An Efficient and Cost-Effective Synthesis of 3-Ethoxy-4-ethoxycarbonyl-phenylacetic Acid:  A Key Acid Synthon of Repaglinide

Abstract

This report describes an efficient and commercially viable synthesis of 3-ethoxy-4-ethoxy-carbonyl-phenylacetic acid (1), a key intermediate for the preparation of repaglinide, an oral hypoglycemic agent, from 2-hydroxy-4-methylbenzoic acid in two steps. Thus, 2-hydroxy-4-methylbenzoic acid was first alkylated with ethyl bromide in a polar aprotic solvent and in the presence of an inorganic base to afford ethyl 2-ethoxy-4-methylbenzoate; deprotonation with lithium diisopropylamide (LDA) and quenching the resulting carbanion with carbon dioxide provided the desired compound with improved yield and excellent purity. This procedure is significantly better than a previously published synthesis which involves five steps and requires use of expensive and hazardous reagents.

Arylethenylbenzofuroxan Derivatives as Drugs for Chagas Disease: Multigram Batch Synthesis using a Wittig−Boden Process

“…The medchem route was evaluated critically and deemed inapplicable for scale-up. First, the benzylic bromination step involves the use of several toxic and potentially hazardous reagents. – Second, reactions with ethanol and sodium hypochlorite, NaClO, have been recently discussed as dangerous for multigram-batch procedures as result of the production of both volatile and explosive ethylhypochlorite . Third, this synthetic route has a low overall yield for the formation of the desired compounds 1 and 2 , and it is inapplicable for the preparation of derivatives 3–6 .…”

Copper-catalyzed N-arylation of amines with aryliodonium ylides in water

“…Arylamines are among the most privileged structural motifs appearing in various natural products, and bioactive molecules [ 1 – 2 ] as well as offer widespread applications in pharmaceuticals, agrochemicals, dyes, and materials science [ 3 – 4 ]. Particularly the pharmaceutical agents containing the arylamine moiety as an integral part of the structural framework includes molecule such as retigabine ( I ) [ 5 ], an anticonvulsant used as an adjunctive agent in the treatment of partial seizures, folic acid ( II ) [ 6 ], a type of vitamin B12 displaying an important role in metabolism, cell growth and during pregnancy, ofloxacin ( III ) [ 7 ], an antibacterial agent, mefenamic acid ( IV ) [ 8 ], an anti-inflammatory agent used to treat mild pain, linezolid ( V ) [ 9 ], an antibacterial agent, repaglinide ( VI ) [ 10 ], used to treat diabetes mellitus type 2, and tolfenamic acid ( VII ) [ 11 ], an anti-inflammatory agent ( Figure 1 ).…”

A New Route for the Synthesis of the Repaglinide Key Intermediate 3-Ethoxy-4-Ethoxycarbonylphenylacetic Acid

“…4 Route b and c: the carbanion, formed from benzylic methyl with lithium diisopropylamide (LDA) was reacted with ethyl chloroformate (b) or 1,3-dimethyl-3,4,5,6tetrahydro-2(1H)-pyrimidinone (DMPU) (c) under -75 °C to give 1. [5][6][7][8] Route d and e: Benzyl bromide product (4) obtained from route a was transformed to compound 1 through carbonyl synthesis (d) or Grignard reaction (e). 9,10 Route f: compound 3 reacted with Boc-anhydride to give the intermediate 7, and then 7 was hydrolysed to afford product 1.…”