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1. WO1999000360 - PROCEDE RELATIF A L'ELABORATION DE 1H-INDOLE-3-GLYOXAMIDES SUBSTITUES

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

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We Claim:
1. A process for preparing a compound of the formula I or a pharmaceutically acceptable salt or prodrug derivative thereof



wherein:
R1 is selected from the group consisting of
-C7-C20 alkyl,



where
R10 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;
R2 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;

R4 is selected from the group consisting of -CO2H,

-SO3H and -P(O) (OH)2 or salt and prodrug derivatives thereof; and
R5, R6 and R7 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C5)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 R8 is (C1-C6) alkyl, aryl or HET;
with SO2Cl2 to form a compound of formula IX


b) 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


aminating and dehydrating a compound of formula VI


with an amine of the formula R1NH2 in the
presence of a solvent that forms and
azeotrope with water to form a compound of formula V;

oxidizing a compound of formula V


by refluxing in 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 form a compound of formula IV


alkylating a compound of the formula IV


with an alkylating agent of the formula XCH2R4a where X is a leaving group and R4a is -CO2R4b,

-SO3R4b, -P(O) (OR4b)2, or -P(O) (OR4b)H, where 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 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:
R1 is selected from the group consisting of
-C7-C20 alkyl,



where
R10 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;
R2 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;
R4 is selected from the group consisting of -CO2H,

-SO3H and -P(O) (OH)2 or salt and prodrug derivatives
thereof; and
R5, R6 and R7 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, halo(C2-C5)alkyl, bromo, chloro, fluoro, iodo and aryl;
which process comprises the steps of:

oxidizing a compound of the formula V


;

by refluxing in 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 form a compound of
formula IV


;

b) alkylating a compound of the formula IV


with an alkylating agent of the formula
XCH2R4a where X is a leaving group and R4a is -CO2R4b, -SO3R4b, -P(O) (OR4b)2, or - P(O) (OR4b)H, wnere 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

optionally hydrolyzing a compound of formula II



to form a compound of formula I; and
e) optionally salifying a compound of formula I

3. The process of Claim 1 or 2 where the
azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of from 150-250°C and a dielectric constant of from 10-20.

4. The process of Claim 1 or 2 where the
azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of from 150-220°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-1,2-dioxyethyl)-2-ethyl-1- (phenylmethyl)-1H-indol-4-yl)oxy) acetic acid .

6. A compound of the formula IV

wherein:
R1 is selected from the group consisting of
-C7-C20 alkyl,



where
R10 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;
R2 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
R5, R6 and R7 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.

7. The compound of Claim 6 which is 2-ethyl-1- (phenylmethyl)-4-hydroxy-1H-indole.

8. A process for preparing a compound of formula

IV



wherein:
R1 is selected from the group consisting of
-C7-C20 alkyl,



where
R10 is selected from the group consisting of halo, C1-C10 alkyl, C1-C10 alkoxy, -S-(C1-C10 alkyl) and halo(C1-C10)oalkyl, and t is an integer from 0 to

5 both inclusive;
R2 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 R5, R6 and R7 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1- C6)alkoxy, halo(C1-C6)alkoxy, halo(C2-C5)alkyl, bromo, chloro, fluoro, iodo and aryl;
comprising the steps of:
a) halogenating a compound of formula X



where R8 is (C1-C6)alkyl, aryl or HET:
with SO2Cl2 to form a compound of formula IX

;

b) hydrolyzing and decarboxylating a compound of formula IX


to form a compound of formula VIII

;

c) alkylating a compound of formula VII

with a compou 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 R1NH2 in the
presence of a solvent that forms an azeotrope with water to form a compound of formula V
;

oxidizing a compound of formula V


by refluxing in 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.

9. A process for preparing a compound of formula

IV



wherein:
R1 is selected from the group consisting of
-C7-C20 alkyl,

where
R10 is selected from the group consisting of halo, C1-C10 alkyl, C1-C10 alkoxy, -S-(C1-C10 alkyl) and halo(C1-C10)oalkyl, and t is an integer from 0 to 5 both inclusive;
R2 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
R5, R6 and R7 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°C and a dielectric constant of at least 10 in the presence of a catalyst.

10. The process of Claim 8 or 9 where the
azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of from 150-250 °C and a dielectric constant of from 10-20.

11. The process of Claim 7 or 8 where the
azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of from 150-220 °C and a dielectric constant of from 12-18.

