of solubility, tissue compatibility, or prolonged release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives, such as esters that are prepared by reacting the acid starter compound with a suitable alcohol, or amides that are prepared by reacting the acid starter compound with a suitable amine. Simple aliphatic esters (eg, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl) or aromatic esters derived from pendant acid groups in the compounds of this invention are the preferred prodrugs. Other preferred esters include morpholinoethyloxy, diethylglycolamide and diethylaminocarbonylmethoxy. In some cases, it is desirable to prepare double ester type drugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkyl esters.

A preferred group of the compounds of the formula I which is prepared by the process of the present invention are those wherein: R1 is; R2 is halogen, cyclopropyl, methyl, ethyl, propyl, O-methyl or S-methyl; R4 is -C02H; and R5, Rd and R7 are H. Compounds that can be made by the process of the present invention include: ((3- (2-amino-1,2-dioxyethyl) -2-methyl-1- (phenylmethyl)) -lH-indol-4-yl) oxy) acetic; Dl-2- ((3- (2-amino-1,2-dioxyethyl) -2-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) propanoic acid; Acid ((3- (2-amino-1,2-dioxyethyl) -l- ((1,1'-biphenyl) -3-ylmethyl) -2-methyl-1H-indol-4-yl) oxy) acetic acid; Acid ((3- (2-amino-1, 2 * »dioxyethyl) -1- ((1,1 '-biphenyl) -4-ylmethyl) -2-methyl-1H-indol-4-yl) oxy ) acetic; ((3- (2-Amino-1, 2-dioxyethyl) -1- ((2,6-dichlorophenyl) methyl) -2-methyl-lH-indol-4-yl) oxy) acetic acid; ((3- (2-Amino-1, 2-dioxyethyl) -l- ((4-fluorophenyl) methyl) -2-methyl-1H-indol-4-yl) oxy) acetic acid; ((3- (2-Amino-1, 2-dioxyethyl) -2-methyl-a- ((naphthalenyl) methyl) -lH-indol-4-yl) oxy) acetic acid; ((3- (2-Amino-1, 2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid; Acid ((3- (2-amino-1,2-dioxyethyl) -1- ((3-chlorophenylmethyl) -ethyl-1H-indol-4-yl) oxy) acetic acid ((3- (2-amino) -l, 2-dioxyethyl) -1- ((1,1'-biphenyl) -2-? lmet? l) -2-ethyl-lH-indol-4-yl) oxy) acetic acid ((3- ( 2-amino-1,2-dioxyethyl) -1- ((1, 1-biphenyl) - -? Lmet? L) -2-propyl-lH-indol-4-yl) oxy) acetic acid ((3 - (2-amino-l, 2-dioxyethyl) -2-cyclopropyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid ((3- (2-amino-1,2-dioxyethyl) 1) -1- ((1,1'-biphenyl) -2-ylmethyl) -2-cyclopropyl-1H-indol-4-yl) oxy) acetic acid: 4- ((3- (2-amino-1) , 2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) butanoic acid; ((3- (2-Amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -lH-indol-4-yl) oxyacetic acid; ((3- (2-amino-1, 2) -diioxyethyl) -2-ethyl-6-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid ((3- (2-amino-1,2-dioxyethyl) -2,6 -dimethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid ((3- (2-amino-1,2-dioxyethyl) -2-methyl-1- (phenylmethyl) -lH- indole-4-yl) oxy) acetic acid ((3- (2-amino-1,2-dioxyethyl) -6-ethyl-l-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy ) acetic acid ((3- (2-amino-1,2-dioxyethyl) -2,6-diethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid ((3- ( 2-amino-l, 2-dioxyethyl) -2-methyl-6-phenoxy-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid ((3- (aminooxoacetyl) -2-ethyl- 6-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid and ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-6-phenoxy-1- ( phenylmethyl) -lH-indol-4-yl) oxy) acetic acid. Of these compounds, preferred compounds include: ((3- (2-Amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -lH-indol-4-yl) oxyacetic acid; ((3- (2-amino-1, 2) -diioxyethyl) -2-ethyl-6-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid ((3- (2-amino-1,2-dioxyethyl) -2,6 -dimethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid ((3- (2-amino-1,2-dioxyethyl) -2-methyl-1- (phenylmethyl) -lH- indole-4-yl) oxy) acetic acid ((3- (2-amino-1,2-dioxyethyl) -6-ethyl-2-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy ) acétic acid- ((3- (2-amino-1,2-dioxyethyl) -2,6-diethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid ((3- ( 2-amino-l, 2-dioxyethyl) -2-methyl-6-phenoxy-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid ((3- (aminooxoacetyl) -2-ethyl- 6-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-6-phenoxy-1- (phenylmethyl) ) -IH-indol-4-yl) oxy) acetic acid or a physiologically acceptable salt thereof Of these compounds, even the most preferred are: ((3- (2-Amino-1,2-dioxyethyl) -2-methyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid and ((3- (2- amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid. The most preferred compound that can be prepared by the present process is ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -lH-indol-4-yl) oxyacetic acid or A pharmaceutically acceptable salt thereof The process of the present invention provides an improved method for synthesizing the compounds of formula I using inexpensive and readily available reagents as shown in the Scheme below.

