CZ466499A3 - Process for preparing 1H-indole glyoxamide being substituted in position 4 and intermediate for this preparation process - Google Patents

Abstract

A process for the preparation of 1H-indole-3-glyoxamides suitable for use herein inhibition of SPLA2 and novel intermediates suitable for preparation of these compounds

Description

Technical field

This application claims the benefit of U.S. Provisional Application Nos. 60/050,877, filed June 26, 1997 and 60/050,891, filed June 26, 1997.

The invention relates to a process for the preparation of certain 1H-indole-3-glyoxamide derivatives useful for inhibiting sPLA ₂ mediated by fatty acid release, for example, in septic shock.

BACKGROUND OF THE INVENTION

Certain 1H-indole-3-glyoxamides derivatives are known to be potent and selective inhibitors of mammalian sPLA ₂ useful for treating diseases such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bromchial asthma, allergic rhinitis, rheumatoid arthritis and sPLA related ₂ induced diseases. Such compounds are described, for example, in European Published Publication No. 0 675 110.

Methods for preparing indole-3-glyoxamides are described in various publications and patent literature.

Certain l-H-indole-3-glyoxylamides and their conversion to tryptamine derivatives have been described by Marc Julia, Jean Igolen and Hanne Igolen in Recherches en serie indolique. VI sur tryptamines substituees, Bull. Soc. Chim. France, pp. 1060-1068 (1962).

Certain 2-aryl-3-indolglyoxylamides having research use for the central nervous systems of mammals have been described by E.

Romeo et al. v 2-Aryl-3-indoleglyoxylamides (FGIN-1): A New Class of Potent and Specific Ligands for the Mitochondrial DBI Receptor (MDR), The Journal of Pharmacology and Experimental Therapeutics, 262, No. 3, pp. 971-978.

Abstract Fragmentation of N-benzylindoles in Mass Spectrometry; Chemical Abstracts, Volume 67, 73028h (1967) discloses various benzyl-substituted phenols including phenols with glyoxylamide groups at the 3-position of the indole nucleus.

U.S. Patent 3,449,363 discloses trifluoromethylindoles having glyoxylamide groups at the 3-position of the indole core.

U.S. Pat. No. 3,351,630 discloses α-substituted 3-indolylacetic acid derivatives and a process for their preparation including glyoxylamide intermediates.

U.S. Patent 2,825,734 discloses a process for preparing 3- (2-amino-1-hydroxyethyl) indoles using 3-indolglyoxylamide intermediates such as 1-phenethyl-2-ethyl-6-carboxy-N-propyl-3-indolglyoxylamide (see Example 30).

U.S. Pat. No. 4,397,850 describes a process for the preparation of isoxazolylindolamines using glyoxylamidindoles as intermediates.

U.S. Pat. No. 3,801,594 discloses analgesics prepared using 3-indolglyoxylamide intermediates.

Various indolyl-3-glyoxamides having the atom replaced

444 $ 4 4 - 4 Λ 4 · 4 4 · 4 »4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 Rubio Herraez in No. 565. - Inhibiteurs denzymes. XII.

Preparation of (propargylamino-2-ethyl) -3-indoles, Bulletin de la Societe Chimique De France, 12, 2883-2888 (1974).

Phenyl-substituted 3-glyoxylamides are described by Gert Kollenz and Christa Labes (Indol-Umlagerung von 1-Diphenylamino-2,3-dihydro-2,3-pyrrolidone, Liebigs Ann. Chem., 1979-1983 (1975)).

U.S. Pat. No. 08 / 469,954, incorporated herein by reference in its entirety, discloses a process for preparing the 4-position of substituted ind-indole-3-glyoxamide derivatives by reacting an appropriately substituted 4-methoxyindole (prepared by a process which: described by RD Clark et al., Synthesis, pp. 871-878 (1991), which is incorporated herein by reference in its entirety), with sodium hydride in dimethylformamide at room temperature (20-25 ° C), treatment with an arylmethyl halide at room temperature, to give 1-arylmethylindole which is O-demethylated using boron tribromide in methylene chloride (Tsung-Ying Shem and Charles A. Winter, Adv. Drug Res., 12, 176 (1977)), which is incorporated herein in its entirety, Alkylation with α-bromoalkanoic acid ester in dimethylformamide using sodium hydride as the base Conversion to glyoxamide is carried out by reaction of the α - [(indol-4-yl) oxy] alkanoic acid ester first. first with oxalyl chloride, then with ammonia followed by hydrolysis with sodium hydroxide in methanol.

The process for preparing the 4-position of the substituted 1H-indole-3-glyoxamide derivatives described above is useful.

However, it uses expensive reagents and environmentally hazardous organic solvents, producing ♦ · «· • *

The furan-containing by-products and the desired product are obtained in a relatively low yield.

The invention relates to an improved process for preparing the 4-position of a substituted 1H-indole-3-glyoxamide derivative. The process of the present invention employs inexpensive, readily available reagents using aqueous solvent systems and achieves better overall yields without producing furan-containing by-products. The following detailed description and the appended claims illustrate the invention in further detail, features and advantages.

SUMMARY OF THE INVENTION

Claims (19)

