Method of preparing COX-2 inhibitors

Details Method of preparing COX-2 inhibitors Method of preparing COX-2 inhibitors

2002-04-08

2003-04-01

Owens, Amelia (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S313000

Reexamination Certificate

active

06541646

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention concerns a method of preparing (4-alkylsulphonyl)-phenyl-2-(5H)-furanones, which are compounds inhibiting cyclooxygenase-2 (COX-2); as well as novel intermediate compounds useful for preparing these compounds.
(4-alkylsulphonyl)-phenyl-2-(5H)-furanone compounds useful as COX-2 inhibitors and their pharmacological applications as anti-inflammatories are known and described in the following documents: WO 97/44027, WO 97/28121, WO 98/41516, WO 96/19469, WO 97/16435 and WO 97/14691.
The synthesis of these compound involves a method in several steps involving an intermediary of the 4-alkylsulphonyl-&agr;-bromoisobutyrophenone type.
Thus WO 97/45420 describes a method of preparing (methyl-4-sulphonyl)-phenyl-2-(5H)-furanones from thioanisole involving five steps.
The second step of this method consists of brominating 4-thiomethyl-isobutyrophenone in order to obtain 4-thiomethyl-&agr;-bromoisobutyrophenone.
In the following step the 4-thiomethyl-&agr;-bromoisobutyrophenone is oxidised to 4-methylsulphonyl-&agr;-bromiosobutyrophene, which is a highly allergenic compound, and this compound is then esterified with a carboxylic acid in order to form a 2-methyl-1-(4′-methylsulphonylphenyl)-1-oxo-prop-2-yl ester.
This reaction is also accompanied by a certain number of by-products, including an elimination product, 4-(4′-methylsulphonylphenyl)-2-methyl-propenone.
The aim of the invention is to propose an alternative to the method described in WO 97/45420 and in particular a general method of preparing substituted (4-alkylsulphonylphenyl)2-(5H)-furanone compounds which avoids the problem posed by the &agr;-bromoisobutyrophenone-type intermediary, is easy to implement, avoids the formation of the elimination by-product and provides an acceptable yield of final product.
SUMMARY AND DESCRIPTION OF THE INVENTION
The work carried out by the inventors has now made it possible to propose a method meeting these expectations, and which in particular avoids passing through a toxic bromosulphone derivative and the formation of the aforementioned by-product.
The object of the invention is thus a method of preparing compounds of general formula I:
in which
R
1
is chosen amongst the groups
(a) OR
5
where R
5
represents a group chosen from amongst
(1) a C
1
-C
6
branched linear or ring alkyl group;
(2) a mono-, di- or tri-substituted phenyl or naphthyl group in which the substituents are chosen from amongst:
hydrogen;
halogen;
(C
1
-C
3
) alkoxy;
CN;
(C
1
-C
3
) fluoroalkyl;
(C
1
-C
3
) alkyl;
COOH;
and
(b) mono-, di or tri-substituted phenyl in which the substituents are chosen from amongst:
hydrogen;
halogen;
(C
1
-C
3
) alkoxy;
CN;
(C
1
-C
3
) fluoroalkyl;
(C
1
-C
3
) alkyl;
COOH;
R
2
represents a (C
1
-C
6
) alkyl group;
R
3
and R
4
represents independently of one another a hydrogen atom or a CHR
6
R
7
group
in which R
6
and R
7
are independently of each other chosen from amongst:
hydrogen;
(C
1
-C
10
) alkyl;
(C
1
-C
10
) alkoxy;
OH;
CN;
CH
2
CN;
OCOR
8
;
(C
1
-C
6
) fluoroalkyl;
halogen;
CON (R
8
)
2
;
mono-, di or tri-substituted phenyl;
mono-, di or tri-substituted heteroaryl;
the substituents being chosen from amongst:
hydrogen;
halogen;
(C
1
-C
6
) alkyl;
(C
1
-C
10
) alkoxy;
CN;
CF
3
;
N
3
;
C (R
9
) (R
10
)—OH;
C (R
9
) (R
10
) —O—(C
1
-C
4
) alkyl;
(C
1
-C
6
) fluoroalkyl;
R
8
is chosen from amongst;
hydrogen;
(C
1
-C
6
) alkyl;
mono-, di- or tri-substituted phenyl, the substituents being chosen from amongst hydrogen, halogen, (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy, (C
1
-C
6
) alkylthio, CN or CF
3
; and
mono-, di or tri-substituted benzyl, the substituents being chosen from amongst hydrogen, halogen, (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy, (C
1
-C
6
) alkylthio, CN or CF
3
;
or two R
8