Reaction I.

Reaction Scheme I (V) (IV) (III) (II) (I) Acetone (V) is dissolved in a suitable solvent, preferably an aprotic solvent such as THF. Other suitable solvents include but are not limited to DMF, dioxane, or toluene. The substrate / solvent solution It can be treated by sound or heated slightly if necessary, to facilitate dissolution.

The amount of solvent used should be sufficient to ensure that all the compounds remain in solution until the desired reaction is complete. The solution is subjected to treatment with a base, preferably a base O sulfinating of the formula RSX wherein R is alkyl (Ci-Ce), aplo or substituted aryl and X is haloalkoxy (C? -C6), or alkyl (C? -C6) -OC02. The sulfinating reagent can be prepared according to the method of J. M. Wilt et al., J. Org. Chem., 1967, 32, 2097. Preferred sulfinating agents include methyl p-tolylsulfinate, methylbenzenesulfinate or p-tolylsulfinicoisobutyric anhydride. Other suitable bases include but are not limited to LDA, sodium methoxide, or potassium methoxide. Preferably, two equivalents of bases are used. Preferably, when the sodium hydride is used, the base is added before the sulfinant reagent. The order of addition of reagents is important when using sodium methoxide. The reaction can be carried out at temperatures ranging from 25 ° C for reflux, preferably the reflux is substantially complete for 1 to 24 hours. The amount of the sulfinating reagent is not critical, however, the reaction is best achieved by using a molar equivalent or an excess relative to the pyrrole raw material (1). The above reactions can be run in the manner of a "single container" process with the reagents being added to the reaction container in the order given above. Dioxane is a preferred solvent in a "one step" process. THF and toluene, respectively, are the preferred solvents and a "two container" process is used as demonstrated in Reaction Scheme I (a), below.