The present invention relates to a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof, wherein: R ¹ is selected from the group consisting of C7-C20 alkyl CH «· φ • φ Φ CH R ίο where R ¹⁰ represents a group selected from halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 -alkyl and C 1 -C 10 haloalkyl, and t is hydrogen; Integer 0-5 including R ² is selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, C 1 -C 2 alkyl; -S-alkyl having 1 or 2 carbon atoms, aryl, aryloxy and HET, R ⁴ is a group selected from the group consisting of -CO ₂ H, -SO ₃ H, -P (O) (OH) _2, or a salt or prodrug thereof, R ⁵ , R ⁶ , R ⁷ are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 haloalkyl 6 carbon atoms, bromine, chlorine, fluorine or iodine atoms and an aryl group; 9 · 99 · · ► ··· • * · · · ♦ * · «·« which consists in that a) halogenating a compound of formula X O (X) wherein R ⁸ is C 1 -C 6 alkyl, aryl or HET, by treatment with sulfuryl chloride to give a compound of formula IX Q Q R Cl (IX) (b) hydrolyzing and decarboxylating the compound of formula (IX); Cl to give a compound of formula VIII O (IX) (VIII) c) alkylating a compound of formula VII (VII) with a compound of formula VIII d) (VIII) to amine and dehydrate to obtain a compound of formula (VI) (VI) with a compound of formula (VI) with an amine of formula R ¹ NH ₂ in the presence of a water-forming azeotrope solvent to give a compound of formula (V) e) oxidizing the compound of formula V by refluxing with a polar hydrocarbon solvent having a boiling point of at least 150 ° C and a dielectric constant of at least 10 in the presence of a catalyst to give a compound of formula IV ··· 9 · 9. «« », ´ · · <9 ·; ί ·· * * · · ♦ • ··. ♦ ·. * · · 9 9 9 «·· 9 ·· 9 ·« _β R (IV) f) alkylating a compound of formula IV (IV) with an alkylating agent of formula XCH ₂ R ^4a , wherein X is a liberated group and R ^4a is -CO ₂ R ^4fc ', -SO 3 R ^4b , -P (O) (OR ^4b ) 2, or -P (O) (OR ^4b ) H, where R ⁴ ' ³ is an acid protecting group, to give a compound of formula III (III) g) reacting a compound of formula III (III) with oxalyl chloride and ammonia to obtain a compound of formula II h) optionally hydrolyzing a compound of formula II i) optionally converting a compound of formula I to its salt. Another embodiment of the invention provides processes for the preparation of a compound of formula I, the process comprising the steps of: (a) oxidizes (V) by refluxing:. in a polar hydrocarbon solvent having a boiling point of at least 150 ^e C and a dielectric constant of at least 10 in the presence of a catalyst to give a compound of formula IV OH (IV) B) alkylating the compound of formula IV R (IV), 4a wherein X is an alkylating agent of formula XCH ₂ R 'is a liberated group and R ^4a is -CO 2 -P (O) (OR ^4b ) 2 or -P (O) (OR ^4b ) H, wherein R is ^4b represents an acid protecting group to give a compound of formula III -SO ₃ R ^4b , (III) reacting a compound of formula III with oxalyl chloride and ammonia to give a compound of formula II (II) d) optionally hydrolyzing the compound of formula II to obtain a compound of formula I and e) optionally converting a compound of formula I to its salt. The present invention further provides novel intermediates of formula (IV) wherein: R ¹ represents a radical from the group consisting of C7 -C20 alkyl / * wherein "···" 1 π R ^υ halogen, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, -S-alkyl having 1 to 10 carbon atoms and haloalkyl having 1 to 10 carbon atoms at integer from 0 to 5 inclusive , R ² is hydrogen, halogen, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, C 1 -C 2 alkyl, -S-alkyl 1 or 2 carbon atoms, aryl, aryloxy and HET, R ⁵ , R ⁶ , R ⁷ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 haloalkyl C uhlíku,, bromo, chloro, fluoro or iodo and aryl. Compounds of formula IV are useful intermediates for the preparation of compounds of formula I. The present invention further provides a process for the preparation of compounds of formula IV which comprises the following steps: ·· ··· 4 • 0 0 ΊΟ _Β * ·· * - » -L3 # ··· * ·· * * · · · · · 9 ·· »· a) halogenating a compound of formula X (X) wherein R ⁸ is C 1 -C 6 alkyl, aryl or HET, sulfuryl chloride to give a compound of formula IX 0 Q R ' R Cl (IX) b) hydrolyzing and decarboxylating the compound of formula IX 0 0 0 'R ~ Cl (IX) to give a compound of formula VIII Cl (VIII) c) alkylating a compound of formula VII (VII) with a compound of formula VIII η an amine of formula RNH ₂ in the presence of a solvent that forms an azeotrope with water to give a compound of formula V, e) oxidizing the compound of formula V (V) under reflux with a polar hydrocarbon solvent boiling at least 150 ° C and having a dielectric constant of at least 10 in the presence of a catalyst. In another embodiment, the present invention provides a process for the preparation of a compound of formula IV which comprises oxidizing a compound of formula V by refluxing in a polar hydrocarbon solvent. a boiling point of at least 150 ^e C and a dielectric con stant at least 10 in the presence of a catalyst. The present invention is described in detail below. In the context of the 1H-indole-3-glyoxylamides of the invention, certain defining terms are used: As used herein, the term alkyl alone or as part of another substituent means, unless otherwise indicated, a monovalent straight or branched chain hydrocarbon group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl, nonyl or decyl and the like. The term C 1 -C 10 alkoxy means, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, connected to the rest of the molecule via an oxygen atom. The term cycloalkyl having 3 or 4 carbon atoms means a cyclopropyl group and a cyclobutyl group. The term cycloalkenyl having 3 or 4 carbon atoms means a cyclopropenyl and cyclobutenyl ring having a double bond at the 1 or 2 position. The term halogen means a fluorine, chlorine, bromine or iodine atom. The term haloalkyl of 1 to 10 carbon atoms refers to an alkyl group of 1 to 10 carbon atoms substituted with 1 to 3 halogen atoms attached to the rest of the molecule by an alkyl group. The term haloalkyl of 1 to 10 carbon atoms also includes the term haloalkyl of 2 to 6 carbon atoms. The term "C 1 -C 6 haloalkoxy" refers to C 1 -C 6 alkoxy substituted by halogen atoms attached to the rest of the molecule by an oxygen atom of the alkoxy group. By aryl is meant a group having a ring structure characteristic of benzene, pentalene, indene, naphthalene, azulene, heptalene, phenanthrene, anthracene, etc. The aryl group may be optionally substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 6 alkyl. carbon (preferably methyl), alkyloxy of 1 to 6 carbon atoms and halogen (preferably fluoro or chloro). The term "aryloxy" refers to an aryl group bonded to the rest of the molecule by an oxygen bonding group. The term liberated moiety refers to a non-electron pairing group that leaves the compound in a nucleophilic substitution reaction. For example, ·· 999 9 • · As the liberating group, it includes a halogen atom, a sulfonate group, an acetate group and the like. HET includes pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, pyrazole, furan, thiophene, thiazole, isothiazole, oxadiazole, thiadiazole, imidazole, triazole and tetrazole. The heterocyclic ring may be attached to the remainder of the molecule by any carbon atom of the heterocyclic ring. The present invention also provides salts of the compounds of formula I. In the case where the compounds of the present invention have an acidic functional group, different salts may be formed which have higher water solubility and are physiologically more suitable than the parent compound. Representative pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, calcium, magnesium, aluminum, and