2-azetidinone

Structural formula
General
Surname	2-azetidinone
other names	Azetidin-2-one β-propiolactam β-alanine lactam 2-azacyclobutanone
Molecular formula	C 3 H 5 NO
Brief description	colorless to beige solid
External identifiers / databases
CAS number 930-21-2 EC number 628-180-1 ECHA InfoCard 100.156.473 PubChem 136721 Wikidata Q21099588
properties
Molar mass	71.08 g mol −1
Physical state	firmly
density	0.9632 g cm −3 at 22.5 ° C
Melting point	73-74 ° C 74-76 ° C
boiling point	106 ° C at 20 h Pa
solubility	very soluble in water, ethanol and chloroform slightly soluble in diethyl ether and benzene
safety instructions
GHS labeling of hazardous substances danger H and P phrases H: 314 P: 280-305 + 351 + 338-310
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

2-Azetidinone is the cyclic amide of the non-proteinogenic amino acid β-alanine and the simplest, four-membered β- lactam . 2-Azacyclobutanones are lead structures in β-lactam antibiotics , such as the monocyclic monobactams and especially in the fused bicyclic penam and cephem skeletons on which the penicillins and cephalosporins are based. As a lactam monomer, 2-azacyclobutanone can be anionically polymerized to poly (β-alanine) or polyamide 3.

Occurrence and representation

The synthesis of (phenyl-substituted) 2-azetidinone by (2 + 2) cycloaddition of diphenylketene to benzalaniline was first described in 1907 by Hermann Staudinger .

The compound 4-acetoxy-2-azetidinone , which can be obtained from vinyl acetate and chlorosulfonyl isocyanate in a (2 + 2) cycloaddition in yields of 44–62%, opens up good access to the target molecule 2-azacyclobutanone .

In the reduction of 4-acetoxy-2-azetidinone with potassium borohydride in water, 2-azetidinone is obtained in 20% yield after short-path distillation .

The analogous cycloaddition of ethylene with chlorosulfonyl isocyanate with subsequent hydrolysis for the synthesis of the unsubstituted 2-azetidinone does not lead to the desired end product 2-azacyclobutanone because of the inertia of ethylene.

The unsubstituted 2-azetidinone was obtained for the first time in 1949 by cyclization of β-alanine ethyl ester with ethyl magnesium bromide in diethyl ether after elaborate isolation and purification in a total yield of only 0.76%.

The Michael addition of benzylamine to acrylic acid ester to form N-benzyl-β-alanine ester, which can be cyclized with ethylmagnesium bromide to form N-benzyl-β-propiolactam, is much more efficient. The reductive cleavage of the benzyl radical with sodium in liquid ammonia gives 2-azetidinone in an overall yield of 50%.

properties

2-Azetidinone is a colorless and odorless solid that dissolves easily in polar solvents such as water and ethanol. Dilute sodium hydroxide hydrolyzes the lactam to the β-alanine sodium salt. β-propiolactam is much less reactive than propiolactone , which reacts completely with methanol at 48 ° C without a catalyst to form β-methoxypropionic acid, while 2-azetidinone shows no reaction.

Applications

Building block in pharmacologically active ingredients

The four-membered lactam ring system of 2-azetidinone is a common structural feature of a number of β-lactam antibiotics , such as. B. the penicillins, cephalosporins, and carbapenems , the β-lactamase inhibitors sulbactam , tazobactam and clavulanic acid and the non-fused monobactams aztreonam , tigemonam and carumonam . Azetidin-2-one itself has no antibiotic activity.

The 2-azetidinone skeleton is also found in the cholesterol uptake inhibitor ezetimibe and in numerous experimental active substances, e.g. B. trypsin - or thrombin - enzyme inhibitors , antidiabetics , analgesics , vasopressin antagonists or Parkinson agents .

Monomer for poly (β-alanine)

The anionic ring-opening polymerization (ROP) of 2-azetidinone yields high molecular weight poly (β-alanine), which can not be obtained by polycondensation of β-alanine.

In contrast to polyamide 6 , which is accessible from seven-membered ε- caprolactam through ROP , poly (β-alanine), also known as polyamide 3 or nylon 3, only melts at temperatures above 340 ° C with considerable decomposition and can therefore not be processed thermoplastically. From solution in formic acid , poly (β-alanine) can be processed into films and fibers that have not yet been used industrially. The immobilized lipase from Candida antarctica (CALB) catalyzes the ROP of 2-azetidinone in toluene , although only average degrees of polymerization DP of 8 are achieved. 2-Azetidinone is of little practical interest because of its comparatively complex production and the limited usefulness of the polymeric nylon 3.

Individual evidence

1. ↑ ^{a b c d e f g} R.W. Holley, AD Holley: 2-Azetidinone (β-Propiolactam) . In: J. Am. Chem. Soc. tape 71 , no. 6 , 1949, pp. 2129-2131 , doi : 10.1021 / ja01174a062 .
2. ↑ ^{a b c d e} data sheet 2-Azetidinone from Sigma-Aldrich , accessed on February 5, 2019 ( PDF ).
3. ^ Carl L. Yaws: Thermophysical Properties of Chemicals and Hydrocarbons, 2nd Edition . Elsevier Inc., Amsterdam, NL 2014, ISBN 978-0-323-28659-6 , pp. 268 .
4. ^ William M. Haynes: CRC Handbook of Chemistry and Physics, 97th Edition . CRC Press, Boca Raton, FL, USA 2016, ISBN 978-1-4987-5429-3 , pp. 3-32 .
5. ↑ U. Holzgrebe: Structure-activity relationships, From penicillin G to tricyclic β-lactams . In: Pharmacy in our time . tape 35 , no. 5 , 2006, p. 410-414 , doi : 10.1002 / 200600186 .
6. ↑ ^{a b c d e} H. Bestian: About poly-β-amides . In: Angew. Chem. Band 80 , no. 8 , 1968, p. 304-312 , doi : 10.1002 / anie.19680800803 .
7. ↑ H. Staudinger: On the knowledge of the ketenes. Diphenyl ketenes . In: Liebigs Ann. Chem. Band 356 , no. 1-2 , 1907, pp. 51-123 , doi : 10.1002 / jlac.19073560106 .
8. ↑ K. Clauß, D. Grimm, G. Prossel: β ‐ lactams with substituents bound via heteroatoms . In: Liebigs Ann. Chem. Band 1974 , no. 4 , 1974, p. 539-560 , doi : 10.1002 / jlac.197419740403 .
9. ^ SJ Mickel, S.-N Hsiao, MJ Miller: Synthesis of a key β-lactam intermediate by a [2 + 2] cycloaddition route: 4-Acetoxyazetidin-2-one In: Organic Syntheses . 65, 1987, p. 135, doi : 10.15227 / orgsyn.065.0135 ; Coll. Vol. 8, 1993, p. 3 ( PDF ).
10. ↑ ^{a b c} L.W. Schwab, R. Kroon, AJ Schouten, K. Loos: Enzyme-catalyzed ring-opening polymerization of unsubstituted β ‐ lactam . In: Macromol. Rapid Commun. tape 29 , no. 10 , 2008, p. 794-797 , doi : 10.1002 / marc.200800117 .
11. ↑ PD Mehta, NPS Sengar, AK Pathak: 2-Azetidinone - A new profile of various pharmacological activities . In: Eur. J. Med. Chem. Volume 45 , 2010, p. 5541-5560 , doi : 10.1016 / ejmech.2010.09.035 .