Intermediates IV can be isolated and purified using conventional crystallization or chromatographic methods. Conventional analytical techniques such as TLC or HPLC can be used to monitor reactions in order to determine when raw materials and intermediates become the product. In an alternative preparation, the sulfinating reagent can be replaced with a disulfide compound of the formula R20SSR20 wherein R20 is alkyl or aryl. Oxidation of the sulfide intermediate can then be easily achieved using an appropriate oxidant reagent such as hydrogen peroxide or m-chloroperbenzoic acid. The indole (IV) can be easily alkylated with an alkylating agent of the formula XCH2R4a wherein X is a suitable residual group and Ra is a carboxyl, sulfonyl or phosphonyl group protected from acids, preferably protected with an ester group, in the presence of one base. Methyl bromoacetate is a preferred alkylating agent. Suitable bases include potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate or potassium hydroxide. Potassium carbonate is preferred. The amount of the alkylating agent is not typical, however, the reaction is best carried out, using a molar excess of an alkylating agent relative to the raw material. Preferably, the reaction is carried out in an organic solvent such as acetone, acetonitrile or dimethylformamide. Other suitable solvents include tetrahydrofuran, methylethylacetone, acetonitrile, toluene, or t-butylethylether. The reaction is carried out at temperatures ranging from 0 to 100 ° C, preferably at room temperature, and is substantially complete in about 1 a 24 hours depending on the reagents that are used and the conditions such as the reaction temperature. Optionally, a phase transfer reagent such as tetrabutylammoniobromide can be employed. 20 The preparation of glyoxamide II is easily achieved in a two-step process, first by treating intermediate III with chloride Oxaryl in concentrations ranging from 0.2 to 1.5 mmoles, preferably, in equimolar concentrations in relation to the raw material. Solvents such as methylene chloride, chloroform, trichlorethylene, carbon tetrachloride, ether or toluene are preferred. Temperatures ranging from -20 ° C to room temperature are suitable, preferably about -5 ° C. In the second stage, the solution is subjected to ammonia treatment; either it is passed through bubbles as a gas or, preferably, a molar excess of 30% aqueous ammonia is used. Typically, the reaction is carried out at temperatures ranging from -25 ° C to 25 ° C, preferably in approximately from -2 ° C to 0 ° C, and is substantially complete for 10 minutes to 1 hour. The hydrolysis of II is accomplished using a base such as potassium hydroxide, lithium hydroxide or sodium hydroxide, preferably sodium hydroxide, in a minor alcohol solvent, such as methanol, ethanol, isopropanol, etc. , or solvents such as tetrahydrofuran, dioxane and acetone.

When using conventional analytical techniques, such as HPLC, the reactions of the Scheme of Reaction I can be monitored to determine when raw materials and intermediates become the product. Reaction Scheme I (a), below, illustrates the two-container procedure, described above, for the preparation of intermediate IV.

Intermediary IV (a) can be isolated and purified by using conventional chromatographic methods.

Reaction Scheme I (a) V »avi It is highly appreciated by the skilled technician, that raw materials and the above procedures are commercially available or can be easily prepared by known techniques of the materials commercially available premiums. For example, sulfinating and sulfinylating reagents can be made according to the procedures of Patai, et al. The chemistry of sulfinic acids, ester and their derivatives; John Wiley and sons, 1990, p.217-236 and 557-600. The raw material V is prepared according to the following procedure.

Reaction Scheme II V R is alkyl (Ci-Cß) or aryl. First, an appropriately substituted propionylacetate X is halogenated upon treatment with sulfuryl chloride, preferably at equimolar concentrations relative to the raw material, temperatures ranging from 0 ° C to 25 ° C, preferably to less than 15 ° C, to prepare IX. Hydrolysis and decarboxylation of IX are achieved by refluxing with an aqueous acid, such as hydrochloric acid, for about 1 to 24 hours. The solution containing the decarboxylated product VIII is neutralized to adjust the pH to about 7.0-7.5, or is reacted with cyclohexanedione VII (preferably in equimolar concentrations) and a base, preferably sodium hydroxide, to produce the triquetona monohydrate VI as a precipitate that can be purified and isolated, if desired. Preferably, the reaction is carried out at temperatures ranging from -20 ° C to room temperature and is substantially complete in about 1 to 24 hours. The above reactions are preferably run in the manner of a "single container" process with the reagents being added to the reaction vessel in the order given above. Preferably, the reaction is allowed to proceed without isolating the compounds of formula IX or VIII, and therefore, exposure to these volatile tear-off agents is avoided. V preparation is achieved by refluxing VI, in a high boiling nonpolar solvent that forms an azeotrope with water, preferably toluene, with an equimolar amount of an amine of the formula H 2, wherein R 1 is as defined above. Solvents with a boiling point of at least 100 ° C are preferred, such as toluene, xylene, cymene, benzene, 1,2-dichloroethane or mesitylene, and therefore, the need for a pressurized reactor is eliminated. Sufficient solvent should be used to ensure that all compounds are kept in solution until the reaction is substantially complete for a period of about 1 to 24 hours. The following examples further illustrate the process of the present invention. The examples also illustrate the preparation of the intermediary compounds of this invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.