the like. Salts are usually prepared from the free acids by treating the acid in solution with a base or by treating the acids with an ion exchange resin. Pharmaceutically acceptable salts include the relatively non-toxic addition salts of the compounds of the invention with inorganic or organic bases such as ammonia, quaternary ammonium and amine cations derived from nitrogen bases sufficiently basic to form a salt of the compounds of the invention (e.g. SM Berge et al., Pharmaceutical Salts, J. Phar. Sci., 66, 1-19 (1977). Prodrugs are derivatives of the compounds of the invention having chemically or metabolically cleaved carboxyl groups and provide solvolysis or under physiological conditions the compounds of the invention that are pharmaceutically effective. in vivo. The derivatives of the compounds of the invention are effective as. both in the form of an acid derivative and in the form of a base derivative, but acid derivatives are often preferred for their solubility, tissue compatibility, and sustained release in a mammalian organism (see H. Budgard, Design of Prodrugs, p. 7 to 9, and 21 to 24, Elsevier Amsterdam, 1985). The prodrugs include acid derivatives well known to those skilled in the art, such as esters, prepared by reacting the parent acid compound with a suitable alcohol, or amides prepared by reacting the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from acid groups pendant on the compounds of the invention are preferred prodrugs. In some cases, it is desirable to prepare double type esters, such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkyl esters. The term acid protecting group is generally known and often used in the synthetic part of organic chemistry and refers to groups that are suitable for protecting an acid group from participating in chemical reactions carried out on some other functional groups of the molecule, but which are readily removable when desired. Such groups are described in the literature (for example, T. W. Greene, Chapter 5 of Protective Groups in Organic Synthesis, John Wiley &amp; Sons, New York, 1981, which is incorporated herein by reference in its entirety). Exemplary acid protecting groups include ester and amide derivatives of acid groups such as methyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, methoxyethoxymethyl, benzyloxymethyl phenylaryl, ethyl, 2,2,2-trichloroethyl, 2-methylthioethyl, tert-butyl, cyclopentyl, triphenylmethyl, p-bromobenzyl, trimethylsilyl, φ · ··· ·> · φ I ΦΦΦΦ · ·..... Ν, Ν-dimethyl, pyrrolidinyl, piperidinyl or o-nitroanilide. A preferred acid protecting group is methyl. Further, preferred compounds prepared by the process of the invention are described. A preferred group of compounds of formula (I) prepared by the process of the invention are those compounds of formula (I), wherein is R ¹ group of formula R ² represents halo, cyclopropyl, methyl, ethyl, propyl, O-methyl or Smethylovou, R ⁴ is -CO ₂ H a R ⁵ , R ⁶ and R ^{7 are} each hydrogen. The compounds which can be prepared by the process according to the invention are: ((3- (2-amino-1,2-dioxyethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid, dl-2 - ((3- (2-amino- 1,2-dioxyethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) propanoic acid, ((3- (2-amino-1,2-dioxyethyl) -1 - (( 1'-biphenyl) -2-ylmethyl) 2-methyl-1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxyethyl) -1 - ((1,1 1-Biphenyl) -3-ylmethyl) 2-methyl-1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxyethyl) -1 - ((1,1 ') (biphenyl) -4-ylmethyl) 2-methyl-1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxyethyl) -1 - ((2,6-dichlorophenyl) (methyl) 2-methyl-1H-indol-4-yl) oxy) acetic acid, ♦ 9 ··· • · 9 94 * ·· 99 •• 9 8 9 9 9 9 · 99 99 ·· · «» 8 · 98 9 · « 9 9> 9 9 9 9 9 99 ((3- (2-Amino-1,2-dioxyethyl) -1- (4-fluorophenyl) methyl) 2-methyl-1H-indol-4-yl) oxy) acetic acid, ((3- (2 -amino-1,2-dioxyethyl) -2-methyl-1 - ((naphthalenyl) methyl) -1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxyethyl)) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxyethyl) -1 - ((3-chlorophenylmethyl) 2-ethyl) (1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxyethyl) -1 - ((1,1'-biphenyl) -2-ylmethyl) 2-ethyl- 1H-Indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxyethyl) -1 - ((1,1'-biphenyl) -2-ylmethyl) 2-propyl-1H) (indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxyethyl) -2-cyclopropyl-1- (phenylmethyl) 1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxyethyl) -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) -1H-indol-4-yl) oxy) butanoic acid, ((3- (2-amino-1) (2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-6- methyl-1- (phenylmethyl) 1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxyethyl) -2,6-dimethyl-1- (phenylmethyl) 1H-indole) -4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxyethyl) -2-methyl-1- (phenylmethyl) 1H-indol-4-yl) oxy) acetic acid, (( 3- (2-amino-1,2-dioxyethyl) -6-ethyl-2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1) (2-dioxyethyl) -2,6-diethyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxyethyl) -2-methyl- 6-Phenoxy-1- (phenylmethyl) 1H-indol-4-yl) oxy) acetic acid, ((3- (aminooxoacetyl) -2-ethyl-6-methyl-1- (phenylmethyl) 1H-indol-4-yl) ) oxy) acetic acid and ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-6-phenoxy-1- (phenylmethyl)) - 21 - * and - 1H-indole- 4-yl) oxy) acetic acid or a pharmaceutically acceptable salt thereof. Among the above compounds, preferred compounds are: ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -1Hindol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2- dioxyethyl) -2-ethyl-6-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxyethyl) -2,6- dimethyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxyethyl) -2-methyl-1- (phenylmethyl) -1Hindol-4) -yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxyethyl) -6-ethyl-2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid , ((3- (2-amino-1,2-dioxyethyl) -2,6-diethyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino) -1,2-dioxyethyl) -2-methyl-6-phenoxy-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid, ((3- (aminooxoacetyl) -2-ethyl-6-methyl) -1- (phenylmethyl) 1H-indol-4-yl) oxy) acetic acid and ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-6-phenoxy-1- (phenylmethyl) 1H) - indol-4-yl) oxy) acetic acid or a pharmaceutically acceptable salt thereof. Among the above-mentioned compounds, the following are particularly preferred: ((3- (2-amino-1,2-dioxyethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid and ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid. The most preferred compound of formula (I) obtainable by the process of the invention is ((3- (2-amino-1,2-dioxyethyl) 2-ethyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid or a pharmaceutically acceptable salt thereof. Preferred intermediates for the preparation of the compound of formula (I) are those of formula (IV) wherein R ^{1 is} the rvA group R @ ² is halogen, cyclopropyl, methyl, ethyl, propyl, O-methyl or S-methyl; and R @ ⁵ , R @ ⁶ and R @ ^{7 are} each hydrogen. The most preferred compound of formula IV is 2-ethyl-1 (phenylmethyl) -4-hydroxy-1H-indole. Other typical examples of compounds of Formula IV useful in the present invention include: 2-chloro-1- (3-methylphenylethyl) -4-hydroxy-6-methoxy-1H-indole, 2-cyclopropyl-1- (4-ethylthiophenylmethyl) -4-hydroxy-5- (2-fluorobutoxy) -1H- indo1, 2- (cycloprop-1-enyl) -1- (5-chlorheptylphenylethyl) -4-hydroxy-5,7-difluoro-1H-indole, 2-methoxy-1- (3-tert-butylphenylmethyl) -4-hydroxy-7-phenyl-1H-indole, 2-methylthio-1- (4-phenylethylphenylmethyl) -4-hydroxy-6-iodo-1H-indole, 2-Phenyl-1-heptyl-4-hydroxy-1H-indole 2-naphthyl-1-octyl-4-hydroxy-6-hexyl-1H-indole, 