ABSTRACT
BMS-317180 (1) is a potent, orally active agonist of the human growth hormone secretagogue (GHS) receptor. This manuscript details the process research and development efforts that enabled the synthesis of the phosphate salt of 1 on a multi-kilogram scale. Key considerations in the development of this process focused on safe execution and the requirement for telescoped synthetic transformations (i.e., without isolation of intermediate products) to contend with a lack of suitably crystalline products.
Subject(s)
Drug Discovery/methods , Receptors, Ghrelin/agonists , Tetrazoles , Carbamates , Humans , Research DesignABSTRACT
A tetrazole-based peptidomimetic 2 (BMS-317180) was discovered as a human growth hormone secretagogue (GHS). Compound 2 is a potent, novel, orally effective GHS that shows an excellent safety profile in preclinical studies. The compound was advanced into clinical development.
Subject(s)
Carbamates/chemical synthesis , Growth Hormone/metabolism , Tetrazoles/chemical synthesis , Administration, Oral , Animals , Biological Availability , Carbamates/pharmacokinetics , Carbamates/pharmacology , Dogs , Esters , Growth Hormone/blood , Human Growth Hormone/metabolism , Humans , Macaca fascicularis , Rats , Solubility , Structure-Activity Relationship , Tetrazoles/pharmacokinetics , Tetrazoles/pharmacology , WaterABSTRACT
The reaction of a variety of methyl esters with dimethylsulfoxonium methylide at 0-25 degrees C affords the chain-extended beta-keto dimethylsulfoxonium ylides. Subsequent treatment with hydrogen chloride in THF proceeds with loss of DMSO to afford the corresponding alpha-chloroketones. This sequence has been utilized to convert the methyl esters of CBZ-protected alanine and valine to the anti N-protected alpha-amino epoxides, which are important pharmaceutical intermediates. When the same protocol is applied to BOC-protected phenylalanine methyl ester, epimerization occurs so that the use of a more reactive aryl ester is required. This chemistry provides a practical route to alpha-chloroketones that avoids the use of toxic and explosive diazomethane.
Subject(s)
Amino Acid Chloromethyl Ketones/chemical synthesis , Diazomethane/chemistry , Amino Acid Chloromethyl Ketones/chemistry , Esters/chemical synthesis , Esters/chemistry , Magnetic Resonance Spectroscopy , Molecular StructureABSTRACT
[reaction: see text] An efficient asymmetric synthesis of the vasopeptidase inhibitor BMS-189921 was accomplished. Two short enantioselective syntheses of the common key intermediate (S)-alpha-aminoazepinone 6b were developed. Olefin 3 was converted to 6b via asymmetric hydrogenation. Alternatively, enyne 12 was converted to racemic alpha-aminoazepinone 15b, which was transformed to 6b by a practical dynamic resolution.