Example 1 Preparation of ((2-ethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid methyl ester A. Preparation of 2- (2-oxobutyl) -1,3-cyclohexanedione-1-benzyl-2-ethyl-4-oxo-4,5,6,7-tetrahydroindole is suspended (1000 grams, 4,995 moles) in ( 6000 ml, 6 vol) of toluene. The mixture is heated to 85 ° C and stirred for 5 minutes. Benzylamine (562.6 grams, 5.25 moles, 1.05 eq) is added dropwise for about 30-45 minutes. After the addition, the mixture becomes an amber colored solution. Heat is applied to the solution and the water is distilled azeotropically until the temperature of the reaction reaches 110 ° C. The reaction is allowed to stir at 110 ° C for 2 hours at which time 400 ml of solvent is distilled at atmospheric pressure. The solution is transferred to a flask and evaporated further to form a viscous amber oil which is used directly in the next step. Oil weight = 1372.24 grams Theoretical weight = 1253.7 grams Power = 87% Molar production = 95.2% B. Preparation of 2-ethyl- (phenylmethyl) -lH-rhodol-4-ol sodium hydride. They are suspended (400 grams, 9.96 moles, 2.5 eq) in THF (5000 mis, 5 vol). To the suspension is added the above compound of part A, (1149 grams, 3.98 moles, 1 eq) and allowed to stir at 20-25 ° C until the bubbling decreases. Add (1121 grams, 6.59 moles, 1.65 eq) of methyltoluene of sulfinate and the mixture is heated to 30 ° C. After approximately 2.5 hours, the mixture darkens as the gas evolves and an exotherm at 47 ° C is observed. The FTA indicates a complete consumption of the raw material. Then, the reaction is cooled from 0 to 5 ° C and quenched with a slow addition of deionized water ((5000 ml, 5 vol) .The reaction is further quenched with very cold acetic acid (600 grams, 10 moles, 2.5 eq) the mixture is diluted with (5000 ml, 5 vol) of toluene and washed with saturated sodium bicarbonate (2500 ml, 2.5 vol.) The upper organic layer is washed with an additional 2500 ml of saturated sodium carbonate. Aqueous layers are combined and extracted inversely with (5000 mis, 5 vol) of toluene. The organic layers are combined and heated to a slight reflux (approximately 80 ° C) and stirred for 2 hours, at which time the complete reaction is confirmed by TLC: the dark solution is concentrated in an atmospheric manner to approximately 4000 ml and wash with saturated sodium bicarbonate (1500 mis X 2). The organic layer is dried over magnesium sulfate and concentrated under a vacuum to obtain a dark colored viscous oil which is used directly in the next step.

