Process for preparing alkanesulfonyl pyridines

Details Process for preparing alkanesulfonyl pyridines Process for preparing alkanesulfonyl pyridines

2002-09-27

2003-07-08

Aulakh, Charanjit S. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S294000, C546S297000

Reexamination Certificate

active

06590103

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a process for the preparation of alkanesulfonyl pyridine derivatives having the formula 1
which are useful as intermediates in the synthesis of pyrazole compounds having the formula 5:
wherein R
1
is unsubstituted (C
1
-C
6
)alkyl; R
6
is phenyl optionally substituted by 1-3 substituents independently selected from the group consisting of halo, hydroxy, cyano, mercapto, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl. (C
1
-C
6
)alkoxy, —OCF
3
, (C
1
-C
6
)alkyl-S—, (C
1
-C
6
)alkyl-S(═O)—, (C
1
-C
6
)alkyl-SO
2
—, amino, (C
1
-C
6
)alkylamino, di[(C
1
-C
6
)alkyl] amino, H
2
N-(C═O)—, (C
1
-C
6
)alkyl-NH-(C═O)—and formyl; R
b
is hydrogen, halo or (C
1
-C
6
)alkyl; and R
c
is (C
1
-C
6
)alkyl optionally substituted with from one to three halo atoms.
The compounds of formula 5 (“the active compounds”) are useful in the treatment or alleviation of inflammation and other Inflammation associated disorders, such as arthritis, neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats or livestock. It Is believed that the active compounds inhibit the biosynthesis of prostaglandins by intervention of the action of the enzyme cyclooxygenase on arachidonic acid.
Compounds of formula 5 and other processes for preparing alkanesulfonyl pyridine derivatives are disclosed in co-pending U.S. application Ser. No. 09/724,446, filed Nov. 28, 2000, which is herein incorporated by reference in its entirety. The PCT International Patent Application corresponding to Ser. No. 09/724,446 was published on Jun. 7, 2001 as WO 01/40216. In application 09/724,446 (and WO 01/40216), the sulfonyl pyridine is prepared according to a two-step process involving a first step of forming a sulfide by either nucleophilic substitution using e.g., alkylsulfide or methylation of a mercapto pyridine followed by a second step which Is oxidation of the sulfide to a sulfonyl group.
In the present invention, the alkyl sulfonyl group R
1
-SO
2
— is added in a single step to the metallated pyridine (i.e., the Grignard reaction product), thereby avoiding the necessity of an oxidation step from a sulfide. In particular, applicants found that the use in step (b) of alkyl sulfonylating reagents such as alkanesulfonyl halides or alkanesulfonyl anhydrides, which are poor electrophiles compared to, e.g., disulfides (see, Wang et al. (2000) Tet. Lett 41:4335-4338), unexpectedly provided the alkane sulfonyl pyridine selectively and in high yield. It is also worth noting that the alkyl sulfonylating reagents such as those disclosed herein are inexpensive and thus particularly suited for commercial production of the compound of formula 1 and upon further modification, production of compounds of formula 5. Finally, the present invention allows both step (a), metallation, and step (b), alkyl sulfonylation, to be carried out at non-cryogenic temperatures, i.e., above −20° C. Accordingly, the present invention provides a direct and regioselective route to the 5-(alkanesulfonyl)-2-bromo-pyridine.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing a compound of formula 1:
which comprises the steps of:
(a) reacting a compound of formula 2
 with a Grignard reagent; and
(b) reacting the product of step (a) with an (C
1
-C
6
)alkyl sulfonylating reagent;
wherein R
1
is unsubstituted (C
1
-C
6
)alkyl.
In an embodiment of the invention, R
1
is unsubstituted (C
1
-C
3
)alkyl. In a preferred embodiment of the invention, R
1
is methyl. In a preferred embodiment of the invention R
1
is methyl and the alkyl sulfonylating reagent is a methyl sulfonylating reagent.
In another embodiment of the invention, the Grignard reagent is a linear or branched (C
1
-C
10
)alkyl magnesium halide, i.e., a compound of the formula RMgX, wherein R is linear or branched (C
1
-C
10
)alkyl and X Is halide. In a preferred embodiment of the invention, the Grignard reagent is a (C
1
-C
4
)alkyl magnesium halide, e.g., methylmagnesium halide, ethylmagnesium halide, propylmagesium halide, isopropylmagnesium halide, butylmagnesium halide or tert-butylmagnesium halide. In a particularly preferred embodiment of the Invention, the Grignard reagent is isopropylmagnesium chloride.
In another embodiment of the invention, step (a) is carried out in a solvent selected from the group consisting of diethyl ether, tetrahydrofuran (“THF”), glyme (1,2-dimethoxyethane) or diglyme (bis(2-methoxyethyl) ether). In a preferred embodiment of the invention, the solvent in step (a) is THF.
In another embodiment of the invention, step (a) is carried out at a temperature of from about −20° C. to about room temperature (about 20° C.-25° C. ). In another embodiment of the invention, step (a) is carried out at a temperature of from about −20° C. to about 10° C. In another embodiment of the invention, step (a) is carried out for a period of from about 30 minutes to about 4 hours, preferably for about 45 minutes.
In another embodiment of the invention, the alkyl sulfonylating agent is a (C
1
-C
6
)alkanesulfonyl halide or a (C
1
-C
6
)alkanesulfonic anhydride. In a preferred embodiment of the invention, the alkyl sulfonylating agent is an alkanesulfonyl halide of the formula R
1
SO
2
X, wherein X is chloro or fluoro. In a preferred embodiment of the invention, the alkanesulfonyl halide is unsubstituted (C
1
-C
3
)alkanesulfonyl halide. In a more preferred embodiment of the invention, the alkanesulfonyl halide is methanesulfonyl fluoride or methanesulfonyl chloride. In a particularly preferred embodiment of the invention, the alkanesulfonyl halide is methanesulfonyl chloride. In another preferred embodiment of the invention, the alkyl sulfonylating agent is an alkanesulfonic anhydride of the formula (R
1
SO
2
)
2
O. In a more preferred embodiment of the invention, the alkanesulfonic anhydride is unsubstituted (C
1
-C
3
)alkanesulfonic anhydride. In a particularly preferred embodiment of the invention, the alkanesulfonic anhydride is methanesulfonic anhydride.
In another embodiment of the invention, step (b) is carried out in THF.
In another embodiment of the invention, the process further comprises preparing a compound of formula 3
by hydrazinolysis of the compound of formula 1 in the presence of an amine, in a suitable solvent. In an embodiment of the invention, the hydrazinolysis is carried out using a hydrazine such as hydrazine hydrate. In an embodiment of the invention, the amine is selected from the group consisting of triethylamine, diisopropylethylamine, 2,6-lutidine and N,N,N′,N′-tetramethylethylenediamine. In a preferred embodiment of the invention, the amine is triethylamine. In another embodiment of the invention, the suitable solvent for hydrazinolysis is selected from the group consisting of water, dichloromethane, dichloroethane and toluene. In a preferred embodiment of the invention, the solvent is water.
The compounds prepared by the processes of the present invention that are basic in nature, e.g., compounds of formula 3, are capable of forming a wide variety of different salts with various Inorganic and organic acids. The acid addition salts of the base compounds prepared by the processes of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
In another embodiment of the invention, the process further comprises treating the compound of formula 3 with an acid in a suitable solvent. In a preferred embodiment of the invention, the acid is hydrochloric acid. In an embodiment of the invention, the acid addition salt of the compound of formula 3 prepared according to the process of the invention Is the hydrochloride salt.
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