A process for preparing (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine
Publication Date: 2010-May-27
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A process for preparing (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine by reacting (3R)-3-(N-amino protected)-4-(2,4,5-trifluorophenyl) butanoic acid or a salt thereof with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine or a salt thereof in the presence of a coupling agent which is preferably T3P.
(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine, hereinafter referred to as compound (I), has the following chemical structure:
Compound (I) is currently marketed in its phosphate monohydrate salt form in the
United Statesand it is indicated to improve glycemic control in patients with type 2 diabetes mellitus. Compound (I) phosphate monohydrate is a glucagon like peptide 1 metabolism modulator, hypoglycemic agent, and dipeptidyl peptidase IV inhibitor which is described in PCT publication No. WO 2005/003135.
The following procedure provides a process for preparing compound (I) according to the synthetic scheme depicted in Scheme 1,
R1 is a suitable amino protecting group which can be easily removed in step (b). Preferably, the amino protecting group is a C1-C4 alkoxycarbonyl, a C1-C4 haloalkoxycarbonyl, a C6-C12 benzyloxycarbonyl, tert-butoxycarbonyl (BOC), trityl, 9-fluorenylmethyloxycarbonyl (F-MOC), or a carbamate having the formula of –CO2R3 (CBZ, R3=Bn), -SO2R4, or –PO(R4)2, wherein R4 is an alkyl, an aryl, or an alkylaryl. More preferably, the amino protecting group is tert-butoxycarbonyl (BOC).
R2 is H, an alkali metal or an ammonium derivative, i.e. triethylammonium. Preferably, R2 is hydrogen or an alkali metal such as sodium.
The process comprises the following steps:
(a) reacting compound (II) with compound (III) or a salt thereof in the presence of an organic base, a coupling agent, and an organic solvent to obtain compound (IV).
Preferably, the amino protecting group of compound (II) is tert-butoxycarbonyl (BOC), and the organic solvent is ethyl acetate.
Preferably, the organic base is triethylamine and the coupling agent is propyl phosphonic anhydride (T3P), or also preferably the organic base is N-methylmorfoline (NMM) and the coupling agent is a carbodiimide such as 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide (EDC) or N,N'-dicyclohexylcarbodiimide (DCC).
Optionally, compound (II) can be obtained from a suitable derivative of compound (II) which can be in situ converted into compound (II). For example, an esterified compound (II) can be saponified in situ to provide compound (II) by adding a stoichiometric amount of a suitable inorganic base.
(b) deprotecting compound (IV) w...