A Practical and Facile Synthesis of Azetidine Derivatives for Oral Carbapenem, L-084

Abstract

An orally active carbapenem L-084, which exhibits high bioavailability in humans, has a 1-(1,3-thiazolin-2-yl)azetidin-3-ylthio moiety at the C-2 position of the 1b b-methylcarbapenem skeleton. We established a practical and cost-effective synthesis of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (1) for further scale-up production of L-084. This synthesis method entails an industry-oriented reaction of azetidine ring-closure to yield N-benzyl-3-hydroxyazetidine (16), which is eventually converted to 1 via key intermediates, Bunte salts 19 and 20.

Reduction with tris(2-carboxyethyl)phosphine (TCEP) enables the use of an S-sulphonate protecting group for thiol-mediated bioconjugation

“…The thiosulphate moiety is a masked thiol and is stable enough to endure further synthetic steps. For example, S-sulphocysteine derivatives have been used during peptide synthesis, 3 the preparation of carbapenem antibiotics, 4 RAFT polymerisation reactions, 5 the preparation of self-assembled monolayers on gold surfaces, 6 or reactions with isobenzofuranone and isoindolone carbocations. 7 S-Sulphonates, also known as Bunte salts or S-alkyl thiosulphates, can be efficiently prepared either by oxidation of thiols in presence of sulphites, 8 or by nucleophilic substitution of alkyl halides with thiosulphate (Scheme 1).…”

Crystal structure of tebipenem pivoxil

“…As shown in the reaction scheme (also see Supporting Information), 3-mercapto-1-(1,3-thiazolin-2-yl)-azetidine hydrochloride (3) was first synthesized according to a method previously reported (Isoda et al, 2006b) with minor optimizations. The side chain 3 was then coupled with the commercially available carbapenem core (2), followed by hydrogenation/deprotection and SN 2 esterification to afford the desired tebipenem pivoxil 1 (Isoda et al, 2006a,b The crystal packing viewed along the crystallographic a axis showing the O-HÁ Á ÁN hydrogen bonds (Table 1) The molecular structure of the title compound, showing the atom labelling and 30% probability displacement ellipsoids.…”

Excellent Preparation of Azetidin-3-Ones from Propargylic Alcohols by Gold-Catalysis

“…Examples in this regard are Penaresidine A and B (actomyosin ATPase activators), 1 Penazetidin A (inhibitor of protein kinase C), 2 Polyoxins (znucleoside antibiotics), 3 Dezinamide (antiepileptic drug), 4 Azelnidipine (antihypertensive drug) 5 and Tebipenem LJC-11,036 (oral carbapenem antibiotics). 6 In addition, azetidin-3-one rings were also found as the building block in a multitude of N-heterocyclic rings, such as polyoximic acid, 7 3,3-dihydroxyazetidine, 8 1,3,3-trinitroazetidine 9 and spiro [3.3]heptanes. 10 It is therefore no surprise that many useful syntheses of azetidin-3-ones have been developed over the years.…”