Method for preparing pyrimidone derivatives with antifungal...

Details Method for preparing pyrimidone derivatives with antifungal... Method for preparing pyrimidone derivatives with antifungal...

2002-09-09

2003-11-25

Rao, Deepak (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S287000

Reexamination Certificate

active

06653475

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a new process for the preparation of pyrimidone derivatives with antifungal activity.
DESCRIPTION OF THE INVENTION
Patent application WO 97/05130 describes a series of pyrimidone derivatives with potent antifungal activity. Amongst the compounds described in this patent, those optically active compounds with a stereochemistry (R,R) are preferred. A particularly preferred compound is (1R,2R)-7-chloro-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl) propyl]quinazolin-4(3H)-one, which is known in the literature as UR-9825.
The process described to date for the preparation of these optically active pyrimidone derivatives suffers from certain disadvantages when considered for industrial scale application. It is therefore necessary to find an alternative process to prepare these optically active pyrimidone derivatives, and specially UR-9825.
DESCRIPITON OF THE INVENTION
The present invention thus relates to a new process for the preparation of pyrimidone derivatives of general formula I,
wherein:
Ar represents phenyl or phenyl substituted with one or more halogen and/or trifluoromethyl groups;
R
1
is C
1
-C
4
alkyl;
R
2
represents hydrogen, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, or cyclopropyl;
A represents a benzene ring or a 5- or 6-membered heterocyclic ring wherein one or more of the ring atoms are selected from the group consisting of N, O and S, which rings can be optionally fused to a benzene ring or to a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, and wherein A can be unsubstituted or have 1, 2, 3 or 4 substituents W in any of the rings;
a group W represents C
1
-C
4
alkyl, C
3
-C
6
cycloalkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy, C
1
-C
4
haloalkoxy, halogen, nitro, cyano, hydroxy, benzyloxy, hydroxymethyl, —NR
3
R
4
, —CONR
3
R
4
, —CH
2
—OCO—R
3
, —CO—R
3
, —COO—R
3
, —SO
z
R
5
, —C(═NR
3
)NHR
6
, —C(═NR
6
)OR
3
, and additionally one of the groups W can also represent 1-pyrrolyl, 1-imidazolyl, 1H-1,2,4-triazol-1-yl, 5-tetrazolyl (optionally substituted with C
1
-C
4
alkyl), 1-pyrrolidinyl, 4-morpholinyl, 4-morpholinyl-N-oxide, a group —X—R
7
, or a group of formula (i)-(iv):
R
3
represents hydrogen, C
1
-C
4
alkyl, C
3
-C
6
cycloalkyl or arylC
1
-C
4
alkyl, wherein aryl represents phenyl or phenyl substituted with one or more C
1
-C
4
alkyl, halogen, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy or C
1
-C
4
haloalkoxy groups;
R
4
represents hydrogen, C
1
-C
4
alkyl, C
3
-C
6
cycloalkyl, —COR
3
or —COCF
3
;
R
5
represents C
1
-C
4
alkyl;
z represents 0, 1 or 2;
R
6
represents hydrogen, —CONH
2
, —COCH
3
, —CN, —SO
2
NHR
3
, —SO
2
R
3
, —OR
3
, —OCOR
3
or —(C
1-4
alkyl)—NH
2
;
X represents a single bond, —O—, —SO
z
—, —NR
3
—, or —C(═O)—;
R
7
represents a phenyl group optionally substituted with one or more groups R
8
;
R
8
represents C
1
-C
4
alkyl, C
3
-C
6
cycloalkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy, C
1
-C
4
haloalkoxy, halogen, nitro, cyano, —NR
3
R
4
, —CONR
3
R
4
, —CH
2
—OCO—R
3
, —CO—R
3
, —COO—R
3
, —SO
z
R
5
, —C(═NR
3
)NHR
6
, —C(═NR
6
)OR
3
, a group of formula (iv) or R
8
represents a phenyl group (optionally substituted with a C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy, C
1
-C
4
haloalkoxy, halogen, nitro or cyano group);
R
9
represents hydrogen or methyl;
R
10
represents hydrogen, isopropyl, cyclopentyl, cyclopropyl, 2-butyl, 3-pentyl, 3-hydroxy-2-butyl, or 2-hydroxy-3-pentyl;
m represents 0 or 1;
R
11
represents halogen, C
1
-C
4
haloalkyl, C
1
-C
4