2-cyclobutyl-1-dodecyl-4-hydroxy-1H-indole, 2- (cyclobut-1-enyl) -1- (2-chlorophenylmethyl) -4-hydroxy-7-butoxy-1H-indole, 2-cyclopropyl-1-octadecyl-4-hydroxy-5- (3-fluorohexoxy) -1H-indole; 2- (cycloprop-1-enyl) -1- (3-pentyloxyphenylethyl) -4-hydroxy-6-methyl-1H-indole, 2-methoxy-1- (2-phenylmethylphenylmethyl) -4-hydroxy-7- (2-chloroethyl) -ΙΗ-indole; 2-ethylthio-1-tetradecyl-4-hydroxy-5,7-dibromo-1H-indole. The method according to the invention is further described. The process of the invention provides an improved process for the synthesis of compounds of formula I using inexpensive, readily available compounds, as shown in the following scheme AND. Scheme I A compound of formula V is dissolved in a polar hydrocarbon solvent having a boiling point of at least 150 ^& C, having a dielectric constant of at least 10, such as diethylene glycol, Cellosolve ^{R, R} Carbitol, glyme, diglyme or triglyme. A preferred solvent is Carbitol ^R. The amount of solvent used should be sufficient to keep all components dissolved until the reaction is complete. Solvents having a boiling point of 150 to 250 ° C and a dielectric constant of 10 to 20 are preferred. Solvents with a boiling point of 150 to 220 Ca with a dielectric constant of 12 to 18 are most preferred. Examples of suitable solvents include m-dichlorobenzene, bromobenzene, m-toluidine, o-toluidine, trans-3-methylcyclohexanol, 1,1,2,2-tetrachloroethane, 2-heptanol, 2-butoxyethanol, o-dichlorobenzene, cresol, 1- octanol, 3-methylcyclohexanol, benzyl alcohol, 2-methylcyclohexanol, 4-methylcyclohexanol, octanenitrile, hexanenitrile, α-tolunitrile, 1,1,2,2-tetramethylurea and triethylene glycol. The solution is heated, preferably to the reflux temperature of the solvent used. It is desirable to carry out the reaction in the presence of a catalyst such as palladium on carbon, platinum on carbon, palladium oxide, platinum oxide, vanadium oxide, cupric oxide, nickel oxide, DDQ and manganese dioxide. Palladium on carbon or palladium oxides are preferred. The reaction is substantially complete in about 30 minutes to 24 hours. The indole of formula (IV) is readily alkylated with an alkylating phas 2S reagent of formula (XCH ₂ R) wherein X is a suitable liberated group and R ^{4a is a} protected carboxy, sulfonyl or phosphonyl group, preferably an ester protected group, in the presence of a base. A preferred alkylating agent is methyl bromoacetate. Suitable bases include potassium, sodium, lithium or cesium carbonate, sodium or potassium bicarbonate, and potassium hydroxide. Potassium carbonate is preferred. The amount of alkylating agent is not critical, but the reaction is preferably carried out using a molar excess of the alkylating agent with respect to the starting material. The reaction is preferably carried out in an organic petroleum solvent, for example acetone, acetonitrile or dimethylformamide. Other suitable solvents include tetrahydrofuran, methyl ethyl ketone, acetonitrile or tert-butyl methyl ether. The reaction is conducted at about 0 to 100 ^e C, preferably at room temperature and is substantially complete in about 1-24 hours depending on the reagents and reaction conditions. Optionally, phase transfer agents such as tetrabutylammonium bromide may be used. The preparation of the glyoxamide of formula (II) is readily accomplished in a two-step process by first treating the intermediate of formula (III) with oxalyl chloride at a concentration of about 0.2 to 1.5 mmol, preferably at equimolar concentrations with respect to the starting material. Solvents such as methylene chloride, chloroform, trichlorethylene, carbon tetrachloride, ether or toluene are preferred. Temperatures of about -20 ° C to room temperature, preferably about -5 ° C, are suitable. In the second step, the solution is treated with ammonia, which is bubbled in gaseous form or preferably using a molar excess of 30% aqueous ammonia. The reaction is generally carried out at a temperature of about -25 to 25 ° C, preferably about -2 to 0 ° C, and is substantially complete in 10 minutes to one hour. The hydrolysis of the compound of formula (II) is carried out using a base such as potassium, lithium or sodium hydroxide, preferably using sodium hydroxide in a lower alcohol solvent such as methanol, ethanol, isopropanol and the like, or in solvents such as tetrahydrofuran, dioxane or acetone. Using methods known per se, such as Φ Φ Φ · ··· * · « Φ Φ « For example, high performance liquid chromatography (HPLC), the reaction of Scheme I can be monitored to determine whether all of the starting materials and intermediates have been converted to the end product. The starting material of formula V is prepared as follows: Scheme II carbon atoms or an aryl group. The appropriately substituted propionyl acetate of the formula X is first halogenated by treatment with sulfuryl chloride, preferably using equimolar amounts with respect to the starting material, at a temperature of about 0 to 25 ° C, preferably lower ♦. • ·? Of more than 15 ^e C for the preparation of a compound of formula IX. Hydrolysis and decarboxylation of the compound of formula (IX) is performed by refluxing with an aqueous acid such as hydrochloric acid for about 1 to 24 hours. The solution containing the decarboxylated product of formula (VIII) is neutralized to adjust the pH to about 7.0 to 7.0 7.5 and the product is reacted with cyclohexanedione of formula VII (preferably at equimolar concentrations) and a base, preferably sodium hydroxide, to give the triketone monohydrate of formula VI as a precipitate which is optionally purified and isolated. The reaction is preferably carried out at -20 ° C to room temperature and is substantially complete in about 1 to 24 hours. The reactions described above are preferably carried out as a single-pot process wherein the reactants are added to the reaction vessel in the above sequence. Preferably, the reactions are carried out without isolation of compounds of formula (IX) or (VIII) so that exposure to volatile tear gas is avoided. Compounds of formula (V) are prepared by refluxing a compound of formula (VI) in a high boiling non-polar solvent which forms an azeotropic mixture with water, preferably toluene, with an equimolar amount of an amine of formula R ¹ NH ₂ , where R ¹ has R ^1. the above meaning. Preference is given to solvents having a boiling point of at least 100 ° C, such as toluene, xylene, cymene, benzene, 1,2-dichloroethane or mesitylene, thus avoiding the need to use a pressure reactor. Sufficient solvent should be used to ensure that all compounds are in solution until the reaction is complete, which is about 1 to 24 hours. Alternatively, an intermediate of formula (IV) may be prepared from a compound of formula (VI) by a process in one or more of the following formula (VI): Without isolating the intermediate of formula V by heating the compound of formula VI with palladium on carbon and a suitably substituted amine of formula R ¹ NH ₂ in a polar hydrocarbon solvent such as Carbitol ^R by the method of Scheme I. The reaction is preferably carried out under reflux and is substantially complete in 1 to 24 hours. The following is a process for preparing an intermediate of formula (IV). The intermediate of formula (IV) can be prepared as described in Scheme I, step (a) and Scheme II. The hydroxyindole of formula IV as an intermediate can be purified by conventional crystallization methods. For example, the reaction product is filtered through diatomaceous earth and rinsed with tert-butyl methyl ether to effectively remove the catalyst. The filtrate is then diluted with an additional amount of tert-butyl methyl ether and rinsed preferably with water. The organic phase is collected, dried and evaporated by known methods. The concentrate is preferably dissolved