C. Preparation of ((2-ethyl-1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid methyl ester. The compound of part B, above, is dissolved in (7500 mis, 7.5 vol) and stirred from 20 to 25 ° C. Powdered potassium carbonate (1360 grams, 9.84 moles, 2.5 eq) and (780 grams, 5.09 moles, 1.3 eq) of methylbromoacetate are added and the light brown mixture is allowed to stir for 16 hours from 0 to 25 ° C, at which time, the complete reaction is confirmed by TLC. The solids are filtered on polypropylene and washed with (1500 ml, 1.5 vol) acetone. The filtered product is evaporate, under a vacuum, until obtaining a dark oil. The oil is dissolved in isopropyl alcohol (10,000 ml, 10 mol) and the resulting mixture is heated to reflux for 30 minutes. The solution is allowed to cool on its own with crystallization occurring at approximately 38 ° C. The mixture is cooled from 0 to 5 ° C for 2 hours. The mixture is filtered and washed with portions of 3-500 ml of very cold isopropyl alcohol. The light brown solids are dried in a vacuum oven at 50 ° C for 16 hours. Dry product weight = 691.53 grams Theoretical grams = 1288.4 grams Production weight = 53.7% Example 2 Preparation of 2-ethyl (phenylmethyl) -lH-indole-4-ol A. preparation of 4-methyl-benzenesulfinic acid, 4-methyl-benzene sulfinic acid anhydride and sodium salt, are suspended (0.9 g, 5 mmol) in (5 mL) of benzene. Add (1 eq) of HCl. Separately, isobutyl chloroformate (0.65 mL, 5 mmol) is added to a very cold solution of (1.2 mL, 15 mmol) of pyridine in (5 mL) of benzene. The solution of the sulfinic acid is added in portions. The resulting solution is stirred for 30 minutes at room temperature. The solvent is evaporated and the residue is subdivided between MTBE and water. The organic layer is dried over sodium sulfate, filtered and evaporated to yield a colorless oil. The oil is redissolved in MTBE and washed with a 0.1N HCl solution until the pyridine is removed. After drying over sodium sulfate and filtering, the solution is evaporated to produce a colorless liquid (0.30 g). 1 H NMR (500 MHz, CDC13) D 7.64 (d, 2 H), 7.35 (d, 2 H), 3.83 (m, 1 H), 3.37 (m, 1 H), 2.45 (s, 3 H), 1.94 ( m, 1 H), 0.95 (m, 6 H).

B. Preparation of 2-ethyl- (phenylmethyl) -lH-indol-4-ol.

The raw material of Example IB above, (0.3 g, 1.2 mmol) is dissolved in 5 mL of THF. Add (0.1 g, 2.6 mmol) of sodium hydride. 4-, Ethyl-benzenesulfinic acid anhydride is added with isobutyl hydrogencarbonate (0.3 g, 1.25 mmol) in 1 mL of THF. The mixture is refluxed for one hour, at which time no raw material is observed. The continuous reflux provides the product.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (6)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1 . A process for preparing a compound of the formula I or a pharmaceutically acceptable salt or a prodrug derived therefrom wherein: R1 is selected from the group consisting of C7-C20 alkyl; where; R10 is selected from the group consisting of halogen, C1-C10 alkyl; C1-C10 alkoxy, -S- (Ci-Cι alkyl) and (C 1 -C 10) haloalkyl and t is an integer from 0 to 5 inclusive of both; R2 is selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -O- (C1-C2 alkyl), -S- (Ci-C2 alkyl), aryl , aryloxy, and HET; R4 is selected from the group consisting of -CO2H, -SO3H, and -P (O) (OH) 2 or a salt or prodrugs derived from these and; R5 is selected from the group consisting of hydrogen, alkyl (C? -C6), alkoxy (C? -6), haloalkoxy (Ci-C?) Haloalkyl (C-C6) bromo, chloro, fluoro, iodo and aryl; the process characterized in that it comprises the steps of: a) halogenating a compound of formula X X wherein R is alkyl (C? -C6), aryl or HET; with S02C12 to form a compound of formula IX b) hydrolyzing and decarboxylating a compound of the formula IX to form a compound of the formula VIII c) to alkylate a compound of the formula VII with a compound of formula VIII to form a compound of formula VI d) Aminating and dehydrating a compound of the formula VI with an amine of the formula R1NH2 in the presence of a solvent forming an azeotrope with water to form a compound of the formula V e) oxidizing a compound of the formula V when heated with a base and a sulfinyl reactant of the formula RSOX wherein R is -alkyl- (Ci-Ce) or aryl and X is alkoxy- (C? -C6), halogen or alkyl (C? -C6) -0C02 to form a compound of formula IV f) renting a compound of formula IV with an alkylating agent of the formula XCH2R4a wherein X is a leaving group and R4a is -C02R4b, -S03Rb, P (0) (0R4b) 2, 0-P (0) (0R4b) H, wherein R4b is an acid protecting group, to form a compound of formula III reacting a compound of formula III with oxalyl chloride and ammonia to form a compound of formula II h) optionally hydrolyzing a compound of the formula II to form a compound of the formula I; and i) optionally salifying a compound of the formula I.

