NO167662B - 4-substituted-2-azetidinone. - Google Patents

Description

The present invention relates to new 4-substituted 2-azetidinone compounds of general formula VII

wherein R g denotes a hydrogen atom, a lower alkyl group or an aralkyl group, or a salt thereof.

Examples of the lower alkyl group shown by R in the preceding general formula VII are straight-chain or branched alkyl groups with 1 to 5, preferably 1 to 3 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group , an isopropyl group, etc., and examples of the aralkyl groups shown by R are aryl-lower alkyl groups such as a benzyl group, a phenethyl group, a naphthylmethyl group, etc.

The new compounds shown by general formula VII are usable as intermediates for the production of therapeutically active compounds shown by general formula I as described in Norwegian patent 158 740.

The compound shown by general formula VII can be prepared by reacting a carboxylic acid shown by formula

or a reactive derivative thereof, and an amine of general formula in which R o has the above meaning, or a reactive derivative thereof. The reaction is a peptide synthesis reaction and can be carried out in a known manner. Furthermore, the invention relates to new 4-substituted 2-azetidinone compounds of general formula 9 in which R denotes

and method for producing these.

The preceding compound is usable as an intermediate for the preparation of the compounds of formula VII, dg is also usable as an intermediate for the preparation of γ-lactam series of antibiotics.

The new intermediate is produced by reacting a carboxylic acid of formula

or a reactive derivative thereof and pentachlorophenol or N-hydroxysuccinimide.

The reaction is an ester synthesis reaction and a known one

esterification method can be suitably chosen.

The invention is further illustrated by the following examples.

The abbreviations used in the examples have the following meaning:

TLC Thin layer chromatography

NMR Nuclear magnetic resonance spectrum

IR Infrared absorption spectrum Mass' Mass analysis spectrum

Z Benzyloxycarbonyl

Bn Benzyl

His Histidine

Pro Proline

DNP 2,4-dinitrophenyl

TS Tosyl

BOC t-butyloxycarbonyl

DMF Dimethylformamide

HOBT N-hydroxy-1,2,3-benzotriazole

DCC Dicyclohexylcarbodiimide

THF tetrahydrofuran

HOSu N-Hydroxysuccinimide

Ph Phenyl

Example 1

10 g (8.68 mmol) of (S)-2-azetidinone-4-carboxylic acid (2) and 24.4 g (8.68 mmol) of pentachlorophenol were dissolved in 200 ml of DMF, after which 17.93 g (8.70 mmol ) DCC was added to the solution under cooling (0 to 5°C).. After stirring the mixture for 5 hours at room temperature, the precipitated dicyclohexylurea was filtered off and the filtrate was concentrated under reduced pressure. The residue formed was dissolved in 200 ml of ethyl acetate by heating and was then cooled. The precipitated crystals were collected by filtration to give 25.6 g of yellowish crystals of (S)-4-pentachlorophenoxycarbonyl-2-azetidinone (58) with a melting point of 177 to 179°C.

NMR (90 MHz, d<6->DMSO-D2O) <6>ppm: 3.23 (1.H, q, azetidinone ring 3-position), 3.57 (1H, q, azetidinone ring 3-position), 4 .70 (1H, q, azetidinone ring 4-position)

IR (KBr) cm"<1>: 3200, 1775, 1755, 1720

Mass: 363 (M<+>), 335, 266, 237

Example 2

690 mg of (S)-2-azetidinone-4-carboxylic acid (2) was dissolved in 20 ml of DMF and after adding 690 mg of HOSu and 1.236 g of DCC under ice cooling, the reaction was allowed to proceed for 30 minutes under ice cooling and then for 4 hours at room temperature . Insolubles were filtered from the reaction mixture after which the solvent was distilled off to give a light brown solid. The product was recrystallized from dioxane-petroleum ether (5:1) to give 750 mg of (S)-4-(2,5-dioxopyrrolidin-1-yl)-oxycarbonyl-2-azetidinone.

