Granted Patent B2

US 8,084,604 · App. 11/922,280 · Granted Dec 27, 2011

Abstract

Claims (96)

1. A process for the preparation of a compound of formula (I)

in which

Ar represents aryl, in which aryl can be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of alkyl, alkoxy, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl, amino, alkylamino, aminocarbonyl and nitro,

in which alkyl can be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, amino, alkylamino, hydroxyl and aryl,

or two of the substituents on the aryl, together with the carbon atoms to which they are bonded, form a 1,3-dioxolane, a cyclopentane ring or a cyclohexane ring and an optionally present third substituent independently thereof is selected from the group mentioned,

R 1 represents hydrogen, amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro or trifluoromethyl,

R 2 represents hydrogen, alkyl, alkoxy, alkylthio, cyano, halogen, nitro or trifluoromethyl,

R 3 represents amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro, trifluoromethyl, alkylsulphonyl or alkylaminosulphonyl

or

one of the radicals R 1 , R 2 and R 3 represents hydrogen, alkyl, alkoxy, cyano, halogen, nitro or trifluoromethyl and the other two, together with the carbon atoms to which they are bonded, form a 1,3-dioxolane, a cyclopentane ring or a cyclohexane ring,

R 4 represents hydrogen or alkyl,

R 5 represents hydrogen or alkyl

or

the radicals R 4 and R 5 are bonded to exactly opposite carbon atoms of the piperazine ring and taken together form a methylene bridge optionally substituted by 1 or 2 methyl groups,

R 6 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,

R 7 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro

and

R 8 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,

comprising the steps of hydrolyzing a compound of formula (II)

in which

Ar, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 have the meaning indicated above, and

R 9 represents C 1 -C 4 -alkyl,

using a base or an acid, and

reacting a compound of formula (III)

in which

R 1 , R 2 , R 3 , R 6 , R 7 and R 8 have the meaning indicated above, and

R 9 represents C 1 -C 4 -alkyl,

in the presence of a base

with a compound of formula (IV)

in which

Ar, R 4 and R 5 have the meaning indicated above, to form the compound of formula (II).

2. The process according to claim 1 , further comprising reacting compound of formula (V)

in which

R 1 , R 2 , R 3 , R 6 , R 7 and R 8 have the meaning indicated in claim 1 , and

R 9 represents C 1 -C 4 -alkyl,

with phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride, in the presence of a base to form the compound of formula (III).

3. The process according to claim 2 , further comprising reacting compound of formula (VI)

in which

R 1 , R 1 , R 3 , R 6 , R 7 and R 8 have the meaning indicated in claim 2 ,

with a compound of the formula

in which

R 9 represents C 1 -C 4 -alkyl,

in the presence of a palladium catalyst and of a base to form the compound of formula (V).

4. The process according to claim 2 , further comprising reacting compound of formula (VII)

in which

R 1 , R 1 , R 3 , R 6 , R 7 and R 8 have the meaning indicated in claim 2 ,

in a first stage with a compound of formula (IX)

in which

R 9 represents C 1 -C 4 -alkyl,

in acetic acid in the presence of a palladium catalyst, of an oxidizing agent and of an acid to give a compound of formula (VIII)

in which

R 1 , R 2 , R 3 , R 6 , R 7 and R 8 have the meaning indicated in claim 2 , and

R 9 represents C 1 -C 4 -alkyl,

and in a second stage with a base to give the compound of formula (V).

5. The process according to claim 1 , wherein the compound of formula (I) is equal to

{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid

the compound of formula (II) is equal to

methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate

the compound of formula (III) is equal to

methyl 2-chloro-8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl)acetate

and the compound of formula (IV) is equal to 1-(3-methoxyphenyl)piperazine

6. The process according to claim 2 , wherein the compound of formula (I) is equal to

{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid

the compound of formula (II) is equal to

methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate

the compound of formula (III) is equal to

methyl 2-chloro-8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl)acetate

the compound of formula (IV) is equal to 1-(3-methoxyphenyl)piperazine

and the compound of formula (V) is equal to

methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydro-quinazolin-4-yl}acetate

7. The process according to claim 3 , wherein the compound of formula (I) is equal to

{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid

the compound of formula (II) is equal to

methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate

the compound of formula (III) is equal to

methyl 2-chloro-8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl)acetate

the compound of formula (IV) is equal to 1-(3-methoxyphenyl)piperazine

the compound of formula (V) is equal to

methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate

the compound of formula (VI) is equal to

N-(2-bromo-6-fluorophenyl)-N′-[2-methoxy-5-(trifluoromethyl)phenyl]urea

and the compound of formula (IX) is equal to methyl acrylate

8. The process according to claim 4 , wherein the compound of formula (I) is equal to

{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid

the compound of formula (II) is equal to

methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate

the compound of formula (III) is equal to

methyl 2-chloro-8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl)acetate

the compound of formula (IV) is equal to 1-(3-methoxyphenyl)piperazine

the compound of formula (V) is equal to

methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydro-quinazolin-4-yl}acetate

the compound of formula (VII) is equal to

N-(2-fluorophenyl)-N′-{2-methoxy-5-(trifluoromethyl)phenyl]urea

the compound of formula (VIII) is equal to

methyl(2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]amino}carbonyl)-amino]phenyl}acrylate

and the compound of formula (IX) is equal to methyl acrylate

Assignments (9)