in methylene chloride / hexanes, filtered through silica and evaporated again. By standard analytical methods, such as HPLC, the reaction can be monitored to find that the starting material and intermediates are converted to the product. One skilled in the art will recognize that the starting materials for all of the above reactions are commercially available or can be prepared from commercially available materials by known methods. For example, the starting compound of formula (X) can be readily prepared as described by D.W. Brooks et al. (Angew. Chem. Int. Ed. Eng. 18, 72 (1979)). Other methods of preparation have been described by R.J. Cregge et al., 9 9 9 9 1 • 9 • 9 • ft Tetrahedron Lett., 26, 2425 (1973); M.W. Rathke et al., J. Am. Chem. Soc., 93, 2318 (1971); M. Hirama et al., Tetrahedron Lett., 27, 5281 (1986); D.F. Taber et al., J. Am. Chem. Soc. 109, 7488 (1987); and T. Hanken, Chem. Ind., P. 325 (1973)). The compound of formula VII can be prepared, for example, by Dieckman's cyclization as described by P. Gramatiga et al. (Heterocycles 24 (3), 743-750 (1986)) and R.L. Frank et al. (J. Am. Chem. Soc. 72, 1645 (1950)). Other methods of preparation have been described, for example, by Y.D. Venkar et al. (Tetrahedron Lett., 28, 551 (1987)); H.E. Zimmerman et al. (J. Am. Chem. Soc. 107 (25), 7732 (1985)); B.D. Hosangadi et al. (Native American J. Chem. 20, 63 (1981)); A.A. Zenyuk et al., Zh. Org. Khim 26 (10), 2232-2233 (1990)); or N.M. Berry et al., Synthesis-Stuttgart (6), pp. 476-480 (1986)). HCl NaOH Pd / C tert-BuOMe MgSO ₄ ch ₂ or ₂ Si ° ₂ to ₂ co ₃ i-PrOH NH ₃ (g) MeOH EtOH The following examples further illustrate the process of the invention. The examples also illustrate methods for preparing intermediates. However, the examples merely illustrate the invention and are not intended to limit the scope of the invention in any way. The following abbreviations are used where appropriate: hydrochloric acid sodium hydroxide palladium on carbon tert-butyl methyl ether magnesium sulfate dichloromethane silicon dioxide potassium carbonate isopropyl alcohol gaseous ammonia methanol ethanol • · • * · 9 9 9 • 9 · 9 MTBE tert-butyl methyl ether Preparation 2-Ethyl- (phenylmethyl) -1H-indol-4-ol Add 750 g (4.12 mol) of 2- (2-oxobutyl) -1,3-cyclohexanedione to a 22 liter flask, add 75 g of 10% palladium on carbon and 7.5 L of carbitol (lot 119WC7) to stirring. To the flask was added 462 g (4.32 mol) of benzylamine and heated to a temperature of 200 ^e C. for about one hour. The reaction mixture was refluxed (at 197 ** 0) for one hour. Thin layer chromatography confirms the disappearance of the starting material. The reaction mixture was cooled to room temperature, filtered through celite to remove the catalyst, washed with 6.0 L toluene and then 2 L water. 12 L of toluene and 6 L of water were added to the filtrate. The reaction mixture was stirred and the layers allowed to separate. The aqueous layer was back extracted with 2 x 4 L methylene chloride. All organic layers were evaporated to give an oil of 1008 g. It is passed through a pad of silica gel using methylene chloride to elute the silica product. All product containing fractions were combined and evaporated to give a solid (775 g). The solid was dissolved in 2 L of toluene at 65 ° C, stirred for 15 minutes and then diluted with 15 L of cyclohexane and stirred for 10 minutes at 65-70 ° C. After cooling to room temperature, the product crystallized and was placed on the joints and the oil was filtered. 0 0 0 0 · refrigerator (temperature 0 ^e C) overnight, then stirred cold for 15-30 minutes, filtered and washed with 2.0 1 of cyclohexane. The product is dried under vacuum to constant weight. 547.4 g are obtained (yield 52.9%). Example 1 ((3- (Aminooxoacetyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid A. Preparation of 2- (2-oxobutyl) -1,3-cyclohexanedione Methyl propionyl acetate (130.15 g, 1.0 mol) was charged to a 2 L Morton flask equipped with a mechanical stirrer, nitrogen inlet, and thermocouple. Outdoor cooling used so long until an internal temperature at 10 ^# C was added dropwise sulfurychlorid (135 g, 1.0 mol) at such a rate to maintain the temperature lower than 15 ° C. Upon complete addition, chromatographic analysis indicated complete conversion to the desired chlorinated compound. 1M Hydrochloric acid (205 ml) was added and the reaction mixture was stirred at reflux for 18 hours. After cooling to room temperature, 4N sodium hydroxide solution was added to adjust the pH to 7.0-7.5. Cyclohexanedione (112.13 g, 1.0 mol) was added and the reaction mixture was cooled in an ice bath. A 5N sodium hydroxide solution (200 mL, 1.0 mol) was added dropwise and the reaction mixture was stirred at room temperature for 18 hours. The thick precipitate obtained is filtered off, washed with water and dried in vacuo to give 101 g (yield 56%) of triketone monohydrate. Mp 96-98 DEG C. Rf = 0.63 _(SiO2 / 9: 1 CH ₂ C1 _2: i-PrOH). ¹ H NMR (CDCl ₃ ) δ 1.04 (t, 3H, J = 7.2Hz), 1.93 (m, 2H), 2.35 (m, 2H), 2.50 (m, 2H), 2.63 (q, 2H, J = 7.2 Hz), 3.51 (s, 2H), 9.97 (s, 1H). IR (CHCl 3) 3018, 1707, 1613, 1380, 1189, 1127 cm ^-1 . ··· t • ♦ ♦ * * * * * * * * * * * * UV (EtOH) λπ, ₈ χ (ε) = 262 (145 00). Elementary analysis: calculated: C 59.98 H 8.05 Found: C, 59.71 H 7.82 MS for C 20 H 24 O 3: m / z = 183 (m + 1 B. Preparation of 2-ethyl-1,5,6,7-tetrahydro-1- (phenylmethyl) -4Hindol-4-one The triketone prepared above (101.14 g, 0.51 mol) was charged to a 2 L flask equipped with a Dean-Stark water separator, mechanical stirrer and dropping funnel. Toluene (600 mL) was added and the reaction mixture was heated to reflux until the distillate became clear and all water was removed. The reaction mixture was gently cooled with the addition of benzylamine (55 g, 0.51 mol) dropwise under exothermic reaction with water generation. After the addition was complete, the reaction mixture was heated to reflux and continued azeotropic water separation (for 3 hours). Chromatography shows the perfect consumption of triketone. The light yellow solution was cooled to room temperature and the color changed to brown. The toluene solution was evaporated to dryness and the remaining brown oil (133.8 g) was used directly for the next oxidation. Mp 59-61 ° C. Rj = 0 _{out of} 37 (SiO2 / 2: 1: 1 hexane: CH2Cl2: EtOAc). 1 H NMR (CDCl 3) δ 1.91 (t, 2H, J = 7.4 Hz), 2.20-2.12 (m, 2H), 2.44-2.48 (m, 4H), 2.60-2.46 (m, 2H), 5.03 (s, 2H), 6 _; 38 (s, 1H), 6.89-6.91 (m, 2H), 7.28-7.32 (m, 3H). ¹³ C NMR (DMSO-d 6) δ 12.9, 19.2, 21.9, 23 _χ 9 _ζ 38.0, 46.9, 101.7, 119.7, 126.4, 127.7, 129, .3, 137.0, 138.0, 144.4, 192.8. »* ··» Elementary analysis: H, 7.56; N, 5.53. Found: C, 80.80; H, 7.67; N, 5.56 MS for C 23 H 25 N 3 O: m / z = 253. IR (KBr) 1640, 1453, 1175, 1137 cm ^-1 . UV (EtOH) λ max (ε) = 284 (7500), 252 (11000), 208 (199000). C. Preparation of 2-ethyl (phenylmethyl) -1H-indol-4-ol A 3-liter Morton flask containing 2 liters was equipped with a mechanical stirrer, a reflux condenser and a stopper. Add to a flask 10% palladium on carbon (26.8 g) followed by a solution (133.8 g) of the compound prepared according to paragraph B in Carbitol ^R (800 mL), 2-ethoxy (ethoxy) ethanol). The resulting mixture was heated to reflux for 18 hours. The reaction mixture was cooled, filtered through diatomaceous earth and rinsed with t-BuOMe to efficiently remove the catalyst. The filtrate was diluted with a total of 1 L of t-BuOMe and washed with water (3 x 2 L). The organic phase was dried (MgSO4) and evaporated to give 166 g of a dark brown oil. Dissolve the oil in methylene chloride: hexanes (3: 1), filter through silica (325 g) and elute with an additional solvent until a colorless solution is obtained. Evaporation gave 132.7 g of the subtitled compound. Melting point 98.5-100 ° C. Rj = 0 _; 74 (SiO 2/2: 1: 1 hexanes: CH 2 Cl 2: EtOAc). 