Practical Large-Scale Synthesis of the 2-Aminomethylpyrrolidin-4-ylthio-Containing Side Chain of the Novel Carbapenem Antibiotic Doripenem

Abstract

The first synthesis using an original procedure and a practical large-scale process using an improved procedure for the synthesis of the N-PNZ-protected 2-aminomethylpyrrolidin-4-ylthio-containing side chain of doripenem hydrate (S-4661), a novel parenteral 1 -methylcarbapenem antibiotic, are described. trans-4-Hydroxy-L-proline (4) was converted in an efficient process to (2S,4S)-4-acetylthio-2-(N-sulfamoyl-tertbutoxycarbonylaminomethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3) in 55-56% overall yield via a six-step sequence, which includes the two alternative routes to intermediate 13. This process requires no chromatographic purifications, no cryogenic temperatures, no haloalkane solvents, and short operating times and is amenable to a multikilogram-scale preparation. Several kilograms of the side chain 3 were successfully prepared by this process.

Synthesis of 1,3‐Diamines Through Rhodium‐Catalyzed CH Insertion

“…The former protocol utilizes BocNHSO 2 NH 2 , as a nucleophile for the Mitsunobu reaction with either primary or secondary alcohols. [9] Alternatively, N-sulfamoylation of a secondary tert-butylcarbamate using CBzNHSO 2 Cl and subsequent hydrogenolytic removal of the CBz group furnishes the desired substrate. Each of the necessary reagents for these respective processes can be prepared in a single step from ClSO 2 NCO, an inexpensive commodity chemical.…”

Large-Scale Carbonyl Reductions in the Pharmaceutical Industry

“…In addition to borane, NaBH 4 in combination with other reagents such as CDI and ethyl chloroformate , (via mixed anhydride formation), CaCl 2 (in situ formation of Ca­(BH 4 ) 2 ), HCl, BF 3 ·OEt 2 (in situ formation of borane), I 2 , and H 2 SO 4 is found in the process literature for the reduction of acids to alcohols. (NaBH 4 alone does not reduce acids to alcohols.)…”

“…(NaBH 4 alone does not reduce acids to alcohols.) THF is the most common solvent for these borohydride reductions, but alternatives such as EtOAc/IPA/H 2 O, EtOH, diglyme/THF, and i -PrOAc have been reported. LAH (1 M in THF) and LiBH 4 (2 M in THF)/TMSCl have also reduced acids to alcohols on large scale on relatively simple substrates.…”

Synthetic Approaches to the 2005 New Drugs

“…The synthesis of darifenacin [17] is depicted in Scheme 5. The N-tosylated alcohol 19 was subjected to Mitsunobu reaction in the presence of methyl ptoluenesulfonate, triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF to afford N-tosyl-3(S)-(tosyloxy) pyrrolidine (20) in 70% yield, which was then condensed with 2,2-diphenylacetonitrile with NaH in refluxing toluene to give 2,2-diphenyl-2-[1-(p-toluenesulfonyloxy)pyrrolidin-2(S)-yl]acetonitrile (21). The 3-(R)-hydroxypyrrolidine (18) was N-tosylated with p-toluenesulfonyl chloride in pyridine yielding compound 19 in 26 % yield .…”