NMR (DMSO-d<6>, TMS) Spppm: 8.70 (broad, 1H), 4.62 (dd, 1H),

3.84 (s, 4H)

IR (KBr) cm<-1>: 3320, 2920, 2840, 1810, 1780, 1750, 1730,

1720, 1650, 1620, 1570

Mass (CI in beam): 213 (M+ + 1), 185, 171, 116

Example 3

In 75 ml DMF was suspended 6.05 g (25 mmol) L-histidine methyl ester-2-hydrochloride (59) and after cooling the suspension to 0 to 5°C 5.05 g (50 mmol) triethylamine was added slowly, dropwise added to the suspension. The mixture was then stirred for 15 minutes at the same temperature.

9.50 g (25 mmol) of compound (58) was added to the mixture as a powder, and after stirring the mixture in

one hour at the same temperature, the mixture was allowed to stand overnight at room temperature. Triethylamine hydrochloride was filtered off, the filtrate was concentrated under reduced pressure. The residue was mixed with 40 ml of ethyl acetate and 30 ml of water followed by shaking, after which the aqueous layer was collected. The ethylacetate layer was extracted twice with 20 ml of water. The aqueous layers were combined and the water was distilled off under reduced pressure. The residue was mixed with acetonitrile and benzene and the mixture was concentrated under reduced pressure. The residue was crystallized from 30 ml of methanol and the crystals were

collected to give 4.1 g of f heirless crystals of N<O1->

[(S)-2-α2etidinone-4-carbonyl]-L-histidine methyl ester (60) mp 142 to 147°C.

NMR (90 MHz, d<6->DMSO) 6ppm: 2.94 (2H, d, 6-position methylene of histidine group), 3.60 (3H, s, methyl group), 4.02 (1H, q, azetidinone ring 4-position), 4.54 (1H, m, a-position methine of histidine group), 6.72 (1H, s, imidazole ring), 7.56 (1H, s, imidazole ring), 8.20 (Hf, s , NH) , 8.56 (1H, d, azetidinone ring NH)

IR (KBr) cm"<1>: 3250, 3100, 2950, 1770, 1750, 1740, 1720,

1650, 1550

Example 4

1.178 g (2 mmol) of histidine benzyl ester, 2-p-toluenesulfonate were dissolved in 20 ml of chloroform, after which 404 mg (2 mmol) of triethylamine was slowly added to the solution under ice-cooling to 0°C. To the solution was added 766 mg (2 mmol) of (S)-4-pentachlorophenoxycarbonyl-2-azetidinone (58) as a powder and the mixture was stirred overnight at 0 to 5°C.

To the reaction mixture was added 30 ml of chloroform and the desired product was extracted twice, each time with 30 ml of water. Then the water was distilled off under reduced pressure and the resulting residue was azeotropically dehydrated with benzene-acetonitrile to form a colorless sticky product. The product was subjected to silica gel column chromatography using 50 ml of Wako gel C-200 and eluted with ethyl acetate-methanol-concentrated aqueous ammonia (60:30:3) to give 470 mg of N et-[(S)-2-azetidinone- 4-carbonyl]-L-histidine benzyl ester (60-1) mp 196 to 199°C as colorless crystals.

NMR (90 MHz, d<6->DMSO) 6ppm: 2/58 MH' m' azetidinone ring 3-position), 2.96 (2H, d, histidine group 6-position methylene), 3.12 (1H, m, azetidinone ring 3-position), 4.00 (1H, m, azetidinone ring 4-position), 4.62 (1H,

m, histidine group a-position methine), 5.10 (2H, s, benzyl position), 6.80 (1H, s, imidazole ring), 7.36 (5H, s, benzene ring), 7.56 (1H, s, imidazole ring), 8.20 (1H, s, NH), 8.58 (1H, d, NH)

IR (KBr) cm"<1>: 3260, 2980, 2760, 1750, 1650, 1540

Claims (2)

1. 4-substituted 2-azetidinone compounds, characterized in that they have general formula (VII) in which R8 denotes a hydrogen atom, a lower alkyl group or an aralkyl group, or a salt thereof. 2. 4-substituted 2-azetidinone compounds, characterized in that they have general formula (X) 9 in which R denotes