haloalkoxy, nitro, amino, cyano, or a group of formula (i);
Y represents —CH
2
— or —C(═O)—; and
Z represents NH or O;
which comprises reacting a compound of formula II
wherein R
1
and Ar have the meaning defined above in relation to formula I, with a compound of formula III
wherein A and R
2
have the meaning defined above in relation to formula I, in the presence of a base.
In the above definitions, the term C
1
-C
4
alkyl, as a group or part of a group, means a straight or branched alkyl group having from 1 to 4 carbon atoms. Therefore, it includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
A C
1
-C
4
haloalkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C
1
-C
4
alkyl group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo), which can be the same or different. Examples thereof include trifluoromethyl, trichloromethyl, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, pentachloroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-chloropropyl, 3,3-dichloropropyl, 3,3,3-trichloropropyl, 2,2,3,3,3-pentachloropropyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3-tetrafluoropropyl, 2,2, 3,3,3-pentafluoropropyl, heptafluoropropyl, 4-chlorobutyl, 4-fluorobutyl, 4-iodobutyl and 4-bromobutyl.
A C
3
-C
6
cycloalkyl group represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
A C
1
-C
4
alkoxy group means a group derived from the union of a C
1
-C
4
alkyl group to an oxygen atom of an ether functional group. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
A C
1
-C
4
haloalkoxy group means a group resulting from the substitution of one or more hydrogen atoms of a C
1
-C
4
alkoxy group with one or more halogen atoms, which can be the same or different. Examples include trifluoromethoxy, fluoromethoxy, 2-chloroethoxy, 2-fluoroethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3-chloropropoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 4-fluorobutoxy, and 4-chlorobutoxy.
Halogen represents a fluoro, chloro, bromo or iodo atom.
An arylC
1
-C
4
alkyl group means a group resulting from the substitution of a hydrogen atom of a C
1
-C
4
alkyl group with an aryl group, wherein aryl is as defined above.
In a preferred embodiment, in the preparation process which is the object of the invention R
2
represents hydrogen, methyl, trifluoromethyl or cyclopropyl; Ar represents 2-fluorophenyl, 4-fluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or 4-chlorophenyl; and A represents a benzene ring, which can be optionally fused to a benzene ring or to a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, or A represents a 5- or 6-membered heterocyclic ring wherein one or more of said ring atoms are selected from the group consisting of N, O and S and which can be optionally fused to a benzene ring, wherein A can be unsubstituted or have 1, 2, 3 or 4 substituents W in any of the rings.
In a more preferred embodiment, R
1
represents methyl; R
2
represents hydrogen; Ar represents 2-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or 4-chlorophenyl; and A represents a benzene ring or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, wherein A can be unsubstituted or have 1, 2, 3 or 4 groups W.
In a still more preferred embodiment, R
1
represents methyl; R
2
represents hydrogen; Ar represents 2-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or 4-chlorophenyl; A represents a benzene ring optionally substituted with 1, 2, 3 or 4 groups W; and each W independently represents halogen, C
1
-C
4
haloalkyl, C
1
-C
4
haloalkoxy or cyano.
In a particularly preferred embodiment, the process of the invention is used to prepare a compound of formula I which is (1R,2R)-7-chloro-3-[2-(2, 4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4 (3H)-one (UR-9825) and it comprises reacting (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane with 7-chloro-3H-quinazolin-4

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