12. The process of any one of Claims 8 to 11 which prepares the compound 2-ethyl-1-(phenylmethyl)-4-hydroxy-1H-indole.

13. A process for preparing a compound of the formula I or a pharmaceutically acceptable salt or prodrug derivative thereof



wherein:
R1 is selected from the group consisting of
-C7-C20 alkyl,

where
R10 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;
R2 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;
R4 is selected from the group consisting of -CO2H,

-SO3H and -P(O) (OH)2 or salt and prodrug derivatives
thereof; and
R5, R6 and R7 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:

halogenating a compound of formula X

where R8 is (C1-C6)alkyl, aryl or HET;
with SO2Cl2 to form a compound of formula IX


;

b) 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


aminating, dehydrating and oxidizing a
compound of formula VI
10


by refluxing in a polar hydrocarbon solvent
having a boiling point of at least 150°C and

15 a dielectric constant of at least 10 in the
presence of a catalyst and an amine of the
formula R1NH2;

to form a compound of formula IV
20

alkylating a compound of the formula IV


with an alkylating agent of the formula XCH2R4a where X is a leaving group and R4a is -CO2R4b,

-SO3R4b, -P(O) (OR4b)2, or -P(O) (OR4b)H, where R4b 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


optionally hydrolyzing a compound of formula
II



to form a compound of formula I; and
optionally salifying a compound of formula I

14. A process for preparing a compound of the formula I or a pharmaceutically acceptable salt or prodrug derivative thereof

wherein:
R1 is selected from the group consisting of
-C7-C20 alkyl,



where
R10 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;
R2 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;
R4 is selected from the group consisting of -CO2H, -SO3H and -P(O) (OH)2 or salt and prodrug derivatives
thereof; and
R5, R6 and R7 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 refluxing in 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 and an amine of the
formula R1NH2 to form a compound of formula
IV


alkylating a compound of the formula IV


with an alkylating agent of the formula
XCH2R4a where X is a leaving group and R4a is -CO2R4b, -SO3R4b, -P(O) (OR4b)2, or - P(O) (OR4b)H, where 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


d) optionally hydrolyzing a compound of formula II

to form a compound of formula I; and
e) optionally salifying a compound of formula I.

15. The process of Claim 13 or 14 where the polar hydrocarbon solvent has a boiling point of from 150- 250°C and a dielectric constant of from 10-20.

16. The process of Claim 13 or 14 where the polar hydrocarbon solvent has a boiling point of from 150- 220°C and a dielectric constant of from 12-18.

17. The process of any one of Claims 13 to 16
which prepares ((3-(2-amino-1,2-dioxyethyl)-2-ethyl-1- (phenylmethyl)-1H-indol-4-yl)oxy) acetic acid .

A process for preparing a compound of formula

IV



wherein:
R1 is selected from the group consisting of
-C7-C20 alkyl,

where
R10 is selected from the group consisting of halo, C1-C10 alkyl, C1-C10 alkoxy, -S-(C1-C10 alkyl) and halo(C1-C10)oalkyl, and t is an integer from 0 to 5 both inclusive;
R2 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
R5, R6 and R7 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 R8 is (C1-C6)alkyl, aryl or HET:
with SO2Cl2 to form a compound of formula IX
;

hydrolyzing and decarboxylating a compound of formula IX


form a compound of formula VIII


;

alkylating a compound of formula VII


with a compound of formula VIII


to form a compound of formula VI
;

aminating, dehydrating and oxidizing a
compound of formula VI


by refluxing in 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 and an amine of the formula R1NH2.

19. A process for preparing a compound of formula IV



wherein:
R1 is selected from the group consisting of
-C7-C20 alkyl,

where
R10 is selected from the group consisting of halo, C1-C10 alkyl, C1-C10 alkoxy, -S-(C1-C10 alkyl) and halo(C1-C10)oalkyl, and t is an integer from 0 to 5 both inclusive;
R2 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
R5, R6 and R7 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1- C6)alkoxy, halo(C1-C6)alkoxy, halo(C2-C5)alkyl, bromo, chloro, fluoro, iodo and aryl;
comprising aminating, dehydrating and oxidizing a compound of formula V



by refluxing in 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 and an amine of the formula R1NH2.

20. The process of Claim 18 or 19 where the azeotrope is toluene and the polar hydrocarbon solvent has a boiling point of from 150-220 °C and a dielectric constant of from 12-18.

21. The process of any one of Claims 18 to 20 which prepares the compound 2-ethyl-1-(phenylmethyl)-4-hydroxy-1H-indole.