2 . A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof or a prodrug derived therefrom wherein: R1 is selected from the group consisting of C7-C20 alkyl; wherein R10 is selected from the group consisting of halogen, C1-C10 alkyl; C 1 -C 10 alkoxy, -S- (C 1 -C 6 alkyl) and (C 1 -C 10) haloalkyl and t is an integer from 0 to 5 inclusive of both; R2 is selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0- (C1-C2 alkyl), -S- (C1-C2 alkyl), aryl , aryloxy, and HET; R4 is selected from the group consisting of -CO2H, -SO3H, and -P (0) (OH) 2 or a salt or prodrugs derived from these and R5 is selected from the group consisting of hydrogen, alkyl (C? -C6), alkoxy (C? -C6), haloalkoxy (C? -C6) haloalkyl (C2-C6) bromo, chloro, fluoro, iodo and aryl; The process is characterized in that it comprises the steps of: e) oxidizing a compound of the formula V when heating with a base and a compound of the formula RSOX wherein R is -alkyl- (C? -C6) or aryl and X is alkoxy- (Ci-Ce), halogen or alkyl (C? -C6) -0C02 for form a compound of formula IV f) renting a compound of formula IV with an alkylating agent of the formula XCH2R wherein X is a residual group and R4a is -C02R4, -S03Rb, P (0) (OR4b) 2, or -P (0) (OR4b) H, wherein R4b is a group acid protector, to form a compound of formula III g) reacting a compound of formula III with oxalyl chloride and ammonia to form a compound of formula II h) optionally hydrolyzing a compound of the formula II to form a compound of the formula I; and i) optionally salifying a compound of the formula i; Y e) optionally salifying a compound of the formula I.

3. The process according to claim 1 or 2, characterized in that the sulfinating agent is p-tolulylsulfinicisobutyric anhydride.

4. The process according to any one of claims 1 to 3, characterized in that the ((3- (2-amino-1, 2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -lH-indole-4-acid is prepared. il) oxy) acetic.

5. A process for preparing a compound of the formula I or a pharmaceutically acceptable salt or a prodrug derived therefrom wherein: R1 is selected from the group consisting of C7-C20 alkyl; wherein R10 is selected from the group consisting of halogen, Ci-Cio alkyl; C1-C10 alkoxy, -S- (Ci-Cycloalkyl) and haloalkyl (d-Cio) and t is an integer from 0 to 5 inclusive of both; R2 is selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0- (C1-C2 alkyl), -S- (Ci-C2 alkyl), aryl , aryloxy, and HET; R4 is selected from the group consisting of -C0H, -SO3H, and -P (0) (OH) 2 or a salt or prodrug derivatives thereof and R5 is selected from the group consisting of hydrogen, alkyl (C? -C6), alkoxy (C? -C6) , haloalkoxy (C? -C6) haloalkyl (C2-C6) bromo, chloro, fluoro, iodo and aryl; which are made in accordance with the process of claim 1.

6. A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof or a prodrug derived therefrom where: R1 is selected from the group consisting of Ct-C alkyl or; wherein R10 is selected from the group consisting of halogen, C1-C10 alkyl; C1-C10 alkoxy, -S- (Cj.-C? alkyl) and (C1-C10) haloalkyl and t is an integer from 0 to 5 inclusive of both; R2 is selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -O- (C1-C2 alkyl), -? - (Ci-C2 alkyl), aryl , aryloxy, and HET; R is selected from the group consisting of -C02H, -SO3H, and -P (0) (OH) 2 or a salt or prodrug derivatives thereof and R5 is selected from the group consisting of hydrogen, alkyl ( C? -C6), alkoxy (Ci-Ce), haloalkoxy (Ci-Ce) haloalkylhalogen (C? -Cβ), bromine, chlorine, fluorine, iodine and aryl; substantially as described hereinabove with reference to any of the Examples.