groups from together with the nitrogen atom to which they are attached a ring with 5 to 7 atoms, and possibly comprising a heteroatom chosen from amongst O, S or NR
9
;
R
9
and R
10
are independently of one another chosen from amongst:
hydrogen; and
(C
1
-C
10
) alkyl; or
form, together with the atom to which they are attached, a ring with 3 to 7 carbon atoms and where applicable a nitrogen atom;
wherein it comprises the following steps:
a) reaction of a compound of general formula II:
in which R
2
, R
3
and R
4
are as defined above and R
12
represents a C
1
-C
6
alkyl group,
with an acid of general formula III:
in which R
1
is as defined previously, in an anhydrous medium, in order to form a compound of formula IV:
R
1
, R
2
, R
3
and R
4
being as defined above;
b) reaction of the compound of formula IV with a strong base in an aprotic solvent in order to obtain an intermediate ring compound of formula V:
which, after elimination of a water molecule, forms a compound of general formula I; and
c) isolation of the compound of general formula I thus obtained.
The reaction of step a) takes place in an anhydrous solvent, preferably an ether, for example diethylether, or methyltertbutylether. The reaction temperature is advantageously between −20 and 40° C. At the end of step a), a compound of general formula IV is obtained as well as secondary products in minor quantities. However, the aformentioned elimination product does not form.
For the reaction of step b), the strong base is advantageously chosen from amongst 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).
The elimination of a water molecule is achieved in a manner known per se, advantageously by thermal dehydration in the presence of a dehydration agent.
The dehydration agent can be chosen in particular from amongst trifuloroacetic acid esters, for example isopropyl trifluoroacetate, trichloracetic acid esters and alkyl or arylsulphonic acid esters.
The reaction preferably takes place in an aprotic solvent such as acetonitrile, N,N-dimethylformamide, N-methylsulphoxide, proprionitrile or nitromethane.
The dehydration is achieved by heating to reflux.
The molar ratio of the ester of formula IV to the strong base is generally between 1:1 and 1:2, a ratio of 1:1.5 being preferred.
The molar ratio of the ring ester of formula V to the dehydration agent is generally 1:1 to 1:2, a ratio of 1:1.2 being preferred.
The reaction is carried out at a temperature preferably between 0° C. and the reflux temperature of the solvent.
Particularly advantageous reaction conditions are achieved by the use of a mixture of 1.2 equivalents of isopropyl trifluoroacetate and 1.5 equivalents of DBU in acetonitrile at reflux. Under these conditions, the reaction is terminated after 24 hours and the product crystallises by the addition of water after partial elimination of the acetonitrile. For more information, reference should be made to the description of the patent application WO 97/45420.
Step c) is carried out in a manner known per se, in particular by elimination of the solvent, precipitation of the product, recrystallisation, etc.
The epoxy compound of general formula II can be obtained by the reaction of a compound of general formula VI:
in which R
2
, R
3
, R
4
and R
12
are as defined above, with an oxidising agent.
Oxidising agents can in particular include organic peracids, such as meta-chloroperbenzoic acid and peracetic acid or dioxiranes such as dimethyldioxirane, generated in situ or not. The reaction temperature is advantageously between −40° C. and 30° C.
The oxidising agent is used in excess with respect to the compound of general formula II (3 to 40 equivalents), so as to oxidise on the one hand the olefin function into epoxide and on the other hand the sulphide function into sulphone.
The compound of general formula VI can be obtained by reaction of a compound of general formula VII:
in which R
2
, R
3
and R
4
are as defined above, with an alcohol of general formula VIII:
HO R
12
  (VIII)
R
12
being as defined above, in the presence of a catalytic quantity of acid and a dehydrating agent.
Advantageously, the acid is chosen from amongst the sulphonic ac

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