1 H NMR (CDCl 3) δ 1.32 (t, 3H, J = 7.4 Hz), 2.67 (q, 2H, J = 7.4 Hz), 4.96 (s, 1H), 5.29 (s, 2H), 6.39 (s, 1H), 6.51 (d, 1H, J = 7.9 Hz), 6 82 (d, 1H, J = 8.2Hz), 6.94-6, 99 (ra, 3H), 7.23-7.26 (m, 3H). • 9 • 9 • 9 • 9 9 9 9 9 9 9 9 9 9 9 99 99 ¹³ C NMR (DMSO-d6) δ 13.1, 19.9, 46.4, 96 _; 2, 101.8, 104.3, 118.0, 122, 1, 126.6, 127.5, 129.1, 139.2, 139.5, 141.0, 150.6. IR (KBr) 1586, 1467, 1351, 1250 cm -1. UV (EtOH) λ .. _χ (ε). 296 (6700), 287 (6500), 269 (8200) 223 (35,000). Elementary analysis: calculated: C 81.24 H 6.82 N 5.57 found: C 80.98 H 6.90 N 5.59 MS for C 27 H 17 NO: m / z = 251. D. Preparation of ((2-ethyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid methyl ester The compound of Part C (3.0 g, 12.0 mmol), potassium carbonate (3.31 g, 24.0 mmol), and acetone (24 mL) were placed in a 100 mL round bottom flask, equipped with a magnetic stirrer. The heterogeneous reaction mixture was stirred at room temperature for 20 minutes. Methyl bromoacetate (1.7 mL, 18.0 mmol) was added dropwise using a syringe and the reaction was stirred for an additional 15 hours. The reaction mixture was filtered through a Buchner funnel, the solid was washed with acetone, and the filtrate was filtered with folded filter paper. The acetone was evaporated in vacuo to give 4.1 g of a white solid. Crystallization from isopropanol (30 ml) gave 3.28 g (yield 84.5%) of the desired substituted intermediate as a colorless crystalline solid. Mp 95.5 DEG-97 DEG C. ^e R _j - = _0; 74 (SiO ₂ / CH ₂ C1 ₂ ) · 1 H NMR (CDCl 3) _? 32 (t, 3H, J = 1.4Hz), 2.67 (q, 2H, J) 9 9 9 99 99 49 99 99 99 99 99 99 45 4 · 9 1.4 Hz), 4.96 (s, 1H), 5 _; 29 (s, 2H), 6 .39 (s, 1H), 6.51 (d, 1H, J = 7 ^ 9 Hz), 6.82 (d, 1H, J = 8 _Z 2 Hz), 6 _of 94-6 _y 99 (m, 3H), 7.23-7.26 (m, 3H). ¹³ C NMR (CDCl ₃ ) δ 12 _; 6, 20.0, 46.7, 52.2, 65.9, 96.0, 101.1, 104.0, 118.8, 121.4, 125.9, 126.0, 127.3, 128, 8, 137, 9, 139.1, 141.9, 151.1, 169.9. IR (CHCl3) 3009, 1761, 1739, 1498, 1453, 1114, 1112 cm &lt; -1 &gt; UV (EtOH) (221) (36500), 271 (9600), 283 (7800), 293 (7700). Elementary analysis: H, 6.55; N, 4.33. Found: C, 73.32; H, 6.64; N, 4.19 MS for ^C 20 ^H 21 ^NO 3 ^{: m / z = 324} · E. Preparation of ((3- (2-Amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid methyl ester The compound prepared according to Part D (4.0 g, 0.0124 mol) was charged to a 100 mL three-necked round bottom flask equipped with nitrogen inlet, magnetic stirrer and gas dispersion tube connected to an ammonia tank. Dichloromethane (28 mL) was added and the resulting yellow solution was cooled in an ice bath. To the cooled solution was added pure oxalyl chloride (1.1 mL, 0.012 mol) slowly via syringe to form a dark green solution. The reaction solution was stirred for 20 minutes at an ice bath temperature and chromatographic analysis (TLC, silica, dichloromethane) confirmed the absence of starting material. Ammonia (gas) was passed through the gas dispersion tube for 15 minutes, converting the dark green solution to a pale yellow precipitate, which was stirred at an ice bath temperature for an additional 20 minutes. The reaction mixture was diluted with dichloromethane (56 mL), filtered with diatomaceous earth, washed with dichloromethane (50 mL), and the filtrate was evaporated in H 2 O 3. φφφ Vacuum to give 4.65 g of a yellow solid. Recrystallization from methanol (15 volumes) gave 3.0 g (61.3% yield) of pale yellow needles. Melting point 179-181 ^and C. R / = 0.16 _(SiO2 / 95: 5 CH ₂ C1 _2: MeOH). 1 H NMR (CDCl ₃ ) δ 1.20 (t, 3H, J = 7.5 Hz), 2.94 (q, 2H, J = 7.54 Hz), 3.78 (s, 3H), 4.74 (s, 2H), 5.35 (s, 2H), 5.66 (br s, 1H), 6.54 (d, 1H) J = 8.0 Hz), 6.58 (br s, 1H), 6.87 (d), 1H, J = 8.5), 7.02-7.07 (m, 3H), 7.25-7.29 (m, 3H). 13 _C NMR _(CDCl3) δ 14.4, 19.1, 47 .0, 52.1, _65/9, 104, 6, 104.8, 111.0, 117.0, 123.7, 126.1, 127.8, 129.0, 136.3, 138.3, 150.2, 151.9, 167.6, 169.7, 188.1. IR (CHCl₃) 3399, 1761 UV (EtOH) λ ^ _χ (ε) = 218 1700, 16461519 1452 1151 cm ^-1 . 333 (5500). (32300) 126000) Elementary analysis: calculated: C, 66.99 H, 5.62 7.10 Found: C, 66.06 H, 5.64 7.61 MS for ^ 22 ^ 22 ^ 2 ^ 5 · Melting point = 395 (m + 1). F. Preparation of sodium salt ((3- (amino-1,2- -dioxyethyl) -2-ethyl- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid The compound prepared according to paragraph E is placed in a 500 ml three-necked round-bottomed flask equipped with a mechanical stirrer and reflux condenser. The solid was suspended in ethanol (150 mL). Add 5N sodium hydroxide solution (9.1 mL, 45.7 mmol) with vigorous stirring of the suspension at room temperature. The reaction mixture was heated to reflux to form a thick white precipitate. The reaction mixture was refluxed for 20 minutes and then cooled to room temperature. Ethanol (150 ml) was added, the solid was filtered off on a Buchner funnel and dried in a high vacuum oven at 60 ° C for 4 hours. to give 13.67 g (89.3% yield) of the title compound. Melting point 296 ° C. 1 H NMR (ϋ ₂ Ο) δ 1 _; 11 (t, 3H, J = 7.6Hz), 2.96 (q, 3H, J = 7.6) Hz), 4.51 (s, 2H), 5.45 (s, 2H), 6.55 (d, 1H, J = 8 Hz), 6.91-7.25 (m, 8H). ¹³ C NMR (DMSO-d 6) δ 14.3, 18.3, 45., 9, 68.3, 103.0, 103, 8, 110.1, 115.8, 123.1, 126.0, 127.3, 128.6, 1-37, .3, 137.5, 148 _; 1, 152, 8, 169.4, 171.8, 190 _{out of} 0. IR (CHCl 3) 3028, 1649, 1411, 1276, 722 cm ^-1 UV (EtOH) λ, _βχ (ε) = 218 (34900), 258 (14900), 337 (5836). Elemental analysis: calculated: C 62.68 found: C 62.43 MS for C ₂₁ H ₁₉ N ₂ O ₅ Na: H 4.76 N 6.96 H 4.78 N 6.69 m / z = 381 (m-21, Na / + H) Example 2 ((3- (Aminooxoacetyl) -2-ethyl-6-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid, sodium salt A. Preparation of 4- (ethoxycarbonyl-5-methyl-1,3-cyclohexanodionate sodium enolate) Ethyl crotonate (32.26 g, 1.06 mol) and ethyl acetoacetate (35.45 g, 1.02 mol) were mixed in a 250 mL three-necked flask. Add sodium ethoxide with stirring over two minutes. The mixture was heated to 78 ° C and maintained at this temperature for one hour and 45 minutes. The reaction mixture was allowed to cool slowly and then cooled in an ice / water bath to 14 ^o C. • 4 ♦ 4 494 4 9 9 4 · 4 ·· 499 • 9 4 4 4 4 4 4 4 4 • 4 4 · * 44 The reaction mixture was filtered, washed twice with ethanol and dried under vacuum to give 36.7 g (63.7% yield) of the sub-title compound. B. Preparation of 5-methylcyclohexanedione In a 5 L flask, 495.9 g (2.25 mol) of the compound prepared according to paragraph A, and a solution of potassium hydroxide (311.0 g in 1250 mL of water) were heated to reflux. After 6.5 hours, 6M hydrochloric acid (1 liter) was added over 25 minutes and the mixture was refluxed until gas evolution ceased for approximately one hour. An additional 100 mL of 6M hydrochloric acid was added and the reaction mixture was again refluxed until gas evolution ceased. Add the last 75 mL of 6M hydrochloric acid, changing the color of the mixture from orange to yellow. The reaction mixture was allowed to cool to 56 ° C and the liquid was evaporated to give 2728 g of material. Ethyl acetate (2.6 L) was added and the solution was transferred to a 22 L bottomed flask and washed with 500 mL of ethyl acetate, 500 mL of MTBE and 500 mL of water. After stirring, the layers were allowed to separate. The organic layer was washed with brine (1.5 L), dried over sodium sulfate, filtered, and the organics stripped to give a thick suspension (377 g). The suspension is filtered and rinsed with pentane (6.5 L) and the minimum amount of ethyl acetate required to remove the yellow color. The product obtained is dried in a vacuum oven to give 161.7 g (yield 56.9%) of the product. Mp 126 DEG -128 DEG C .; C. Preparation of ((3- (aminooxoacetyl) -2-ethyl-6-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid Using the procedure of Example 1, Steps A through F, using (160.5 g) of the compound of Part B, 7.62 g (yield) was obtained. 