PREPARATION OF KETONE AMIDES
The present invention discloses a novel process to prepare ketone amides, which are useful intermediates for the preparation of antagonists of CCR5 receptor and therefore useful for the treatment of HIV virus infected mammals. It specifically discloses a novel process to synthesize 1-(2,4-dimethylpyrimidine-5-carbonyl)-4-piperidone, 1-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4-piperidone and related compounds. A salient feature of the invention is the use of a three-phase reaction medium with an organic phase and a buffer salt slurry.
1 . A process for preparing a ketone amide of formula 5′:
where R 1 is a substituent selected from alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl substituents, with the proviso that R 1 does not contain a primary or secondary amine,
said process comprising:
(i) reacting a carboxylic acid of formula 1:
with a chlorinating reagent for substituting a chlorine atom for a hydroxy radical in the carboxylic acid, utilizing a catalyst and a non-protic solvent to produce a solution of the acid chloride of formula 2:
(ii) separately preparing a multiphase reaction medium with a concentrated aqueous salt phase and an organic phase comprising a suitable non-protic solvent and the compound of formula 3:
and adding said solution of the acid chloride to reaction medium to yield the ketone amide of formula 5′:
2 . The process of claim 1 , wherein R 1 is:
3 . The process of claim 1 , wherein R 1 is:
4 . The process of claim 1 , wherein said chlorinating reagent in step (i) is oxalyl chloride, thionyl chloride or phosphoryl chloride.
5 . The process of claim 4 , wherein said chlorinating reagent is oxalyl chloride.
6 . The process of claim 4 , wherein said chlorinating reagent is thionyl chloride.
7 . The process of claim 1 , wherein said catalyst in step (i) is dimethyl formamide (DMF).
8 . The process of claim 1 , wherein said non-protic solvent in steps (i) and (ii) is separately selected from the group consisting of, propionitrile, benzene, toluene, xylene, chlorobenzene, dichloro-benzene, C 5 -C 12 ether, 1,2-dimethoxyethane, 1.2-diethoxyethane, diglyme, 1,4-dioxane, tetrahydrofuran, C 1 -C 5 ester and said chlorinating reagent.
9 . (canceled)
10 . The process of claim 1 , wherein the temperature of said reaction in step (i) ranges from −20 to 60° C.
11 . The process of claim 10 , wherein the temperature of said reaction ranges from −10 to 20° C.
12 . The process of claim 11 , wherein the temperature of said reaction ranges from −5 to 5° C.
13 . The process of claim 1 , wherein the multiphase reaction medium is a three phase reaction system comprising an aqueous salt slurry and a non-protic solvent.
14 . The process of claim 1 , wherein the concentrated aqueous salt phase comprises a buffer system with K 3 PO 4 and KH 2 PO 4 .
15 - 16 . (canceled)
17 . The process of claim 14 , wherein said buffer system in step (ii) maintains the pH in the range of 7.5-9.5.
18 . The process of claim 14 , wherein said buffer system maintains the pH in the range of 8.0-9.0.
19 . The process of claim 1 , wherein the temperature of said reaction in step (ii) ranges from −15 to 60° C.
20 .- 21 . (canceled)
22 . A process for the preparation of the compound of formula 5 from a solution of an acid chloride of formula 2′, said process comprising adding a solution of the acid chloride of formula 2′ to multiphase reaction medium containing a compound of formula 3, which reaction medium contains a concentrated aqueous salt phase and an organic phase comprising a suitable non-protic solvent, to produce the compound of formula 5, in accordance with the following equation:
and wherein said non-protic solvent is propionitrile, benzene, toluene, xylene, chlorobenzene dichlorobenzene C 5 -C 12 ether, 1,2-dimethoxyethane, 1.2-diethoxyethane, diglyme, 1,4-dioxane, tetrahydrofuran, or C 1 -C 5 ester and said chlorinating reagent.
23 .- 24 . (canceled)
25 . The process of claim 22 , wherein the multiphase reaction medium is a three phase reaction system comprising an aqueous salt slurry and a non-protic solvent.
26 . The process of claim 22 , wherein said compound of formula 5 is further converted to the compound of formula:
27 . The process of claim 22 , wherein said compound of formula 5 is further converted to the compound of formula:
28 . The process according to claim 1 , wherein after step (i) the reaction is aged at 0° C. for 2 hours.