Patent EA-002119-B1 (EA)
Title: Process for preparing 4-substituted -1h-indole-3-glyoxamides
Inventor: KHAU VIEN VAN
IPC: C07D209/12
Filed: 1998-06-22
Abstract: 1. A process for preparing a compound of the formula I or a pharmaceutically acceptable salt or prodrug derivative thereof   wherein: R<1> is selected from the group consisting of -C7-C20 alkyl,   where R<10> is selected from the group consisting of halo, C1-C10 alkyl, C1-C10 alkoxy, -S-( C1-C10 alkyl) and halo(C1-C10)alkyl, and t is an integer from 0 to 5 both inclusive; R<2> is selected from the group consisting of hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -O-(C1-C2 alkyl), -S-( C1-C2 alkyl), aryl, aryloxy and HET; R<4> is selected from the group consisting of -CO2H, -SO3H and -P(O)(OH)2 or salt and prodrug derivatives thereof; and R<5>, R<6> and R<7> are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, halo(C2-C6)alkyl, bromo, chloro, fluoro, iodo and aryl; which process comprises the steps of: a) halogenating a compound of formula X   where R<8> is (C1-C6)alkyl, aryl or HET; with SO2Cl2 to form a compound of formula IX   b) hydrolyzing and decaxboxylating a compound of formula IX   to form a compound of formula VIII   c) alkylating a compound of formula VII   with a compound of formula VIII   to form a compound of formula VI   d) aminating and dehydrating a compound of formula VI   with an amine of the formula R<1>NH2 in the presence of a solvent that forms and azeotrope with water to form a compound of formula V; e) oxidizing a compound of formula V   by refluxing in a polar hydrocarbon solvent having a boiling point of at least 150 degree C and a dielectric constant of at least 10 in the presence of a catalyst to form a compound of formula IV   f) alkylating a compound of the formula IV   with an alkylating agent of the formula XCH2R<4a> where X is a leaving group and R<4a> is -CO2R<4b>, -SO3R<4b>, -P(O)(OR<4b>)2 or -P(O)(OR<4b>)H, where R<4b> is an acid protecting group 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 formula II   to form a compound of formula I; and i) optionally salifying a compound of formula I. 2. A process for preparing a compound of the formula I or a pharmaceutically acceptable salt or prodrug derivative thereof   wherein: R<1> is selected from the group consisting of -C7-C20 alkyl,   where R<10> is selected from the group consisting of halo, C1-C10 alkyl, C1-C10 alkoxy, -S-(C1-C10 alkyl) and halo(C1-C10) alkyl, and t is an integer from 0 to 5 both inclusive; R<2> is selected from the group consisting of hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -O-(C1-C2 alkyl), -S-( C1-C2 alkyl), aryl, aryloxy and HET; R<4> is selected from the group consisting of -CO2H, -SO3H and -P(O) (OH)2 or salt and prodrug derivatives thereof; and R<5>, R<6> and R<7> are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, halo(C2-C6)alkyl, bromo, chloro, fluoro, iodo and aryl; which process comprises the steps of: a) oxidizing a compound of the formula V   by refluxing in a polar hydrocarbon solvent having a boiling point of at least 150  degree C and a dielectric constant of at least 10 in the presence of a catalyst to form a compound of formula IV   b) alkylating a compound of the formula IV   with an alkylating agent of the formula XCH2R<4a> where X is a leaving group and R<4a> is -CO2R<4b>, -SO3R<4b>, -P(O) (OR<4b>)2 or -P(O) (OR<4b>)H where R<4b> 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 (biTnLiki II   to form a compound of formula I and e) optionally saiifying a compound of formula I. 3. The process of claim 1 where the azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of from 150-250 degree C and a dielectric constant of from 10-20. 4. The process of claim I where the azcotrope is toluene and the polar hydrocarhon solvent has a boiling point of from 150-220 degree C and a dielectric constant of from 12-18. 5. The process of any one of claims 1 to 4 which prepares ((3-(2-amino-l,2-dioxyethyl)-2-ethyl-l-(phenylmethyl)-1H-indol-4-yl)oxy) acetic acid. 6. A process of preparing a compound of formula IV     wherein: R<1> is selected from the group consisting of -C7-C20 alkyl   R<10> is selected, from the group consisting of halo, C1-C10 alkyl, C1-C10 alkoxy, -.S-( C1-C10 alkyl) and halo(C1-C10)alkyl and t is an integer from 0 to 5 both inclusive; R<2> is selected from the group consisting of hydrogen, halo C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -O-(C1-C2 alkyl). -S-( C1-C alkyl), aryl, aryloxy and HET: and R<5>, R<5> and R<7> are each independently selected from the 'group consisting of hydrogen, (C1-C6) alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, halo(C2-C6)alkyl, bromo, chloro, fluoro, iodo and aryl; comprising the steps of: a) halogenating a compound of formula X   where R<8> is (C1-C6)alkyl, aryl or HET: with SO2Cl2 to form a compound of formulu IX   h) hydrolyzing and decarboxylating a compound of formula IX   to form a compound of formula VIII   c) alkylaling a compound of formula VII   with a compound of formulu VIII   to form a compound of formula VI   d) animating and dehydrating a compound of formula VI   with an an-amine of the formula R<1>NH2 in the presence of a solvent that forms an azcotrope with water to form a compound of formula V   e) oxidizing a compound o f formula V   by rcfluxing in a polar hydrocarbon solvent having a boiling point of at least 150 degree C and a dielectric constant of at least 10 in the presence of a catalyst. 