91.2%) of the desired compound as the sodium salt, Elemental analysis for ^c 22 ^H 21 ^N 2 ° 5 ^Na: Calculated: C 63.46 H 5.08 N 6.72 Found: C 63.69 H 5.16 N 6.79 _ Q bk 7 - 40 · φ »40 40 40 40 Φ ΦΦΦΦ Φ · Φ φ φ φ (((| | (| | | | | PATENT CLAIMS A process for the preparation of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof (I) wherein: R ^J is from the group consisting of where R ¹⁰ is selected from the group consisting of halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 -alkyl, and haloalkyl. 9 9 9 9 9,999 9 9 • 9 9 9999 99 dialkylamino having 1 to 10 carbon atoms and t is an integer from 0-5 inclusive, the ^"R j ^e is selected from the group consisting of hydrogen, halogen, alkyl of 1-3 carbon atoms, cycloalkyl having 3 or 4 carbon atoms , cycloalkenyl of 3 or 4 carbon atoms, O-alkyl of 1 or 2 carbon atoms, -S-alkyl of 1 or 2 carbon atoms, aryl, aryloxy and HET, R ⁴ represents a group selected from the group consisting of -CO ₂ H, -SOgH, -P (O) (OH) ₂ or salt or prodrug, R ⁵ , R ⁶ , R ⁷ are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 haloalkyl C 6, bromine, chlorine, fluorine or iodine and an aryl group, characterized in that: a) halogenating a compound of formula X wherein R ⁸ is C 1 -C 6 alkyl, aryl or HET by treatment with sulfuryl chloride to give a compound of formula IX (b) hydrolyzes IX and decarboxylate the compound of formula O. <9 R Cl (ix) to give a compound of formula VIII (VIII) c) alkylating a compound of formula VII (VII) with a compound of formula VIII Cl (VIII) to give a compound of formula VI (VI) d) aminating and dehydrating the compound of formula VI 9 9 9 9 9 9 e) 9 9 9 Which forms an azeotrope with water to give a compound of formula (V), the compound of formula (V) is oxidized by refluxing with a polar hydrocarbon solvent at a temperature of boiling at least 150 ° C and having a dielectric constant of at least 10 in the presence of a catalyst to obtain a compound of formula IV (IV) (IV). Alky φ φ an alkylating agent of formula XCH ₂ R ^4a , wherein X is a liberated group and R ^4a is -CO ₂ R ^4b , -SO ³ R ^4fc , -P (O) (OR ⁴ * ⁵ ) ₂ or -P (O) ( OR ^4b ) H, wherein R ^4b is an acid protecting group, to provide a compound of formula III (III) g) reacting a compound of formula III (III) with oxalyl chloride and ammonia to obtain a compound of formula II (n: (h) optionally hydrolyzing a compound of formula (II) and R '(II) 9 9 9 • 9 9 999 to give a compound of formula I a i) optionally converting a compound of formula I to its salt. A process for the preparation of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof C7-C20 alkyl; z = V (R ¹⁰ ) _t where R ¹⁰ is selected from the group consisting of halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 -alkyl and C 1 -C 10 haloalkyl; 4 4 · 4 4 4 4,444 « 4 4 4444 44 4 · 44 44 · 4 • 4 44 444 44 «4 • · 4 4 4 4 4 » 4 4 4 4 • 4 4 4 4 4 4 t is an integer from 0 to 5 inclusive, R is selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, C 1 -C 2 alkyl, -S-alkyl having 1 or 2 carbon atoms, aryl, aryloxy and HET, R ⁴ is a group selected from the group consisting of -CO ₂ H, -SO ₃ H, -P (O) (OH) _2, or a salt or prodrug thereof, R ⁵ , R ⁶ , R ⁶ are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, haloalkyl of 2 to 6 carbon atoms, bromine, chlorine , fluorine or iodine and an aryl group, characterized in that: a) oxidizing the compound of formula V by refluxing in a polar hydrocarbon solvent boiling at least 150 ° C and having a dielectric constant of at least 10 in the presence of a catalyst to give a compound of formula IV OH -F | (IV) · · · φ φ t ií ií ií ií ií ií ií ií ií ií ií · · · · · ““ φ φ φ φ φφ φφ b) alkylating a compound of formula IV (IV) with an alkylating agent of formula XCH ₂ R ^4a , wherein X is a liberated group and R ^4a is -CO ₂ R ⁴ , -SO ³ R ^4b , -P (O) (OR ⁴ ) ₂ or -P (O) (OR ⁴ ^) H, where R ⁴ ^ represents an acid protecting group, to give a compound of formula III (III) c) reacting the compound of formula III (III) with oxalyl chloride and ammonia to obtain a compound of formula II (II) d) optionally hydrolyzing a compound of formula II * 5 to obtain a compound of formula I and e) optionally converting a compound of formula I to its salt. A process according to claim 1 or 2 wherein the azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of 150 to 250 ° C and a dielectric constant of 10 to 20. A process according to claim 1 or 2 wherein the azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of 150 to 220 ° C and a dielectric constant of 12 to 18. Process according to any one of claims 1 to 4, characterized in that ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -1H-indole-4) is prepared). -yl) oxy) acetic acid. 6. A compound of formula (IV) (IV) in which: R ¹ is -C 7 -C 20 alkyl, (R ¹⁰ ). R ¹⁰ is halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 -alkyl, and C 1 -C 10 haloalkyl, and an integer of 0 to 5 inclusive , R ² is hydrogen, halogen, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, C 1 -C 2 alkyl, -S-alkyl 1 or 2 carbon atoms, aryl, aryloxy and HET, R ⁵ , R ⁶ , R ⁷ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 haloalkyl 6 carbon atoms, bromine atom, chlorine. ί ΐ. * ··: *::: *:.,:, ... .. - 50 r, fluorine or iodine and an aryl group. The compound of claim 6 which is 2-ethyl-1- (phenylmethyl) -4-hydroxy-1H-indole. A process for preparing compounds of formula IV (IV) wherein: R ¹ is -C 7 -C 20 alkyl, - (CH 3 O a): where it means R ¹⁰ is halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 -alkyl, and C 1 -C 10 haloalkyl, and an integer of 0 to 5 inclusive , 9 · 9 9 9 9 99 9 ·· ’. ···: · i: *! ·· ·· ·· ··· ·· - 51 R ² is hydrogen, halogen, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, C 1 -C 2 O-alkyl, -S -alkyl of 1 or 2 carbon atoms, aryl, aryloxy and HET, R ⁵ , R ⁶ , R ⁷ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 haloalkyl 6 carbon atoms, bromine, chlorine, fluorine or iodine atoms and an aryl group, characterized in that it comprises the following steps: a) halogenating a compound of formula X oo (x) 10 wherein R ⁸ is C 1 -C 6 alkyl, aryl or HET, sulfuryl chloride to give a compound of formula IX 0 Q R '' 0 '' R Cl (IX) b) hydrolyzing and decarboxylating the compound of formula IX R \ O R Cl o O (IX) to obtain a compound of formula VIII (VIII) Cl c) alkylating a compound of formula VII (VII) with a compound of formula VIII Cl (VIII) to give a compound of formula VI (VI) d) aminating and dehydrating the compound of formula VI (VI) with an amine of formula R ¹ NH ₂ in the presence of a solvent which forms an azeotrope with water to give a compound of formula V, I «» »» »$ 9 <9 9 9 * «· 9 9 r 9 9 9 l · · 9 99 99 e) oxidizing the compound of formula V (V) under reflux with a polar hydrocarbon solvent boiling at least 150 ° C and having a dielectric constant of at least 10 in the presence of a catalyst. 9. A process for the preparation of compounds of formula IV R (IV) wherein R ¹ represents a radical from the group consisting of C7 -C20 alkyl. / = Y ^{1 R} 't • CH. (CH,) // // ^and ··· «* · * ·· · ♦ · where means R ¹⁰ is halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 -alkyl, and C 1 -C 10 haloalkyl, and an integer of 0 to 5 inclusive , R ² is hydrogen, halogen, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, C 1 -C 2 alkyl, -S-alkyl 1 or 2 carbon atoms, aryl, aryloxy and HET, R ⁵ , R ⁶ , R ⁷ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 haloalkyl 6. A carbon atom, a bromine, chlorine, fluorine or iodine atom and an aryl group having the general formula (V) by oxidizing the compound at reflux in a polar hydrocarbon solvent at a boiling point of at least 150 ^C C and a dielectric constant of at least 10 in the presence of a catalyst. 