Efficient One-Pot Synthesis of the Side-Chain of a New Antiobiotic, Ertapenem

Ertapenem is a new parenteral broad-spectrum antibiotic with a unique efficacy profile in the late stages of development at Merck USA (Brands K M J et al, J Org Chem, 2002, 67, 4771).  It is likely to be useful as a treatment for serious upper and lower respiratory tract, urinary tract, skin, obsteric and gynaecologic infections due to its long pharmacokinetic half-life.

The standard retrosynthesis for ertapenem (1) leads to (2) and (3).  (2) is commercially available on large scale from Takasago, Kaneka and Nisso in Japan, so the main target was compound 3.  The strategy for synthesising (3) was to use the hydroxyproline (4) as raw material and to proceed via (5) to (3) (see also Matsamura H et al, Heterocycles, 1995, 41, 147 for a similar approach from a Sumitomo team, and a preliminary communication Tetrahedron Lett, 1996, 37, 2919 from the Merck team).  The Merck team have found that conversion of (4) to (3) via 5 can proceed in one pot.

The choice of solvent for the one-pot approach was critical – see table:

The yield depended critically on the amount of sodium sulphide, according to the graph below:

Reaction of (5) with m-aminobenzoic acid (MABA) was sluggish under standard conditions possibly because of zwitterionic species.  Use of acetic acid as solvent, however, gave the desired ring opening, and on addition of small amount of conc HCl, deprotection was also achieved to give the required (3).

Isolation of the product (3) as the HCl salt from the AcOH-HCl mixture proved difficult, since residual acetic acid was retained in the crystal.  Dissolution of the wet solid in butanol-water (9:1) followed by azeotropic removal of acetic acid/water gave after cooling crystals of the desired (3) as the HCl salt.  Under slightly different conditions a butanol solvate was also observed.

The overall yield over the 6-step 1 pot sequence was 70-75% on a 2 kg scale.