7. A process for preparing a compound of formula   wherein: R<1> is selected from the group consisting of -C7-C20 alkyl.   where R<10> is selected from the group consisting of halo C1-C10 alkyl, C1-C10 alkoxy, -.S-( C1-C10 alkyl) and halo(C1-C10))alkyl, and t is an integer from 0 to 5 both inclusive: R<2> is -selected from the group consisting of hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl; -O-(C1-C2 alkyl), -S-(C1-C2 alkyl), aryl aryloxy and HET: and R<5>, R<5> and R<7> are each independently selected from the 'group consisting of hydrogen, (C1-C6) alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, halo(C2-C6)alkyl, bromo, chloro, fluoro, iodo and aryl; comprising oxidizing a compound of formula V   by refluxing in a polar hydrocarbon solvent having a boiling point of at least 150 degree C and a dielectric constant of at least 10 in the presence of a catalyst. 8. The process of claim 6 where the azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of from 150-250 degree C and a dielectric constant of from 10-20. 9. The process of any one of claims 6-8 which prepares the compound 2-ethyl-1-(phenylmethyI)-4-hydroxy-lH-indole. 10. A process for preparing a compound of the formula I or a pharmaceulically acceptable salt or prodrug derivative thereof   wherein: R<1> is selected from the group consisting of -C7-C70 alkyl     where R<10> is selected from the group consisting of halo C1-C10 alkyl, C1-C10 alkoxy, -.S-( C1-C10 alkyl) and halo(C1-C10))alkyl, and t is an integer from 0 to 5 both inclusive: R<2> is -selected from the group consisting of hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl; -O-(C1-C2 alkyl), -S-(C1-C2 alkyl), aryl aryloxy and HET: and R<4> is selected from the group consisting of CO2H, SO3H and -P(O)(OH)2 or salt and prodrug derivatives thereof; and  R<5>, R<5> and R<7> are each independently selected from the 'group consisting of hydrogen, (C1-C6) alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, halo(C2-C6)alkyl, bromo, chloro, fluoro, iodo and aryl; which process comprises the steps of: a) halogenating a compound of formula X   where R<8> is (C1-C6)alkyl, aryl or HET: with SO2Cl2 to form a compound of formula IX   h) hydrolyzing and decarboxylating a compound of formula IX   to form a compound of formula VIII   c) alkylating a compound of formula VII   with a compound of formula VIII   to form a compound of formula VI   d). aminating, dehydrating and oxidiy.inu a compound of Ibrmula VI   by refluxing in a polar hydrocarbon solvent having a boiling point of at least 150 degree C and a dielectric constant of at least 10 in the presence of a catalyst and an amine of the formula R<1>NH2: to form a compound of formula IV   e). alkylating a compound of the formula IV   with an alkylating agent of the formula XCH2R<4a> where X is a leaving group, and R<4a> is -CO2R<4b> -SO3R<4b>, -P(O)(OR<4b>)2 or -P(O)(OR<4b>)H, where R<4b> is an acid protecting group to form a compound of formula III   f). reacting a compound of formula III   with oxalyl chloride and ammonia to form a compound of formula II   g) optionally hydrolyzing a compound of formula II   to form a compound of formula I: and h) optionally salifyiny a compound of formula I. 11. A process for preparing a compound of the luri-nuia 1 or a pharmaceutical ly >icccplable salt or prodruy derivative thereof   wherein: R<1> is selected from the group consisting of -C7-C20 alkyl   where R<10> is selected from the group consisting of halo C1-C10 alkyl, C1-C10 alkoxy, -.S-( C1-C10 alkyl) and halo(C1-C10))alkyl, and t is an integer from 0 to 5 both inclusive: R<2> is -selected from the group consisting of hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl; -O-(C1-C2 alkyl), -S-(C1-C2 alkyl), aryl, aryloxy and HET: and R<4> is selected from the group consisting of CO2H, SO3H and -P(O)(OH)2 or salt and prodrug derivatives thereof; and  R<5>, R<5> and R<7> are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, halo(C2-C6)alkyl, bromo, chloro, fluoro, iodo and aryl; which process comprises the steps of: a) aminating, dehydrating and oxidizing a compound of the formula VI   by