10. A process according to claim 8 or 9 wherein the azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of 150-250 [deg.] C. and a dielectric constant of 10-20. 11. The process of claim 7 or 8 wherein the azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of 150-220 [deg.] C and a dielectric constant of 12-18. Process according to one of Claims 8 to 11, characterized in that 2-ethyl-1- (phenylmethyl) -4-hydroxy-1H-indole is prepared. A process for the preparation of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof R '(I) wherein R ¹ is selected from the group consisting of -C7-C20 alkyl R ¹⁰ represents a group selected from halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 -alkyl and C 1 -C 10 haloalkyl, and t is hydrogen; Integer 0-5 including R ² is selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, C 1 -C 2 O-alkyl -S-alkyl having 1 or 2 carbon atoms, aryl, aryloxy and HET, R ⁴ is a group selected from the group consisting of -CO ₂ H, -SO ₃ H, -P (O) (OH) _2, or a salt or prodrug thereof, R ⁵ , R ⁶ , R ⁷ are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 haloalkyl 6 carbon atoms, bromine, chlorine, fluorine or iodine and an aryl group, 0 0 # 0, 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4 - 57 » 0 0 0 ♦ · Characterized in that they comprise the following steps; a) halogenating a compound of formula X (X) wherein: R ⁸ represents a C 1 -C 6 alkyl group, an aryl group or HET, a sulfuryl chloride to give a compound of formula IX 0 Q R \ o'R Cl (ix) b) hydrolyzing and decarboxylating the compound of formula IX 0 0 (0) R \ 0 ' R Cl to give compound of formula VIII (VIII) Cis. 2 R c) alkylating the compound of formula VII (VII) with a compound of formula VIII with a compound of formula VIII ## STR2 ## ··· · ··· ··· ·· ·· - 58 Cl 'V (VIII) to give a compound of formula VI R (VI) d) aminating and dehydrating and oxidizing the compound of formula VI (VI) under reflux with a polar hydrocarbon solvent boiling at least 150 ° C and having a dielectric constant of at least 10 in the presence of a catalyst and an amine of formula R ¹ NH ₂ to give of formula IV (IV) e) alkylating the compound of formula IV OH R (IV) 4 · · - 59 an alkylanic agent of the formula XCH ₂ R ^4a , wherein X is a released group and R ^4a is -CO ₂ R ⁴ , -SO ³ R ^4b , -P (O) (OR ⁴ ) ₂ or -P (O) (OR ⁴⁾ ^) H, wherein R is ^4-one acid group-protecting group to give a compound of formula III R (III) f) reacting a compound of formula III R (III) with oxalyl chloride and ammonia to give a compound of formula II (II) g) optionally hydrolyzing a compound of formula (II) ^0CH , R ^4a0 in '-0 (II) - 60 · ·>> 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 v v v 9 9 9 v To obtain a compound of formula (I) and h) optionally converting a compound of formula I to its salt. A process for the preparation of a compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof, wherein: R ¹ is selected from the group consisting of C ₇ -C ₂₀ alkyl; / = V <r '\ -ICHj),., - where R ¹⁰ represents a group selected from the group consisting of φφφφφ φφφφφφφφφφφφφφφφ Halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 -alkyl, and C 1 -C 10 haloalkyl. t is an integer of 0-5 inclusive, R2 _is: selected from the group consisting of hydrogen, halogen, alkyl of 1-3 carbon atoms, cycloalkyl having 3 or 4 carbon atoms, a cycloalkenyl group having 3 or 4 carbon atoms, O -alkyl of 1 or 2 carbon atoms, -S-alkyl of 1 or 2 carbon atoms, aryl, aryloxy and HET, R ⁴ is a group selected from the group consisting of -CO ₂ H, -SO ₃ H, -P (O) (OH) _2, or a salt or prodrug thereof, R ⁵ , R ⁶ , R ⁷ are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 haloalkyl 6 carbon atoms, bromine, chlorine, fluorine or iodine atoms and an aryl group, characterized in that it comprises the following steps: a) aminates and dehydrates and the formula VI is oxidized with the compound (VI) φ φ φ φ φ φ φ ΦΦΦ φ φ - 62 refluxing with a polar hydrocarbon solvent boiling at least 150 ° C and a dielectric constant of at least 10 in the presence of a catalyst and an amine of formula R ¹ NH ₂ , to give a compound of formula IV (b) alkylation of a compound of formula IV (IV) with an alkylating agent of formula XCH ₂ R ^4a wherein X is a liberated group and R ^4a is -CO ² R ⁴ , -SO ³ R ^4b , -P (O) (OR 4 R ³ ) _2, or - P (0) (OR @ ⁴⁾ H, wherein R ⁴ · * ³ acid protecting group, to give a compound of formula III (III) c) reacting a compound of formula III with oxalyl chloride and ammonia to obtain a compound of formula II d) optionally hydrolyzing a compound of formula II to give a compound of formula I and e) optionally converting a compound of formula I to its salt. 15. A process according to claim 13 or 14, wherein the polar hydrocarbon solvent has a boiling point of 150-250 [deg.] C and a dielectric constant of 10-20. 16. A process according to claim 13 or 14 wherein the polar hydrocarbon solvent has a boiling point of 150 to 220 [deg.] C. and a dielectric constant of 12 to 18. Method according to one of Claims 13 to 16, characterized in that it is 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 A process for preparing ((3- (2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid. A process for the preparation of a compound of formula IV (IV) wherein * 1 R- ¹ is a group selected from -C7-C20 alkyl, 1 Π R ( ^1U) is halogen, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -S-alkyl of 1 to 10 carbon atoms, and haloalkyl of 1 to 10 carbon atoms and an integer of 0 to 5 inclusive , (C až-C alky) alkyl group having 3 or 4 carbon atoms with 3 or 4 carbon atoms, (a) halogenate the compound of general ο, R is hydrogen, halogen, carbon atoms, cycloalkyl, cycloalkenyl having 1 or 2 carbon atoms, -S-alkyl having 1 or 2 carbon atoms, aryl, aryloxy and HET, R ⁵ , R ⁶ , R ⁷ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 haloalkyl 6 carbon atoms, bromine, chlorine, fluorine or iodine atoms and an aryl group comprising the following steps: of formula X (X) wherein R ⁸ represents a C 1-6 alkyl group, an aryl group or HET, a sulfuryl chloride to give a compound of formula IX b) hydrolyzing and decarboxylating the compound of formula IX> · -ww9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 (IX) to give a compound of formula VIII (VIII) ^{CK +} V c) alkylating the compound of formula VII (VII) with a compound of formula VIII (VIII) to give a compound of formula VI R (VI) (VI) is refluxed with a polar hydrocarbon solvent at a boiling point of at least 150 ° C and a dielectric constant of at least 10 in the presence of a catalyst and an amine of the formula R ¹ NH ₂ . A process for preparing a compound of formula IV (IV) wherein η R is -C7-C20 alkyl, R ¹⁰ is halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 -alkyl, and C 1 -C 10 haloalkyl, and an integer of 0 to 5 inclusive, R ² is hydrogen, halogen, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, C 1 -C 2 alkyl, -S-alkyl 1 or 2 carbon atoms, aryl, aryloxy and HET, κ 6 7 R, R, R 'are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, haloalkyl of 2 to 6 atoms carbon, bromine, chlorine, fluorine or iodine and an aryl group, characterized in that the compound of formula VI is aminated, dehydrated and oxidized by refluxing with a polar hydrocarbon solvent boiling at least 150 ° C and a dielectric constant of at least 10 v presence of a catalyst and an amine of the formula R ¹ NH ₂ . 20. The process of claim 18 or 19 wherein the azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of 150-220 [deg.] C and a dielectric constant of 12-18. 4 4 4 44 444 4 · 4444 44 69. A process according to claim 18, wherein 2-ethyl-1- (phenylmethyl) -4-hydroxy-1H-indole is prepared.